1. health and fitness
2. disease
3. cholesterol

Low-Fat, Low-Salt, Whole-Food Vegan
Staying Lean and Healthy
into Ripe Old Age
Mark F. McCarty
NutriGuard Research, Inc.
Second Edition:
December 2008
 2008
Mark F. McCarty
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Table of Contents
1. A Diet You Can Live With……………………………………………….…5
2. The Whys and Wherefores – Preventing Coronary Disease……….………11
3. Obesity and Diabetes – Preventable and Reversible………………………32
4. Avoiding Hypertension, Stroke – and Dementia?…………………………45
5. Preventing and Controlling Cancer………………………………………..61
6. Preventing and Treating Autoimmune Disorders…………………………97
7. Bones and Joints – Staying Intact……………………………………… 103
8. Coda – A Few Odds and Ends………………………………….……… 109
References…………………………………………….………………….136
Appendix – The NutriGuard Learn to Burn Leanness Program…………211
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I. A Diet You Can Live With
Since my days as a medical student, I have been keenly interested in nutritional impacts
on health. In particular, I have been studying for years in an effort to determine why
many Third World societies, as long as they maintain their traditional diets and lifestyles,
are relatively immune to so many of the disorders that take a devastating toll on the
health and finances of elderly Americans. I have come to some provisional conclusions
and recommendations that, while hardly original, are nonetheless quite controversial in
some respects – at loggerheads not only with the health-destructive dietary practices of
most Americans, but also with certain faddish views gaining popularity among many
health scientists and the general public. It is precisely because my conclusions are
controversial that they are worth setting down.
If I were asked to describe in one sentence the type of diet that, in my opinion, would
minimize risk for the chief killing and crippling diseases of Western civilization –
scourges that include coronary heart disease, stroke, diabetes, hypertension, the major
cancers, autoimmune disorders such as rheumatoid arthritis, and Alzheimer’s disease – I
would suggest the following:
Eat a very-low-fat, low-salt, whole-food vegan diet, very rich in potassium and
relatively low in glycemic index.
This single sentence encapsulates six separate pieces of advice, which I will explain in
more detail before summarizing the evidence that motivates this recommendation.
Very-low-fat: By this, I mean a diet in which fat constitutes not more than 15% of
calories – the type of diet popularized by Nathan Pritikin and, more recently, Dr. Dean
Ornish. This should not be confused with the so-called “low-fat” diet recommended by
the American Heart Association, providing 25-30% of its calories as fat. Since the diet I
endorse is vegan – thus excluding all fatty animal products – it is relatively easy to
achieve the suggested fat target by simply moderating one’s intake of the few plantderived foods that are high in fat: avocados, olives, nuts, seeds, and the oils and butters
derived therefrom. Most grains, fruits, vegetables, and legumes – the core of a healthful
vegan diet – are inherently low in fat. When buying processed foods, read the labels
carefully and avoid foods that have significant amounts of added oils – saturated and
partially hydrogenated fats are particularly bad for your vascular health. If your diet is
quite low in fat in other respects, it may be appropriate to include not more than an ounce
per day of unsalted nuts (or nut butter) in which monounsaturates predominate: almonds
and hazelnuts are best in this regard. Occasional use of modest amounts of virgin olive
oil or avocado – both monounsature-rich – is also acceptable.
Low-salt: Try to get your salt intake below 5 grams daily (which corresponds to 2 grams
of sodium); the ideal target – not easy to achieve in modern society – is closer to 2.5
grams daily (1 gram sodium). Minimize or eliminate the use of table salt in your cooking
– explore the wealth of alternative seasonings that are available. Fortunately, with the
exception of dairy products (cows are fed salt to improve milk yields), natural
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unprocessed foods are inherently low in salt. But most of us eat some of our meals in
restaurants, or rely on certain processed foods that come pre-salted; it is estimated that at
least 80% of the salt in our diet comes, not from our use of the salt shaker at the table or
in our cooking, but from the salt pre-added to processed foods or restaurant meals. So
when you purchase processed foods, examine the sodium content, and choose brands that
go light on the sodium. If the milligrams of sodium in a serving is no higher than the
number of calories (kcals) it provides, then it can be considered acceptably low in salt –
particularly if you make a point of including a number of unsalted foods in your daily
diet. You may need to shop in a health-food store to find a sufficient variety of unsalted
or lightly salted processed foods. When dining in restaurants, don’t be afraid to ask the
waiter to have your food prepared without salt – while this often won’t be feasible (they
may rely on processed ingredients or on large pre-cooked batches of food they have
already salted), it doesn’t hurt to ask.
Whole-food: By this, I refer to food that not only retains all or most of its original
nutrient/phytochemical/fiber content, but that also, to the extent feasible, retains the intact
structure of the food as it grew from the soil. For example, whole grain flour is certainly
far more nutritious than refined flour – but whole kernel grains are even better for your
health. Structurally intact grains are usually more slowly digested than are finely-ground
flours (implying a lower glycemic index - see below), and the relatively high water and
fiber content of whole foods often means that their calorie content is more dilute – you
tend to get filled up before you have eaten an excessive number of calories in one sitting.
When cooking vegetables, try to use cooking methods – such as steaming – that don’t
leach out the protective micronutrients, phytochemicals, and potassium that they provide.
By all means, avoid processed foods that contain a significant amount of added sugars or
oils – these are “empty calories” that effectively rob your diet not only of essential
nutrients, but also of fiber, phytochemicals, and potassium.
Vegan: This implies the absence of all animal products – flesh foods, dairy products, and
eggs. While it is commonly accepted that the saturated fat and cholesterol found in most
animal products (excluding non-fat dairy) are bad for vascular health, I subscribe to the
much more avant garde view that animal protein is likely to be an important factor in our
high rates of “Western” cancers, and may also contribute to high serum cholesterol and
possibly even obesity. (This latter point will require some clarification, as I do not
dispute the fact that diets high in animal protein can be useful for reducing appetite and
achieving weight loss.) Contrary to much propaganda, a vegan diet featuring whole
grains and legumes can provide more than enough protein to support buoyant health.
Since strictly vegan diets are virtually devoid of vitamins B12 and D, and may often be
suboptimal sources of calcium and selenium, vegans are well advised to use
comprehensive nutritional supplements (“nutritional insurance formulas”). Furthermore,
the long-chain omega-3 fatty acids found in cold-water fish (EPA/DHA) can provide
various health benefits that cannot be adequately reproduced by the shorter-chain omega3s (α-linolenic acid) found in some plants; for this reason, I violate my veganisn to the
extent of taking an enriched fish oil supplement (a strategy endorsed by Dr. Ornish).
Certain other non-essential nutrients found primarily in flesh foods – e.g. carnitine,
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taurine, creatine – may be beneficial to health in certain circumstances, and can be
provided in supplements; nonetheless, since the human body is capable of manufacturing
these nutrients, vegans are rarely significantly deficient in them.
A vegan food which may have extraordinary potential for health promotion – as will be
discussed below - is spirulina, a microalga (or, more properly, a cyanobacterium) that
has remarkable antioxidant activity. I make a point of ingesting spirulina daily, in
smoothies.
High-Potassium: Potassium appears to be Nature’s “antidote” to the harmful health
consequences of salted diets. Our pre-agricultural ancestors ate unsalted diets
exceptionally rich in potassium – whereas, thanks to the introduction of refined grains,
sugars, and oils, our salted modern diets are substantially depleted of this crucial nutrient.
To maximize your intake of naturally-occurring potassium, you will need to boost your
intake of fruits, vegetables, and their juices, which typically are high in potassium on a
per-calorie basis. Legumes and tubers (potatoes, yams) are also potassium-rich, and
whole grains, while not potassium powerhouses, are about 3 times as rich in potassium as
are refined grains. Thus, in pursuit of a high intake of potassium, you will get the
concurrent benefits of the protective phytochemicals and fiber provided by fruits,
vegetables, legumes, and other whole plant foods. A few processed foods and
condiments are available that are potassium-enriched (e.g. Low-Sodium V-8 Juice);
these can profitably be included in your diet. However, make sure that the bulk of your
dietary potassium comes from the naturally-occurring potassium in fruits and vegetables.
Low-Glycemic-Index: Starchy or sugary foods which are gradually digested and thus
produce a modest but sustained rise in blood sugar, are preferable to rapidly digested
carbohydrates that lead to an abrupt spike in blood sugar. Foods of the former type are
said to have a “low glycemic index”. In non-diabetics, the harm from high-glycemicindex meals comes not from the rise in blood sugar per se, but from the large surge of
insulin secretion which they evoke (as will be discussed below). Structurally intact
grains are likely to have a lower glycemic index than flours do. However, many other
factors play a role in determining the glycemic index of a food. For example, starch
comes in two chief varieties, amylose and amylopectin. Amylose is an unbranched starch
that, because of its compact chemical structure, is more gradually degraded by digestive
enzymes than is the highly branched starch, amylopectin; thus, starchy foods in which
amylose predominates tend to have a low glycemic index. A high content of soluble fiber
likewise tends to lower glycemic index, and certain phytochemicals (such as some found
in beans) can also slow the process of digestion.
Beans – especially home-cooked beans, as opposed to canned beans that usually have
been pressure cooked – are particularly notable for a low glycemic index, owing to their
high content of amylose, soluble fiber, and phytochemicals. Long-grain rice is usually
higher in amylose – and thus lower in glycemic index – than the sticky short-grain rice
preferred in Oriental cuisine; parboiling renders the rice kernel harder to digest, so longgrain parboiled rice is the best. High-amylose corn has been developed, but is not yet
readily available in supermarkets. Fruits that are relatively low in glycemic index include
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apples, pears and oranges, whereas ripe bananas and melons are relatively high in this
regard. Surprisingly, juicing or pureeing fruit has little impact on its glycemic index,
which is determined primarily by its fructose content - fructose has a very low glycemic
index. As far as breakfast cereals go, old-fashioned (not instant) oatmeal and bran are
good choices; most breakfast cereals are made from fine flours and are high in glycemic
index (not to mention loaded with salt).
Sadly, the chief sources of starch in American diets – wheat flour products and potatoes –
have a high glycemic index. The baked potato is particularly notorious in this regard
(though it has the compensating merits of being rather calorically dilute and rich in
potassium). Wheat flour (and this includes whole wheat flour) is not quite as high in
glycemic index, but, possibly owing to its rather high protein content, provokes an insulin
surge as dramatic as that produced by potatoes. A very fortunate exception is pasta –
owing to the way in which the starch molecules are packed together, pasta has a much
lower glycemic index than other wheat flour products. Unleavened bread – like pita bread
– has a lower glycemic index than leavened products; the minute air pockets introduced
by the leavening process gives the digestive enzymes readier access to the starch
granules. Even lower in glycemic index are sprouted-grain breads, which contain
structurally-intact kernels rather than fiber. For more information on the comparative
glycemic indices of foods, you can consult tables such as that found in the book The
Glucose Revolution; a comprehensive listing has also been published in the scientific
literature.1
Here’s a useful trick: as outlined in The Glucose Revolution, there is recent evidence that
an ample intake of vinegar with meals (a little over a tablespoon) slows the absorption of
carbohydrate and blunts the post-meal rise in glucose and insulin; the mechanism
responsible for this effect is still obscure. So, instead of using oils on my salads, I
smother them with my favorite balsamic vinegar. A wide range of flavorsome vinegars is
available – try them out. Perhaps the old folk myth about the health-promoting properties
of vinegar is more than just a myth!
In a Nutshell…
In brief, what I am proposing is a diet comprised of virtually the entire range of fruits,
vegetables, legumes (beans and soy products), and whole grains, complemented by a
modest intake of monounsaturated-rich nuts or nut butters, and prepared with minimal
added salt, oil, or added sugars, but seasoned liberally with all other spices as desired.
Grains should be as structurally intact as feasible, though pasta is an excellent choice.
Foods with a notably high glycemic index – wheat flour products (other than pasta) and
baked potatoes, for example – should be avoided, as should all animal products (other
than supplemental fish oil). For most people, moderate consumption of beer or wine is
desirable (as will be discussed below), and including spirulina in one’s daily diet may
also be wise.
Although these directives are consistent with a wide range of taste-tempting gastronomic
possibilities, I will not pretend that they will be easy to follow within the context of the
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typical meals that most Americans have been trained to prepare and consume. A friend
of mine once showed me a list that the eminent Berkeley nutritionist Dr. Gladys Block
had compiled of the 100 food items most consumed by Americans. On surveying the list,
I was shocked to note that I could approve of only two of the first 25 items on the list!
(One of these was spaghetti with marinara sauce – though even there, one could bet that
the pasta would be made from white flour, and the marinara sauce was too high in salt.
The other item was – alcoholic beverages!) Needless to say, most of the meals and
convenience foods you will find in typical restaurants and supermarkets won’t make your
task a lot easier. You will need to use your intelligence, resourcefulness, and selfdiscipline to follow through on the suggestions I offer.
Let’s face facts. Our current dietary habits have evolved in total ignorance of – and
virtual indifference to – their consequences for long-term health. And there is no reason
to expect that minor “practical” fixes of these habits will have much major impact
healthwise. If your goal is to stay healthy, you need to rip those old habits out by the
roots and start afresh, guided not by tradition or your old personal preferences, but by
solid medical evidence. The good news is that, once your tastebuds have had a chance to
adapt and you’ve made progress in finding the right recipes and the right restaurants,
your healthful meals can be both delicious and satisfying.
But suffice it to say, I am not planning to win any popularity contests, and I’m not
interested in telling people what they want to hear. If you are looking for confirmation
that meat, grease, and salt are actually good for your waistline and your health, goodness
knows there are plenty of faddishly popular books on the best-seller lists these days that
will provide the self-delusive rationales you are seeking. But if you are looking for an
honest perspective on the dietary and lifestyle habits that can give you the best chance of
avoiding the whole range of major killing and crippling degenerative diseases of Western
civilization, this little volume may have much to offer you.
I am reasonably confident that, sooner or later, (probably later than sooner!) the major
medical organizations will endorse the recommendations which I offer, at least in large
part. Actually, a reasonable proportion of medical experts might be willing to endorse
them now in theory – but they won’t do so in practice because they presume that you,
dear reader, are too lacking in self control to follow them; instead, they advise minimal
“practical” modifications to the typical American diet that correspondingly will have
minimal (if any) impact on subsequent disease risk. (Indeed, the subsequent discussion
will provide examples of how ineffectual this approach has been.) As a result we are
faced with a Catch 22: Until medical organizations have enough moxie to give people the
straight scoop on what they should be eating, there will be little motivation for restaurants
and suppliers of convenience foods to provide truly healthy alternatives for healthoriented consumers. But until such alternatives are more readily available, it is indeed
rather hard for consumers to eat as well as they might like – thus confirming the views of
the “experts” that truly optimal diets aren’t practical!
However, that’s not the whole story. There is in fact serious disagreement among
medical experts regarding the type of diet that is best. In particular, there is considerable
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support for diets high in monounsaturate-rich oils, or for “paleolithic” flesh-rich diets;
and most medical people probably currently view a strictly vegan approach as
unnecessarily extreme – if not harmful. Rather than dodging prominent points of view
that run contrary to mine – or subjecting them to cartoonish misrepresentations – I intend
to confront them head on and actually acknowledge the medical evidence that can be
marshalled in their favor. It’s really only within this context that I can make a truly
credible case that my recommendations offer the best overall health protection.
Don’t let these provisos discourage you. If you are truly dedicated to eating in a way that
will best preserve your long-term health, you can find the means to do it. You won’t
succeed (I know that I don’t) – in living up to your best intentions at every opportunity in
every particular, but you can succeed often enough that your health and physique will be
vastly the better for it. And, if you decide to “live to eat” instead (at least until your first
heart attack or your first cancer surgery radically change your priorities) – well, that is
your perfect privilege. All that I intend to do is spell out your options. If you are willing
to do what you need to do to prevent, reverse, or at least greatly retard the progression of
coronary disease, obesity, diabetes, stroke, many cancers, possibly even dementia – the
tools are available to you now – you don’t need to wait for pie-in-the-sky gene transplants
or mega-buck new wonder drugs. The fact of the matter is, the diseases that kill most
Americans are virtually unnecessary, and indeed have been extremely rare in certain
societies. To find out more, read on….
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II. The Whys and Wherefores – Preventing Coronary Disease
Now that I have summarized the what and how of my recommendations, it’s time to get
to the real “meat”of the issue – the why.
It is no secret that coronary heart disease – the type of heart disease that results from
atherosclerotic inflammation of the arteries feeding the heart, the type that is involved in
almost all heart attacks – is extremely rare if not non-existent in Third World societies
whose traditional diets are low in fat and animal products. It was this observation that
prompted Nathan Pritikin to organize clinics that treated heart patients with a very-lowfat near-vegan whole food diet and regular aerobic exercise. The published clinical
experience of these clinics indicates that within three weeks, this regimen typically
achieves substantial improvements in key risk factors, most notably marked reductions in
LDL cholesterol. Exercise-induced heart pain – angina – also often improves promptly,
and significant “spontaneous” weight loss is typical.2-5
More recently, Dr. Dean Ornish undertook the task of evaluating the long-term clinical
results of a comparable regimen (in which he included stress reduction techniques).6-8
His one-year follow-up evaluation created a scientific sensation when he was able to
report that his regimen achieved a modest but statistically significant regression in the
narrowing (stenoses) of the coronary arteries – whereas, in a control group of patients
following the standard guidelines of the American Heart Association, their arteries
continued to narrow progressively. Ornish reported the same dramatic and rapid
improvement in angina symptoms that the Pritikin Clinics had claimed, and after five
years of treatment, he noted that the incidence of serious coronary events (heart attacks,
or severe symptoms necessitating cardiac bypass surgery or angioplasty) had been about
60% lower in his treated patients than the control group. And Dr. Caldwell Esselstyn has
had even more dramatic success with a low-fat vegan diet – but more on that in a
moment. The findings of these clinical studies with heart patients are very consistent
with the findings of other studies that have examined the blood fats of healthy vegans –
they are found to be much lower than those of either omnivores or dairy/egg-consuming
vegetarians. Similarly, total and LDL cholesterol levels have usually been found to be
very low in the quasi-vegan cultures where coronary heart disease is rare or non-existent.
Reducing Cholesterol
Why do these regimens produce such rapid and substantial improvement in coronary
disease? Substantial reductions in LDL cholesterol no doubt play an important part. The
modest reductions in saturated fat and total fat intake recommended by the American
Heart Association tend to reduce LDL cholesterol by just a few percentage points – not
more than about 5%. In contrast, the Pritikin/Ornish regimens typically decrease this risk
factor by about 20% or more. Very-low-fat vegan diets are extremely low in saturated fat
– the type of fat which tends to raise serum cholesterol by inhibiting the liver’s capacity
to manufacture receptors that remove LDL cholesterol from the bloodstream.9 Such diets
also tend to be low in saturates relative to total fat intake – in other words, they have a
high unsaturate-to-saturate ratio; this is important because the level of saturated fatty
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acids in the liver will reflect not only the absolute dietary intake of these compounds, but
also the proportion of total dietary fat which they represent.
In addition, the fact that vegan diets are essentially cholesterol-free (plants don’t
manufacture cholesterol) contributes significantly to their cholesterol-lowering efficacy.
In the population as a whole – most of whom are omnivores - each 100 mg increase in
daily cholesterol intake translates into an increase of only about 2.2 (mg/dl) in serum
cholesterol – barely more than a 1% increase in most people.10, 11 However, this increase
tends to be notably higher in people whose baseline dietary cholesterol intake is quite low
– most notably vegans; as Dr. Paul Hopkins notes, “modest amounts of cholesterol added
to a cholesterol-free diet would be expected to most efficiently elevate serum
cholesterol".10 Dietary cholesterol also raises serum cholesterol more efficiently in
people who are lean12 – which most long-term vegans are. Furthermore, since vegans
tend to have quite low serum cholesterols, a given absolute increase in serum cholesterol
has a larger impact percentage-wise. So it is clear that the virtual absence of cholesterol
in strict vegan diets contributes quite meaningfully to their favorably low LDL
cholesterol values.
You should be aware that flesh foods somewhat lower in fat or in saturated fat than red
meats – for example, poultry and fish – are just as high in cholesterol as red meat is.
With respect to eggs – a rich source of cholesterol (about 250 mg per egg) that is rather
low in saturated fat – some recent studies conclude that egg consumption in moderation
does not increase the cardiovascular risk of non-diabetics.13 Vegans should be aware that
these studies examined populations that contained few if any vegans, and that this result
therefore cannot be presumed to apply to them – and almost certainly doesn’t.
The protein content of vegan diets also contributes to a reduction in serum cholesterol.
For decades, it has been known that if you feed rabbits diets featuring any of a number of
plant-derived proteins – in comparison to diets that are identical in every respect save that
they feature animal protein – their serum cholesterol levels will be decisively lower on
the plant protein diet.14 Though a number of these studies made use of soy protein –
inasmuch as soy protein isolates are readily available – other types of plant protein were
comparably efficacious in this regard. The mechanism responsible for this effect has
never been clearly pinpointed, though the fact that plant proteins tend to be somewhat
lower in certain essential amino acids – and thus are considered of “poorer quality” – is
thought to be of key importance.14, 15
These rabbit studies were the inspiration for the original efforts by Dr. Cesare Sirtori and
colleagues to lower elevated cholesterol in humans by feeding diets high in soy protein.16,
17
These studies compared low-fat omnivore diets (featuring lean meats and reduced-fat
dairy products) with virtually vegan diets high in texturized vegetable protein (a soy
product). To insure that the studies tested the impact of protein per se, the diets were
designed so that the quantity and type of dietary fat were nearly identical on the soy and
omnivore diets; total protein intakes also remained nearly constant. The researcher found
that, when the patients switched from the omnivore diet to the soy-based diet, total and
LDL cholesterol dropped by about 20%! Although the low-fat omnivore diet contained a
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small amount of cholesterol, theoretical considerations, as well as a study in which the
soy diets were supplemented with cholesterol, indicated that absence of cholesterol was
not primarily responsible for the dramatic fall in blood cholesterol during the soy diets.
Subsequent similar studies, often enrolling subjects whose initial cholesterol was less
elevated, often did not see such dramatic results, and it became clear that soy-based diets
had their greatest impact on patients with high cholesterol. A “meta-analysis” (a
statistical analysis which lumps together the results of many comparable studies) of 38
controlled studies of soy protein diets concluded that, on average, both total and LDL
cholesterol fell by about 20 points on the soy diet (corresponding to a reduction of about
13% in dangerous LDL cholesterol).18
It is important to note that these studies compared omnivore diets with vegan diets that
happened to be high in soy products. They did not show that you could simply add some
soy protein to your omnivore diet and achieve marvelous improvements in your blood
fats – contrary to the expectations of many consumers who are now being hustled to buy
soy products. Nor am I aware of any evidence that adding soy protein to a relatively low
protein vegan diet has any important effect on serum cholesterol. Furthermore, the
common assumption that the isoflavone content of soy protein concentrates was largely
responsible for the cholesterol-lowering benefit appears to be dead wrong – Sirtori
recently assayed the texturized vegetable protein used in his initial studies and found that
it was essentially devoid of these phytoestrogens!19 The obsessive focus on soy and soy
isoflavones ignores that fact that virtually all plant proteins are associated with low serum
cholesterol in rabbit studies. Thus, while texturized soy protein products can come in
handy if you want to eat a vegan diet while pretending to be an omnivore, there is no
strong reason to expect that vegan diets in which other types of plant protein predominate
will not have a comparably beneficial impact on LDL cholesterol. (As we shall see,
regular consumption of soy isoflavones may indeed provide some valuable health
benefits – albeit reduction of serum cholesterol is not one of them!)
One theory regarding the favorable effect of plant proteins on cholesterol levels is that
plant proteins tend to provoke less insulin secretion (and greater secretion of a competing
hormone known as glucagon) than animal proteins do.20, 21 While this is unlikely to be
the whole explanation – the quality of dietary protein can influence liver metabolism in
more direct ways - it is clear that high insulin levels have effects on the liver that would
tend to increase blood cholesterol and triglyceride levels, including an increase in the
level and activity of the rate-limiting enzyme for cholesterol synthesis.20, 22-24
Insulin secretion can also be moderated by choosing whole foods with a relatively low
glycemic index. The Pritikin and Ornish clinics have always emphasized the importance
of whole foods and have discouraged use of added sugars. When Dr. David Jenkins and
colleagues – progenitors of the glycemic index concept – put healthy young men on two
strictly controlled diets that differed only in glycemic index, serum cholesterol was about
15% lower during the low-glycemic-index diet.25
13
Thus, a number of interacting factors contribute to marked cholesterol reduction on an
optimal vegan diet: a very low intake of saturated fat, the absence of dietary cholesterol,
the characteristic impact of plant protein, and a low glycemic index. In the long run, a
substantial reduction in body fat (we’ll discuss this later) often amplifies this benefit.
A classic study provides insight into the magnitude of the benefit achievable when such a
diet is consumed in the long term. Back in the 1970s, Dr. Frank Sacks and colleagues
from Harvard did a survey of macrobiotic vegan communes in the Boston area.26 The
people in these communes work in a range of ordinary jobs in the outside community, but
get together to share their meals communally. The macrobiotic diet which they practice
is low-fat, whole-food vegan, but they don’t put any strictures on salt, and they try to
keep fruit intake low, their calories coming chiefly from whole grains (especially brown
rice), beans, and fresh vegetables. Some members eat fish once or more a week. Of
particular note is the fact that they ban all wheat flour products, and don’t use added
sugars – thus eliminating the chief sources of high-glycemic-index carbohydrate in the
American diet. Thus, aside from the facts that they don’t discourage salt and they
minimize fruit intake, their dietary practices are highly consistent with my
recommendations.
You may be aware that a total cholesterol level over 200 is considered in the “danger
zone”, whereas a cholesterol below 150 is thought to be extremely safe. Sacks found that
the average total cholesterol in these Boston communes was 126! In contrast, a group of
control subjects drawn from the Boston area, matched by age and sex to the commune
subjects, had an average cholesterol of 184. The fact that most of the people in the
commune were under 30 certainly contributed to their exceptionally low cholesterol
readings – but the handful of commune residents over 40 had an average cholesterol of
only 146. Also of note is the fact that the triglyceride levels of the commune members
were also low, averaging 59 (mg/dl) as compared to 86 in the controls. (As we will see,
this is an intriguing finding given the fact that the macrobiotic diet is extremely high in
carbohydrates – and high-carbohydrate diets are said to raise triglycerides!) Some
members of these communes use occasional eggs or dairy, and Sacks found that recent
consumption of these foods did indeed correlate with higher cholesterol levels.
Sacks reported the case history of one commune member who evidently was genetically
prone to high cholesterol.. After 18 months at the commune, his cholesterol was 123. He
then left the commune for 6 weeks, at the end of which time his cholesterol had shot up
to 219. He returned to the commune, and after 3 weeks his cholesterol was back down to
116. Evidently, having “bad genes” does not mean that you have an inexorable date with
the coronary care unit!
The effortless leanness of these vegans no doubt was an important factor in their low
blood fat levels – their average skinfold thickness (a measure of subcutaneous fat) was
only about one-third that of the control subjects. We’ll return to this important point
soon.
14
Sacks is not the only investigator to have noted the highly favorable blood fat levels of
free-living American or European vegans.27-29 One of these described a vegan diet as “a
model for risk reduction”.29 Evidently, the exceptionally low cholesterol levels enjoyed
by rural Asians – and their virtual freedom from coronary heart disease - are not just a
function of semi-starvation, chronic infection, or good genes, as some might assume.
.
Insulin Resistance – a Case of “Fat Poisoning”
However, LDL cholesterol is not the only important determinant of heart disease risk.
Insulin resistance – the failure of skeletal muscle and adipose tissue to respond efficiently
to the key hormone insulin – is associated with a substantially increased risk for heart
attack and coronary disease. People who are insulin resistant tend to have a syndrome
(called “insulin resistance syndrome”, or “metabolic syndrome”) characterized by high
fasting serum insulin levels, high triglycerides, relatively low HDL cholesterol (the
“protective” cholesterol), an increased number of LDL particles which tend to be small
and dense, and increased blood pressure. (LDL particle number is determined by
measuring blood levels of apolipoprotein B, one molecule of which is present in each
LDL particle.) To appreciate the impact of this syndrome on cardiovascular health, it is
instructive to consider the results of an epidemiological study conducted in Quebec by
Lamarche and co-workers.30 These scientists compared the subsequent heart attack risk
of subjects whose fasting insulin and LDL particle number (i.e. apoprotein B) were above
average and LDL particle size below average, with subjects whose fasting insulin and
LDL particle number were below average and LDL particle size above average; the
former group was found to be at 18-fold higher risk for a heart attack than the latter
group! Note that the risk factors in the former group are all typical components of the
insulin resistance syndrome.
Insulin resistance is a key component of type 2 (so-called “mature-onset”) diabetes, and
people who are insulin resistant are at greatly increased risk of becoming diabetic, even
though they may not yet show impaired regulation of blood sugar. Insulin resistance and
most type 2 diabetes appear to arise from a common problem – excessive exposure of the
body’s tissues to fat (fatty acids).31-38 Insulin resistance syndrome and type 2 diabetes are
hardly ever encountered in Third World societies where people eat very-low-fat diets and
remain lean for life. Conversely, people who are overweight – especially those that have
an increased depot of abdominal fat – are known to be at greatly increased risk for insulin
resistance and diabetes. This probably reflects the fact that their swollen fat cells are
constantly spewing out excessive amounts of fatty acids into the circulation; moreover,
these cells do an inefficient job of trapping the fatty acids derived from recent fatty
meals. After a fatty meal, absorbed fat circulates in the bloodstream; properly
functioning fat cells, in response to the hormone insulin, take up this fat and store it, so
they can release it back to the blood later when glucose (and thus insulin) levels are low
and the body’s tissues need fat for metabolic fuel. But when fat cells become overstuffed
with fat (as they do in people who are overweight), they become resistant to the action of
insulin, and as a result don’t efficiently trap and store meal-derived fat. This “homeless”
fat is thus more likely to end up in other tissues, at a time when they don’t need fat for
15
fuel. Since these tissues aren’t ready to burn this fat, they store it (as triglycerides) and
also convert it to other chemical compounds.
Moreover, bloated fat cells that are poorly responsive to insulin tend to spew out fat into
the circulation throughout the day, since they are insensitive to the insulin signal.
(Insulin tells fat cells to take up fat and hold onto it – which is why excessive insulin
activity tends to promote obesity.) So blood levels of free fatty acids tend to be
constantly elevated in overweight people, even when glucose and insulin levels are high
and fat isn’t needed as fuel. This problem is exacerbated following fatty meals.
As a result, skeletal muscle, the endothelial linings of arteries, and other tissues
experience chronic excessive exposure to fat, even when they don’t need it. If they
rapidly convert this fat to stored triglycerides, little immediate harm is done. But they
can also convert this fat to certain chemical compounds that can cause metabolic havoc –
in skeletal muscle, these compounds impede the efficiency of insulin signaling; in the
endothelial cells that line the arteries, they cause oxidative stress and inflammation,
which play a key role in the induction of atherosclerosis, including coronary heart
disease.39-42 (LDL particles likewise have a pro-inflammatory effect on the arterial lining
– which is largely why high blood levels of LDL cholesterol (or of apolipoprotein B)
promote atherosclerosis.)
The notion that “fat poisoning” is at the root of insulin resistance and vascular damage
associated with insulin resistance syndromes has received support from recent studies
showing that the extent to which skeletal muscle is insulin resistant correlates directly
with the amount of fat stored as triglyceride in the skeletal muscle fibers themselves.43-47
In point of fact, the triglyceride per se is not the problem – rather, it is a marker for the
fact that skeletal muscle has been exposed to too much fat at the wrong time. (Curiously,
the correlation between muscle triglyceride levels and insulin resistance breaks down in
people who are endurance athletes; in such people, triglycerides levels in muscle fibers
often are high even though the fibers are usually insulin sensitive. This presumably
reflects the fact that, owing to a high fuel requirement, the muscle fibers of endurance
athletes are adapted to do a very efficient job of converting fat to stored triglycerides –
which means that relatively little of this fat is converted to the alternative compounds that
cause insulin resistance.)
The reason why different types of fat have differing impacts on risk for insulin resistance,
diabetes, and atherosclerosis – aside from the well-known fact that they have differing
effects on LDL cholesterol levels – is that they vary in their ability to give rise to
chemical compounds that create metabolic problems. In rat studies, a high dietary intake
of fat of any type (with the notable exception of omega-3 fats such as those in fish oil)
usually leads to insulin resistance and weight gain. Olive oil is not an exception to this
rule; some strains of mice become obese and diabetic if you feed them olive-oil-rich diets
(whereas they remain lean and insulin sensitive on a carbohydrate-rich diet).48
Nonetheless, saturated fats induce insulin resistance and endothelial inflammation more
efficiently than other types of fat.49 In particular, the prominent saturated fat palmitic
acid, unlike unsaturated fats, can give rise to the compound ceramide, which works in
16
various ways to compromise insulin function and promote arterial inflammation.50-54
Saturated fats can also be converted to diacylglycerol, another compound which promotes
insulin resistance, oxidative stress, and inflammation. Not surprisingly, a number of
studies have concluded that people whose tissues have a relatively high proportion of
saturated fat, or whose diets are estimated to be relatively high in saturated fat, tend to
have poorer insulin sensitivity.55, 56 Thus, reduction of LDL cholesterol may not be the
only reason why the low saturated fat content of vegan diets protects the vascular system.
The inordinate contribution of saturated fats to the insulin resistance syndrome may help
to explain why vegetarians have been found to be at substantially lower risk for diabetes,
even when compared to omnivores of comparable body size.57
Excessive tissue exposure to unsaturated fats – oleic acid is the most common of the
monounsaturated fats, and linoleic acid the most common of the “omega-6”
polyunsatures – can also compromise insulin function and promote inflammation under
certain circumstances, presumably because they also can also promote the synthesis of
the chemical mediator diacylglycerol.58, 59 However, as contrasted with saturated fats,
they are more likely to be converted to innocuous triglycerides, so they typically have a
less harmful impact.52, 60, 61 And oleic acid can sometimes exert a favorable effect by
agonizing the conversion of palmitic acid to ceramide.52, 60 Some researchers conclude
that oleic acid is less likely than linoleic acid to compromise insulin function or promote
arterial inflammation62-64 – though contrary results have also been reported.65 As
contrasted to linoleic acid, oleic acid has the further advantage that it is not readily
peroxidized by oxidative stress; thus, when oleic acid is the predominant component of
cellular membranes, oxidative stress has a somewhat less harmful effect on cellular
function. For these reasons, many nutrition researchers now commend monounsaturaterich oils and nuts (such as virgin olive oil and almonds) as more compatible with health
than other sources of dietary fat66-68– consistent with the relatively good vascular health
observed in populations which traditionally followed an oleate-rich “Mediterranean”
diet.69
If insulin resistance does in fact reflect “fat poisoning”, then it would be reasonable to
expect that a very-low-fat diet would tend to have a corrective impact on this syndrome.
In fact, this is precisely what has been demonstrated in clinical studies – diets in which
fat provides no more than 10-15% of calories, even when high in sugars or rapidly
digested starches, tend to produce notable improvements in insulin sensitivity.70-72 The
experience of the Pritikin Clinics provides a dramatic illustration of this principle: in
patients whose baseline fasting serum insulin is high (indicative of insulin resistance, as
the body manufacturers increased amounts of insulin to compensate for the poor
responsiveness of the body’s tissues to this hormone), serum insulin tends to fall by an
average of 40% during 3 weeks of the Pritikin regimen.4 (While daily walking exercise
no doubt contributes to this benefit, other studies not incorporating exercise have similar
shown the insulin-sensitizing efficacy of very-low-fat diets.)
To understand current scientific controversies, it is important for you to know that lesser
degrees of fat restriction – e.g. the 25-30% fat diets recommended by official bodies like
the American Heart Association and the American Diabetes Association – do not seem to
17
have much of an impact on insulin resistance. In other words, when it comes to dietary
fat restriction, half-way measures seem to be of little benefit. Indeed, modulating the
amount of dietary fat in the range of 20-40% of calories appears to have little impact on
insulin sensitivity (although in the longer term it may influence one’s ability to achieve
and maintain leanness). It’s important to realize that a very-low-fat diet, as implemented
by the Pritikin and Ornish clinics, has no more than half as much fat as the “low-fat” diet
recommended by the American Heart Association; bear this in mind the next time you
hear the media report that a “low-fat diet” has failed to achieve benefits.
As noted, obesity – or at least an excess accumulation of abdominal adipose tissue – can
be a major contributor to insulin resistance. It is thus relevant to observe that, in the
long-term, very-low-fat vegan diets that emphasize whole foods tend to be associated
with substantial reductions in body weight and body fat. The experience of Dr. Ornish’s
heart patients is illustrative: during the first year of the study – during which the subjects
were allowed to eat as many calories as they wished – weight loss averaged 22 pounds!8
(This despite the fact that most of the patients weren’t consciously trying to lose weight.)
Dramatic rapid weight reduction is also the typical experience of the Pritikin Clinics.
While regular walking exercise presumably contributes to this weight loss, it is pertinent
to note that almost equally dramatic weight loss was seen in a recent clinical study in
which type 2 diabetics were placed on a very-low-fat whole-food vegan diet, without
explicit exercise advice.73 These reports are paralleled by the observation that American
vegans tend to be much lighter than either omnivores or lacto-ovo-vegetarians – even
when their diets are not exceptionally low in fat.74 (Thus, reduced fat intake does not
seem to provide a complete explanation for the relatively low body mass of vegans.) The
exceptional leanness of the macrobiotic vegans surveyed by Sacks presumably reflects
the fact that their diets are both vegan and low in fat. It is of course well known that
Third World peoples whose traditional diets are quasi-vegan and low in fat tend to be
very lean throughout life; studies in rural China show that this phenomenon is not
primarily attributable to reduced calorie intake.75 The long term favorable impact of a
low-fat vegan diet on body fat levels no doubt reinforces its shorter-term favorable
impact on insulin resistance syndrome.
(Believe it or not, the weight loss achieved with the Ornish and Pritikin regimens has
been used to denigrate the value of their dietary recommendations. More than one
“health expert” has noted that it is difficult to evaluate the inherent merits of the diets
which Pritikin and Ornish recommend because their regimens “include weight loss”.
This objection might have some force if these regimens included extra gimmicks, such as
conscious caloric restriction or appetite-suppressant drugs, intended to accelerate weight
loss – but of course they don’t. The weight loss is the natural consequence of the diet and
daily walking exercise.)
Why do vegans tend to be so much leaner than omnivores? I suspect that part of the
explanation is that a vegan diet tends to provoke lesser amounts of insulin secretion
following a meal.76 This is because protein – especially animal protein – while, by itself
a relatively weak stimulus to insulin secretion, can dramatically potentiate the insulin
response to co-ingested carbohydrate.77, 78 Recent studies examining urinary C-peptide
18
and serum sex hormone-binding globulin – two clinical parameters that can be used to
estimate daily insulin secretion – suggest that, even in the short term before substantial
weight is lost, daily insulin secretion tends to be relatively low on vegan diets;79, 80 in
one of these studies, addition of 32 grams of fat-free egg protein to a moderately lowprotein vegan diet (substituted for 14 grams of fat) boosted urinary C-peptide output by a
dramatic 60% - suggesting a major increase in daily insulin secretion. Even though there
is not much difference in the glycemic indices of wheat flour and the “sticky” white rice
consumed in the Orient, the insulin response to wheat flour is much higher – likely
because the protein content of wheat is twice that of rice.81 (It’s a very good bet that the
macrobiotic vegan diet – banning wheat flour and sugars, and stressing intact whole
foods – is associated with very low daily insulin secretion.) And the propensity of plant
proteins to evoke greater secretion of glucagon than animal proteins do21 may also
contribute to leanness in vegans – glucagon promotes fat burning in the liver.
Insulin is the hormonal signal that tells the body to store and retain fat, rather than burn it.
If you manage to keep your insulin levels relatively low while minimizing your ingestion
of fat - a trick which very-low-fat whole-food vegan diets seem to accomplish – it is
reasonable to expect a progressive loss of body fat until your body fat stores equilibrate at
a lower set-point – precisely what is observed clinically with diets of this type.82 It stands
to reason that your benefit in this regard will be even greater if you emphasize whole,
low-glycemic-index carbohydrate foods in your diet, that, by definition, provoke less
insulin secretion. Recent studies are demonstrating that dietary glycemic index does
indeed have an impact on weight control, whether or not you are consuming a vegan
diet.83-85
Much of the reduction in daily insulin secretion associated with vegan diets reflects the
favorable impact of such diets on the insulin sensitivity of skeletal muscle. Even when
vegan diets aren’t notably low in fat, the fact that such diets feature a notable
predominance of unsaturated over saturated fat alleviates “fat poisoning” and promotes
efficient insulin function in skeletal muscle. The body necessarily compensates for this
by decreasing daily insulin secretion (thereby preventing hypoglycemia). This
phenomenon doubtless contributes importantly to the characteristic leanness of vegans.
In this regard, it should be noted that people who follow “Mediterranean diets” – in
which fish is the chief flesh food, dairy products are consumed sparingly, and olive oil is
the predominant source of fat – likewise have been found to be leaner, on average, than
those eating a more typical Western diet replete with fatty animal products.86-90 Like a
vegan diet, a Mediterranean diet is associated with a predominance of unsaturated over
saturated fat, and a favorable impact on insulin sensitivity.89-91
In addition to the favorable impacts of low-fat, whole-food vegan diets on blood fat
profiles and insulin function, such diets may beneficially affect other risk factors as well.
For example, there is preliminary evidence that blood viscosity – another heart disease
risk factor – is lower on such diets – in other words, your blood becomes more fluid.92
The rapid improvement in angina symptoms reported by heart patients attending the
Pritkin and Ornish clinics is not likely to reflect re-opening of clogged coronary vessels;
19
although this happens to a modest degree, symptomatic improvement is of much more
rapid onset. Rather, it may reflect a lessening of endothelial inflammation (improving the
efficiency of homeostatic vasodilator mechanisms which boost blood flow to oxygendeprived regions of the heart), as well as the fact that carbohydrate is a more efficient fuel
than fat when tissue oxygen levels are low;93 it takes more oxygen to derive a given
amount of biochemical energy (ATP) from fat than from glucose. (Which is why –
incredibly – pharmaceutical companies have been trying to develop drugs that inhibit fat
burning as treatments for angina; one would think that the short-term symptomatic
benefits of these drugs would be offset by a long-term adverse impact on obesity and
“fat-poisoning”. Very-low-fat diets, as well as high supplemental intakes of the the
dietary cofactor carnitine,94, 95 likewise have the potential to promote selective use of
carbohydrate in poorly-oxygenated heart tissues – while promoting leanness.93)
Bringing Heart Disease to a Halt
Dr. Caldwell Esselstyn, a distinguished surgeon at the Cleveland Clinic, has devised a
simple lifestyle regimen that appears to stop serious coronary heart disease in its tracks.96,
97
He began with the provocative observation by his friend Dr. William Castelli that, in
the massive Framingham study, people whose total cholesterol remained under 150
(mg/dl) were virtually immune to heart attack. Similarly, cholesterol levels are typically
below 150 in the Third World societies where heart disease is very rare. Although many
factors contribute to the coronary atherosclerosis that gives rise to heart attacks, an excess
of the LDL particles that carry most of the cholesterol in the blood appears to play an
obligate role in this regard. This is because LDL particles promote inflammation of the
endothelial lining of the arteries while also inducing the formation of “foam cells”
beneath the endothelial surface; foam cells are immune cells (macrophages) which ingest
oxidized LDL particles and in the process are stimulated to release pro-inflammatory
hormones. When the level of LDL particles is low – as it typically is in people whose
total cholesterol level is below 150 – significant atherosclerosis of coronary arteries is
rarely encountered.
Dr. Esselstyn reasoned that, by recommending a very-low-fat whole-food vegan diet, he
could usually reduce cholesterol dramatically; nonetheless, the experience of Ornish and
of the Pritikin Clinics suggests that, in heart patients, such a regimen on average reduces
cholesterol to about 170 – good, but possibly not good enough. So, in patients whose
cholesterol didn’t fall below 150 with diet alone, he implemented aggressive drug therapy
– usually the drug lovastatin, sometimes in conjunction with cholestyramine – to push the
cholesterol below 150.
In 1985, Esselstyn recruited 24 patients with serious symptomatic heart disease who were
willing to try his diet-drug regimen. He found that, in every case, he could reduce
cholesterol below the 150 barrier with this approach. After about a year, he found that he
had to exclude 6 patients from the study owing to their failure to comply with the dietary
advice, but the remaining 18 patients were very compliant for a number of years. After 5
years, he could report that his compliant patients had achieved modest regressions of
coronary blockages similar to the experience of Ornish, and that symptomatic angina was
20
substantially improved. But the results of the recent 12-year follow-up are the most
impressive. Of these 18 patients, one patient, who had been in heart failure on entrance
to the study, experienced a serious cardiac arrhythmia (heart electrical failure) and died –
though autopsy showed that he had not experienced a heart attack. One other patient
elected to have an angioplasty because, although his angina had substantially improved, it
had not gone away altogether. With these exceptions, there were no other serious cardiac
events in the 18 compliant patients over 12 years of follow-up - this despite the fact that
these patients had experienced a total of 49 serious cardiac episodes in the 8 years prior to
their enrollment in the study! In other words, even in patients with serious pre-existing
heart disease, the Esselstyn regimen seems to have brought the progression of coronary
disease to a halt! For practical purposes, coronary heart disease may be essentially
“curable” with the proper diet/drug regimen, despite the fact that only a modest
regression of coronary blockages is achieved; this regimen evidently alleviates the
inflammatory process in the endothelial cells lining the coronary arteries, such that the
arterial lining becomes much less prone to rupture and trigger blood clots.
These findings are all the more impressive in light of the fact that, except in patients who
have a degree of heart failure or have very severe multi-vessel occlusions, the very
expensive and somewhat risky surgical procedures currently used to treat coronary
disease (bypass surgery or angioplasty) do not reduce subsequent risk for a heart attack –
they are only of symptomatic benefit in patients with angina. (Think about that next time
you hear about the ever-escalating medical costs that are burdening our economy.) This
reflects the fact that, more often than not, heart attacks are triggered by inflammatory
rupture of small coronary arteries – whereas surgical procedures only alleviate the
strictures in large coronary arteries (which contribute to anginal pain during exercise). In
contrast, with a lifestyle/drug regimen whose modest cost involves prescribing and
monitoring some relatively inexpensive off-patent drugs, Esselstyn has demonstrated that
heart attack can be almost totally prevented! (To learn more about Dr. Esselstyn’s work,
go to www.heartattackproof.com, or read his excellent new book Prevent and Reverse Heart
Disesase.)
You had better not make the assumption that you can live your life precisely as you wish,
and then, when you develop heart disease, go on the Esselstyn regimen and save your
life. The flaw in this strategy is that, in about half of all cases, the first symptom of
coronary heart disease is sudden death! (Not even Dr. Esselstyn resurrects the dead!)
And, unfortunately, common diagnostic tools like treadmill tests and angiograms do a far
less than perfect job of assessing risk for heart attack. (There are numerous cases of
people who passed an EKG stress test with flying colors – and then dropped dead the
next day; noted newsman Tim Russert is a case in point. These stress tests, while they
can reveal blockages in large coronary arteries, tell us little about the health of smaller
coronary arteries.) The safest strategy is to assume that you are in the process of
developing coronary heart disease – most Americans are – and put yourself on the
Esselstyn program now. This will entail going on the very-low-fat, whole-food vegan
diet recommended here, monitoring the subsequent course of your serum cholesterol, and
then taking whatever drugs or supplemental nutrients may be required to get your
cholesterol below 150 if the diet alone does not suffice.
21
Another assumption you shouldn’t make is that, by getting your cholesterol under 150
with drugs alone, you can expect the same degree of protection as that achieved by the
Esselstyn regimen. Although Dr. Esselstyn has emphasized the impact of his regimen on
cholesterol levels, his very-low-fat approach can also be expected to have a very
favorable impact on fatty acid-induced arterial inflammation and on insulin resistance
syndrome, which markedly boost coronary risk; very likely, this phenomenon contributed
importantly to the protection enjoyed by Dr. Esselstyn’s patients. I am unaware of any
studies using cholesterol-lowering drugs that have succeeded in virtually eliminating
future heart risk. Even though a lifelong cholesterol level below 150 may imply very low
coronary risk, reducing cholesterol below 150 once you already have severe coronary
atherosclerosis may not by itself be sufficient to achieve complete protection. However, I
should also point out that a diet/lifestyle approach by itself may be insufficient for
optimal benefit – the longterm results of Dr. Ornish’s regimen, which eschews
cholesterol-lowering drugs, while impressive, are not nearly as impressive as those of Dr.
Esselstyn.
Statins Have Versatile Benefits
Statin drugs are particularly appropriate, as there is recent evidence that they can directly
dampen the inflammation of arterial endothelial cells, independent of their impact on
serum cholesterol.98-101 They also can reduce elevated blood levels of C-reactive protein,
which, like elevated LDL, is a risk factor for atherosclerotic disease that exerts a proinflammatory effect on the arterial lining; in patients with “normal” cholesterol levels but
elevated C-reactive protein, statin therapy prevents heart attacks.102 Elevated C-reactive
protein is a feature of insulin resistance syndrome, and, like “fat poisoning”, acts on the
arterial wall to provoke oxidative stress and inflammation.103-106
Some statins occur naturally in a special strain of yeast, and high-statin strains of red
yeast rice, a traditional Oriental food, are now available as cholesterol-lowering
supplements that don’t require a prescription.107 However, a note of caution: in a very
small percentage of cases, statin therapy can induce a dangerous muscle damage
syndrome – although this has not yet been reported in people using red yeast rice
(possibly because the statin dose provided by recommended doses is less than 10 mg,
which is half as high as the lowest prescribed dose of lovastatin), you should promptly
discontinue your use of this supplement if you notice unexplained persistent muscle pain
or weakness, and see your physician. Furthermore, statins can decrease your body’s
synthesis of the protective antioxidant coenzyme Q10, so supplemental intakes of this
nutrient might be warranted when you use statins108, 109 – although there isn’t clear
evidence that such compensatory supplementation improves health outcomes. In
particular, coenzyme Q10 deficiency does not appear to be responsible for the muscle
damage syndrome occasionally evoked by statins.110 However, in light of evidence that
supplemental coenzyme Q10 can be therapeutically beneficial in congestive heart failure,
and that low serum levels of this cofactor predict increased mortality in this syndrome, it
might be wise for statin users who also have heart failure, or who are at risk for heart
failure, to supplement with coenzyme Q10;108, 111, 112 hopefully, future clinical studies
22
will evaluate this strategy. Coenzyme Q supplementation can also be useful in the
control of elevated blood pressure;113 whether it might be more useful for this purpose in
statin-users than in non-users has not been studied.
Statins may confer health benefits that extend beyond the vasculature. Recent evidence
suggests that, in addition to improving endothelial function and lowering dangerous
blood fats, statins may help to maintain bone density and lower fracture risk,114-116 and
possibly even decrease risk for Alzheimer’s disease.117-119 These are precisely the
reasons why many women choose to use prolonged estrogen replacement therapy
following menopause. However, unlike estrogen, statins do not increase risk for female
cancers or induce the pro-coagulant effects that render estrogen’s vascular benefits
somewhat equivocal.
Natural Aids for Cholesterol Control
If your cholesterol remains in the 150-200 range after you adopt a low-fat vegan diet, it
would be prudent to reduce it further. However, since medicine considers this range
“normal” (despite the fact that coronary care units are filled which patients whose
cholesterol is in this range!), it may be difficult for you to find a doctor willing to give
you a prescription for a statin under these circumstances. Red yeast rice and other natural
aids for cholesterol control can be used as an alternative. In one controlled clinical study,
2.4 grams daily of a standardized preparation of red yeast rice decreased elevated LDL
cholesterol by an average of nearly 20%.107
Berberine, a commercially-available natural compound derived from several Chinese
herbs, has recently been shown to complement the cholesterol-lowering activity of
natural or synthetic statins.120, 121 Like statins, berberine increases the liver’s production
of LDL receptors (which remove LDL particles from the circulation, thereby lowering
LD cholesterol levels) – but it does so by a mechanism that is different from, and
complementary to, to effect of statins in this regard.122-124 So concurrent use of berberine
may potentiate the efficacy of red yeast rice for cholesterol control.120 Moreover,
berberine can aid blood sugar control in diabetics, working in a manner analogous to the
widely-prescribed drug metformin.125, 126 Unfortunately – as is the case with metformin –
about a third of people using barberine initially experience some gastrointestinal upset –
but this effect is often transitory. A dose of 500 mg, three times daily, has been reported
to aid control of blood sugar and cholesterol in diabetics.125
Other natural agents which have the potential to lower elevated LDL cholesterol at least
modestly (they aren’t likely to work as well as statins in this regard) include supplemental
soluble fiber – glucomannan may be of particular merit in this regard127, 128 –
phytosterols,129 and tocotrienols. Since phytosterols work by inhibiting intestinal
absorption of cholesterol,130 their efficacy will likely be greater in omnivores than in
vegans; however, some efficacy would be expected, as vegans can reabsorb cholesterol
secreted in the bile. Tocotrienols are natural fat-soluble antioxidant compounds,
structurally closely allied to vitamin E, that are richly supplied by palm oil and rice oil.
Whereas statins directly inhibit the rate-limiting enzyme for cholesterol synthesis (HMG-
23
CoA reductase), the tocotrienols act to suppress the production of this enzyme by cells.131
The limited clinical literature on tocotrienols suggests that these compounds are not as
consistently or as potently effective for lowering blood cholesterol levels as statins
are;132-134 nonetheless, some clinical and animal research studies suggest that tocotrienols
can inhibit atherogenesis to a degree that is disproportionate to their cholesterol-lowering
activity.132, 135 I suspect that tocotrienols have the same favorable impact on the function
of vascular endothelial cells that statins do – which would be expected if they succeed in
reducing the activity of HMG-CoA reductase in endothelial cells. If this is the case, their
health benefits may be quite parallel to those of the statins. A total daily intake of 200
mg appears to have clinically useful effects. These compounds also have potential
cancer-preventive or –retardant activity, as documented in rodent studies.136
The Nay-Sayers – Are Carbohydrates Bad for You?
In the very-low-fat diets recommended by Pritikin, Ornish, and Esselstyn, at least 70% of
the calories are provided by carbohydrate. This is also true of the macrobiotic vegan
regimen, and of the diets practiced by most rural Asians. In societies where the
traditional diet is predominantly carbohydrate, coronary heart disease is rarely
encountered. It may thus strike you as more than a bit odd that a number of prominent
medical authorities are now maintaining that high-carbohydrate diets are harmful to heart
health!137-142
The scientists making this assertion are comparing what they call “low-fat diets” with
diets that are lower in carbohydrate and higher in monounsaturated fat (e.g. olive oil).
The key point to recognize is they are not testing the sort of very-low-fat whole-food
vegan diet that has shown such a favorable impact on heart disease and insulin
sensitivity, but rather the “low-fat diet” advocated by the American Heart Association,
which provides 25-30% of calories as fat, is omnivore, and does not place any special
emphasis on whole or low-glycemic-index foods. As far as I can tell, the only merit of
such a diet – as contrasted to the slightly higher fat diets typically consumed by average
Americans – is that it produces a very modest decrease in serum LDL cholesterol. But
similar reductions can be achieved with diets that are equivalently low in saturated fat,
but which are lower in carbohydrates and higher in monounsaturated fats. A number of
investigations have shown that, when these two types of diets are compared, the diet
higher in monounsaturates is associated with lower fasting triglyceride levels, higher
HDL cholesterol, and larger, less dense LDL particles – all suggestive of lower
cardiovascular risk.137-139 Note that the favorable shifts in blood fat profile associated
with the monounsaturate-rich diet would tend to reverse some of the risk factors
associated with insulin resistance syndrome. Nonetheless, there is no evidence that such
diets improve insulin sensitivity as contrasted to the effects of a 25-30% fat diet – they
appear to ameliorate some of the risk associated with insulin resistance without getting to
the root of the syndrome itself, which is fat poisoning. Yet neither does a 25-30% “lowfat” diet improve insulin sensitivity – and, since it is omnivore and only modestly lower
in fat, it doesn’t have much long-term impact on body fat either.
24
What is the metabolic basis for these effects? Daily insulin secretion is likely to be
higher on a 25-30% fat diet than on a diet lower in carbs and higher in monounsaturates –
in part because the former diet does not improve insulin sensitivity and thus does not tend
to lower fasting insulin levels. Although skeletal muscle has the capacity to break down
and take up the triglycerides circulating in the blood (via an enzyme known as lipoprotein
lipase), insulin acts to inhibit this capacity – so triglycerides levels tend to be higher
because muscle does a poorer job of clearing them from the circulation.143-147 The
chronic elevation of serum triglycerides associated with high-insulin-response diets, in
turn, has metabolic effects that tend to reduce the number of protective HDL particles,
decrease the size of LDL particles, and boost the capacity of blood to clot – changes
suggestive of increased cardiovascular risk. In addition, slow removal of circulating
triglycerides after fatty meals results in higher levels of particles known as chylomicron
remnants; some experts suspect that these chylomicron remnants contribute to the
progression of atherosclerosis.148, 149
An obvious implication is that, if you emphasize low-glycemic-index carbohydrates in
your diet, while avoiding animal protein – or take other steps to moderate daily insulin
secretion – the tendency of high-carbohydrate diets to raise fasting or post-meal
triglyceride levels will be blunted. Thus, scientists have often noted that the
carbohydrate-rich diets have little impact on triglycerides if high-fiber foods are
chosen.147, 150 You will recall that triglyceride levels of the Boston macrobiotic vegans
were considerably lower than those of the control subjects whose diets were undoubtedly
lower in carbohydrates – evidently a function of the low daily insulin secretion of these
vegans. Aerobic exercise training and supplemental fish oil – both of which I strongly
recommend - have also been show to blunt the impact of increased carbohydrate intake
on blood triglycerides;147, 151 exercise accomplishes this by increasing muscle’s capacity
to take up triglycerides,152 whereas fish oil decreases the liver’s synthesis of triglycerides.
There is another issue that the advocates of high-monounsaturate diets fail to address.
Free fatty acid levels are almost certainly higher following high-fat meals than lower-fat
meals. There is some reason to believe that the exposure of tissues to high levels of free
fatty acids following meals contributes to the insulin resistance syndrome and
cardiovascular risk.153 Recent studies show that the healthful protective function of the
vascular endothelium is impaired for several hours after a fatty meal154-156 – even a meal
rich in monounsaturates - possibly owing to free fatty acid excess. This effect may
counterbalance to some degree the more favorable impact of high-monounsaturate diets
on fasting blood fat levels. Thus, it really isn’t a “slam dunk” to predict that a
monounsaturate-rich diet will result in lower overall cardiovascular risk than the 25-30%
fat diets to which it has been compared.
What is the relevance of these concerns to the very-low-fat, whole-food vegan diet
recommended here? Not much! In practice, fasting triglycerides often fall on such a
regimen150 – particularly if exercise is also recommended.3, 4, 157 This may reflect the fact
that fiber-rich vegan meals provide a relatively modest stimulus to insulin release, even
though carbohydrate intake may be high. Furthermore, in the longer term, people on
such diets tend to lose substantial amounts of body fat – and this ultimately translates into
25
reduced triglyceride synthesis in the liver and thus lower blood triglycerides. With
respect to concerns about post-meal triglyceride levels and chylomicron remnants, the fat
content of very-low-fat meals (10% fat) is so low that there will be very little post-meal
rise in triglycerides – this essentially becomes a non-issue. Even when fasting
triglycerides rise slightly, as they did in Ornish’s study, this increase in triglycerides was
accompanied by a regression of coronary stenosis, marked symptomatic improvement,
and increased survival;158 evidently, whatever modest adverse effect the rise in
triglycerides exerted was overwhelmed by the overall positive impact of the regimen.
Fasting triglyceride levels are also modestly elevated in the Tarahumara Indians159 – the
people whose virtual freedom from coronary disease motivated Pritikin to initiate his
diet-based clinical program for heart patients.
In this regard, it should be noted that the increased cardiovascular risk associated with
elevated triglycerides in the general American population in part reflects the fact that
high triglycerides are often associated with the insulin resistance syndrome – in other
words, this syndrome may be the main mediator of the increased risk, rather than the
triglycerides themselves. The increase of blood triglycerides induced by highcarbohydrate diets arises by a completely different mechanism, and does not imply
insulin resistance - in fact, such diets tend to improve insulin sensitivity if they are
sufficiently low in fat - so it is by no means certain that this rise in triglycerides has the
same negative significance for cardiovascular health.147, 160 Moderate rises in
triglycerides per se probably have a modestly negative impact on vascular health – they
can catalyze a decrease in HDL level and a reduction in LDL size - but they are unlikely
to represent the health disaster that some would suggest.
It should be noted that the formal clinical studies comparing 25-30% fat diets with highmonounsaturate diets have attempted to maintain steady calorie intakes on these diets so
that the tendency of low-fat diets to provoke weight loss is negated; this obviously would
tend to make the long-term effects of low-fat diets seem worse than they actually would
be when people consume them in ad libitum amounts.161, 162
Nonetheless, one is now constantly confronted with pronouncements by medical
authorities and self-proclaimed health experts that high-carbohydrate diets are potentially
harmful to heart health, particularly in people with insulin resistance syndrome or
diabetes. Indeed, some popular authors claim that high-glycemic-index highcarbohydrate diets are the chief cause of insulin resistance syndrome. (This latter claim
is truly remarkably inane when you consider that the rural Chinese are virtually immune
to insulin resistance, obesity and diabetes as long as they continue to eat their 70%
carbohydrate traditional diet featuring high-glycemic-index sticky rice! More generally,
the societies which have the highest carbohydrate intakes – and thus the lowest fat intakes
– are the least likely to develop insulin resistance.)
Why is it that the advocates of high-monunsaturate diets persist in comparing such diets
with the rather half-witted recommendations of the American Heart Association, as
opposed to the very-low-fat approach of Pritikin et al that has documented dramatic
26
efficacy in heart patients? Possibly because they consider such a diet too impractical to
merit testing. Dr. Gerald Reaven, a firm proponent of monounsaturates who has made a
classic contribution to our understanding of insulin resistance syndrome, states that
“increased carbohydrate intake…within the boundary of menus that can be followed in
the free-living state have not been shown to decrease insulin resistance directly, by
enhancing insulin sensitivity, or indirectly, by producing and maintaining fat loss.”137
(My emphasis added.) In other words, he discounts the practicality of very-low-fat vegan
diets – which demonstrably do improve insulin sensitivity and promote weight loss. This
will come as news to the patients of Ornish and Esselstyn who managed to maintain
compliance to such diets for many years – or to the patients in Dr. Neal Barnard’s recent
study (to be described below) who staged a “patient insurrection” and refused to go back
to their former fatty diets when the study protocol demanded it!80
Although I disagree with Dr. Reaven with respect to the practicality of the diet I
recommend, I nonetheless must commend him for qualifying his comments so that
people will know that they do not pertain to the very-low-fat approach. The popular
pundits currently denigrating “high-carbohydrate” diets generally take no such pains,
with the result that many lay people are left to conclude that Pritikin, Ornish and
Esselstyn are killing their poor patients with those lethal carbohydrates!
Ironically, Dr. Reaven was one of the first scientists to demonstrate conclusively that
insulin sensitivity improves substantially on a very-low-fat, high-carbohydrate diet. In
work conducted during the 1970s, Reaven and colleagues recruited healthy non-obese
middle-aged volunteers and compared the effects of two formula diets, one of which
supplied only 10% fat calories and 75% carbohydrate, and the other, 42% fat calories and
43% carbohydrate; the volunteers were started on the higher-fat diet, and then were
switched to the very-low-fat diet. The carbohydrate provided in these formula diets was
primarily maltodextrin – which has a very high glycemic index – and dairy protein was
the protein source, so the high-carbohydrate diet in particular was guaranteed to provoke
heavy insulin release following meals. The researchers found that, after 2 weeks on the
high-carbohydrate diet, a phenomenon known as “insulin receptor down-regulation” had
occurred – the number of insulin receptors on the body’s tissues had decreased,
presumably in response to the high insulin secretion associated with the highcarbohydrate diet. Yet, despite the fact that there were fewer receptors to transmit the
insulin “signal”, insulin’s ability to promote glucose uptake and storage by muscle was
dramatically increased by the high-carbohydrate diet.71 Evidently, even though there
were fewer insulin receptors, each receptor did a much more efficient job of
accomplishing insulin’s metabolic mission – unencumbered by the fat over-exposure
induced by fatty diets. (Very likely, the improvement in insulin function would have
been even more dramatic if the insulin receptor down-regulation had been avoided by
using lower glycemic index carbohydrate and plant protein in the formula diets.) I have
yet to see this study – or any of the other studies demonstrating a marked insulinsensitizing effect of very-low-fat diets – cited in the treatises that blame carbohydrates for
the modern epidemic of insulin resistance and diabetes. Yet they commonly refer to
insulin receptor down-regulation as the mechanism whereby high-carb diets allegedly
induce insulin resistance.
27
The take-home lesson is this: if you are only willing to make very modest changes in
your current diet, then cutting back on foods high in saturated fat and compensatorily
increasing your intake of monounsaturate-rich foods, may give you a slightly better
outcome than replacing saturated fats with high-glycemic-index carbohydrates. (Whether
this is true or not might hinge on whether you would lose some weight on the lower fat
diet.) On the other hand, if you are willing to take the pains to do something more
definitive for your heart health (and, I would argue, your overall longevity), then a verylow-fat whole-food vegan diet has remarkable documented efficacy in this regard, and
can render you virtually “heart attack proof” if you take such adjunctive steps as are
needed to keep your cholesterol below 150.
I must register a strenuous objection to the notion that, operating on the presumption that
most people are ill-disciplined and a bit dense, health experts should be dispensing
watered-down advice that presumably will be more acceptable to the public – pablum for
the masses, so to speak - rather than informing people about the lifestyles that provide
truly optimal health benefits. This is the mind-set that resulted in the virtually useless
current dietary recommendations of the American Heart Association - which now serve
as such a convenient target for the ridicule of the monounsaturate clique. In point of fact,
a goodly proportion of the public is at least as bright and self-disciplined as the pompous
medical authorities who are talking down to them.
And what precisely is so difficult about a low-fat whole-food vegan diet? It is very easy
to understand: Avoid animal products – flesh foods, dairy and eggs. Go easy on the few
high-fat plant foods – olives, avocados, seeds, nuts, and the oils and butters derived
therefrom – and eat to your heart’s content from fruits, vegetables, beans, and whole
grains, preferably in structurally intact form. Unlike diets where you attempt to count
calories and measure out portion sizes of fatty meats – diets that are cumbersome in
practice and have poor long-term compliance (in part because their results are so paltry) –
the low-fat vegan approach is simple and discrete: there are foods that you can eat, and
foods that you don’t eat – period. I’ve done this for a number of years, and, if you set
your heart and mind to it, you can too. After you’ve lost the first ten or twenty pounds –
without ever once counting a calorie – your cholesterol has plummeted, and you’ve
trashed your blood pressure medication, you’re likely to be so enthusiastic that you’ll
have found your new lifestyle!
What would be the outcome if Ornish and Esselstyn encouraged their patients to eat large
amounts of monounsaturates? My guess is that the high fat intake would compromise the
ability of their regimens to promote insulin sensitivity and weight loss. However, it
would be preferable to replace such speculation with hard results from well-designed
clinical studies – hopefully, such studies will be forthcoming. One recent study has
demonstrated that, when women adopt a diet that is near-vegan (animal protein intake
was cut by 75%) and that emphasizes low-glycemic-index whole foods – yet that allows
use of olive oil, seeds, and nuts (fat content averaged 30% of calories) – weight loss
averages 9 pounds over 4 months, and this is associated with a worthwhile improvement
in insulin sensitivity.163 Thus, whole-food vegan diets need not be exceptionally low in
28
fat to provide some benefit. Of course, these benefits might have been even better with a
very-low-fat regimen – but why not resolve this issue with clinical studies?
Going Nuts
The observant reader will recall that, whereas I do not recommend a high-fat diet of any
kind, I do recommend a modest daily intake – up to an ounce – of monounsaturated-rich
nuts, particularly almonds or hazelnuts. (These nuts are distinguished by the fact that
their monounsaturate content is over twice as high as the sum of their saturated fat and
omega-6 content; an ounce of these nuts provides about 10 grams of oleic acid.) In the
context of a very-low-fat diet, this will help to insure that oleic acid is the predominant
fatty acid in your body’s tissues, and in circulating LDL particles. (Under ordinary
circumstances, humans synthesize little fat - most of the fat in our bodies is diet-derived –
so you can determine the nature of your body fat by modulating your dietary fat.) Unlike
polyunsaturated fats, oleic acid is not readily oxidized, and thus does not encourage
oxidative stress. Indeed, feeding almonds has been shown to have a favorable impact on
blood markers for oxidative stress.164 Since oxidative damage to LDL particles is thought
to increase their toxicity to the vascular system, a diet in which monounsaturates
predominate may make these particles less pathogenic. The fact that monounsaturate-rich
oils are less atherogenic than polyunsaturate-rich oils in cholesterol-fed hamsters may
reflect this phenomenon64 (albeit – perplexingly – other researchers have found
monounsaturates to be more atherogenic in rodents!65)
Moreover, there is now strong and consistent epidemiological evidence that regular
consumption of nuts (tree nuts as well as peanuts) is associated with a marked reduction
in heart attack risk.165-168 (Peanut butter does not always emerge as protective, possibly
owing to the additives – including hydrogenated oils – added to most commercial peanut
butter.) In particular, nuts (like omega-3 fats) appear to reduce risk for sudden-death
heart attacks, precipitated by cardiac electrical disturbances. The fatty acid profile of nuts
does not offer an adequate explanation for this phenomenon – evidently there is
something else protective in nuts. Nuts are rich in essential minerals, fiber, plant protein,
and phytochemicals; which of these might be primarily responsible for the observed
protection is not year clear. Frequent nut consumption has also been linked to reduced
risk for type 2 diabetes169, 170 – possibly reflecting the fact that monounsaturates have a
less negative impact on insulin sensitivity than do saturated fats, and may act as a
functional antagonist of saturated fats in this regard. Also, oleic acid increases the ability
of the intestinal tract to produce a hormone, glucagon-like peptide-1, which may aid in
control of blood glucose and in diabetes prevention.171
A further consideration is that, even if you eat a very-low-fat diet and are lean, you will
still have body fat, and fatty acids will circulate in your bloodstream. Since, aside from
the omega-3 fats, oleic acid seems to provoke less “fat poisoning” than other fats, won’t
raise LDL cholesterol, and is resistant to oxidation, it makes sense to insure that oleic
acid is the predominant fatty acid stored in your body. This can be achieved by adding a
modest amount of nuts, nut butters, or olive oil to a very-low-fat diet. In other words, I
am arguing, not for a high-fat diet rich in monounsaturates, but rather for a very-low-fat
29
diet in which monounsaturate predominance is achieved by regular intentional
consumption of modest amounts of monounsaturate-rich foods. Almonds or hazelnuts
may be the best choices in this regard, since the health impact of nuts emerges as very
favorable in epidemiological studies – and these particular nuts are exceptionally high in
oleic acid, and low in both saturated and polyunsaturated fats. If you add up to an ounce
of nuts or nut butter to a plant-based daily diet that is otherwise devoid of fatty foods,
your daily fat intake is not likely to be more than 15% of total calories. Dr. David
Jenkins, a Toronto-based researcher who happens to be a vegan, has conducted numerous
studies of almond-supplemented diets, and the effects he has observed are often
favorable, and no worse than benign.172-175 And perhaps I should mention the fact that
almonds are delicious!
In regard to olive oil, however, caution is in order. One study has demonstrated that
consuming 50 grams of olive oil with a meal can acutely provoke arterial
inflammation.176 Olive oil contains a modest but meaningful fraction of saturated fat, and
even oleic acid can exert a pro-inflammatory effect in excess. Dr, Esselstyn tells the
story of a pastor who adopted a wholly plant-based diet after quadruple bypass surgery –
a diet, however, which included large amounts of olive oil. After his angina returned, Dr.
Esselstyn convinced him to lay off the oil, and his angina remitted.177 And I have heard
anecdotes from people who gained unwanted weight after they began to lace their
previously very-low-fat diets with copious amounts of “heart healthy” olive oil. Recall
also the mice who became fat and diabetic on an olive oil-drenched diet.48 So if you elect
to include olive oil in your diet, it may be wise to use it only occasionally and in small
amounts (like a teaspoon). And heart patients who choose to follow the clinically-proven
recommendations of Drs. Esselstyn and Ornish and avoid all fatty foods, have my full
respect. Nonetheless, I am unaware of any evidence that modest intakes of nuts can harm
arterial health – and I doubt that such evidence will be forthcoming.
Spirulina vs. Oxidative Stress
Spirulina is a lot less delicious than almonds – but it may be even more protective.
Here’s why:
One of the key reasons why elevated levels of LDL particles, fatty acids, C-reactive
protein, glucose, and also elevated blood pressure promote atherosclerosis is that they
induce arterial oxidative stress by activating an enzyme complex known as “NADPH
oxidase”. Excessive activity of NAPDH oxidase also plays a key role in the progression
of congestive heart failure, in hypertension and hypertensive complications, in the
development of aortic aneurysms, and in the tissue damage provoked by a heart attack or
stroke.178-189 Thus, many experts on cardiovascular medicine view NADPH oxidase as a
key target for cardiovascular-protective pharmaceuticals. Indeed, one reason why statins
may confer such versatile protection is that they can modestly reduce the activity of this
enzyme complex.181, 190
Fortunately, nature has an answer for excessive NAPDH oxidase activity. Our body’s
cells make increased amounts of a compound known as bilirubin when they are subjected
30
to high oxidative stress; bilirubin provides feedback inhibition of NADPH oxidase.191-194
People who inherit a variant gene that causes them to have chronically elevated blood
levels of free bilirubin, are known to be at greatly reduced risk for coronary disease.195, 196
While this suggests the utility of bilirubin as a protective nutraceutical, there are no
concentrated natural sources of this compound (aside from ox bile!), and it is very
expensive to synthesize. But microalgae, including notably spirulina, are very rich in a
compound known as phycocyanobilin (PhyCB - about 0.6% of the dry weight of
spirulina) that is a close chemical relative of bilirubin. Inside human cells, PhyCB is
rapidly converted to phycocyanorubin,197 which is even closer in structure to bilirubin,
and which likewise is a very potent inhibitor of NADPH oxidase activity.198 This
probably explains why oral administration of spirulina (or of phycocyanin, the chief
protein in spirulina, which contains PhyCB as a component) has exerted such a
remarkable range of anti-inflammatory and antioxidant effects in rodent studies.198, 199
Very recently, French researchers have observed that oral administration of spirulina or
of phycocyanin nearly completely prevents the early signs of atherosclerosis in
cholesterol-fed hamsters.200
Although efforts are now underway to develop PhyCB-enriched spirulina extracts as a
nutraceutical, nothing prevents you from using spirulina now as a food. Extrapolating
from rodent studies, it has been estimated that 1-2 rounded tablespoons daily (15-30
grams) might be likely to reproduce the potent antioxidant effects observed in rodents.198
Although it would be premature to declare spirulina a “wonder food” for cardiovascular
protection – the available clinical literature is sparse, and generally employs very low
doses – it would be perfectly reasonable to use this food now instead of waiting for “all
the evidence to be in”. Indeed, spirulina was used as a dietary staple by the Aztecs, and
has been found to be very safe in rodent toxicology studies.201 One recent clinical study
observed worthwhile reductions of blood pressure and LDL cholesterol – accompanied
by a significant rise in HDL cholesterol - in healthy volunteers consuming 4.5 grams
daily.202 Although it doesn’t taste very good – and smells decidedly worse! – it can be
rendered reasonably palatable by including it in smoothies.
I should add that excessive activation of NAPDH oxidase is believed to play a mediating
role in a wide range of other disorders – including insulin resistance and the
complications of diabetes, neurodegenerative conditions such as Alzheimer’s and
Parkinson’s diseases, hepatic cirrhosis, asthma, osteoarthritis, erectile dysfunction,
periododontal disease, and sun-induced skin damage – to name just a few.203 If spirulina
and PhyCB live up to their promise as safe, natural inhibitors of NADPH oxidase
activity, the future implications for health may be extraordinary.
(By the way, in case you are wondering why certain nutritional antioxidants - such as
vitamins E and C - have failed to benefit cardiovascular risk in controlled clinical studies:
their antioxidant activity is selective, and they don’t influence the main adverse metabolic
effects of NADPH oxidase activity.)
31
III. Obesity and Diabetes – Preventable and Reversible
As noted above, the typical response to a very-low-fat whole-food vegan diet – without
any conscious effort to count or restrict caloric intake – is rapid and substantial weight
loss (at least in people who have significant body fat stores). Owing to the fact that a
low-fat vegan diet usually has a relatively low caloric density, you can find yourself
eating a greater volume of food – while progressively losing weight! Hence the title of
Dr. Ornish’s diet book – Eat More – Weight Less. Studies which compare the body
masses of vegans with those of omnivores or lacto-ovo-vegetarians consistently find that,
at any given height, vegans weigh less.
A rational strategy for getting lean and staying lean is to keep daily insulin secretion as
low as feasible within the context of a very low fat intake. Insulin is the body’s signal to
store fat; it inhibits the burning of fat while promoting use of carbohydrate. Keeping
insulin low therefore tends to increase the rate at which stored fat is burned – and this fat
will not be wholly replaced by dietary fat if fat intake is kept very low. Bear in mind that
a very-low-fat vegan diet has only about half as much fat as the “low-fat diet”
recommended by many health authorities. It is easy for vegans to achieve this level of fat
restriction, because their diets lack fatty animal products. Of course, you won’t go on
losing fat indefinitely with such a strategy; as you get leaner, fat will become less
available for use as fuel, and your daily rate of fat burning will decline until it equals the
rate at which you ingest fat. At that point, you will have achieved a new leaner
equilibrium that you should maintain as long as you stick with your lifestyle.
A very-low-fat vegan diet can be expected to reduce daily insulin secretion because it
improves the insulin sensitivity of muscle (which necessitates a compensatory reduction
in insulin production), while minimizing the potentiating impact of dietary protein on
meal-evoked insulin secretion. The tendency of “poor quality” plant protein to promote
glucagon secretion more avidly than animal protein does may also aid fat loss, since
glucagon acts on the liver to promote fat burning and appetite control.
To optimize the decrease in meal-induced insulin secretion, it is important to emphasize
lower-glycemic-index foods – in other words, lay off the wheat flour products (other then
pasta) and baked potatoes, and emphasize structurally intact whole foods that are
gradually digested. Recent studies show that if you eat a meal that produces a sharp
spike in insulin levels, you are likely to be quite hungry several hours later (as your blood
sugar bottoms out in response to the insulin spike) – whereas meals which produce
gentle sustained rises in blood sugar and insulin promote satiety for hours to come.84
There is now evidence that, even in the context of diets that are neither vegan nor low fat,
selecting meals that moderate the postprandial insulin rise tends to aid weight loss.83, 85
Dr. Marthinette Slabber coined the phrase “low-insulin-response diet” to characterize
diets of this sort; she proceeded to show that, even when the calorie content and the
macronutrient profile of the diet (its relative proportions of fat, protein and carbohydrate)
were kept constant, dieters lost more weight with a low-insulin-response diet than on a
higher insulin response diet.83 Slabber achieved low insulin response by emphasizing
low-glycemic-index starchy foods and banning the co-ingestion of animal protein and
32
significant amounts of carbohydrate – in other words, the volunteers could eat both meats
and starches, but they had to be segregated into separate meals. (As you will remember,
protein – particularly animal protein – potentiates the insulin response to carbohydrate.77)
Vegans achieve the same benefit by simply omitting the animal protein altogether.
However, since low-fat vegan diets are quite high in carbohydrates, it is all the more
important for vegans to choose low-glycemic-index starchy foods if they wish to achieve
the best weight control benefits.
(Incidentally, the idea of banning co-ingestion of animal protein and starch did not
originate with Slabber – this has been a cardinal principle of “food-combining” regimens
for years, like that set forth in the best-seller Fit for Life. The rationales offered for these
regimens have been folkloristic and frankly rather inane – inviting the withering ridicule
of academic nutritionists – but the fact of the matter is, the dietary advice most likely
does help people to achieve weight loss.)
Exercising for Optimal Fat Loss
It virtually goes without saying that regular exercise – both aerobic and resistance – can
substantially potentiate the weight control benefits of a prudent diet. Several surveys
have examined the strategies of people who have succeeded not only in losing large
amounts of weight, but in keeping the weight off for several years. The great majority of
these people report that they are doing at least two things – trying to avoid fatty, caloriedense foods, and exercising regularly.204
Dr. Jean-Pierre Flatt has noted that, when done in the proper manner, aerobic exercise
and a low-fat diet can synergize in promoting fat loss.205 The key is to exercise in a way
that promotes selective utilization of stored fat. This can be achieved by exercising on an
empty stomach (first thing in the morning is an excellent time), and doing an aerobic
exercise that is moderate in intensity and prolonged in duration. If you eat carbohydrate
before you exercise, the resulting spike in insulin will tend to keep your fat in your fat
cells while your exercise does a wonderful job of burning the carbohydrates you have just
ingested – which really misses the point! A moderate intensity is important because
highly intense exercise can only be sustained by rapidly drawing down your stored
glycogen; furthermore, a moderate pace enables you to sustain exercise for a longer
period of time; the longer you exercise, the more selectively you burn fat.
Flatt recognised that, after you have exercised, your body will eventually feel the urge to
reload the glycogen stores depleted by the exercise. If you do this with a meal that is
quite low in fat, and if you have exercised in a way that achieves substantial oxidation of
stored fat, then the amount of fat ingested with the meal will be less than the amount of
fat you have just burned – your body fat content will be a bit lower, but your glycogen
stores will be repleted. Repeat this strategy on a daily basis, and you will inevitably get
leaner, until a new leaner set-point is reached.206 Evidently, the very-low-fat whole-food
vegan diet recommended here should be an ideal complement to a fat-burning aerobic
exercise program – and vice versa.
33
The relatively selective fat burning induced by a prolonged session of aerobic exercise
can persist for several hours if no food is ingested during this time. And this is actually
more practical than it might sound, since the hepatic fat burning triggered by aerobic
exercise tends to suppress hunger.207-209 Certain nutraceuticals – carnitine,
hydroxycitrate, and pyruvate salts – may have the potential to amplify the liver’s capacity
to burn fat in the post-exercise period, thereby aiding hunger control.210-212
These considerations have given rise to a novel lifestyle strategy for fat loss which can be
described as “mini-fast with exercise”. In this protocol, each session of exercise is nested
within a 12-14 hour “mini-fast”, achieved by skipping one meal. For example, instead of
eating breakfast, one does morning exercise and doesn’t eat until lunchtime. I have been
using this strategy for over a decade – in conjunction with a low-fat vegan diet – and this
has helped me keep my body fat in the 5% range. Dr. Babak Bahadori has generalized
this strategy so that exercise can be done at mid-day or in the evening, as desired.213, 214
A clinical study which evaluated this regimen with overweight volunteers at Oasis of
Hope Hospital found that, on average, 25% of initial body fat was lost after 12 weeks –
without calorie counting, and without significant supervision.215 For a more detailed
explanation of this strategy, see the appendix: The NutriGuard “Learn to Burn”
Leanness Program.
Although medical experts commonly recommend exercise training as an aid for weight
control, it is more than a little odd that almost no attention is devoted to the context
within which exercise is done. Exercising after a carb-rich meal or snack, or eating right
after exercise, insures that you will burn relatively little stored fat. It is the proper
integration of exercise and eating habits that promotes optimal leanness.
Although aerobic training, in the long term, can have a favorable impact on insulin
sensitivity because it promotes loss of excess body fat, exercise also has an acutely
favorable impact on the insulin responsiveness of the muscles that are exercised.
Therefore, aerobic exercise or resistance training that involves large muscle groups can
achieve an acute improvement in insulin sensitivity.216, 217 However, this benefit lasts for
no more than 48 hours after the last exercise session. This implies that, if you want to use
exercise training to optimize your insulin sensitivity, you shouldn’t go two consecutive
days without exercise. Thus, it is advisable to do significant exercise at least four days
per week.
Type 2 Diabetes is Reversible
As noted earlier, there is good reason to believe that insulin resistance syndrome as well
as most cases of type 2 diabetes reflect “fat poisoning”. Muscle insulin resistance plays a
fundamental role in both syndromes. Insulin, whose release is triggered by the increase in
blood sugar that follows meals, acts on muscle fibers to promote their efficient uptake
and storage of meal-derived glucose. In skeletal muscle, the insulin signaling mechanism
can be impaired by exposure to excessive levels of free fatty acids, at times when these
fats aren’t needed as fuel; chemicals synthesized from these unneeded fatty acids are
responsible for the resulting impairment of insulin signaling. The offending fatty acids
34
are derived from bloated insulin-resistant fat cells, fatty meals, as well as from excessive
triglycerides stored in the skeletal muscle fibers themselves. The longer-chain saturated
fatty acids found in fatty animal products and palm oil are especially potent in their
adverse impact on insulin signaling, whereas monounsaturated and omega-6
polyunsaturated fatty acids have an intermediate impact, and omega-3 fatty acids are not
harmful. (This helps to explain why insulin resistance and diabetes are less common in
vegans – even those who aren’t notably lean or whose diets are not especially low in
fat.57) Fat poisoning also impairs the insulin sensitivity of the liver, which, like skeletal
muscle plays a key role in glucose metabolism. The liver stores and synthesizes glucose,
and releases glucose continually to the bloodstream at a rate which insures that glucose
levels remain high enough to fuel the brain and other vital organs. Insulin acts on the
liver to slow its release of glucose, insuring that blood sugar doesn’t go inappropriately
high.
Despite inefficient insulin function, most people who are developing insulin resistance
manage to maintain reasonably normal blood sugar levels owing to a compensatory
increase in insulin secretion by the beta cells of the pancreas. Their insulin levels remain
elevated throughout the day, and blood glucose rises after meals may be on the high side,
but glucose eventually returns to a normal fasting level. Despite relatively normal
glucose levels, chronic fat poisoning of the endothelial lining of the arteries means that
people with compensated insulin resistance are at increased risk for atherosclerosis, heart
attack, and stroke.
Unfortunately, chronic excessive exposure of pancreatic beta cells to joint elevations of
glucose and fatty acids can induce a phenomenon known as “glucolipotoxicity”.218
Marked elevations of blood sugar after meals, provoked by ingestion of high-glycemic
index carbohydrates, can contribute to this excessive glucose exposure.
Glucolipotoxicity decreases the capacity of beta cells to detect rises in blood sugar, with
the result that insulin secretion doesn’t increase appropriately after a meal, and insulin
levels may be inadequate to slow glucose release from the insulin-resistant liver. The
failure of beta cells to respond to elevated glucose with adequate increases in insulin
secretion can result in blood sugar levels that are continuously elevated, even during
fasting metabolism. Moreover, fat poisoning is exacerbated, since insulin does an
inefficient job of promoting fat storage and retention in adipose tissue at times when
glucose is elevated and fat is not needed for fuel. As a result, exposure of beta cells to
glucose and fatty acids is further enhanced, and glucolipotoxicity is reinforced; hence,
once beta cell glucolipotoxicity is in force, it tends to be sustained by a vicious metabolic
cycle.
Glucolipotoxicity not only impairs the function of beta cells – it also hastens their
death.219 In all tissues in which cells are proliferating, the birth of new cells is
compensated by programmed cell death – a “cell suicide” phenomenon known as
“apoptosis”. (That’s why our organs don’t continually expand as we age.) In the
pancreas, new beta cells continuously arise by cell division – but this is matched by an
equal rate of cell death via apoptosis. Glucolipotoxicity does not influence the rate of
beta cell multiplication, but it boosts the rate at which beta cells die via apoptosis. As a
35
result, the total mass of beta cells tends to fall gradually in diabetics, such that, when
diabetes is in an advanced stage, they may have less than half as many beta cells as
normal healthy people do. Thus, failure of physiologically appropriate insulin secretion
in diabetics reflects not only not only improper function of beta cells, but also a deficit of
total beta cell mass.
The key role of hyperglycemia (elevated blood glucose) in the genesis of
glucolipotoxicity helps to explain why, as demonstrated by epidemiological studies, diets
that have a high glycemic index tend to increase risk for diabetes.220-222 Conversely,
measures which slow the absorption of carbohydrate following meals, such as the drug
acarbose, have been shown to help prevent or postpone the onset of diabetes.223
However, a high dietary glycemic index alone doesn’t seem to provoke beta cell failure
unless it is also accompanied by fat overexposure; this explains why diabetes is rare in
lean Asians whose dietary staple is high-glycemic-index short-grain rice, but whose diets
are low in fat.
Eliminate the Fat!
Fat poisoning is the fundamental problem that underlies both insulin resistance syndrome
and type 2 diabetes. The evident remedy is to minimize dietary fat (particularly saturated
animal fat), decrease body fat, and burn off the triglycerides stored in muscle. The very
positive results of the Pritikin Clinics with diabetic patients suggests that a very-low-fat
whole-food vegan diet, coupled with substantial daily walking exercise, does a good job
of accomplishing these goals. The relatively low glycemic index of the whole foods
employed by these Clinics may likewise have a beneficial impact on glucolipotoxicity in
diabetics, and thereby aid recovery of their beta cell function.
Doctors at the Pritikin Clinic have published their experience with 652 type 2 diabetic
patients who went through their 3-week diet/exercise program.224 71% of the patients
taking oral medication and 39% of those taking insulin were able to discontinue their
medication – and, despite this reduction in medication, fasting blood sugar dropped by an
average of 15%. Blood fat levels and blood pressure also tend to decline to a very
worthwhile extent, often enabling other medications to be reduced. (With respect to
concerns regarding the impact of high-carbohydrate diets on serum triglycerides, it
should be noted that, on average, triglycerides fell 33% in these patients – a reduction
even more striking than the accompanying 22% decline in LDL cholesterol – so much for
“high-carbohydrate” diets being bad for diabetics!)
As noted previously, the Pritikin Program likewise achieves a substantial improvement in
the insulin sensitivity of non-diabetics with insulin resistance syndrome – as indicated by
an average 40% reduction in fasting insulin levels.4
No doubt, some scientific skeptics will call into question the genuine benefits of the
Pritikin diet by noting that the patients were engaged in regular exercise (as if daily walks
could be expected to produce benefits anywhere near this great!) So it is of particular
interest to look at a more recent study in which type 2 diabetics were treated with a low-
36
fat whole-food vegan diet, without caloric restriction and without explicit exercise
advice. Dr. Andrew Nicholson and colleagues have reported that, in type 2 diabetics
consuming such a diet for 12 weeks, fasting blood sugar dropped by an average of 28%
and the average weight reduction was an impressive 16 pounds.73
These impressive clinical results are entirely consistent with the fact that, in societies
whose traditional diets are low in fat and quasi-vegan, obesity, insulin resistance, and
type 2 diabetics are very rarely encountered – even when calorie intakes are ample.
There are also indications that, independent of its impact on blood sugar, a vegan diet
may reduce risk for some the crippling complications of diabetes. A high intake of
animal protein puts a stress on kidney function that tends to accelerate the kidney failure
associated with diabetes and various kidney diseases. Conversely, a relatively lowprotein vegan diet appears to be protective in this regard.225-227 Furthermore, there are
anecdotal reports that a program incorporating a low-fat whole-food strictly vegan diet
and daily exercise often leads to rapid improvement in the painful and annoying
symptoms associated with diabetic nerve damage (diabetic neuropathy);228, 229 if these
reports are confirmable, it is an important development, because these symptoms are
usually very hard to control with standard therapy.
Finally, we shouldn’t lose sight of the fact that the chief reason why type 2 diabetics die
prematurely is accelerated coronary heart disease. Variations of serum cholesterol, even
within the so-called normal, healthy range (150-200) have a substantial impact on this
risk230. Alhough Dr. Esselstyn did not enroll diabetics in his landmark study, it is only
commonsensical to expect that his strategy – lowering cholesterol dramatically with a
low-fat vegan diet and potentiating this benefit with cholesterol-lowering medication as
needed – will likewise have a major impact on the heart disease risk of diabetics.
A word about the value of low-glycemic-index foods in the management of diabetes is in
order. Such foods may help diabetics to control their weights, but they have the added
advantage of moderating the rises in blood sugar produced by meals.231-233 In diabetics,
excessive blood glucose levels act like a toxin on the body’s tissues – safe dietary
measures which help to keep these glucose levels down can be expected to reduce risk for
future complications, and can also help beta cells to recover from glucolipotoxicity if
concurrent measures are taken to reverse fat poisoning.
The Monounsaturate Alternative?
In light of the demonstrable dramatic benefits of a low-fat, high-carbohydrate whole-food
vegan diet in type 2 diabetics, it is particularly distressing to read, both in the popular
media and the scientific literature, the repeated claim that high-carbohydrate diets are bad
for diabetics, and that the ideal diabetic diet should provide 45-50% of its calories from
monounsaturate-rich fat.234, 235
In light of the fact that fat poisoning is at the root of insulin resistance and type 2
diabetes, what rationality can there be in recommending a high-fat diet of any type for
37
diabetics? The high-monounsaturate alternative only looks good in comparison to the
virtually pointless recommendations of the American Diabetes Association - a 25-30%
fat omnivore diet that does not improve insulin sensitivity, has minimal impact on body
weight, and only modestly lowers cholesterol. As compared to this diet, the highmonounsaturate alternative has a somewhat more favorable impact on the blood fat
profile235 – but it is no more successful in restoring insulin sensitivity, controlling fasting
blood sugar, or in promoting weight loss. Nonetheless, since it doesn’t cause a further
deterioration in insulin sensitivity, and is lower in carbohydrates, blood sugar levels after
meals tend to rise less markedly, so it probably does provide some modest benefit in
regard to glucose toxicity.234 On the other hand, it is likely that free fatty acid levels after
the fattier meals will be higher on the monounsaturate regimen, which potentially could
exacerbate the impairment of endothelial function associated with diabetes. Thus it is not
entirely clear whether the monounsaturate regimen would be preferable in regard to
coronary risk, but lower post-meal glucose levels suggest that it would be preferable from
the standpoint of the complications of diabetes induced by hyperglycemia.
But, even if the monounsaturate enthusiasts are correct in their contention that a highmonounsaturate approach is better for diabetics than is the “high-carbohydrate” ADArecommended diet – so what? Neither of these regimens addresses the fundamental,
underlying problem in type 2 diabetes – the continual excessive exposure of the body’s
tissues to fat. A very-low-fat, whole-food vegan diet, especially when complemented by
exercise training designed to burn stored fat, does address this issue – in part because, in
the longer run, it promotes substantial fat loss.
Strategies for Reversal – the Fasting “Cure”
The inherent reversibility of type 2 diabetes is revealed by the experience of surgeons
who treat severely obese diabetics with stomach stapling operations.236 In the majority of
instances, as patients gradually lose massive amounts of weight, the diabetes simply goes
away – normal blood sugar control is achieved without drugs. While it isn’t feasible to
treat the average diabetic with this draconian and expensive approach (such surgery is
only considered appropriate for grossly obese patients; it entails a measure of risk, often
leads to unpleasant side effects – and many patients ultimately regain the weight), the
medical treatment of diabetes should strive for the same outcome – getting to the root of
the syndrome by getting the fat out of the diet, achieving and sustaining a substantial
reduction in body fat, reducing the fatty acid and triglyceride content of the blood, and
minimizing the fat content of muscle fibers.
There is some reason to suspect that fasting – when used in conjunction with proper lowfat diet and exercise – may have a role in a “cure” for diabetes. Although fat
overexposure – fatty diets feeding fatty bodies - seems to be the fundamental cause of
most type 2 diabetes, many diabetics fail to completely normalize their control of blood
sugar even after they have adopted a very-low-fat diet and lost substantial body fat. This
may result, at least in part, from a vicious cycle in which persistent hyperglycemia and
fatty acid overexposure induce glucolipotoxicity in beta cells – impairing their function
so that glucose and fatty acids remain elevated, and glucolipotoxicity is reinforced.237-239
38
A possible way around this vicious cycle may be offered by prolonged fasting.240 During
a fast, blood sugar tends to fall into the normal range even in type 2 diabetics, giving the
beta cells a respite from glucose overexposure and enabling them to gradually improve
their function. (Although fatty acid levels tend to be high during a fast, they don’t harm
beta cell function unless glucose levels are concurrently elevated.) Indeed, many
research groups have noted that, following a prolonged fast, the glucose control of
diabetics tends to be improved to a greater degree than could be attributed to the weight
loss achieved by the fast; these researchers have pinpointed improved beta cell function
as perhaps the key reason for this “excessive” improvement in diabetic control.241-244
Unfortunately, this benefit usually has proved transitory, as still-overweight diabetics go
back to eating the fatty foods that made them diabetic in the first place, and
glucolipotoxicity is rapidly re-established.
But Dr. Joel Fuhrman, a strong advocate of very-low-fat, whole-food vegan diets for
prevention and treatment of diabetes, reports that, if a fast of 2-3 weeks duration is
preceded by a months of proper eating and exercise that achieves substantial weight loss
and improved diabetic control, and if the fast is followed up by resumption of proper diet
and exercise, glucose control is often normalized, without medication, when the fast is
discontinued; moreover, this “cure” of diabetes persists as long as the prescribed diet and
exercise program is maintained.245 Dr. Fuhrman does not take primary credit for this
discovery – he notes that this technique was used successfully to “cure” type 2 diabetics
by clinical researchers at the Rockefeller Institute for Medical Research in New York
who published their findings in 1915!246 These researchers emphasized that lasting
benefit could only be achieved if the patients remained “below weight” and if dietary fat
was rigorously avoided; they note that “the addition of some quantity of butter or olive
oil to the diet will bring back the glycosuria, ketonuria and other symptoms immediately
or within a short time.” (So much for the miracle of olive oil in diabetes!) Presumably,
the remarkable insights of the Rockefeller researchers were virtually forgotten when
insulin was developed as a diabetes treatment in subsequent years.
A couple of cautions are in order. First, the reports by Fuhrman and the Rockefeller
researchers require further independent verification before they can be considered
adequately proved. Secondly, it is highly advisable to have the guidance and supervision
of a properly-trained physician when embarking on prolonged fasts – particularly the
water-only fasting that Dr. Fuhrman practices. A so-called protein-sparing fast may be
inherently safer, and would seem likely to have a comparable beneficial impact on
diabetes, but even with this strategy a physician’s guidance is very desirable. For
example, insulin and certain oral medications must be discontinued when diabetics fast,
to avoid induction of hypoglycemia; a doctor’s guidance in this regard is crucial.
One potential “fly in the ointment” which may trip up efforts to re-establish normal
pancreatic function in type 2 diabetics is the fact that, as noted above, the total number of
pancreatic beta cells tends to decline by about 50% or more in diabetics, owing to an
elevated rate of cell death induced by glucolipotoxicity.247 This loss of beta cell mass
tends to become more severe as diabetes persists over years. Even if prolonged fasting
manages to normalize the function of a diabetic’s beta cells, the loss of beta cell mass can
39
not be rectified in this comparatively brief time, so the remaining beta cells will evidently
have to “work harder” to re-establish normal glucose control. If the remaining mass of
beta cells is large enough, and if virtually normal beta cell function is restored, this may
be feasible, but under less favorable circumstances it may not prove feasible to
completely reverse glucolipotoxicity. This may be one key reason why diabetes appears
to be more inherently reversible in patients whose diabetes was recently diagnosed, as
opposed to patients who have been diabetic for many years. The take-home lesson is
this: if you have been diagnosed with type 2 diabetes, take aggressive measures now to
reverse it – don’t wait until your beta cell mass has further declined.
We thus have the option of attempting to “manage” diabetes – trying to postpone its
horrendous complications and the premature cardiac death which awaits most patients –
or we can try to reverse it, restoring normal glucose control and alleviating the insulin
resistance syndrome largely responsible for the excess coronary risk. If you were
diabetic, which would you prefer? Pritikin has pointed the way to a definitive resolution
of this devastating disease – but we must accept the challenge of carrying his work
further.
Spirulina vs. Diabetic Complications
As I mentioned earlier, increased oxidative stress produced by activated NADPH oxidase
is one of the key mechanisms by which persistent hyperglycemia and fat poisoning lead
to the characteristic long-term complications of diabetes – blindness (retinopathy), kidney
failure, nerve damage (neuropathy), and the accelerated atherosclerosis that leads to heart
attacks and strokes.248 Bilirubin, in its free form, functions physiologically as an inhibitor
of NADPH oxidase. Dr. Toyoshi Inoguchi, who has devoted much of his career to
defining the fundamental role of NADPH oxidase overactivity in the genesis of diabetic
complications, recently did an intriguing epidemiological study in which he assessed the
risk for major diabetic complications in diabetics who also have Gilbert syndrome; you
may recall that people with this syndrome are characterized by chronically elevated blood
levels of free bilirubin. He found, that, as compared to comparable diabetics not known to
have Gilbert syndrome, diabetics with Gilbert syndrome were only about one-third as
likely to develop retinopathy, kidney failure, or coronary disease!249
Since the chief phytonutrient in spirulina, PhyCB, can mimic the inhibitory effect of its
chemical relative bilirubin on NADPH oxidase activity, there is reason to suspect that
regular consumption of ample amounts of spirulina (or of PhyCB derived from spirulina)
will have a very favorable impact on risk for diabetic complications. Potentially, this
could be of benefit not only to type 2 diabetics, but also to type 1 diabetics whose
diabetes is inherently irreversible (at least until beta cell transplantation is perfected). So
adding spirulina to a very-low-fat, whole-food vegan diet may be a very smart move for
diabetics – though clinical confirmation of this strategy may still be many years away.
Overactivation of NADPH oxidase is also suspected to play a mediating role in the
induction of insulin resistance, as well as the beta cell failure caused by
40
glucolipotoxicity.248, 250, 251 Thus, regular consumption of spirulina may also aid the
prevention and reversal of type 2 diabetes.
High Protein for Weight Loss
High protein approaches to weight control have received more media attention over the
last decade than low-fat strategies – although thankfully the heyday of the Atkins craze
appears to have passed. Although I recommend the vegan approach, there is indeed
reason to believe that high-protein diets can promote weight loss.
I tend to divide high-protein diet regimens into two categories – those that are reasonably
responsible, and those that aren’t. In the latter category belong those diets – like the
Atkins diet – that exhort their adherents to eat as many fatty animal products as their
hearts desire. Pile on the steak, the omelets, the cheese, the bacon, the butter and cream –
just avoid the carbs, and the weight will drop off. This approach appeals to beef addicts
whose only real concern is achieving (temporary) cosmetic weight loss. Naturally the
weight loss will only last as long as the dieter manages to stay off the carbohydrates.
In point of fact, such a diet often does work to achieve weight loss. In people whose
usual diets are high in fatty animal products (which is true of a high proportion of fat
Americans), switching to a low-carb Atkins regimen often does not lead to a major
increase in animal product intake. And since the carbohydrates have been dropped, the
net effect is a substantial reduction in daily calorie intake and steady weight loss (for
awhile). This is possible because the fat-burning ketogenesis unleashed by such diets can
have a major impact on appetite control. In effect, at Atkins diet is just a vulgarized
version of the protein-sparing modified fast – a well-documented temporary strategy for
achieving rapid weight loss.252 Such modified fasts provide sufficient pure protein to
avoid loss of lean mass, while avoiding carbohydrates and fats altogether. Atkins
modifies this by providing protein from fatty animal products – implying a concurrent
high intake of animal fat – as well as the token low-calorie salad. But whereas advocates
of protein-sparing fasts have never represented them as more than temporary expedients
that must be followed up by effective maintenance regimens, the Atkins diet masquerades
as a sustainable lifestyle.
The inherent problem with such strategies is that, in the long run, your equilibrium body
composition will be determined by the effectiveness of the maintenance regimen – so you
might as well go right to the maintenance regimen! The common experience with
protein-sparing fasts is that patients tend to gain back the lost weight once they go on the
“maintenance regimen” – many maintenance regimens have little inherent efficacy, or the
patients are poorly compliant once ketosis is no longer suppressing their hunger. The
logical way to salvage such strategies is to repeat the fasting phase at regular intervals, so
that weight is never allowed to rebound to baseline levels. In effect, the “mini-fast”
strategy described above takes this insight to its logical limit, integrating short-term
fasting into daily lifestyles.
41
The ability of an Atkins regimen to promote rapid weight loss is not in question. Much
of the initial weight loss reflects loss of water weight resulting from glycogen depletion;
although this is of no benefit to health, it gives immediate positive feedback to the dieter,
and doubtless accounts for much of the faddish popularity of this regimen.
Despite the fact that the Atkins diet has been around for several years, pertinent
published clinical data regarding its longer-term health effects are scarce – presumably
because few people manage to continue such drastic carb avoidance in the long term. Of
particular interest in this regard is a study published recently by Dr. Richard Fleming, a
cardiologist who uses drug therapies to address a wide range of risk factors in his
patients. He also asks these patients to eat a low-fat diet that allows a moderate intake of
lower-fat animal products. However, some of his recent patients have been resistant to
his dietary advice, preferring instead to adopt the Atkins approach. Fleming compared
the clinical course of those patients who followed his dietary advice with those who went
the low-carb route; note that all patients in the study benefited from similar drug
therapies. What he found was that, after one year, coronary artery disease had regressed
significantly and heart blood flow had improved in those on low-fat diets, whereas these
parameters had worsened significantly in those who had adopted low-carb diets.253
(Which brings to mind a personal experience: a friend of a friend of mine was doing very
well on the Atkins program – the weight was really coming off – until he suffered his
heart attack!)
A careful reading of Fleming’s paper shows that, after one year, those who had tried lowcarb diets were no lighter than at baseline; evidently, they hadn’t remained faithful to
these diets. Presumably, Atkins could contend that Flemings’ study wasn’t a fair test of
his strategy. But this raises the issue of compliance – how many people are capable of
remaining on a very-low-carb diet indefinitely? Human beings, unlike cats, are not strict
carnivores, and I question whether lean active humans can function well and feel well on
a very low carbohydrate intake.. My suspicion is that, as excess weight is lost and stored
fat becomes less available as a metabolic fuel, people become hungrier on such a diet,
and eventually increase their intake of carbohydrate. This would terminate the ketosis
that promotes appetite control, likely triggering gorging and rebound weight gain. The
burden of proof should be on the advocates of these diets to demonstrate otherwise.
There’s no doubt that many people can lose weight quickly on an Atkins regimen – the
real question is whether they can keep up this regimen for years – and if so, what are its
health consequences? With respect to low-fat diets, the evidence is plain – in societies
whose traditional diets are low in fat, people tend to remain lean for a lifetime.
A related concern is whether the Atkins diet is consistent with the sort of vigorous and
prolonged aerobic exercise that has such a commendable impact on overall health - and
that is so helpful for maintaining weight loss. Glycogen – stored carbohydrate – is
usually crucial for fueling such exercise; when endurance athletes run low on glycogen,
they experience a burn-out popularly known as “hitting the wall”. Ultra-endurance
athletes eating high-fat diets develop metabolic adaptations which enable them to make
better use of stored fat; we don’t know whether the same can be said for Atkins’ patients.
But my suspicion is that exercise is the last thing on their minds – they want a quick and
42
easy fix that won’t interfere with their psychological addiction to greasy animal products.
In fact, a recent clinical study compared response to aerobic exercise in people
consuming either a ketogenic very-low-calorie diet or a reduced-carbohydrate, highprotein regimen (similar to “the Zone”, as discussed below). Not surprisingly, those on
the ketogenic diet reported more fatigue and negative moods during exercise.254
The more responsible advocates of high-protein regimens typically recommend lower-fat
cuts of meat, poultry and fish, and permit reasonable intakes of lower-glycemic-index
starchy foods. (The “Zone” diet falls into this category.) As compared to the very-lowcarb Atkins approach, these regimens are much more sustainable as continuing lifestyles,
and perhaps could be useful as maintenance regimens for those who have lost weight
with an Atkins diet. There is reason to believe that these regimens do have a favorable
impact on appetite control that can promote gradual weight loss. Even though protein
potentiates the insulin response to starch, the carbohydrate intake on these regimens is
relatively low – only about 40% of calories when protein and fat each supply 30% – and
thus, if the carbohydrates have a moderate glycemic index, the insulin response to meals
tends to be modest.84 But it seems likely that high protein intakes promote satiety by
other mechanisms as well.
Danish scientists recently published a fascinating clinical study in which they evaluated
the impact of two “low-fat” ad-libitum diets on body weight – one providing 12% of
calories as protein, the other 25%.255 Both diets contained no more than 30% fat calories
(in fat-drenched Denmark, this qualifies as radically low-fat!) The overweight
participants were allowed to eat as many calories as they wished, but a clever
experimental design insured that each group consumed protein, fat, and carbohydrate in
the specified proportions. After the six-month study was concluded, the results were
dramatic. Both groups had lost substantial weight – presumably because their baseline
diets had been very high in fat – but the high-protein group had lost substantially more
weight – an average of 20 pounds, as compared to 11 pounds in the lower-protein group;
fat loss showed a similar disparity. The reason? Analysis of food intake records
indicated that the subjects eating the high-protein diet had chosen to consume about 20%
fewer calories than the lower-protein group! This clearly indicates that, at least in people
who are overweight, high protein intakes can quell appetite. Some years previously, a
study conducted with rhesus monkeys had reached the same conclusion.256
So there is definitely some method to the madness of the high-protein advocates – these
diets are popular because they do tend to promote weight loss. It seems that the average
American diet contains just enough animal protein to promote maximal obesity! If you
either eliminate the animal protein altogether, or you double it, you are likely to lose
weight.
My chief objection to this high-animal-protein strategy is that the long-term health impact
of such a regimen is terra incognita. These diets typically contain a fair amount of
animal fat – and of course animal protein – so their impact on vascular risk factors is
likely to be less favorable than that of a low-fat vegan regimen.257 The impact of such
diets on diabetes has not been reported – although the associated weight loss is likely to
43
be of some benefit, the relatively high fat content of these regimens suggests that they
won’t be as effective as the low-fat vegan approach. As we will note subsequently, the
quasi-vegan nature of rural Asian diets may be primarily responsible for the very low
incidence of “western” cancers in these societies; there is little reason to believe that
high-protein diets would be comparably effective for preventing cancer (though a leaner
physique and decreased insulin secretion would presumably be of some merit in this
regard). The possible adverse impact of high-protein diets on bone health (as discussed
below) is a matter of concern to many nutritionists. Finally, from an ecological
standpoint, no more than a small proportion of the world’s population could feasibly
indulge in such diets – the livestock industry is vastly inefficient in its use of land and
water, and effectively deprives us of the land needed to raise crops for underfed humans.
Despite these telling objections, I am willing to admit that, for people unwilling to adopt
the vegan alternative, a high-protein diet may be better for your health than staying fat on
an ordinary American diet. And it is at least theoretically feasible to eat a high-protein
vegan diet by making heavy use of soy products. (Thus, Dr. Barry Sears has recently
introduced The Soy Zone.) The health impacts of relatively high protein vegan diets
remain to be explored. As we shall see, high intakes of “poor quality” plant proteins
appear unlikely to increase cancer risk – yet possibly could aid appetite control. In
particular, frequent servings of beans may be helpful to dieters, as they are low in
glycemic index, and high in both fiber and plant protein.
Although I can’t recommend a high-protein diet as a continuing lifestyle, I think we owe
a debt of gratitude to the advocates of these diets for stressing the importance of the
glycemic index concept and of the post-meal insulin surge. Although Pritikin always
emphasized the desirability of whole foods, I can’t recall that he ever had anything bad to
say about whole-wheat bread or baked potatoes (sans the grease). This really isn’t his
fault - the term “glycemic index” hadn’t even been invented when he did his most
important work. Now, however, we have a stand-off in which the Ornishites stress the
dangers of dietary fat, whereas the Zonies blame high-glycemic-index carbs for all our
health ills. Perhaps the proper resolution is (as it often is in acrimonious disputes
between men of good will): they’re both right! If we manage to avoid both fat and highglycemic-index carbohydrates – like the macrobiotic vegans have long advocated - our
health and our waistlines should be all the better for it.
Several years ago I had occasion to recommend a low-fat vegan diet to an acquaintance
who had some health concerns. A few months later, he called me back, with the rueful
news that his cholesterol had gone up since following my advice! I began to question
him about his diet. Did he eat a lot of pasta? No, didn’t particularly like pasta. Did he
eat a lot of beans? No, not fond of beans. How about rice? No, never was a rice person.
By now I was starting to catch on. I’ll bet you eat a lot of bread. Yes, an awful lot of
bread. And I bet that you like baked potatoes, don’t you? Yes, I eat a lot of those.
Clearly, his insulin was going sky-high after every meal. The moral of this story is: if
you’re a bread-and-potatoes vegan, don’t expect health miracles!
44
IV. Avoiding Hypertension, Stroke – and Dementia?
Hypertension (high blood pressure) is associated with increased risk for heart attack, and
if your heart muscle has been damaged by previous heart attacks, it increases risk for
heart failure by increasing the work load on the heart. But hypertension has an even
more dramatic impact on risk for stroke – both ischemic (blood clot-induced) and
hemorrhagic stroke. And there is recent evidence that high blood pressure in mid-life
increases your risk for Alzheimer’s disease later in life. Elderly hypertensives tend to
experience a more rapid decline in cognitive function with age, even when they do not
progress to dementia.258 And one recent clinical study suggests that pharmacological
control of hypertension in the elderly may reduce their risk for developing
Alzheimer’s.259, 260 So keeping your blood pressure low-normal throughout life may be
the best strategy for insuring that your intellect remains sharp during your retirement
years.
Studies comparing the blood pressures of vegetarians and omnivores – even when the
two groups are matched for body size – usually observe lower blood pressure in the
vegetarians.261 The recent celebrated DASH study confirmed that diets relatively low in
saturated fat and high in potassium-rich fruits and vegetables tend to reduce blood
pressure – most substantially in hypertensives.262 Since vegetarian diets are often high in
fruits and vegetables, and relatively low in saturated fat, these factors may explain at least
part of the impact of vegetarian diets.
When Dr. Frank Sacks and colleagues assessed the blood pressures of the Boston
macrobiotic vegans that I mentioned previously, the average values he observed were
astoundingly low.263 Among those under the age of 30, the average blood pressure was
106/60 – an outstandingly protective value. Among the older people, average blood
pressure wasn’t much worse: about 112/67. One of the most intriguing observations was
made when Dr. Sacks stratified that group into those that stringently avoided animal
products (less than 5% of calories from animal products) and those that were slightly
more liberal in this regard: blood pressure was consistently lower in the strict vegans.
Obesity and insulin resistance – typically associated with high blood insulin levels - are
risk factors for hypertension; insulin promotes salt retention by the kidneys and boosts
the activity of the sympathetic nervous system (even in people who are “insulin
resistant”), effects which tend to raise blood pressure.264-269 Nature probably “intended”
these effects of insulin to compensate for the fact that insulin also vasodilates arteries
feeding muscle to promote efficient glucose storage – but this vasodilatory response is
impaired in insulin resistance;270 thus, insulin resistance and the associated increase in
insulin secretion appear to collaborate in raising blood pressure. As I’ve noted above,
macrobiotic diets tend to be low in glycemic index (wheat flour is banned), and
macrobiotics are usually quite lean and insulin sensitive; their daily insulin secretion is
thus probably quite low. These factors doubtless play a role in the exceptionally low
blood pressures of young macrobiotics. It should be noted that macrobiotic diets – and
those of vegetarians in general – are not notably low in salt, and about half of the vegans
in the Sacks study indicated that they salted their meals at the table.
45
The vascular risk associated with a given blood pressure tends to increase with increasing
blood pressure throughout the normal range. (In this respect, it is similar to the impact of
LDL cholesterol on coronary risk.) Thus, it is likely that the exceptionally low (but
physiologically adequate) blood pressures of macrobiotics are associated with greater
vascular protection than would be a so-called normal value of 120/70.
Most low-fat whole-food vegan diets are relatively rich in potassium – particularly if they
are high in fruit, vegetables, tubers, and beans. Studies have repeatedly demonstrated
that, in people eating their usual salty diets, a substantial increase in potassium intake
causes a reduction in blood pressure.271 In part, this reflects the fact that potassium acts
on the kidney to increase its capacity to rid the body of salt.272, 273 Additionally, the
modest increase in blood potassium levels typically seen when potassium intakes increase
can have a direct favorable impact on the endothelial lining of the blood vessels, boosting
its capacity to generate the protective vasodilator nitric oxide.274, 275 Whether or not this
leads to a reduction in blood pressure, it is likely to reduce your risk for heart attack or
stroke; nitric oxide helps to ward off atherosclerosis and blood clots – it is virtually
nature’s antidote to vascular disease. These considerations may rationalize the
epidemiological finding that, independent of any impact it might have on blood pressure,
a high potassium diet greatly decreases your risk for stroke.276-278
Another dietary factor which has emerged in recent studies as beneficial for blood
pressure control is protein. In epidemiological studies, people who have relatively high
protein intakes tend to have lower blood pressure and to be at lower risk for an increase
in blood pressure.279-284 In some studies conducted in the U.S., plant protein appears to
be more protective in this regard.283, 284 It is not clear whether this reflects some inherent
property of plant protein (for example, a decreased propensity to promote insulin
secretion?), or perhaps simply reflects the fact that diets rich in animal protein tend to
also be high in saturated fat, which boosts insulin levels by compromising insulin
sensitivity. Why protein should have a favorable influence on blood pressure is not yet
well understood, but it should be noted that the amino acid arginine and the sulfurcontaining amino acids can be metabolized to yield two hormone-like factors which
promote vasodilation: nitric oxide and hydrogen sulfide. Regular ingestion of beans, soy
products, and nuts may therefore aid blood pressure control in vegans; indeed, each of
these foods has been linked to decreased risk for hypertension.285-288
Salt – The Fundamental Cause of Essential Hypertension
Dietary salt appears to be the most profound determinant of risk for hypertension.
Terrestrial animals have evolved in an environment in which sodium was scarce and
potassium was plentiful; our kidneys therefore became adept at holding on to sodium and
excreting potassium. Since humans rather recently learned how to mine salt and use it as
a seasoning – and even more recently developed the art of stripping our food of
potassium by refining grains and lacing our meals with refined sugars and oils – our
kidneys must now accomplish the reverse feat, retaining potassium while getting rid of
46
sodium. The physiological shifts which this has entailed evidently have not had an
entirely benign impact on our health.
Medical anthropologists, examining tribal groups not yet “blessed” with the bounty of
modern civilization, have repeatedly observed that essential hypertension (the most
common type of high blood pressure, not attributable to kidney damage or hormoneproducing tumors) is literally absent in societies that don’t add salt to their food.289, 290
The age-related rise in blood pressure seen in most Americans – even those who don’t
become hypertensive – is also absent in these populations. But as soon as these cultures
acquire salt, hypertension and the age-related rise in blood pressure have followed in its
wake.
Skeptics have suggested that some other changes – increased body fat, more
psychological stress, or reduced dietary potassium – may have been the real cause of the
onset of hypertension in these groups. This view has been put to rest by a classic study in
chimpanzees conducted by Dr. Derek Denton and colleagues.291 These researchers
worked with a captive chimpanzee colony in West Africa, dividing it into two well
matched groups. All the chimps continued to get the potassium-rich, salt-free fruit and
vegetable diet they were use to, but they also received a special liquid formula. For half
of the chimps, this formula was laced with salt. For 20 months, the scientists gradually
raised the salt content of the formula, making sure that total salt intakes remained within
the usual human dietetic range. Sure enough, average blood pressures progressively rose
in the chimps receiving salted formula; the pressure increases were dramatic in some
chimps and small or nonexistent in others – much as one would expect in humans. In
contrast, blood pressures remained stable in the chimps not receiving salt. After 20
months, the salt was removed from all formulas, and the elevated chimp blood pressures
gradually fell back down to the normal range. Since chimps are almost genetically
identical to humans, this study constitutes very strong evidence that the introduction of
salt was a major factor in the onset of hypertension in acculturated Third World societies.
Of course, other factors such as onset of obesity and insulin resistance, a more sedentary
lifestyle, and depletion of dietary potassium are likely have played an ancillary role in
this regard.
Ecologic epidemiological studies – those in which lifestyle factors in various populations
are correlated with disease risks in those populations – suggest that salt is an important
risk factor for stroke and cardiac hypertrophy, to some degree independent of its impact
on blood pressure.292 (Except when it is an adaptive response to healthful exercise,
cardiac hypertrophy – an increase in the mass of the left ventricle of the heart – is
associated with increased risk for congestive heart failure and for potentially lethal
disorders of the heart’s electrical rhythm.) In other words, even if salt doesn’t notably
raise your blood pressure, it may still be raising your risk for stroke and heart failure.
Salted diets, for reasons that are still obscure, also tend to increase loss of calcium in the
urine – which in the long term can be expected to have a negative impact on bone
density, while increasing risk for painful kidney stones.293-296 Such diets also seem to
increase the intensity of asthma, at least in males.297-299 And the societies that have the
highest salt intakes are also those with the highest incidence of gastric pathology – gastric
47
ulcer and gastric cancer.300, 301 Scientists are currently attempting to determine whether
salt has an impact on the virulence or pathogenic impact of Helicobacter pylori,302 the
microorganism that seems to be the chief mediator of gastric disease.
Clearly, the common notion that dietary salt is something you need to be concerned about
only if you have hypertension, is simply mistaken.303
Why does salt have such a plethora of adverse effects? Salt seems to be most toxic to
those peoples whose kidneys have a diminished capacity to excrete it. The resulting
increase in vascular fluid volume triggers compensatory hormonal mechanisms which
boost the kidney’s capacity to excrete salt and thereby correct the fluid retention – but
these hormones apparently have some adverse health impacts. In particular, salted diets
evoke the production of certain hormonal compounds structurally related to the heart
drug digitalis in susceptible individuals.304-307 These hormones inhibit the “sodium
pump” in the kidney tubules, thereby aiding sodium excretion. But these sodium pumps
are found on cells throughout the body – including the vascular endothelial cells that play
a major role in determining whether we develop hypertension, heart attack, or stroke. I
suspect that a hormone-mediated disruption of endothelial function308 is at the root of the
vascular risk associated with salted diets, and that the endothelium of the small resistance
arteries of the cerebral vasculature is particularly susceptible to this adverse hormonal
influence.309
Lessons from Kitava
About a decade ago, Swedish medical scientist Dr. Staffan Lindeberg and colleagues did
a survey of the population of the island of Kitava – a Melanesian culture off the coast of
Papua New Guinea – to test an interesting hypothesis.310, 311 The Kitavans are one of the
few cultures remaining that still does not add salt to food. They cook some of their meals
in sea water, so they do get some salt in their diet – about 2.5 grams of salt daily
(corresponding to 1 gram of sodium), about one-quarter as much as most Americans get.
And their diets are extremely rich in potassium, owing to the fact that they get the
majority of their calories from potassium-rich tropical tubers (yams, sweet potatoes); I
estimate that they get about 8 grams of potassium daily – about triple the average
American intake. In other words, their intake of salt and potassium is very similar to that
of our paleolithic forbears. The Kitavans remain very lean and insulin sensitive
throughout life312 – their diet is near-vegan (they get a small amount of fish) and their
chief foods are low in glycemic index and caloric density. Yet they have a fairly ample
intake of saturated fat from coconuts, and as a result their cholesterol levels are not all
that low – about 180 in the men and 220 in the women. (Presumably, the Kitavans
maintain good insulin sensitivity, in part, because the saturated fat in coconut milk is of
medium chain length and, unlike the longer-chain saturated fats found in fatty animal
products, does not impair insulin sensitivity.50) And almost all of the adults smoke
tobacco – this is virtually the only Western habit they have adopted, a stunning tribute to
the addictive powers of nicotine!
48
Dr. Lindeberg was able to confirm that, like other salt-free cultures that have been
examined, the Kitavans were free of essential hypertension. But he wanted to take this a
step further and see whether this translated into a low risk for stroke. So he conducted
physical exams on dozens of elderly Kitavans, and also sought to determine whether any
members of the tribe had ever seen or heard of symptoms suggestive of a stroke in other
members of the tribe. He also looked into risk for coronary heart disease and heart attack
by doing EKG studies and asking appropriate questions.
His conclusions were stunning: he was unable to uncover any evidence that anyone in the
tribe had ever suffered a stroke, heart attack, or angina. The closest that he could come in
this regard was a report that a 70-old man had suddenly fallen dead on the beach for no
apparent reason – during the late nineteenth century! Yet, with 2500 residents, a fair
proportion of whom were elderly (a few in their nineties), this absence of vascular
disease could not be attributed to a lack of elderly Kitavans. (More generally, the
common idea that Third World societies with relatively short average life expectancies
lack elderly citizens, is bunk – once a person in these societies reaches the age of forty,
he may have a better chance to achieve an advanced old age than a 40-year-old American
does, owing to low risk for the degenerative diseases that typically kill us; the low life
expectancy in these societies typically reflects high infection-mediated mortality in
infancy and childhood.)
The apparent absence of stroke is quite a stunning finding, because stroke is reasonably
common in many lean Third Word cultures in which heart attack is very rare (cultures
which salt their food, of course). On its face, the absence of coronary disease in Kitava is
less striking, because this disease has been rare in many Third World cultures – but this
should be viewed in the context of the fact that cholesterol levels in Kitava are not low
and most adults are tobacco addicts! Lindeberg’s findings strongly suggest that an
unsalted, high-potassium diet, in conjunction with excellent insulin sensitivity, has an
extraordinarily protective impact on vascular health.
But Lindeberg noted something even more remarkable. He was unable to find any
evidence, either from direct physical examination or report, that anyone on Kitava had
ever suffered from senile dementia! Senile dementia was a concept absolutely foreign to
the Kitavans. Lindeberg found a couple of mentally retarded young Kitavans, but onset
of dementia with age was unheard of. Consider the fact that full-blown senile dementia is
not subtle – if a person couldn’t recognize his own children, it wouldn’t be long before
virtually everyone on the island knew about it.
But Lindeberg may not have been the first to note this phenomenon. Dr. Hugh Trowell,
an expert on the diseases of Africa, recounts the experiences of a British psychiatrist
practicing in Nairobi in the 1930s.313 At this time, the use of salt among average black
Kenyans was still rare, and stroke was very rarely seen. This psychiatrist noted that the
psychiatric ward where he practiced displayed the full range of mental disorders common
in Western society – with the exception that “senile dementia was a notably absentee.”
49
Could senile dementia – including Alzheimer’s disease – be a disease of civilization
made possible by salted diets?!
This possibility is not altogether far-fetched. A growing number of scientists – myself
included - have independently postulated that a healthy cerebral vasculature may
somehow minimize risk for Alzheimer’s disease (and, of course, the so-called vascular
dementia that results from strokes).314-322 Many risk factors for stroke and vascular
disease are likewise risk factors for Alzheimer’s. The recent striking discovery that
therapy with statin drugs may greatly diminish risk for this disease117, 118 fits this
hypothesis, as it is known that statins have a protective impact on the vascular
endothelium and can reduce stroke risk.98, 323 Perhaps maintaining effective brain blood
flow somehow dampens the process that gives rise to Alzheimer’s. Or perhaps some
diffusible product of the healthy cerebrovascular endothelium – such as nitric oxide –
functions to prevent the self-perpetuating inflammatory process involved in Alzheimer’s
from gaining a foothold.
Whatever the answer to this riddle may be, it is not unreasonable to posit the following: if
you keep your cerebral vasculature so healthy that it is virtually immune from
stroke, you may also greatly diminish, if not eliminate, your risk for Alzheimer’s.
Recent discoveries suggest that salty diets might also increase Alzheimer’s risk by
promoting oxidative stress in the brain. Excessive oxidative stress produced by brain
scavenger cells known as “microglia” is believed to be a key cause of the neuronal death
and dysfunction that characterizes Alzheimer’s disease.324, 325 In certain salt-sensitive
strains of rats (prone to develop hypertension on salty diets), a salty diet leads to an
increase in brain sodium content that in turn leads to increased brain activity of the
hormone angiotensin-II.326-328 This increase in cerebral angiotensin-II activity results in
the development of hypertension in these rats – but this hormone can also act on
microglia to boost their production of oxidant stress.329, 330 More specifically,
angiotensin II does not activate microglia directly, but rather potentiates their response to
other activating signals. Thus, it would be reasonable to postulate that salty diets could
make some sensitive individuals prone to Alzheimer’s by exerting a “priming” effect on
microglia, increasing their propensity to produce oxidants. In this regard, it is intriguing
that hypertension in one’s middle years is a strong risk factor for Alzheimer’s;331
conversely, treatment with anti-hypertensive drugs that antagonize angiotensin II activity
has been linked to a marked decrease in risk for Alzheimer’s, and a slowing of its
progression.332-335 While the protection seemingly afforded by these drugs might be
attributed to favorable effects on vascular function, some researchers suspect that
inhibition of angiotensin II activity in the brain also contributes in this regard336-338 – in
part because drugs which can penetrate the blood-brain barrier seem to be more effective
for dementia prevention.332, 333 It should be noted, however, that it is not yet known
whether salty diets can increase angiotensin-II activity and microglial activation in those
specific regions of the brain where Alzheimer’s neurodegeneration occurs – much further
research will be required to determine whether salty diets can promote the oxidative
stress that kills and disables neurons in Alzheimer’s disease.
50
Prevention of Alzheimer’s is an extremely important challenge. The incidence of this
horrible disorder – possibly more horrible for the victim’s family than for the victim
himself – increases progressively with increasing age, until its prevalence in people over
85 is said to be about 50%. What would be the point of taking elaborate precautions to
protect yourself from killer diseases like heart attack, diabetes, and cancer, if your reward
is to spend your “Golden Years” in a state of imbecility, while your children cope with
heartache and ruinous expenses?
Current evidence suggests that the most fundamental key to keeping your cerebral vessels
healthy into old age is a low-salt diet. Other factors which minimize stroke risk include a
high potassium intake, good insulin sensitivity, regular aerobic exercise, keeping blood
pressure low (through dietary and/or pharmaceutical measures), and statin therapy
(despite the fact that LDL cholesterol is not an important stroke risk factor). The diet and
exercise strategies which I recommend should help to accomplish many of these aims.
Even if the alleged connection between vascular health and Alzheimer’s ultimately
proves to be a red herring, the worse that you could expect from following these
guidelines is a greatly diminished risk of stroke – in itself, no mean blessing!
A cautionary note: don’t assume that these measures will be useful for treating
Alzheimer’s once it is already firmly established. The inflammatory process, once it
builds up a head of steam, may be self-perpetuating and very hard to slow or stop. If
simple dietary measures could halt Alzheimer’s, we’d almost certainly know about it by
now. So don’t wait until the horse is already out of the barn to shut the door!
By the way, in light of the fact that fish oil has anti-inflammatory effects and Alzheimer’s
is in essence a low-grade chronic inflammatory disorder of the brain, it is not
unreasonable to speculate that omega-3s may decrease Alzheimer’s risk316 – and a limited
amount of epidemiology suggests that this disorder may indeed be somewhat rarer in
fish-eating cultures.339 You will recall that Kitavans eat a modest amount of fish, which
conceivably could contribute to their protection in this regard.
Dangers of Salt Restriction?
By now you have probably figured out that no piece of dietary advice, no matter how
seemingly benign and laudatory, goes unchallenged in the modern media. And so it goes
with the advice to restrict salt.
To help the kidney retain sodium on a low-sodium diet, the body manufactures increased
amounts of the hormones renin and angiotensin II.340 (Curiously, a high-salt diet boosts
angiotensin II activity within the brain, whereas a low-salt diet increases angiotensin II
production in the systemic circulation.) Potentially, this can have adverse consequences;
angiotensin II in excess can promote constriction of blood vessels – thus raising blood
pressure – and can also promote the process of atherosclerosis, as it is a growth factor for
vascular smooth muscle. (The vasoconstrictive activity of angiotensin II presumably
reflects the fact that it evolved to help animals survive hemorrhage; its sodium-retaining
51
activity is also useful in this regard, as this helps to maintain vascular volume.) The rise
in angiotensin II production during salt restriction is triggered by a concurrent rise in the
hormone renin; several studies have concluded that people with relatively high renin
levels are at increased risk for heart attack.341, 342
This increased production of angiotensin II evoked by low-sodium diets may be largely
responsible for an odd phenomenon known as “salt resistance”: although most people
achieve at least a modest reduction in blood pressure when dietary salt is reduced, in
some people blood pressure doesn’t fall at all or may even rise slightly; these people are
characterized as “salt resistant”, whereas those who respond favorably to the salt
reduction are call “salt sensitive”. Studies show that salt-resistant people tend to
experience above-average increases in angiotensin II when put on low-sodium diets.343,
344
We thus have a bit of a paradox: although salted diets seem to be a sine qua non for
development of essential hypertension, many people with elevated blood pressure fail to
achieve a reduction in this pressure when they cut back on dietary salt. Evidently, the
hypertension genie is not always easy to put back in the bottle! It seems that years of
exposure to a heavily salted diet can have long-lasting effects on the structure and
function of the vascular system that are not readily reversible.
An illustration of this principle is provided by a study in infants.345 Dutch pediatricians
conducted a clinical study in which half of a group of newborn infants were given a lowsoldium diet for their first six months of life, whereas the other half received the amount
of salt ordinarily given to Dutch infants. It didn’t surprise anyone that blood pressures
were lower in the low-salt group after the six months were up. The real surprise came 15
years later, when the insightful investigators had the idea of measuring blood pressure
again in the now teenage participants in that study: they found that the blood pressures of
the teens who had been in the low-salt group were still significantly lower than those who
hadn’t been sodium restricted as infants – this despite the fact that both groups
presumably had been eating the same salty diet after 6 months of age! Evidently, salt
restriction at an early age has long-lasting effects on blood pressure regulation.
Conversely, it is clear that many years of a high-salt diet has effects that cannot be
immediately reversed by cutting way back on dietary salt.
Studies of severe and sudden salt restriction in salt-addicted Western populations have
noted another potential adverse effect: an impairment of insulin sensitivity;346-350 there is
disagreement as to whether more moderate salt restriction is harmful in this regard.351-354
This effect is most dramatic when people’s salt intake it cut to very low levels – i.e., only
about half of the salt intake of Kitavans. (As you will recall, the Kitavans have excellent
insulin sensitivity on a salt intake low enough to prevent hypertension and stroke.) There
is some indication that the magnitude of this effect tends to wane with time.349
Furthermore, when more realistic levels of salt restriction are tested – for example,
cutting current salt consumption in half – the effect is modest and in some studies nonexistent. The physiological basis of this effect is still unknown. (I have a suspicion that a
reduction in the level of the hormone bradykinin may play a role; this hormone promotes
insulin sensitivity, and there is a recent report that its blood levels decline during salt
restriction.355 Alternatively or additionally, increased activity of the sympathetic nervous
52
system – the “fight or flight” neural activity evoked by stress or hemorrhage – may be
responsible for this effect.356-358)
If salt restriction can impair insulin sensitivity and raise angiotensin II production, why
are low-salt societies like Kitava almost universally characterized by good insulin
sensitivity and a near absence of vascular disease? Conceivably, the extreme leanness of
these groups acts as a compensatory factor – this clearly plays a role in their good insulin
sensitivity. Furthermore, it is now known that the nitric oxide produced by healthy
vascular endothelium acts to blunt the actions of angiotensin II;359 conceivably, the
leanness and excellent insulin sensitivity of low-salt cultures aids this production of nitric
oxide and thus renders them resistant to the potentially adverse impact of elevated
angiotensin II levels. The high potassium intakes of most low-salt cultures may also
provide some protection in this regard.
In any case, the fact that some the physiological effects evoked by salt restriction can
potentially have an adverse impact on vascular health, has led some medical scientists to
question the wisdom of recommending salt restriction for everyone.340, 360 This point of
view has been further encouraged by the fact that epidemiological studies attempting to
correlate the habitual salt intakes of Americans with their subsequent risk for heart attack
have had conflicting outcomes. Such studies are hampered by the fact that it is very
difficult to get an accurate assessment of people’s habitual salt consumption by analyzing
a single sample of urine or a short food diary. Furthermore, unless a person is
aggressively avoiding salt, it is almost impossible for a modern American to achieve a
salt consumption as low as that of Kitavans – so the findings of such studies may not be
very germane to assessing the benefits of a lifelong diet that is truly low in salt. It should
be noted that one study – much ballyhooed in the popular press for its conclusion that
people eating diets relatively low in salt were at increased risk for heart attack361 – has
been thoroughly discredited, as the technique for assessing salt intakes was clearly very
flawed.290, 362 A more recent and more credible study has concluded that lower-salt diets
are associated with decreased mortality from heart attack and stroke in overweight
subjects, but not in lean subjects.363 Yet another recent study found that overall mortality
and cardiovascular mortality were somewhat greater in people eating saltier diets.364
(Ironically, the popular media presented this latter study as evidence that low-sodium
diets increase risk for mortality, since the data indicated that low daily sodium intakes
correlated with increased mortality. However, this finding reflected the fact that people
who are sickly and inactive tend to consume fewer calories, and thus less sodium; when
the data were analyzed on a sodium-per-calorie basis, saltier diets were found to confer
greater risk. This is a good example of how sensationalist media often misrepresent
scientific evidence in pursuit of a “hot” story.)
A Role for ACE Inhibitors – Drugs and Peptide Nutraceuticals
I will readily admit that, whereas lifelong salt restriction in lean Third World populations
with minimal atherosclerosis appears to be remarkably protective, it is not necessarily the
case that institution of salt restriction in middle-aged salt-addicted, overweight,
atherosclerotic Americans will be equivalently beneficial. Nonetheless, I believe that,
53
under the right circumstances, moderate salt restriction is highly recommendable. For
one thing, the impairment of insulin function associated with moderate salt restriction is
at most modest (if not non-existent), and certainly can readily be compensated by other
lifestyle measure that promote good insulin sensitivity – such as those discussed above.
Secondly, there are drugs as well as nutrients that can directly antagonize the adverse
effects of angiotensin II on the vascular system. In particular, so-called ACE inhibitor
drugs, commonly used to treat hypertension, inhibit the production of angiotensin II.
(ACE – the acronym for “angiotensin-I converting enzyme” – is a protease enzyme that
generates angiotensin II by cleaving a short precursor protein.) Dr. Graham McGregor, a
forthright and compelling advocate of moderate salt restriction for control and prevention
of hypertension, has demonstrated that, in so-called salt-resistant patients whose blood
pressure fails to decline during salt restriction, concurrent treatment with an ACE
inhibitor enables salt restriction to achieve its intended favorable effect on blood
pressure. This therapeutic combination – salt restriction plus ACE inhibitor – produces
substantial reductions in the blood pressure of most hypertensive patients, regardless of
their salt sensitivity status.365 Of related interest is the fact that ACE inhibitor therapy has
been shown to prevent the negative effect of severe salt restriction on insulin sensitivity
(possibly because these drugs boost bradykinin levels).366
ACE inhibitors are generally well tolerated, and, rather like statins, have a versatile
protective impact on vascular health. If you have high blood pressure, I suggest that you
discuss with your physician the advisability of using an ACE inhibitor in conjunction
with salt restriction. However, ACE inhibitors cannot be used by a small percentage of
people, in whom they induce a chronic cough; a new type of drug that inhibits the
angiotensin receptor may be more appropriate for them. Furthermore, for the majority of
people who are normotensive and who would like to enjoy the health benefits of salt
restriction, it is not feasible to use a prescription drug. Fortunately, there is a natural
alternative – the omega-3 fats found in fish oil somehow act as antagonists to angiotensin
II activity367-372 – which is one reason why they often help to lower elevated blood
pressure. In analogy to the synergism of ACE inhibitors and salt restriction in control of
hypertension, there is limited clinical evidence that the combination of supplemental fish
oil and salt restriction can have a more substantial favorable impact on blood pressure
than either measure alone.373 (And it may be germane to note that the Kitavans obtain
fish omega-3s from their moderate consumption of fish – the only significant animal
product in their diet.) Thus, especially if you have hypertension or pre-existing coronary
disease, it may be wise to supplement with fish oil when you institute salt restriction. As
little as 3 grams of fish omega-3 per day appear to be beneficial in this regard.
Yet another intriguing possibility looms on the horizon. Over a decade ago, scientists
discovered that when they partially hydrolyzed certain food proteins with special
enzymes, some of the resulting short proteins (peptides) were potent inhibitors of ACE;
furthermore, they found that some of these ACE-inhibitory peptides were immune to
destruction by digestive enzymes, and thus could be absorbed intact after oral
administration.374-387 Scientists, particularly in Japan, have been working to develop
food-derived partially hydrolyzed proteins as ACE-inhibitory nutraceuticals, and their
efforts are now reaching fruition with a product manufactured from bonito – a sort of cat-
54
food-grade tuna that the Japanese traditionally use as the condiment “katsuobushi”.378, 380,
387
In oral daily doses as low as 1.5 grams, a ”katsuobushi peptide” product has been
shown to act effectively as an ACE inhibitor and to lower elevated blood pressure – by an
average of 10 points systolic, 6 points diastolic in a recent controlled study recruiting
patients who were mildly hypertensive.387 This product emerges as very safe in
toxicology tests, and so far has not been linked to chronic cough when used clinically; in
part, its safety reflects the fact that, like other food proteins, it is simply metabolized to
the amino acids your body requires. It is currently being sold as a nutraceutical in Japan,
and is now becoming available to nutritional distributors in the U.S. Efforts to produce
products with comparable efficacy from plant proteins – such as soy, buckwheat, and
wheat germ – are in progress. It can be anticipated that the use of such products in
conjunction with moderate dietary salt restriction will have a very favorable effect on
elevated blood pressure in almost every hypertensive.
However, one reason why the advent of natural food-peptide ACE inhibitors is so
exciting, is that there is growing evidence that, even in people who have “normal” blood
pressure, ACE inhibitor therapy is likely to slow the progression of atherosclerosis, and
reduce risk for heart attack and stroke.388-392 This benefit is at least partially attributable
to the fact that, as mentioned above, ACE inhibitors boost the level of bradykinin, a
hormone-like compound that has a favorable effect on arterial health as well as insulin
sensitivity. This latter effect may rationalize recent evidence that ACE-inhibitor therapy
seems to decrease risk for type II diabetes.393-398 The availability of nutraceutical ACE
inhibitors will mean that all of us will have access to this protection, whether or not we
are hypertensive or can afford expensive prescription drugs.
Arguably, the statins and the ACE inhibitors have become the “superstars” of
cardiovascular medicine; these usually-well-tolerated drugs have demonstrated
considerable efficacy for prevention of heart attack and stroke, and there is evidence that,
when used in combination, they have complementary efficacy in this regard.399-403 For
example, a study using cholesterol-fed hamsters examined the ability of a statin and an
ACE inhibitor, alone or in combination, to prevent early arterial damage; either drug
alone reduced the damage by about a third, while the combination reduced it by twothirds (and note that the ACE inhibitor was protective even though the hamsters had
normal blood pressure).399
Additional Nutraceutical Strategies
In addition to nutraceutical ACE inhibitors and fish oil, there are several other
supplemental nutrients that have potential for aiding blood pressure control. These
include the amino acid arginine, the “metavitamins” taurine and coenzyme Q10, and
cocoa flavanols.404-410 The latter are of particular interest. The Kuna Indians of Panama
are known to be free of hypertension as long as they follow their traditional diet – which
is as salty as American diets! They also appear to be at very low risk for stroke.411 What
distinguishes the Kuna is their heavy daily intake of flavanol-rich raw cocoa.412 The
ability of cocoa flavanols to reduce elevated blood pressure has been demonstrated in
recent studies, and appears to reflect the fact that these flavanols can act directly on the
55
arterial lining to provoke increased production of the vasodilator nitric oxide.413
Spirulina and its key phytonutrient PhyCB may also have potential for blood pressure
control, inasmuch as excessive activity of NADPH oxidase, both in the vasculature and
the brain, appears to play a key role in the induction and maintenance of hypertension.187
(You will recall that PhyCB can inhibit NADPH oxidase.) Moreover, NADPH oxidase is
an important mediator of the adverse effects of angiotensin II – so spirulina might
function as an angiotensin antagonist. In a recent open clinical study which enrolled
healthy volunteers, ingestion of 4.5 grams of spirulina daily for 12 weeks was associated
with average reductions of 10 points in systolic pressure and 7 points in diastolic pressure
– a very large effect given that most of the participants were not considered
hypertensive.202
(Since we have touched on dementia in this chapter, it is also appropriate to note that
NADPH oxidase in the brain is believed to be the major source of the oxidative stress that
kills and disables brain neurons in Alzheimer’s disease.414-416 Ingested PhyCB likely has
access to the brain, as suggested by rodent studies in which spirulina feeding has
prevented chemically-induced brain damage.417, 418 So it’s reasonable to suspect that
spirulina may have potential for preventing Alzheimer’s disease, as well as other
common neurodegenerative conditions linked to cerebral oxidative stress, such as
Parkinson’s disease and ALS.419-421)
The possible utility of nutraceuticals for managing hypertension – and for reducing stroke
risk independent of blood pressure – is an area that deserves far more clinical
investigation, particularly since it is not feasible to put half the adult population on
expensive prescription drugs.
Restricting Chloride?
Sodium gets a lot of bad press as a contributory factor in hypertension. But in fact,
sodium chloride is the toxin that makes hypertension possible – other forms of sodium,
like sodium bicarbonate or sodium citrate, appear to be harmless.422 It is the combination
of sodium and chloride that is harmful – sodium without the chloride – or chloride
without the sodium – doesn’t adversely affect blood pressure. In other words, to avoid
hypertension and other complications of a salted diet, we need to restrict sodium or
chloride – but not necessarily both. Several researchers have found that, when people are
put on a low-salt diet, concurrent administration of sodium citrate can prevent the
induced rise in angiotensin II levels. The sodium citrate also prevents an increase in the
activity of the sympathetic nervous system that could be potentially harmful to heart
patients. Yet, unlike sodium chloride, sodium citrate does not raise blood pressure or
increase loss of calcium in the urine.423, 424 So far, no one has looked at the impact of
sodium citrate on the insulin resistance evoked by salt restriction; such research seems
advisable. These considerations suggest that the adverse hormonal responses to salt
restriction represent the body’s effort to conserve sodium, not salt or chloride. At present,
there is no clear evidence that relying on the modest amounts of chloride occurring
naturally in whole-food diets has any adverse hormonal consequences. Thus, by adding
non-toxic organic sources of sodium to a low-salt diet – while keeping chloride
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consumption low - it is conceivable that salt restriction would have a more unequivocally
positive impact on heart health. People often thoughtlessly equate sodium with salt – in
fact, the most protective strategy might be to restrict chloride, rather than sodium.
However, it is clear that more clinical research is needed on this issue before definitive
conclusions can be drawn or recommendations made; one disquieting note is that serum
potassium levels are reported to decline when people on low-salt diets are given sodium
citrate.425 Another study reports that dietary sodium citrate, like sodium chloride,
increases the potency of certain hormones for triggering rises in blood pressure – even
though it didn’t increase blood pressure in the absence of hormone infusions.426 The fact
that sodium citrate supplementation doesn’t raise blood pressure and has a favorable
impact on angiotensin II and activity of the sympathetic nervous system, doesn’t
necessarily mean that it couldn’t influence vascular health negatively in other respects
Salt Restriction – Key to Cerebrovascular Health
Even if we assume that – as suggested in a recent major study363 – the impact of
moderately low salt intakes on heart attack risk in lean people is equivocal, doesn’t this
somewhat miss the point? We have already discussed how hearts attacks can be almost
totally prevented – even if you have pre-existing heart disease – and rigorous salt
restriction is not necessary to achieve this protection. The main point of salt restriction
should be to prevent stroke and optimize your cerebrovascular health. A salted diet
appears to be a sine qua non for hypertension and – as suggested by studies in Kitava and
East Africa – stroke as well; its impact on cerebral health is thus parallel to that of LDL
cholesterol on heart health. The real question that remains is, how low do you have to get
your salt intake to achieve substantial protection in this regard – and how early in life do
you need to start? Current evidence suggests that, if you are overweight, moderate
restriction provides substantial protection,363 whereas more substantial restriction (closer
to the salt intake of Kitavans) may be required in lean people. While optimal protection
may require consuming a low-salt diet from infancy, it seems most likely that an
adequate degree of salt restriction intiated later in life will provide at least some benefit to
most people, and thus is recommendable. The prospect of achieving virtually total
protection from stroke and perhaps even dementia is exciting indeed, and we shouldn’t
allow the quibbling about salt’s impact on heart risk to distract us from this fundamental
goal.
Many vegans are rather smug about their vascular health, presuming that their low
cholesterol levels make them invulnerable in this regard. So it is important to stress that,
with respect to strokes that result from occlusion of small cerebral arteries, LDL
cholesterol is not clearly established as a risk factor – and low LDL cholesterol is actually
associated with increased risk for hemorrhagic stroke.427-429 In quasi-vegan Third World
societies where heart attack is rare – and dietary salt intakes are commonly high – stroke
is a leading cause of death.430-432 So vegans would be well advised to insure that their
diet is rich in potassium, and moderately low in salt.
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Bear in mind that, even if salt restriction doesn’t have a major impact on your blood
pressure, the protective impact of low-salt, high-potassium diets on stroke risk, heart
hypertrophy, bone health, and quite possibly dementia are in large measure independent
of any impact on blood pressure per se. And, even when salt restriction doesn’t have
much effect on your current blood pressure (which is likely to be the case if your current
pressure is relatively low), remember that low-salt diets tend to prevent the typical agerelated rise in blood pressure. These fact are usually conveniently ignored by the pundits
who claim that salt restriction often has minimal impact on blood pressure and has
unknown long-term health effects. All in all, the potential health benefits of a low-salt,
high potassium natural diet are so substantial and versatile – especially if such a diet is
instituted at an early age – that I am inclined to recommend it with minimal if any
reservations. In particular, if you want to maximize your chances for maintaining healthy
brain function when you achieve an advanced age, a low-salt, potassium-rich diet is the
way to go!
The Genie Back in the Bottle - A Way Around the “Salt Paradox”?
The fact that many people don’t achieve a really useful reduction in elevated blood
pressure when dietary salt is reduced – what I call the “salt paradox” – encourages
skeptics to question the role of salt in the genesis of hypertension, and to doubt the
wisdom of recommending universal salt restriction. “Salt resistance” may often reflect
structural changes in small arteries – a thickening of the artery walls known as medial
hypertrophy – that are induced by long-term hypertension, and that can maintain
excessive resistance to blood flow even after salt is removed from the diet. But it is
likely that certain metabolic vicious cycles also play a role in this phenomenon. In other
words, salted diets may trigger some maladaptive patterns of metabolic activity that
become self-sustaining, and work to keep blood pressure elevated even when salt is
withdrawn from the diet. Could there be a way to break these metabolic vicious cycles so
that a low-salt diet could then “cure” essential hypertension?
Work by Dr. Alan Goldhamer suggests that there may indeed by quite a simple way to
put the hypertension genie back in the bottle. It has been known for many years that,
during prolonged fasting, blood pressure tends to drop – and it drops most dramatically in
people who are hypertensive, often coming all the way down to the normal range. Of
course, most people go back to their old eating habits after a fast, and – unless they’ve
lost a lot of excess weight during the fast – their blood pressure goes right back up. But
what if people were to adopt a low-salt vegan diet when they terminate the fast – could
the reductions in blood pressure be sustained?
Goldhamer and his colleagues have been testing precisely this strategy.433 He puts his
hypertensive patients on a water-only fast for about 10 days – or however long it takes for
blood pressure to fall back into the normal range. Then his patients are transitioned to a
diet that is entirely consistent with that which I am recommending here – a vegan diet
that is low in salt, low in fat, and emphasizes lower-glycemic-index whole foods (i.e. no
wheat flour products). Goldhamer has summarized the results achieved with 174
hypertensive patients treated with this regimen. The most encouraging obsevation is that
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the blood pressure of his patients tends to fall a bit further after they terminate their fast
and start to eat the low-salt vegan diet – which suggests that it may be possible to
conserve the blood pressure reductions achieved by the fast. On average, this regimen
slashed the blood pressure of the patients from an intial value of 159/89 to a very
satisfactory 122/76, well within the so-called normal range. In fact, only 11% of his
patients failed to achieve “normal” blood pressure. This benefit is all the more striking in
the context of the fact that Goldhamer discontinues any anti-hypertensive medications
during the fast.
The chief problem with Goldhamer’s remarkable study is that he doesn’t have long-term
follow-ups on most of his patients – so we don’t know for sure how well the benefits are
conserved in the longer term. A high proportion of his patients come from out-of-state,
spend several week’s at Goldhamer’s clinic, and then go back home – making it hard for
the doctor to determine how well they are doing. Nevertheless, Goldhamer has been able
to monitor the long-term progress of 42 of the patients in the study, who live near
Goldhamer’s clinic. He reports, that, an average of 27 weeks after the fasting regmen
was completed, the blood pressure in these 42 patients averaged 123/77 – despite the fact
that these patients were using no anti-hypertensive drugs. This sounds to me a lot like a
“cure” for essential hypertension – though it seems likely that this “cure” will persist only
as long as the patients persist with their low-salt vegan diet. Dr. Goldhamer informs me
that, thanks to an agreement with a local labor union, he is now planning a study that will
have the thorough-going long-term follow-up required to provide decisive proof of the
value of his therapy.
It’s important to realize that most of Goldhamer’s hypertensive patients are not obese,
and the primary intent of the fast is not to achieve weight loss. It is of course well known
that obese people who manage to lose large amounts of weight on therapeutic fasts or
other diets tend to achieve sustained reductions in elevated blood pressure – but that is
not what Goldhamer is trying to do. The modest amount of fat loss his patients achieve
during about 10 days of fasting may be modestly beneficial for their blood pressure
control – but can hardly explain the massive reductions in systolic pressure – on average,
a remarkable 37 points, about triple the reduction seen with most drug therapies –
achieved with his regimen. The most likely explanation is that fasts of sufficient duration
can break some of the vicious cycle mechanisms that act to sustain hypertension in saltresitant subjects.434 I suspect that the substantial reductions in insulin secretion achieved
during a fast435 – reductions that are sustained to some degree by the low-fat, whole-food
vegan diet the patients adopt afterwards – have a lot to do with the dramatic impact of
Goldhamer’s regimen. Perhaps medial hypertrophy accounts for the fact that a small
minority of patients fail to normalize their blood pressure during the fast.
Dr. Goldhamer uses water-only fasting – a technique that, in the longer term, can induce
a substantial loss of lean mass, and can be potentially hazardous without the careful
supervision of a physician – so his fasts are conducted on an in-patient basis in his clinic.
(If you would like to learn more about Goldhamer’s Center for Conservative Therapy, its
website is www.healthpromoting.com.) However, I think that it is likely that a proteinsparing modified fast (PSMF)436-438 – a fast which is modified by administration of high-
59
quality protein (from flesh foods or powders), potassium salts, vitamins, and minerals –
would be as effective, or nearly as effective, as the water-only fasting that Goldhamer
endorses. The PSMF was developed to enable obese people to fast safely for many
months at a time, while maintaining most of their lean mass and preserving good
nutritional status – but it is also safe and appropriate for shorter-term fasts in people who
are not massively overweight, and can be conducted on an out-patient basis (though it is
prudent to have a doctor’s supervision during any type of therapeutic fasting) So, for
people who would prefer to control their high blood pressure naturally with a healthprotective diet - rather than just relying on drugs to provide mediocre control – a PSMF
of 10-14 days duration, followed by a low-salt, low-fat, whole-food vegan diet, may
perhaps be the key to success. In any case, a modified fast of moderate length is unlikely
to hurt you – and will shed a few pounds of fat that you probably don’t really need.
I should however emphasize that this “fasting cure” of high blood pressure still needs
more clinical documentation before we can be sure that it works; while there is no doubt
that fasts tend to lower blood pressure, the ability of low-salt vegan diets to preserve this
benefit requires further verification. Nevertheless, though this approach is still
“unproven”, it’s not likely that you will hurt yourself trying it – particularly if your doctor
is willing to supervise your fast.
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V. Preventing and Controlling Cancer
You may have read about a hyperexpensive clinical study, sponsored by the National
Cancer Institute, which attempted to determine, once and for all, whether “low-fat, highfiber” diets would reduce risk for colon cancer - or more accurately, the benign colon
tumors (adenomas) that often give rise to cancer; the subjects chosen for this study had
previously experienced such adenomas. Half of the participants in the study were asked
to cut back on fatty meats and increase their intake of fiber-rich plant foods, whereas the
other half were ask to maintain their habitual food intake. To the considerable
consternation of the study’s authors, the findings of this ambitious four-year study were
entirely negative – the dietary recommendations had no impact on the subsequent
occurrence of colon adenomas.439
In a letter responding to the published study, Dr. Dean Ornish was scathing regarding the
fact that the study’s participants had achieved only rather trivial modifications of their
diets – saturated fat intake, on average, was reduced only about 20% in the “low-fat”
group, and fiber intakes were increased only modestly.440 Nonetheless, I don’t think that
Ornish’s critique, although accurate, cuts to the heart of the issue. The real crux of the
matter, I believe, is that “low-fat, high-fiber diets” per se do not prevent colon cancer –
low-fat vegan diets do!
The protocol of this colon cancer prevention trial had mandated that the participants
asked to cut back on fatty meats should simultaneously increase their intakes of lower-fat
poultry, fish and dairy products – thus, their intake of animal products and animal protein
did not decline at all. Presumably, the scientists who designed the study buy into the
popular notion that ample intakes of dietary protein – especially “high quality” animal
protein – are crucially important to good nutrition and health. (The popularity of this
view – encouraged for many decades by propaganda sponsored by dairy and livestock
interests - is such that vegan advocates are constantly questioned as to how one could
possibly get an adequate protein intake with a vegan diet.)
You probably are aware that the incidence of many of the chief types of cancers
prominent in Western society, including cancers of the breast, colon, prostate, pancreas,
ovary and uterine endometrium – cancers which, in conjunction with lung cancer, are
responsible for the bulk of our cancer mortality – are relatively rare throughout rural Asia
and Africa. These cancers are rare not only on an absolute, but also on an age-adjusted
basis – in other words, at any given age, people in these societies are far less likely to
develop these cancers than we are. For many of these cancers, it is clear that genetic
factors are not primarily responsible for this rarity, since these cancers are reasonably
common in Asian-Americans and African-Americans. And the disparity in risk for these
cancers is large and important; we are talking about manyfold variations in risk - up to
tenfold or more in the case of prostate cancer. In other words, if we could figure out why
these cancers are comparatively rare in the Third World and institute the necessary
corrective measures in the West, the impact on cancer mortality would be astounding.
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By the 1970s, as medical scientists became better aware of the stark international
disparities in age-adjusted cancer incidence and mortality, the first efforts were made to
explain this remarkable phenomenon. Suspicion first fell on dietary fat, since the average
daily dietary fat intake in various countries throughout the world was found to correlate
quite nicely with the incidence of the “western” cancers in these countries. Seemingly
consistent with this hypothesis was the fact that fat-enriched diets (with the notable
exception of fish-fat) could markedly increase the yield of carcinogen-induced cancer in
many animal studies. With respect to colon cancer specifically, dietary fiber was
suspected to be protective; it was thought that dietary fiber might bind to putative
carcinogens or cancer-promotional agents, lessening their access to the cellular lining of
the colon.
Unfortunately, these neat theories soon began to fall apart. Closer examination showed
that international incidences of these cancers tended to correlate with saturated or animalderived fat intake, but showed no correlation whatever with fats derived from plants
sources. And yet, in animal studies, the polyunsaturated omega-6 fats (as found in many
vegetable oils) were more effective than saturated or other types of fat in promoting
cancer induction. Furthermore, so-called case-control epidemiology in Western
populations – studies which compare the diets of people who come down with a disease
to the diets of roughly comparable people who don’t – are only partially confirmatory of
a link between these cancers and dietary fat; in the case of breast cancer, no such link is
found, even when saturated fat is considered separately.441
Meanwhile, the fiber hypothesis of colon cancer has received little support from animal
studies, and equivocal support from epidemiological surveys. And scientists in Africa
have noted that, as crude maize meal has been progressively replaced by refined lowfiber maize meal as a dietary staple in rural African populations, the incidence of colon
cancer has remained low.442 The N.C.I. study cited above, as well as a large companion
study that specifically examined the impact of supplemental wheat-fiber on colon
adenoma incidence and found no effect,443 appear to have delivered the coup de grace to
the fiber theory of colon cancer prevention.
I myself was in quite a quandary on this issue, which had fascinated me since my medical
school days. Back in the 1970s, I had made some of my own correlations between
dietary fat and “western” cancer incidence, and had become convinced that dietary
factors were at the root of the vast international disparities in risk. But over the course of
time it became apparent that the fat and fiber hypotheses didn’t hold a lot of water.
Vegan Diets vs. Growth Factors
A few years ago, I became interested in nutritional determinants of growth factor
activities. One growth factor in particular, IGF-I (insulin-like growth factor-I) appears to
have an important influence not only on lean mass (it promotes the synthesis and
retention of protein in muscle, mediating the influence of growth hormone in this regard),
but on cancer induction. It turns out that genetically altered cells that are prone to give
rise to cancer – cells that have sustained certain heritable mutations in their DNA that can
62
potentially disrupt their growth control mechanisms – have mechanisms that somehow
“sense” that these cells are genetically flawed, and that then often direct these cells to
“commit suicide” in a natural process known as apoptosis. It is now known that
apoptosis is a crucial regulator of the cell population in most tissues; the number of cells
in a tissue is determined by the balance between cell multiplication and apoptosis, which
must proceed at roughly equal rates if the cell number in adult tissues is to remain
constant. Apoptosis plays an essential role in embryonic development (we wouldn’t have
discrete fingers if the tissue between them didn’t die off in planned apoptosis), and it is
becomingly increasingly clear that effective apoptosis is crucial for prevention of both
cancer and autoimmune disease.444-446
A number of hormonal growth factors are capable not only of promoting cell
multiplication, but also of suppressing apoptosis in various tissues. Of key importance in
this regard is IGF-I, which appears to suppress apoptosis in most tissues. Most of the
IGF-I in the blood is produced in the liver, which secretes it into the bloodstream;
however, other normal tissues as well as certain tumors can make enough of this hormone
to influence their own growth. Most types of multiplying cells express receptors for IGFI during some stage of their cell cycle, and activation of these receptors by IGF-I not only
promotes cell replication, but also usually makes these cells less susceptible to
apoptosis.447-449 In particular, this appears to apply to many pre-cancerous tissues, in
which apoptosis provides crucial protection from cancer induction.446, 447 The versatile
activity of IGF-I in blocking apoptosis in many tissues thus suggests that IGF-I may be a
nearly universal “cancer promoter”. IGF-I does not directly induce mutations in cellular
DNA – these may arise as a result of free radical damage or attack by carcinogens – but it
may increase the rate at which mutations occur by boosting the rate of cellular
proliferation; risk of mutagenic DNA damage is greatest during DNA replication, which
is necessary for cell proliferation. Moreover, once a cell has sustained dangerous precancerous mutations (which becomes more common as we age and our cells
progressively accumulate mutations), high IGF-I activity will increase the chances that
that cell and its progeny will survive to give rise to a cancer.
Not surprisingly, one strategy that mutant cells adopt to avoid apoptotic death is to
increase their production of IGF-I receptors, so that they will be more sensitive to the
available IGF-I. It has recently been discovered that one of the prime purposes of many
so-called “tumor suppressor” genes is to decrease expression of the IGF-I receptor.450, 451
When these suppressor genes are rendered non-functional by mutation, increased
amounts of this receptor are produced, making the cells less vulnerable to apoptosis.
Heritable mutations of the BRCA1 suppressor gene are linked to increased risk for breast
and ovarian cancers; a key role of this gene in breast and ovary cells is to suppress
production of the IGF-I receptor. Researchers thus surmise that “activation of the
overexpressed receptor by locally produced or circulating IGFs may be a crucial step in
breast and ovarian cancer progression.”451 A likely implication is that women who carry
this mutation could lower their cancer risk by diminishing their IGF-I activity.
You have probably heard or read that underfeeding rodents – giving them 20-40% fewer
calories than they would consume spontaneously when given free access to food –
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literally slows their aging process and increases their maximal achievable longevity by
25% or more. One reason why these rodents tend to live longer is that they are less
susceptible to cancer – although their lifelong risk for cancer may not be low, their ageadjusted risk (their incidence at any given age) is substantially decreased. Recent studies
pinpoint a decrease in IGF-I activity as the likely mediator of this effect. Caloric
restriction markedly depresses both the levels and the activity of IGF-I in the
bloodstream; if calorie-restricted rodents are given a concurrent infusion of IGF-I to
prevent a reduction in IGF-I activity, the calorie-restricted diet fails to prevent cancer.452,
453
Beginning with the pioneering study of Dr. June Chan, who found that risk for prostate
cancer was several-fold higher in men with moderately elevated IGF-I levels,454
epidemiological studies have begun to look at the impact of circulating IGF-I levels on
risks for various cancers. So far, relatively high blood levels of IGF-I have been linked to
significantly increased risk for prostate, colon, and pre-menopausal breast cancer.455-459
(Note that these are some of the most important “western” cancers.) Actually, to be a bit
more accurate, it is the level of free IGF-I in the blood that is emerging as a risk factor.
Most of the IGF-I in the blood is bound to certain proteins (not unreasonably known as
“IGF binding proteins”) that prevent it from exerting its activity; only the IGF-I that
breaks free from the grasp of these proteins has biological activity.
Which leads us to a rather obvious question: how do dietary factors regulate IGF-I
activity? The impact of dietary restriction in this regard makes it clear that diet can have
an important impact in this regard. And this makes a good deal of sense: when calorie
availability is low, what sense would it make for animals to have high anabolic growth
factor activity (e.g.high IGF-I activity) if sufficient calories aren’t available to support the
growth and maintenance of an enlarged tissue volume? Thus, calorie-restricted animals
tend to be small and lean (not unlike the rural Asian populations at low risk for “western”
cancers!)
Calorie intake appears to regulate IGF-I activity primarily by modulating insulin
secretion. High insulin secretion – as is seen when animals eat large amounts of calories
and/or are fat – acts on the liver to promote IGF-I synthesis and to inhibit production of a
factor (known as IGF binding protein-1, or IGFBP-1 for short) that binds to IGF-I,
suppressing its activity460-463. Thus, the low daily insulin secretion associated with lowfat, whole-food vegan diets (or other low-insulin-response diets) would presumably
decrease circulating IGF-I activity. Furthermore, the fact that dietary saturated fat has a
particularly obnoxious impact on muscle insulin sensitivity – and thus tends to provoke a
compensatory increase in insulin secretion – may help to explain the adverse impact of
dietary animal products on cancer risk. Insulin sensitivity is also compromised in
obesity, but is improved by exercise – thus offering a satisfying explain for the fact that a
great many cancers are more common in people who are overweight,464 and less common
in those who exercise regularly.465 The characteristic leanness of vegans is evidently an
advantage in this respect.
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But another primary determinant of IGF-I activity is the availability of essential amino
acids – the nutritionally essential building blocks of protein that are richly supplied by
most dietary animal protein.466-468 Thus, it is not surprising that diets low in protein, or in
which the protein is provided by plant proteins relatively low in certain essential amino
acids (such as soy!) have been found to have an effect somewhat similar to underfeeding
in decreasing cancer yields in carcinogen-treated rats.469-473 One scientist, cognizant of
the fact that soy protein tends to be a bit deficient in the essential amino acid methionine,
wanted to see what would happen if a supplement of methionine was added to the soybased diets of carcinogen-treated animals; sure enough, the addition of methionine
largely abrogated the ability of soy-based diets to reduce cancer yield,473 (It is ironic that
many nutrition experts have suggested that methionine be added to dietary soy products
to improve the “quality” of their protein!)
Plant proteins, as opposed to animal proteins, tend to be relatively low in certain essential
amino acids – most notably methionine and lysine. Since vegan diets also tend to be
lower in total protein than omnivore diets are, it is apparent that essential amino acid
nutrition tends to be somewhat poorer in vegan diets – albeit sufficient to support a
healthy life and normal development. You will also recall that, in lean long-term vegans,
daily insulin secretion tends to be relatively low despite high carbohydrate intakes – in
part because of their good insulin sensitivity, but also owing to the absence of dietary
animal protein. (This latter effect can be amplified by choosing whole foods that are low
in glycemic index.) There is thus a logical basis for predicting that IGF-I activity will be
lower in vegans.
Recent surveys in British vegans indicates that their blood IGF-I levels in fact are about
10% lower than those observed in omnivores or ovo-lacto-vegetarians.474, 475 But this
underestimates the true disparity in IGF-I activity, as vegans were also found to have
elevated levels of the IGFBP-1, an antagonist of IGF-I activity. Studies examining the
IGF-I activity of the very lean vegans of rural Asia have yet to be done, and are urgently
needed.
An intriguing aspect of this British work is that higher intakes of “poor quality” plant
protein (non-soy plant protein) were found to correlate negatively with IGF-I –
suggesting that plant protein can actually suppress the liver’s production of IGF-I. This
may reflect the fact that the non-essential amino acids in plant protein provide a highly
effective stimulus to secretion of the pancreatic hormone glucagon,476-478 which acts on
the liver to boost the metabolic breakdown of amino acids, including methionine.479
Thus, ingestion of “poor quality” protein may actually decrease liver levels of some
essential amino acids by promoting their metabolic disposal. In effect, “poor quality”
protein can act as a functional antagonist of essential amino acids – thereby reducing
IGF-I synthesis. (This raises an interesting possibility – could supplementation with nonessential amino acids be used to decrease IGF-I production in omnivores?477) These
considerations suggest that the dietary ratio of essential to non-essential amino acids may
be as important a determinant of IGF-I levels as the absolute amount of essential amino
acids is.
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Another interesting finding by the British researchers was that, among vegans, frequent
soy milk consumption was associated with a considerable increase in IGF-I. This may
reflect the fact that soy protein is of relatively high quality compared to many other plant
proteins; it’s a relatively good source of the lysine that is poorly supplied by grain
proteins. While adding soy products to an omnivore diet may tend to reduce its protein
quality, this would tend to enhance net protein quality in vegans – while of course also
increasing essential amino acid intake. So vegans might be well advised to avoid heavy
consumption of soy. (Yet soy isoflavone supplements may be warranted, as there is
evidence that these phytoestrogens may reduce risk for prostate, breast, and colon cancer,
as discussed below.)
Greek physicians performed a study of related interest in type 1 diabetics, who lack the
capacity to make their own insulin.225 Type 1 diabetics are at high risk for kidney failure,
but, as we noted above, vegan diets appear to be protective in this regard. The physicians
therefore studied the impact of two different diets on their diabetic patients; each diet had
moderate yet fully adequate protein content (around 1 gram per kilogram of body weight
per day), but one diet was omnivore whereas the other was vegan. While they confirmed
the expected favorable effects of the vegan diet on kidney function, they also determined
that IGF-I levels were nearly 20% lower on the vegan diet than on the omnivore diet.
Since the respective diets were not modulating insulin secretion in these patients, these
results may be directly reflective of the impact of protein “quality” on liver function.
Moreover, there is evidence that low-fat, whole-food vegan diets may reduce blood sex
hormone activities. As you know, steroid sex hormones (estrogens, androgens) act as
growth factors for certain tissues, and can influence the induction and growth of various
cancers. The reduction in daily insulin secretion associated with diets of this type would
be expected to boost the liver’s production of the sex hormone-binding globulin (SHBG),
a protein which circulates in blood and reduces the effective activities of steroid sex
hormones by binding tightly to them.480-482 Moreover, IGF-I acts in various ways to
promote sex hormone synthesis, so a decrease in IGF-I activity might be expected to
decrease this synthesis.22, 483 These two mechanisms are likely responsible for the
decrease in blood levels of free estrogen that has been repeatedly observed in women
who adopt low-fat vegan diets.80, 163, 484, 485 Increased fecal excretion of estrogens has
been observed during consumption of fiber-rich vegetarian diets, and may also contribute
to this effect.486
The impact of such diets on free testosterone in men is less clear. The recent study
examining British vegans reported that their free testosterone levels were no lower than
those of omnivores, despite the fact that their SHBG levels were higher.474 On the other
hand, studies from the Pritikin Clinic indicate that total blood testosterone levels do not
change during the Pritikin program, yet SHBG levels increase by about 30%.487, 488
Taken together, these observations imply a reduction in free testosterone; unfortunately,
the measurements of testosterone and of SHBG were made in two separate studies on two
different groups of men, so this conclusion is a bit shaky. (Bear in mind that Pritikin
patients differ from many free-living vegans in that they eat a very-low-fat diet and
exercise daily – their insulin sensitivity is thus likely to be superior.) Other studies
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comparing vegetarians with omnivores have reported that total or free blood testosterone
levels are lower in the vegetarians.489, 490 Evidently, more clinical research is needed on
this issue. It will also be of interest to determine whether vegan diets influence the
conversion of testosterone to its more active derivative dihydrotestosterone. Blood levels
of the chief metabolite of dihydrotestosterone - androstanediol glucuronide – are reported
to be decreased in vegetarians and in Chinese;489, 491 however, one recent study found no
such decrease.474 Some Japanese dermatologists have noted that Japanese men prone to
male-pattern baldness seem to be balding at an earlier age than in past generations;
conceivably this could be indicative of an increase in testosterone activity as the Japanese
diet has changed from quasi-vegan to one much higher in fatty animal products.
In some tissues, IGF-I and sex hormone activity seem to interact synergistically as cancer
promoters. For example, in estrogen-responsive breast cancers – and presumably healthy
breast tissue as well – estrogen acts to greatly potentiate the response to IGF-I by
increasing the availability of IGF-I receptors and of certain proteins that are crucial for
effective transmission of the IGF-I “signal” (most notably the protein IRS-1).492-496 Thus,
estrogen and IGF-I interact synergistically in promoting proliferation and blocking
apoptosis in cancerous and pre-cancerous breast tissue. Conversely, it would seem to
follow that the moderate reductions in both estrogen and IGF-I achieved by a low-fat,
whole-food vegan diet would likewise interact syngergistically to provide protection
from breast cancer. It is not unlikely that similar reasoning applies to certain other
cancers arising from sex hormone-responsive tissues. For example, in an androgenresponsive prostate cancer, IGF-I only has growth factor activity if an androgen is
simultaneously present.497
Although insulin can function indirectly as a growth factor by acting on the liver to boost
circulating IGF-I activity, there is credible speculation that it may also have direct growth
factor activity in some circumstances. In regard to risk for pancreatic cancer – one of the
most inexorably lethal of cancers – the proximity of at-risk pancreatic cells to the insulinsecreting beta cells means that these cells are exposed to far higher concentrations of
insulin than other tissues see; at these high concentrations, insulin can activate the
receptor for IGF-I – in effect, mimicking IGF-I activity.498 There is also evidence that
many pancreatic tumors express high levels of insulin receptors that promote cell growth
when activated.499 In other tissues, although physiological concentrations of insulin have
little direct growth factor activity, they have the potential to potentiate response to other
growth factors 500-503 Considerable evidence now links elevated insulin secretion to
increased risk for colon cancer;504, 505 perhaps colonic insulin receptors help to mediate
this phenomenon. For all of these reasons, keeping daily insulin secretion low appears to
be a very rational strategy for reducing cancer risk.
Clinching Evidence from China
My thinking about vegan diets, IGF-I, and cancer risk really crystallized when I
encountered the fascinating findings of Dr. Colin Campbell and the China Health Project,
the most massive epidemiological study yet attempted. This study has characterized a
wide range of dietary, lifestyle, and blood parameters in a large number of rural provinces
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of mainland China, and has attempted to correlate these with the pattern of disease in
these provinces. Most of the people in these provinces are quite poor, and although they
are not ethically or intellectually committed to veganism, they are usually too poor to
incorporate animal products into their diets except on an occasional basis. Nonetheless,
the provinces vary in the extent to which animal products are eaten.
Since a strictly vegan diet is cholesterol-free, whereas all animal products (other than
non-fat dairy) contain cholesterol, the addition of animal products to a vegan diet
typically leads to an increase in serum cholesterol level. For this reason, serum
cholesterol can be used as a marker for animal product ingestion in rural China. Also of
rough utility in this regard is serum urea, a metabolic product of protein breakdown.
Campbell reports that, in rural China, risk for the entire range of “western” diseases –
including coronary disease, diabetes, and a number of prominent cancers (including those
of the breast, colon and prostate) – correlates positively with serum levels of both
cholesterol and urea.506 This strongly suggests that the extent to which animal products
are included in rural Chinese diets is a chief determinant of their risk for “western”
diseases, including the “western” cancers. Campbell notes that there does not appear to
be a threshold below which animal products are no longer dangerous – minimal risk was
found in those provinces that were most strictly vegan.
(Actually, vegan diets also appeared to offer protection from cancers of the stomach and
liver – cancers more common in Third World cultures where sanitary conditions are often
poor; this is an important point, since some scientists have questioned whether vegan or
high-carbohydrate diets might be partially responsible for high rates of these cancers in
Third World cultures. In fact, endemic infectious hepatitis and heavy consumption of salt
and of microbially-contaminated salt-preserved or fermented foods – typical of societies
that lack refrigeration - appear to be the chief environmental causes of these cancers.
There does not appear to be any notable excess of these cancers in American vegetarians,
and these cancers are comparatively rare in economically advanced countries.)
One key finding in Campbell’s China research is that, by and large, rural Chinese are not
undernourished from the standpoint of calorie intake. Indeed, rural Chinese typically
have a calorie intake that is substantially higher, per pound body weight, than that of
Americans, even if they are not engaged in vigorous manual labor.75 This should put to
rest the common notion that rural Asians have low cancer rates simply because they
periodically undergo involuntary caloric restriction.
Vegan Diets Prevent Cancer – More Evidence
Campbell’s observations were by no means unprecedented. Several previous (and
subsequent) international epidemiological studies, attempting to correlate characteristic
dietary intakes in various countries with their age-adjusted cancer incidence or mortality,
have noted that estimated intakes of animal protein correlate just as tightly with
“western” cancer risk as animal fat (or saturated fat) intake does.507-516 A reasonable
interpretation of this is that when scientists demonstrated correlations between total fat or
saturated fat intake and cancer risk, the fat intakes were just serving as markers for
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animal product intake. Other studies have looked at the rising incidence of “western”
cancers throughout Asia (especially urban Asia) over the last several decades; several
studies have shown that increases in animal product consumption correlate nicely with
the cancer incidences observed about ten years later.517, 518 Increased animal product
consumption has likewise been linked to increasing cancer rates in Mediterranean
countries whose diets used to be predominantly plant-based.519
It is a little known fact that the age-adjusted death rate from total cancer tripled in
African-American males during the twentieth century;520, 521 only about half of this
increase can be attributed to the smoking epidemic. This cancer holocaust occurred
despite the fact that access to competent medical care presumably increased for AfricanAmericans during this period. I suspect that this phenomenon is mechanistically similar
to that now being observed in Asia, where “western” cancer rates are rising steadily
wherever economic status is improving. Whenever people emerge from Third World
status – whether in Asia or in the rural South – their increased economic power translates
into greater consumption of (relatively expensive) animal products – and rates of
“western” cancers soon climb commensurately.
Physicians practicing in sub-Sahara Africa during the last century frequently noted that
risks for “western” cancers seemed to be extremely low among black Africans – even
prostate cancer, to which African-Americans are particularly prone.522 These impressions
square well with the fact that traditional diets in this region were quasi-vegan.
Unfortunately, the lack of reliable cancer registries in most of sub-Saharan Africa have
made it difficult to compare the cancer rates of Africans with those of black Americans.
The Third World is not the only place where rates of “Western” cancers have been
comparatively low. These rates were relatively low in Crete during the middle of the last
century, when the residents of this island were practicing the prototypical “Mediterranean
diet”: low in animal products (except for fish, which provides cancer-retarding omega-3
fats), and high in fruits, vegetables, and olive oil. Although insulin sensitivity was
probably not optimal on this relatively high-fat diet, the residents of Crete at that time
were physically active and relatively lean, which would have a compensating impact in
this regard. Furthermore, the meal-induced stimulus to insulin release was presumably
rather low owing to the paucity of animal protein and the moderate carbohydrate content
of meals; thus, daily insulin secretion was probably much lower than in most other
Western societies. The low intake of animal protein might have been associated with a
modest reduction in IGF-I production, and the increased phytochemical intake provided
by a diet rich in fruits and vegetables would have also been protective. These
considerations thus provide a satisfying explanation for the relatively low rates of cancer
which the people of Crete used to enjoy. (Unfortunately, Crete and the rest of the
Mediterranean world have been gravitating toward diets richer in fatty animal products
over the last few decades – and this is reflected in their climbing cancer rates.)
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Prostate Cancer
Let’s now take a closer look at the many types of cancer that appear to flourish wherever
people adopt diets rich in fatty animal products. These include major killers such as
cancers of the prostate, breast, colon and (with an essential assist from tobacco!) lung jointly responsible for well over half of all cancer mortality in the U.S. - as well as a
number of other malignancies that are somewhat less common but no less deadly.
The case of prostate cancer is particularly illuminating. In 1998, Dr. James Hebert and
colleagues of the University of Massachusetts Medical School published an intriguing
paper that provides the age-adjusted death rates for prostate cancer (circa 1985-1989) and
estimated average daily food intakes (circa 1979-1981) for 59 countries, based on data
provided by the World Health Organization and Food and Agriculture Organization of
the United Nations.523 I arbitrarily defined as “quasi-vegan” those countries for which
estimated intake of animal product calories was 10% or less of estimated total calorie
intake; six countries – Egypt, Guatemala, Honduras, South Korea, Sri Lanka, and
Thailand – fell into this category. I averaged their age-adjusted prostate cancer death rate
and came up with a figure of 1.96 (per 100,000 male population). In contrast, this death
rate in the U.S. was 32.19 – over sixteenfold higher! (And the death rate in black
Americans is much higher than this.) Skeptics might note that total calorie intakes were
relatively low in some of these countries, but the estimated intakes in Egypt and Korea
(with death rates of 2.75 and 0.90, respectively) were not. I then averaged the death rates
in the 20 countries whose estimated daily intake of animal products exceeded 1,000
calories, and came up with a figure of 29.91 – just about fifteen-fold the rate of the quasivegan countries. (Evidently, the high rate in the U.S. was no fluke.) Among these heavy
consumers of animal products, the lowest prostate cancer death rate was in Poland –
22.46.
Since these figures deal with death rates, and it is probably reasonable to presume that the
relatively poor people in quasi-vegan countries get poorer quality medical care than
people in richer omnivorous countries do, the disparity in the incidence of clinically
significant prostate cancer is probably considerably greater than fifteen-fold! The fact
that international risk for prostate cancer varies so substantially may be largely
attributable to the fact that several different hormonal activities – presumably IGF-I,
testosterone, and possibly insulin, all of which would usually be lower in vegans –
interact in a multiplicative fashion to promote prostate cancer development.
Bear in mind that, among non-smoking American males, prostate cancer is the leading
cancer killer. These large international disparities in prostate cancer death rates are thus
hugely significant in regard to human suffering and premature death.
But the pertinent scientific findings offer a ray of hope. Migrant studies show that
middle-aged men who come to the U.S. rapidly assume the high risk of prostate cancer
typical of the U.S.524 This presumably means that hormonal activities prevalent in midlife or late-life have a major impact on prostate cancer risk. Conversely, it would be
reasonable to presume that, if you don’t yet have clinically apparent prostate cancer, by
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lowering those key hormonal activities with a protective diet and lifestyle, you can
rapidly decrease your risk for this cancer.
Breast Cancer
Dr. Hebert and colleagues did a very similar analysis of the determinants of the large
international variations in breast cancer mortality.516 Though not quite as impressive as
the huge disparities in prostate cancer mortality, these variations in breast cancer
mortality are important: age-adjusted breast cancer death rates vary by a factor of about
six-fold, with North American and Western European rates near the top – this despite the
fact that the availability of early detection programs makes breast cancer a frequently
curable disease in the technologically advanced countries. Using complex statistical
methods (multiple regression analysis), Hebert concluded that consumption of calories
from animal products was likely to be the chief determinant of risk, whereas consumption
of fish, cabbage, and grain products appeared to be protective; a high population growth
rate was associated with an additional measure of protection, probably because early
pregnancy is known to reduce a woman’s subsequent risk for breast cancer. (The
statistical analysis made it clear, however, that the seeming impact of animal product
calories was not just a trivial consequence of the fact that animal product consumption
tends to be low in poverty-stricken societies with high fertility rates.)
The protection associated with fish intake has emerged in other international studies
examining breast cancer rates.525 This is likely to reflect the fact that the omega-3 fats
found in fish can help to prevent breast cancer; diets high in fish oil have been shown to
suppress the induction and slow the growth rate of breast cancer (including human breast
cancers) in rodents.526-528 Once again, we are led to the conclusion that, whereas a vegan
diet may be highly protective, a vegan diet supplemented with fish oil (or the omega-3
fats found in fish oil) may be even more protective. And bear in mind that a given intake
of omega-3 fats should be all the more protective in the context of a diet that is overall
quite low in fat.
Nutrition at an early age may have a decisive impact on breast cancer risk. In Third
World populations at low risk for breast cancer, girls typically have a late menarche –
they may not become fertile until age 17 or 18. The trend in Western society – and more
recently, in parts of Asia that have become economically advanced, like Japan – is for a
steady decline in the age of menarche; not uncommonly, girls in the U.S. now can
conceive by age 12 or even earlier. An increase in effective IGF-I activity, dependent on
a sufficient increase in body fat, appears to play a role in triggering menarche;529 thus,
increased intakes of animal products and calorie-dense foods may be keys mediators of
the downward trend in the age of menarche.530 The relevance of this is that late
menarche is known to be associated with a substantial reduction in subsequent breast
cancer risk.
Case-control studies of breast cancer – that is, studies in which women who develop
breast cancer are compared to somewhat similar women who haven’t - have been
especially perplexing, because, at least in Western countries, they by and large have
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failed to incriminate saturated fat or animal product consumption as a risk factor for
breast cancer.441 (In this respect, breast cancer has been notably different from prostate
and colon cancer.) I suspect that, in order to enjoy the rather substantial protection from
breast cancer seen in rural Asia, it is necessary to consume a vegan or near-vegan diet
throughout life - and particularly in childhood, such that menarche is substantially
delayed. The fraction of American women who would satisfy this criterion is vanishingly
small, and thus the protection afforded by such a regimen will not emerge in American
epidemiological studies. (A study which examined breast cancer risk in Seventh-Day
Adventists, only a small fraction of whom are strict vegans, reported that women
describing themselves as vegans had about one-third the risk for breast cancer as that
seen in other women, but that this difference failed to achieve statistical significance
because the number of vegans was so low.)531 The extent to which Americans are
infatuated with dietary animal products can be gauged by examining the massive Nurses’
Health Study: in the bottom quintile of animal protein consumption (the 20% of women
consuming the least animal protein), animal protein accounted for 12% of total calorie
consumption532 – an amount which may well be sufficient to support maximal IGF-I
production.
A crucial role of early nutrition in breast cancer risk is borne out by migrant studies. As
noted above, when Asian men migrate to the U.S. in mid-life, and their diet shifts to a
more typically American pattern, their risk for prostate cancer rapidly climbs toward that
experienced by American-born Asian-Americans. In contrast, when adult Asian women
migrate, their breast cancer risk remains more characteristic of their place of birth.524 The
practical implication of this is that we shouldn’t expect adoption of a vegan diet in middle
age to have a really dramatic impact on subsequent breast cancer risk. If you would like
to protect your daughter from this all-too-common cancer, initiating a strict vegan diet
early in childhood (or even in utero?) may be the most effective strategy.
The thesis that a diet must be rather rigorously vegan to provide important protection
from breast cancer also appears to be consistent with trends in cancer mortality in
African-Americans during the last century – whereas death rates from many cancers
tripled during this time, the death rate from breast cancer increased by only one-third.520,
521
This suggests that animal product intake among American blacks during the early
decades of the twentieth century, while low by today’s standards, may have been
sufficient to confer a substantial risk for breast cancer, such that subsequent further
increases in animal product intake did not have a really dramatic impact on this risk.
Although much research attention has been directed to the possibility that dietary fat
influences breast cancer risk – as it certainly does in rodent studies – most epidemiology
conducted in the U.S. or other Western countries has failed to observe a notable effect of
total fat consumption on breast cancer risk. And yet, in the China Health Project,
increased dietary fat per se (that is, independent of animal product intake) was found to
be a risk factor for breast cancer. More recently, a case-control study in Indonesia –
where fat intake still averages only about 15% of total calories – has found that breast
cancer was dramatically more frequent in women whose fat intake was relatively high; in
the total group studied, women whose pre-marriage fat intake was in the upper 25% were
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8-fold more likely to have breast cancer than the women whose pre-marriage fat intake
was in the bottom 25%! (Post-marriage fat intake also was associated with breast cancer
risk in this study, albeit somewhat less dramatically.)
Why is it that studies in East Asia indict dietary fat as a notable risk factor for breast
cancer, whereas Western studies generally do not? You will recall from a previous
chapter that diets very low in fat (under 15% fat calories) typically have a very favorable
impact on insulin sensitivity – associated with a marked reduction in insulin secretion; in
contrast, varying fat intakes within the range commonly encountered in the U.S. appears
to have little influence on insulin sensitivity. There is good evidence that, even within
Western populations, insulin sensitivity (independent of body weight) impacts breast
cancer risk – women who are insulin sensitive are at lower risk. A recent study
conducted in Shanghai concluded that women whose insulin secretion was relatively high
during morning fasting metabolism were almost three times more likely to have breast
cancer than women with relatively low insulin secretion. These findings seem to be quite
reasonable in light of the fact that elevated insulin secretion can boost the effective
activities of growth factors and sex hormones. A possible resolution of our seeming
paradox is now at hand: in Asian communities where fat intake is traditionally quite low,
an increase in dietary fat tends to impair insulin sensitivity – whereas no such effect in
seen in the West, where virtually everyone consumes a fatty diet. Within the West,
however, there is a slight trend toward reduced breast cancer risk in subjects who eat less
saturated but more monounsaturated fat – which parallels the fact that monounsaturates
are less harmful to insulin sensitivity than are saturates.
Dietary choices can influence breast cancer risk via their impact on obesity. Overweight
women are at increased risk for post-menopausal breast cancer, and also have poorer
prognosis when they develop this disease. At least in part, this may reflect the fact that
overstuffed fatty tissue has an increased capacity to convert circulating androgens (yes,
women make them too!) to estrogen, which of course is a breast cancer promoter.533 This
fat-produced estrogen is the chief source of estrogen activity after menopause. (By the
way, this also explains why overweight men sometimes develop enlarged breasts!)
Moreover, this estrogen would be expected to have greater bioactivity, since sex
hormone-binding globulin levels would tend to be lower in overweight women who are
insulin resistant. Additionally, obesity is associated with fat cell overproduction of
leptin, a hormone which may act directly on breast tissue to boost breast cancer risk and
to promote the progression of pre-existing breast cancer.534-536 Evidently, achieving and
maintaining leanness – with a low-fat vegan diet, exercise, or other measures – is a smart
way to decrease breast cancer risk.
In overview, the available data are reasonably consistent with the proposition that a verylow-fat vegan diet, consumed throughout life – in particular, during the childhood and
teen years, when the breasts are developing – will notably decrease risk for breast cancer.
To the extent that such a diet promotes lifelong leanness, it will lessen breast cancer risk
postmenopausally by diminishing breast exposure to certain fat-produced hormones. On
the other hand, efforts to reduce breast cancer risk in middle-aged Western women by
instituting moderately-low-fat omnivore diets are likely to be abject failures.
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Colon Cancer
Let’s return for a quick look at colon cancer. Risk for colon cancer (and for the benign
adenomas that give rise to them) appears to correlate with the extent to which cells in the
colonic mucosa (the epithelial lining of the colon) are undergoing replication. This can
be quantified by careful observation of biopsy specimens, and is known as the
“proliferative fraction”. One of the growth factors which can increase the proliferative
fraction is IGF-I;537, 538 thus, it is not surprising that increased blood levels of IGF-I (or of
free IGF-I) have been shown to be a risk factor for colon cancer.539-543 Some years ago,
scientists at Loma Linda University (which is affiliated with the Seventh-Day Adventist
Church, and thus has a special interest in vegetarianism) compared the proliferative
fraction of the colon of vegetarians with that of omnivores. Nearly half of the vegetarians
they examined in this study were strict vegans. Can you guess what they found? The
proliferative fraction of the vegetarians was about half that of the omnivores!544
Perhaps the heavyweight intellects at the NCI who designed the recent colon cancer
prevention trials should have taken this evidence into account. It’s rather remarkable that
scientists can look at the diets practiced by Third World groups at low risk for colon or
other “western” cancers and see only “low fat” or “high fiber” – the fact that these diets
are quasi-vegan appears to escape them. One gets the impression that most Americans
are so biased toward viewing protein as health-promoting that it simply never occurs to
them that a needlessly high intake of protein or of essential amino acids might be as grave
a risk to health as an excess of fat or of calories.
Increased insulin secretion emerges as a potent risk factor for colon cancer in recent
studies504, 505, 542, 545-549 – consistent with evidence that obesity increases, and exercise
diminishes, colon cancer risk. Increased insulin exposure has been shown to promote
colon carcinogenesis in rodents.550, 551 These findings are not surprising in light of the
fact that high insulin levels increase effective IGF-I by suppressing the liver’s production
of IGFBP-1. However, it is conceivable that insulin has a direct impact on colon
epithelial cells.545 Furthermore, inasmuch as insulin acts on the brain to stimulate activity
of the sympathetic nervous system (which, as we have seen, is one reason why fat people
tend to be hypertensive), it is interesting to note that, in rodents, sympathetic activity
increases the incidence of colon tumors in carcinogen-treated animals, apparently
because it somehow boosts the proliferation of the colonic epithelial cells.552, 553 Whether
this phenomenon occurs in humans does not seem to be known, but such an effect might
explain the increased risk for colon cancer in chronic heavy smokers554 (since nicotine
activates the sympathetic nerves.)
In epidemiological studies examining the international variations in colon cancer
mortality, calorie intake from animal products and saturated fat – as in the cases of breast
and prostate cancer – correlates strongly with risk.510, 555 However, in studies focusing on
American or European populations, in which animal protein intake is almost uniformly
high, some interesting distinctions emerge; most notably, consumption of red meat
emerges as a strong risk factor, the impact of poultry or fish is more neutral, whereas
dairy products appear to be protective in some though not all studies.556, 557 This latter
74
finding has lent some fuel to speculations that dietary calcium may lower colon cancer
risk – as suggested by recent controlled studies558, 559 - by lessening the exposure of colon
epithelial cells to certain irritative fat-soluble compounds (namely fatty acids and bile
salts) that have the potential to increase the proliferation of these cells;557, 560, 561 in the
colon, calcium binds to these compounds, sequestering them in a way that renders them
harmless. On the other hand, colonic exposure to these irritants is boosted by fatty diets;
fatty meals stimulate bile acid secretion, and of course directly increase the free fatty acid
content of the colon. Whether chronic colonic exposure to fatty acids and bile acids does
indeed play a significant role in human colon carcinogensis is still unclear. The nature of
the apparent “toxic” influence of dietary red meat on the colon is likewise unclear,
though there is evidence that heme iron, which imparts the distinctive color to red meat,
can exert an irritant pro-oxidant effect on the colon lining that stimulates proliferation of
colonic epithelial cells and induces formation of carcinogenic nitrosamine compounds.562566
In any case, it is not unreasonable to speculate that a low-fat vegan diet, featuring lowerglycemic-index starches and supplemented with calcium, could minimize colon cancer
risk by two distinct yet complementary mechanisms: decreasing the activity of the key
growth factors IGF-I and insulin, and minimizing the exposure of the colonic epithelium
to certain irritative compounds that likewise can promote epithelial proliferation.
If the IGF-I thesis of cancer risk has validity, dietary animal protein is unlikely to be the
only culprit. High-glycemic-index and high-caloric-density carbohydrate foods
(especially those designed by food manufacturers to be addictively delicious), as well as
dietary fat, can play a role in promoting the excessive insulin secretion and weight gain
that can likewise boost IGF-I activity. The unholy triumvirate of animal protein, highglycemic-index carbs, and fat – most notably, saturated fat - undoubtedly collaborate in
the induction of a number of “western” diseases. (Nonetheless, in the absence of fat or
animal protein, the relatively high-glycemic-index sticky rice that predominates in most
rural Asian diets doesn’t seem to do much harm, cancer-wise.)
In regard to glycemic index, Dr. Campbell informs me that risks for certain cancers tend
to be higher in regions of rural China where wheat is the staple crop, as compared to
regions where rice predominates. As noted above, the insulin response to wheat flour is
particularly strong, possibly because wheat flour not only has a high glycemic index, but
also has a relatively high protein content – whereas the insulin response to rice is more
moderate; this is reflected in the fact that levels of sex hormone-binding globulin tend to
be higher in the rice-consuming provinces.567 Dietary glycemic index may well be a
determinant of cancer risk,568 a view consistent with the findings of a recent Italian
study.549
Smoking-Linked Cancers: Lung, Pancreatic, Bladder, and Renal
Now that American women “have come a long way, baby”, lung cancer is the chief
cancer killer in both sexes in the U.S. I don’t need to remind you that cigarette smoking
is the chief cause of the twentieth century lung cancer epidemic; it has been estimated
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that, in U.S. men, smoking avoidance would prevent 90% of lung cancer (which was an
uncommon malignancy before machine-rolled cigarettes were popularized during World
War I). Nonetheless, there is considerable evidence that certain dietary factors can
modulate risk for lung cancer in smokers.
The first attempts to correlate international human cancer rates with typical dietary fat
intakes pinpointed lung cancer as one of the tumors which showed such a correlation.569
More refined subsequent analyses concluded that this correlation was specific to animal
fat (vegatables oils didn’t appear to increase risk), and that this correlation was
independent of, and complementary to, the impact of cigarette smoking.570-573 One of the
scientists chiefly responsible for linking lung cancer risk to animal fat intake – the late
Dr. Ernst Wynder – is notable for having conducted the definitive epidemiological
studies that firmly established cigarette smoking as the primary cause of lung cancer574
(at a time when mainstream medical opinion was severely skeptical of this connection,
and doctors were doing cigarette ads!)
Wynder drew particular attention to the fact that, whereas men in Japan are now about
twice as likely to be smokers as men in the U.S., and Japanese smokers tend to smoke
more heavily than American men (albeit they tend to start smoking a bit later in life),
their age-adjusted mortality rate from lung cancer is only about half that of American
men.573 Wynder thought that a far lower intake of saturated fat was protecting the
Japanese from lung cancer. (Arguably, a greater intake of fish oil also contributes to their
protection.)
By and large (though not invariably), studies in Western nations comparing the typical
diets of lung cancer patients with those of healthy controls (matched for age and smoking
habits) have found a higher dietary intake of saturated fat and/or cholesterol in the lung
cancer patients – consistent with the results of the international studies.575 Conversely, a
high intake of fruits and vegetables emerges as protective in these studies.
Several epidemiological studies have looked at the possible impact of IGF-I activity on
lung cancer risk; the results have been inconsistent, but several do conclude that high
circulating levels of IGF-I or free IGF-I are associated with increased lung cancer risk.576578
This would not be unexpected, as lung tissue is known to respond to this growth
factor.
In light of these considerations, I propose that, in the many studies linking saturated fat
and/or cholesterol intake to lung cancer risk, the fat and cholesterol have in effect just
been serving as markers for increased animal product intake, and it is the global impact
of dietary animal products on effective IGF-I activity that is the primary mediator of this
association. If this is indeed the case, then smokers who choose a low-fat vegan diet high
in fruits and vegetables should be able to lower their lung cancer risk to a very
worthwhile degree. (Supplemental fish oil579-583 and selenium584-586 might also be useful
in this respect.)
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However, I would be remiss not to note that by far the most effective way to prevent lung
cancer is to avoid cigarettes (as well as second-hand tobacco smoke). I wish I could say
that the diet I recommend would make it easier to break nicotine addiction, but I don’t
have any reason to think that this is true. If you are a nicotine addict and smoking
cessation programs haven’t worked for you in the past, you might consider doing what a
friend of mine has done – become a nicotine gum addict! While nicotine per se is
probably bad for your vascular health, it’s not likely to be injurious to your lungs when
you obtain it from gum rather than cigarettes.
Another cancer linked to smoking is pancreatic cancer; although not one of the most
common of cancers, its rapid and inexorable lethality now make it the #4 cancer killer in
the U.S. Smoking approximately doubles risk for this malignancy. Although little is
known at this point regarding the role of IGF-I as a risk factor for this cancer,
international epidemiology shows a clear correlation between animal product
consumption and pancreatic cancer risk.515 However, recent evidence that insulin
resistance (or, more accurately, glucose intolerance, which is usually associated with
insulin resistance) is an important risk factor for pancreatic cancer498 has focused
attention on the possibility that increased insulin secretion plays a role in the induction of
this cancer – particularly because insulin levels are exceptionally high in the immediate
environment of the pancreatic cells that give rise to cancer.498, 499 This suggestion is
consistent with evidence that type 2 diabetics – in whom fasting insulin levels are often
elevated – are at increased risk for this malignancy,587 whereas treatment of rats with
drugs that destroy their capacity to make insulin (effectively turning them into type 1
diabetics) inhibits the induction of pancreatic cancer.588 Furthermore, insulin has been
shown to act as a growth factor for many human pancreatic cancers.499
Between 1950 and 1995, the age-adjusted pancreatic cancer death rate (which, sadly, is
virtually equivalent to pancreatic cancer incidence) rose nine-fold in Japan;589 a five-fold
increase in the death rate during the middle decades of the last century was observed in
African-Americans.520 Since smokers approximately double their risk for this cancer, the
smoking epidemic can account for only a modest portion of these stark increases. It is
reasonable to suspect that marked increases in the consumption of animal products and of
high-glycemic-index carbohydrate were largely responsible for the surge in pancreatic
cancer deaths. Conversely, it is likewise reasonable to expect that long-term
consumption of a low-fat, whole-food vegan diet that avoids higher-glycemic-index
starches and sugars would keep insulin secretion low and thus minimize pancreatic
cancer risk.
Yet another prominent cancer linked jointly to smoking and diet is bladder cancer.
Smoking appears to at least double risk for this malignancy, and may be responsible for
about a third of the bladder cancer incidence in the U.S. However, in international
epidemiology, bladder cancer emerges strongly as one of the “Western” cancers
associated with high intakes of fats and animal products. Fortunately, Dr. Hebert has
published an analysis of bladder cancer mortality analogous to his studies of prostate and
breast cancer.590 I used his data to make some calculations similar to that reported above
for prostate cancer – in other words, I determined the average age-adjusted bladder
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cancer mortality of males in the countries with the lowest animal product intake – in this
case, Guatemala, Honduras, Korea, and Thailand – with that of the 18 countries with the
highest intake of animal product calories. For the quasi-vegan countries, this average
mortality was 2 (per 100,000 population per year), whereas it was 17 in the countries
with high animal product intakes. It is evident that differences in smoking habits can’t
possibly explain this huge disparity in mortality. And most likely the gap in incidence is
even broader, because bladder cancer is reasonably curable in advanced societies with
good quality medical care (its incidence in the U.S. is about 5 times higher than the
mortality rate).
Hebert’s analysis showed that bladder cancer mortality correlated most tightly with total
fat consumption. Although animal fat correlated much more tightly than vegetable fat,
the latter nonetheless correlated better than tobacco intake. The correlations with intakes
of animal protein, meat, and milk products were only slightly less tight than those with
total or animal fat. Hebert’s statistical calculations led him to conclude that total fat
intake was likely to be the most important determinant of bladder cancer risk. A similar
conclusion emerges from a study which lumped together the results from a number of
studies comparing the dietary habits of bladder cancer patients with those of healthy
controls.591 This latter analysis also concluded that a high intake of fruits and vegetables
was likely to be protective in this regard. A study examining bladder cancer risk in
Seventh-Day Adventists – a substantial proportion of whom are vegetarian, and very few
of whom smoke – reported that consuming flesh foods 3 or more times weekly was
associated with a 2.6-fold increase in risk.592
One study has reported that IGF-I levels tend to be higher in patients with bladder cancer
than in matched control subjects.593 Furthermore, two studies have reported that all
human bladder cancers examined express functional receptors for IGF-I, and that, to a
greater or lesser degree, their proliferation is stimulated by this growth factor.594, 595
Moreover, the most aggressive cancers tend to express the highest level of this receptor.
Thus, it is reasonable to suspect that increased IGF-I activity encourages the development
of bladder cancer, and that, to the degree that low-fat vegan diets lower IGF-I activity,
they will be protective with respect to bladder cancer risk. However, the strong
correlations with total dietary fat suggest that fat per se may have some additional role in
the induction of bladder cancer (independent of its effect on IGF-I activity). If a high fat
intake can act directly on skeletal muscle to impair insulin sensitivity, it presumably
could have direct metabolic effects on the bladder or other tissues as well that might
influence cancer risk Alternatively, it has been suggested that high-fat diets might
increase the absorption of fat-soluble mutagens.590 Regardless of how this issue is
resolved, it seems highly likely that you could minimize your risk for bladder cancer by
eating a low-fat vegan diet rich in fruits and vegatables – and of course not smoking.
Yet another smoking-linked “Western” cancer is renal (kidney) cancer; a two-pack-a-day
habit roughly doubles risk. This cancer is virtually untreatable once it spreads beyond the
kidney, so, despite the fact it gets little media attention, it kills about 11,000 Americans
annually.596 When back in 1975 noted epidemiologists Bruce Armstrong and Richard
Doll published a truly classic analysis correlating cancer rates with estimated food intakes
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in the world’s nations, they included a chart showing a remarkably linear correlation
between daily intake of animal protein and renal cancer incidence in men.507 This
incidence ranged from no more than 1 (per 100,000/year) in Japan, Jamaica, and Nigeria,
to over 10 in the U.S., Nordic countries, and New Zealand. The correlation of renal
cancer incidence with total protein intake was much looser, and the correlation with
intake of beans and nuts was strongly negative. A case-control study in Shanghai found
that men whose meat intake was in the bottom 25% were less than a third as likely to
develop renal cancer as those with higher meat intakes – whereas high intakes of fruits
and vegetables were associated with low risk.597 (Fruits and vegetables appear to be
strongly protective with respect to both renal and bladder cancer; conceivably, this
reflects the fact that the kidney and bladder are exposed to relatively high concentrations
of water-soluble mutagens in urine, and various phytochemicals offer protection from
these mutagens by inducing detoxifying enzymes.) Some case-control studies in Western
populations likewise correlate high intakes of animal protein or total protein with
increased renal cancer risk,596, 598 although one such study found that calorie intake
seemed to be the true determinant.599
Obesity and diabetes have been clearly established as strong risk factors for renal cancer.
Although these conditions are associated with increased IGF-I activity (owing to
suppression of IGFBP-1), it is conceivable that the increased insulin levels typically seen
in overweight people have a more direct cancer-promoting effect on the kidney (similar
to the likely role of insulin in pancreatic cancer induction. High levels of functional
receptors for both IGF-I and insulin are expressed by renal cancers, and for some
unknown reason these receptors appear to be hyperactive600 – though whether insulin
might have growth-promoting activity for these cells has not been established. The
involvement of IGF-I in the development of renal cancer, however, seems to be highly
likely; a heritable gene mutatation (“von Hippel-Lindau syndrome”) associated with high
risk for renal cancer, has been shown to boost some of the key effects of IGF-I in renal
cells; and in fact about 70% of renal cell cancers harbor a mutant form of this gene.601
One recent study shows that administration of IGF-I stimulates the growth and spread of
a human renal cancer implanted in immunodeficient mice; curiously, however this effect
is lost once the cancer reaches an advanced estrablished stage.602
Gynecological Malignancies: Ovarian and Endometrial Cancers
Ovarian cancer is rather akin to pancreatic cancer in that it is difficult to detect before it
has spread beyond the point of surgical curability. This is the malignancy that deprived
us of two of our most brilliant comediennes – Gilda Radner and Madeleine Kahn – at far
too young an age. The international incidence of ovarian cancer tends to parallel that of
breast cancer – high in the developed world and relatively low in Japan and the Third
World.603 However, the incidence of this cancer in Asia and southern Europe has been
rising in the last several decades – in parallel to increased dietary intakes of animal
products – whereas it has remained stable in most economically advanced countries
during this time.603, 604 Not surprisingly, the international incidence of ovarian cancer has
been reported to correlate with intakes of saturated fat and/or animal products,510, 604-606
and some but not all studies comparing the habitual diets of ovarian cancer patients with
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those of healthy control subjects report increased intake of saturated fat, cholesterol,
and/or various animal products in the cancer patients.607-609
As in the case of breast cancer, reproductive factors have an important impact on risk for
ovarian cancer, independent of nutritional factors. Ovarian cancers usually arise from the
epithelial covering of the ovary, and this epithelium is breached every time an ovulation
occurs, thus in effect inducing a wound that is repaired by epithelial proliferation. It is
therefore easy to understand why a woman’s risk for ovarian cancer tends to be
proportional to the number of ovulatory cycles during her reproductive years. Thus,
some circumstances which block ovulation – such as pregnancy or use of oral
contraceptives – tend to reduce risk for ovarian cancer;610 for example, prolonged use of
oral contraceptives cuts risk approximately in half. Although frequent pregnancy may
explain part of the reduction in risk for ovarian cancer noted in the Third World, the use
of oral contraceptives is more common in economically advanced countries, so
reproductive factors do not adequately account for the international variations in risk for
this cancer.
The limited available epidemiology on IGF-I and ovarian cancer risk suggests that
increased blood levels of IGF-I may increase risk in younger women (under 55), but not
in older women.611, 612 However, a high proportion of ovarian cancers make their own
IGF-I, and tumors which show the greatest expression of this growth factor tend to
behave more aggressively.613 Almost all human ovarian cancers examined have been
shown to express IGF-I receptors, which appear to be functional and indeed necessary for
proliferation of the tumors.614-618 IGF-I receptors have also been detected in the normal
epithelium from which most ovarian cancers arise.615 A heritable mutation of the
BRCA1 gene, which is associated with greatly increased risk for both breast and ovarian
cancers, results in increased expression of IGF-I receptors in the ovary and in ovarian
cancers.451
There is suggestive evidence that increased activity of estrogens as well as of androgens
may also increase ovarian cancer risk. Thus, a recent study indicates that women who
use estrogen replacement postmenopausally may nearly double their risk for this
cancer.619 Previous studies suggest that the impact of estrogen replacement may be less
dramatic than this,620 but the balance of evidence is now in favor of estrogens increasing
risk somewhat. This appears consistent with recent evidence that estrogens can increase
the proliferation of normal ovarian epithelium.621 There is also reason to believe that
increased androgenic activity (believe it or not, women make larger amounts of
androgens than of estrogens!) likewise boosts ovarian cancer risk.610, 622 Insulin and
possibly IGF-I act on the ovary to promote androgen synthesis,623 and these androgens
tend to be more active in women with high insulin because insulin concurrently
suppresses the liver’s production of sex hormone-binding globulin. Women who are
obese or have previously suffered from polycystic ovary syndrome – conditions typically
associated with insulin resistance and a compensatory increase in insulin levels – are
known to be at increased risk for ovarian cancer.610 Postmenopausally, obesity may also
contribute to ovarian cancer risk by increasing the body’s production of estrogens – fat
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cells are capable of converting other circulating steroid hormones to estrogens, and this
effect is more substantial in women who are overweight.
High intakes of the dietary sugar galactose are toxic to the ovaries of rodents, and women
with a genetic abnormality of galactose metabolic are prone to ovarian dysfunction.624, 625
This has given rise to the speculation that diets high in the dairy sugar lactose – which,
when digested, yields galactose – might be associated with risk for ovarian cancer.
Despite promising initial findings,626 epidemiological studies have generally failed to
confirm that lactose-rich diets confer an increased risk for this cancer, though some
studies suggest that a very high intake of lactose might have some impact in this
regard.627, 628 Suffice it to say that the jury is still out on this association – the possibility
that very high intakes of lactose might increase ovarian cancer risk in genetically
susceptible women remains open.
These considerations enable us to predict that a low-fat, low-glycemic-index vegan diet,
by working in various ways to keep insulin secretion low, promoting leanness, and
moderating the activities of IGF-I, estrogens, and androgens, would lower risk for
ovarian cancer. This supposition is certainly consistent with the low risk for ovarian
cancer noted in societies that derive most of their calories from plant foods.
The most common gynecological malignancy is endometrial cancer – cancer arising from
the endometrial lining of the uterus. Although the high incidence of this cancer has
remained fairly steady in the U.S. over the last half-century, mortality has declined
markedly owing to earlier detection and effective use of surgery and radiation for
treatment; thus, mortality from endometrial cancer is now only about half of that from
ovarian cancer. Increased exposure to estrogen boosts risk for this cancer, whereas the
hormone progesterone helps to prevent it. For this reason, women who experience
chronic elevations of progesterone activity – for example, those who have multiple
pregnancies or use oral contraceptives – are at decreased risk; conversely,
postmenopausal estrogen replacement therapy can substantially boost risk, but most of
this excess risk is alleviated if progestins (compounds with progesterone-like activity) are
included in the regimen. The hormonal environment associated with obesity and type 2
diabetes also greatly increases risk.629, 630 In part, this reflects the aforementioned fact
that, postmenopausally, an enlarged adipose mass promotes increased synthesis of
estrogen. However, these conditions are also associated with increased blood levels of
insulin, which seems to work both directly and indirectly to increase endometrial cancer
risk.
Cancer of the uterine endometrium is clearly one of the “Western” cancers, much more
common in societies where animal products make up a substantial portion of the diet;606,
631
the higher incidence of obesity and type 2 diabetes in economically advanced societies
obviously contributes to, but does not entirely explain this phenomenon. In some studies
comparing the habitual diets of endometrial cancer patients with those of controls, an
increased intake of animal products emerges clearly as a risk factor – although not all
such studies agree on this point. The most dramatic findings in this regard have been
reported from Shanghai – presumably because animal product intake remains relatively
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low among a significant portion of the population. The Shanghai researchers found that,
even after making statistical corrections for differences in body size, women whose
caloric intakes from fat or protein were in the upper 25% of the population, experienced
4-fold and 3-fold higher risk (respectively) for endometrial cancer; more careful analysis
revealed that “the association of fat and protein with endometrial cancer risk was
confined to foods of animal origin in the diet….These results suggest that diets rich in
animal fat and protein may play an important role in the etiology [cause] of endometrial
cancer.”632 Understandably, this relationship does not emerge as strongly in societies
where nearly everyone obtains a substantial proportion of daily calories from animal
products; nonetheless, studies from Hawaii and Northern Italy likewise indict fatty
animal products, while noting that starchy foods, fruits, and vegetables appear to be
protective.629, 633
In light of these findings, you won’t be unduly surprised to learn that IGF-I plays an
important role as a growth factor both for normal endometrium and endometrial cancer
cells.634-636 This accords well with the findings of a recent Japanese study comparing
endometrial cancer patients with healthy control subjects; serum IGF-I levels were
significantly elevated and IGFBP-1 levels were significantly diminished in the cancer
patients, implying a substantial excess of IGF-I activity in the patients.637
Furthermore, the impact of sex hormones on endometrial proliferation and on
endometrial cancer risk appears to reflect modulation of IGF-I activity. Thus, estrogen
induces the endometrium to make more of its own IGF-I,634 and promotes increased
expression of the IGF-I receptor in some endometrial cancer cells.638 Conversely,
progesterone inhibits proliferation of endometrial tissue – and reduces cancer risk – by
inducing endometrial tissues to release IGF-I’s functional antagonist, IGFBP-1.639
Insulin has just the opposite effect, suppressing endometrial production of IGFBP-1, just
as it does in the liver.639 Thus, we would expect elevated insulin to work in multiple ways
to increase endometrial cancer risk – suppressing production of IGFBP-1 both in the liver
and endometrium, while increasing estrogen activity by suppressing the liver’s
production of sex hormone-binding globulin. The drug tamoxifen, which acts as an
estrogen antagonist in the breast and thus is useful for preventing and treating breast
cancer, has the unfortunate side effect of increasing risk for endometrial cancer; there is
recent evidence that tamoxifen therapy boosts synthesis of IGF-I in uterine tissue, while
concurrently suppressing production of IGFBP-1.640 In aggregate, these findings go a
long way to rationalize the facts that elevations of insulin, free IGF-I and free estrogen –
as well as tamoxifen therapy - constitute risk factors for endometrial cancer, whereas
progesterone and progestins are protective in this regard.
Hematological Cancers: Leukemias and Lymphomas
Cancers arising from the white blood cells – the leukemias and lymphomas – appear to
fall into the category of “Western” cancers, although they have received fairly little
attention in this regard. Some statistics published by Dr. Wynder illuminate this point.641
Back in 1955, the age-adjusted mortality from adult leukemias in Japanese males was
about 3 (per 100,000/year), whereas among U.S. males it was 11; with respect to the
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lymphomas, the death rate among Japanese males was 5, as opposed to 14.5 in U.S. men.
Similar disparities were seen among women. These death rates rose steadily in Japan
over the next 30 years, whereas they remained relatively stable in the U.S.
Wynder’s perceptive analysis also provides data on dietary intakes. In the early 1950s,
the estimated per capita daily intake of red meat in Japan was 8 grams (as opposed to 231
grams in the U.S.), and of eggs was 7 grams (as opposed to 60 grams in the U.S.).
Japanese dairy product intake was negligible, whereas fish intake was significant but not
very high – 53 grams. Japanese intake of added fats and oils was also quite low – 5
grams daily – as was sugar and fruit intake. Thus, the characteristic Japanese diet in the
early 1950s consisted primarily of starchy foods – primarily white rice and tubers – with
modest amounts of vegetables, soy products and fish (no doubt copiously laced with
salt!) Of their daily protein intake of 61 grams, only about 16 grams came from animal
sources, and all but about 3 grams of this came from fish (rich in protective omega-3
oils). So the Japanese at that time might be aptly characterized as pesco-vegan.
Wynder’s data show that animal product intakes rose steadily and substantially over the
next 30 years; daily red meat intake averaged 105 grams in 1985 – still far lower than
U.S. intakes, but a long way from veganism. (In addition to data on mortality from
leukemia and lymphoma, he provides statistics on a number of other cancers – I have
assembled the data pertaining to “Western” cancer mortality circa 1955 in Figure 1.)
There are several reasons for suspecting that IGF-I activity has an impact on risks for
leukemias and lymphomas. For one thing, these cancers derive from cell lines for which
IGF-I is a growth factor, and many of these cancers are themselves IGF-I responsive.642,
643
The ability of caloric restriction to slow the induction or growth of leukemias in rats
has been traced to a reduction in IGF-I activity.644, 645; furthermore, surgical removal of
the pituitary gland – which abolishes secretion of growth hormone and, consequently,
minimized hepatic IGF-I production – prevents the induction or growth of leukemias in
rats.646, 647 Another key point is that children who were heavy at birth are known to be at
increased risk for childhood leukemias; boys are also more likely to develop this cancer
than girls.648-650 Greek researchers analyzed the IGF-I and IGFBP-3 levels of a large
group of healthy children ranging in age from infancy to 14 years; they found that
birthweight was strongly predictive of IGF-I levels, and that girls tended to have higher
levels of the IGF-I antagonist IGFBP-3. Thus, risk for childhood leukemia seemed to
correlate with effective IGF-I activity.651 These researchers also did a case-control study
comparing leukemic children with children of identical age hospitalized for acute nonmalignant diseases; they found that lower levels of IGFBP-3 were associated with
increased risk for leukemia – again pinpointing IGF-I activity as a leukemia risk factor.652
There is also a report that chldren who develop the most common type of childhood
leukemia (acute lymphoblastic) tend to have greater height for their age than the general
population of children.653 Of related interest is the fact that leukemia is more likely to
develop in children from families of upper socioeconomic status.654 These findings
appear consistent with the possibility that post-natal over-nutrition may also have a
significant impact on childhood leukemia risk.
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Figure 1
Age-Adjusted Cancer Mortality – U.S. vs. Japan - 1955
(Per 100,000 persons/year)
Males
U.S.
Females
Japan
U.S.
Japan
Lung
92
16
11
7
Pancreas
20
7
11
4
Colon
28
6
31
6
Bladder
11
3
4
2
Breast
-
-
26
2
Ovary
-
-
25
3
Prostate
15
2
-
-
Lymphomas
14
5
8
2
Leukemias
13
3
9
2
Aside from studies demonstrating that various types of leukemias or lymphomas do (or
do not) express IGF-I receptors and respond to IGF-I, there so far is little published
literature examining the impact of IGF-I activity on adult risk for these malignancies. A
number of reports indicate that multiple myeloma – a type of cancer that arises from
antibody-producing B lymphocytes – is dependent on IGF-I as a growth factor,655, 656 and
one of these studies showed that injections of IGF-I doubled the growth rate of a human
multiple myeloma cell line transplanted into immunodeficient mice;655 it would therefore
be reasonable to expect that dietary or pharmaceutical measures which reduce a person’s
IGF-I activity might therefore retard the induction or growth of multiple myeloma. One
intriguing report describes a T-cell lymphoma which lacks IGF-I receptors but responds
avidly to insulin as a growth factor.657 In any case, the relatively low incidence of these
cancers in quasi-vegan cultures – and the steady increase in their incidence in Asian
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societies gradually adopting a more Westernized diet – is consistent with the possibility
that relatively low IGF-I activity helps to prevent the white cell-derived malignancies.
A final relevant point – as noted below – is that there are a couple of venerable clinical
reports suggesting that low-protein vegan diets may have some cancer-retardant efficacy
in the treatment of childhood leukemias.658, 659 If that is indeed the case, would it not be
reasonable to suspect that such a diet during childhood might lower risk for leukemias?
The typically slower growth and sexual maturation of children raised as vegans is
presumably indicative of decreased growth factor activities. It is also of interest to
speculate whether women who are vegans and follow a vegan diet during pregnancy
might be less prone to deliver high-birth-weight infants. In this regard, gestational
diabetes – a common cause of high-birth-weight deliveries – would seem to be less likely
in long-term vegans, who tend to be relatively lean.
The other common malignancies of early childhood – Wilm’s tumor and neuroblastoma –
have likewise been shown to occur more commonly in children with high birth weight,
suggesting that these cancers may also be promoted by high growth factor activities.660-662
It is quite conceivable - though admittedly still speculative - that if you allow your
children to overeat a fatty, over-refined omnivore diet that “optimizes” their growth, you
may be increasing not only their long-term risk for many adult disorders, but also their
more immediate risk for pediatric malignancies.
Ancillary Cancer-Preventive Benefits of Vegan Diets
To recap, I propose that low-fat, whole-food vegan diets are usually associated with
decreased blood levels of insulin and of the free active forms of IGF-I and sex hormones.
If this thesis is correct, it may go a long way toward explaining the low risk for
“Western” cancers enjoyed by quasi-vegan societies.
A simple way to look at this is that the body regulates the activities of key anabolic
(tissue-building) hormones – as well as sex hormones, which effectively are anabolic if
they lead to pregnancy – to reflect the “perceived” availability of the food calories (from
meals, or stored as fat) and essential amino acids that are required to build and sustain an
increase in body mass. Boosting your anabolic activity at a time when the availability of
fuel and structural materials is low would make about as much sense as building a big
chain of luxury hotels in the middle of a prolonged recession – when times are lean,
resources need to be conserved so that the structure and function of the body’s vital
organs can be preserved. The body relies on insulin as a key indicator of fuel status;
insulin secretion reflects both the quantity and the glycemic index of dietary
carbohydrate, the concurrent intake of protein, and the availability of stored fat. The liver
acts as a sensor – it monitors the availability both of carbohydrate and of essential amino
acids, while concurrently monitoring insulin levels, and uses this information to regulate
its production of IGF-I as well of the binding proteins that suppress IGF-I and sex
hormone activities. When people eat a low-fat, low-glycemic-index vegan diet in the
long term, the low glycemic response to meals, the moderate intake of “low quality” plant
protein, and low body fat stores all collaborate to keep daily insulin secretion low and to
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convince the liver that essential amino acids are in short supply. In effect, such a diet
represents a way of tricking your body into “thinking” that you are slightly underfed –
without having to endure the hunger pains or energy deficit associated with genuine
caloric restriction. As a result, IGF-I and sex hormone activities are kept relatively low –
and with less hormonal support to drive proliferation and suppress apoptosis, precancerous tissues are less likely to give rise to cancer.
Consideration should also be given to the possibility that a low-fat, whole-food vegan
diet may also influence production of “autocrine” hormones by pre-cancerous tissues.
Although tissues commonly respond to hormones circulating in the bloodstream, they
also often make hormones to which they are self-responsive – known as autocrine
hormones - and some of these hormonal activities may act as cancer promoters. For
example, some tissues manufacture their own IGF-I – or other hormones with growthpromoting activity, such as epidermal growth factor. Whether nutritional factors might
modulate these autocrine hormonal activities so far has received little study.
Furthermore, it is not impossible that nutritional conditions (such as essential amino acid
availability) could directly influence the behavior of pre-cancerous tissues independent of
any effect on hormone production, in such a way as to modulate cancer risk. In this
regard, there is growing evidence that increased activity of an enzyme known as
“mammalian target of rapamycin” – or “mTOR” – which supports cell multiplication by
boosting the efficiency of protein synthesis, plays a role in the induction of many cancers
by supporting proliferation and blocking apoptosis in pre-cancerous tissues; conversely,
inhibition of mTOR activity has been shown to decrease cancer incidence in rodents.663
mTOR activity decreases in cells that experience a relative deficiency of one or more
essential amino acids;664 thus, independent of circulating levels of insulin or IGF-I, it is
conceivable that the relatively low intakes of methionine or lysine that characterize most
vegan diets could modestly decrease mTOR activity in at-risk tissues, thereby helping to
prevent cancer. (It should be noted that one way that IGF-I and insulin boost cancer risk
in some tissues is by activating mTOR.)
No doubt, the mechanisms by which dietary factors influence risk for Western cancers
are complex and only partially understood at this time. While epidemiology points to
elevated levels of free IGF-I and insulin as key factors in the induction of many Western
cancers, it is also quite clear that these are not the only mediators of the impact of diet
and lifestyle on Western cancer incidence.
One way in which vegan diets might afford cancer protection is by limiting the
production or activation of mutagens that play a role in cancer induction. In particular,
attention has been drawn to the fact that surface charring of flesh foods during cooking
causes chemical reactions that produce potent carcinogens known as heterocyclic
amines.665, 666 (These aren’t formed in plant products because the compound creatine –
found only in animal flesh – is a key precursor to these carcinogens.) Heterocyclic
amines readily give rise to mutations and cancers in animals. The extent to which they
play a role in inducing cancer in omnivores is still a matter of speculation, but in any case
it is unlikely that these compounds are entirely innocuous in humans, whether or not they
are having a large impact on cancer risk. Their possible role in induction of colon cancer
has attracted particular interest. One recent study demonstrated measurable levels of
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heterocyclic amines in the breast milk of human omnivores – whereas these agents were
not found in the breast milk of a vegetarian; the authors suggest that these carcinogens
may play a significant role in induction of human breast cancer.667
The heterocyclic amines have been shown to induce lymphomas – cancers arising from
immune cells known as lymphocytes – in rodents;668 the most common type of human
lymphoma, non-Hodgkins lymphoma (NHL), has been linked to increased intakes of
animal fat and protein in epidemiological studies, both in international studies, and in
case-control studies in the U.S.508, 669-671 Unlike most other major cancers not clearly
linked to tobacco, the age-adjusted incidence of NHL in the U.S. has been sky-rocketing,
rising 73% between 1973 and 1991, such that it is now our fifth leading cancer killer.670
(The incidence of prostate cancer has also gone up dramatically, but this is thought to
reflect the fact that physicians are now much more adept at detecting prostate cancer at a
very early, non-aggressive stage.) The relatively stable incidence of most cancers over
the last 50 years in the U.S. suggests that environmental exposure to man-made mutagens
does not play a major role in their genesis. However, there is considerable reason to
suspect that the striking increase in NHL might in fact be attributable to such mutagens;
particular suspicion falls on certain pesticides, herbicides, and organic solvents, as
workers who use these products have often been found to be at greatly increased risk for
NHL.672-675 If you don’t have high occupational exposure to these fat-soluble toxins,
your exposure will come primarily through ingestion of fatty animal products; farm
animals ingest these toxins in their feed or forage, and store them in their fat cells.676 To
the extent that fat-soluble mutagens do indeed play an important role in the induction of
NHL and perhaps other cancers, you can evidently minimize your exposure by eating a
vegan diet.
Dr Eldon Savage and colleagues assessed the content of a number of organic pollutants in
the breast milk of women who were longtime vegans, in comparison to the levels found
in the general U.S. population. Although the level of polychlorinated biphenyls (PCBs)
did not differ, the levels of the 6 pesticides and herbicides assessed were vastly lower in
the vegans – only about 1-2% of the levels found in the general population, if detectable
at all. These researchers concluded that “diet may indeed be a major predictor of
chemical pollutants in the body.”677 A subsequent Scandinavian study comparing the
breast milk of lacto-ovo-vegetarians with that of omnivores reached similar conclusions,
although the disparities in pollutant levels were not so dramatic, presumably because
many of the vegetarians ate fatty dairy products and eggs; however, in this study, PCB
levels were significantly lower in the vegetarians.678
Because vegetarian diets are devoid of heme iron – a type of iron found in flesh foods
(most notably red meats) whose absorption is high and poorly regulated – the body iron
stores of vegetarians tend to be only about half as high as those of omnivores.679-682
(Nonetheless, the great majority of vegetarians make adequate amounts of red blood cells
and are not anemic; vegetarian diets typically contain ample amounts of non-heme iron,
and the body absorbs enough of this to prevent iron deficiency.) Free iron atoms can
bind to chromosomes and, by interacting with the oxidant hydrogen peroxide, can
generate the vicious hydroxyl radical capable of inflicting mutagenic damage on
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DNA.683, 684 The extent to which iron is a catalyst for the “spontaneous” mutagenesis
which contributes to human cancer induction is not yet clear, but many scientists believe
that iron plays an important role in this regard. Several epidemiological studies have
found increased cancer risk in people with above-average body iron stores;685-687 such
studies are hard to interpret, since iron stores tend to be higher in people who eat flesh
foods that likewise have been linked to increased cancer risk.
More definitive evidence on this point has been provided by a recent epidemiological
study and two controlled clinical trials. The epidemiological study concluded that,
among a large group of blood donors, those who had donated the most blood (and thus
had depleted themselves of the most iron) were at significantly lower risk for cancer than
those who had donated the least blood.688 But perhaps the most provocative evidence on
this point stems from a controlled clinical trial which attempted to determine whether
regular phlebotomy (blood drawing) would reduce risk for heart attack in patients who
had peripheral arterial disease. During a follow-up period averaging 4.5 years, the
researchers were disappointed to learn that the phlebotomy therapy did not significantly
influence heart attack risk – but it was associated with a significant 30% reduction in the
incidence of new serious cancers!689 Phlebotomy therapy has also been shown to quite
markedly reduce risk for liver cancer in patients with chronic hepatitis C.690 These
findings suggest that the relatively low (but usually adequate) iron status of vegetarians
may indeed reduce their cancer risk.
In summary, we see that a vegan diet helps to minimize exposure to at least three
categories of agents with mutagenic/carcinogenic potential: heterocyclic amines, fatsoluble environmental toxins, and iron.
Another key point is that vegan diets are often high in phytochemicals – especially if
these diets emphasize whole foods that are rich in potassium. Certain phytochemicals
have shown cancer-preventive activity in rodent studies, either because they modulate
enzyme activities in ways that lessen carcinogen activation, or because they have “antipromotional” effects that increase the rate of apoptosis in pre-cancerous tissues. Many
epidemiological studies suggest that a high intakes of fruits, vegetables, or legumes are
linked to lower cancer risk – and phytochemicals may be important mediators of this
effect.691-693 The isothiocyanates derived from cruciferous vegetables (such as cabbage
and broccoli),694 the polyphenols found in green tea,695 and the lycopene found in tomato
products,696 are currently attracting particular attention as putative cancer-preventive
factors. Many of these compounds are so-called “phase 2 inducers”, which boost
cellular expression of the antioxidant glutathione and of a number of enzymes that aid
antioxidant defense and promote detoxification of carcinogens.697
Another category of phytocyhemicals with cancer preventive potential are the
phytoestrogens, most notably the isoflavones found in soy. Although estrogens are
usually thought to act as cancer promoters, at least for breast and endometrial cancer, the
safety of soy isoflavones reflects the fact, that in blood concentrations that can be
achieved by ordinary dietary intakes of soy, these agents selectively activate the betaform of the estrogen receptor.698, 699 There are two different forms of estrogen receptor;
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the alpha receptor is responsible for the feminizing effects of estrogen, and mediates the
adverse impact of estrogen exposure on breast and uterine cancer risk. In contrast, the
beta estrogen receptor does not have feminizing effects (which is why men can eat soy
without growing breasts!), and in fact appears to have cancer preventive activity in many
of the tissues in which it is expressed. In particular, there is reason to suspect – stemming
from epidemiology, animal studies, and theoretical considerations – that frequent
consumption of soy isoflavones may reduce risk for cancers of the prostate, colon, and
breast.699 Although there are a few studies reporting that isoflavone administration can
boost mammary cancer growth in rodents, a careful examination of these studies reveals
that they employ extraordinarily high isoflavone doses that couldn’t possibly be obtained
from a natural diet; at these very high levels, activation of the cancer-promoting alpha
receptor could be expected.
I should also comment briefly on the cancer-preventive potential of olive oil. Some casecontrol studies focusing on Mediterranean populations where olive oil is in common use
have noted decreased risks for certain cancers – most notably breast cancer - associated
with increased intakes of this oil.700-703 I suspect that this may reflect the fact that, within
the context of diets that are not notably low in fat, substituting olive oil for other sources
of calories may not have a major adverse impact on either insulin sensitivity or body
weight, and may thus act to lower daily insulin secretion while decreasing dietary protein
content – effects that could be expected to lower blood growth factor activities. There is
also speculation that antioxidant phytochemicals in extra-virgin olive oil might provide
some cancer protection.704, 705 Nonetheless, I must reiterate that adding large amounts of
olive oil to a very-low-fat whole-food vegan diet would appear likely to compromise the
ability of such a diet to improve insulin sensitivity and promote appropriate weight loss.
In light of the fact that such low-fat diets have demonstrated a really profound cancerpreventive potential in Asian and African cultures – corresponding to “Western” cancer
rates much lower than those seen in any Mediterranean country – I am not inclined to
recommend high-fat diets of any kind. Nonetheless, if you are unwilling to make the
often substantial dramatic dietary changes necessary to minimize your dietary fat intake,
current evidence suggests that increasing your intake of olive oil is not likely to increase
your risk for cancer, and indeed might even lower it.
What About the “Third World” Cancers?
Scientists who are inclined to skepticism (or nihilism) occasionally point out that the
international correlation studies that relate high-carbohydrate, quasi-vegan diets to low
risk for “Western” cancers, also demonstrate high rates of certain “Third World” cancers
in societies consuming those diets. In particular, rates of gastric, hepatic, esophageal, and
cervical cancer are often high in these societies. As an example, the low cancer mortality
rates for 1955 Japan displayed in Figure 1 do not imply that mid-century Japan enjoyed
an Edenic freedom from this dreaded disease – death rates from gastric, hepatic,
esophageal, and cervical cancers were substantially higher in Japan than the U.S. at that
time. However, a strong case can be made that the true correlate of these cancers is not
high-carbohydrate diets, but rather poverty.
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The chief causes of “Third World” cancers appear to be preventable endemic infections
and/or foodstuffs that are microbially contaminated and/or excessively salty. For
example, hepatitis B infection – usually preventable by appropriate hygiene – appears to
be at the root of most of the world’s liver cancer; it is certainly responsible for most liver
cancer in Japan and China. Chronic infection of the stomach lining with the bacterium
Helicobacter pylori is now known to underlie most gastric pathology – both stomach
cancer and stomach ulcers And most cervical cancer now appears to be a late
complication of venereal infection with human papillomavirus. (In medical school, I was
impressed by the fact that nuns are at low risk for cervical cancer, but high risk for
endometrial cancer; you will remember that the latter is prevented by multiple
pregnancies and oral contraceptives.)
Mutagens such as nitrosamines present in microbially-contaminated foods also play a
role in the induction of “Third World” cancers, most notably esophageal and gastric
cancer. Such contamination usually reflects poor access to refrigeration; gastric cancer
rates have plummeted around the world as effective refrigeration became more widely
available during the twentieth century.706-708 The use of heavily salted foods – a secondbest alternative to refrigeration for food preservation – is typical of societies at high risk
for gastric cancer. How such foods promote gastric cancer is not yet entirely clear – they
may be more prone to microbial contamination than refrigerated foods (and thus contain
gastric mutagens), the nitrite content of the crude salts used for such purposes may
promote mutagen formation, and/or their concentrated salt content may somehow
increase the propensity of Helicobacter pylori to colonize the stomach and promote
stomach cancer. In any case, now that refrigeration is readily available, the use of salt for
food preservation is now unnecessary, and, as noted above, there are many other good
reasons to keep your salt intake low. In Asian cultures, certain fermented foods (a case of
intentional microbial contamination!) are known to contain mutagens, and may
contribute to risk for esophageal and gastric cancers. High intakes of fruits and fresh
vegetables rich in antioxidants – notably vitamin C – appear to be protective with respect
to gastric cancer, possibly because the antioxidants block the intra-gastric formation of
mutagens from food-borne precursors;709 societies at the highest risk for gastric cancer
are characterized by high intakes of salt and low intakes of vitamin C.708, 710-712
I am unaware of any cogent evidence – or any credible theoretical grounds for suspecting
- that high-carbohydrate diets featuring lightly-salted fresh foods can increase risk for any
“Third World” cancer. There are no reports indicating that Western vegetarians are at
increased risk for these cancers. Indeed, as noted above, the provinces of China with the
lowest intakes of animal products appear to be at lowest risk for gastric and hepatic
cancer – suggesting that, not surprisingly, the growth factors which promote induction of
“Western” cancers can also promote the development of certain cancers prevalent in the
Third World. Indeed, the best evidence that diets low in animal protein can reduce
cancer risk in rodents comes from studies focusing on liver cancer.469, 470, 713, 714 Dr.
Campbell’s research indicates that low-protein diets not only prevent liver cancer, but
also impede the progression of hepatitis B infection in rats.715 His interest in dietary
protein as a stimulant to cancer induction had its origins in his experiences as a young
epidemiologist investigating an epidemic of liver cancer among Philippine children; these
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children were found to have ingested peanut butter contaminated with aflatoxin, a potent
hepatic carcinogen produced by a species of mold that can grow on improperly stored
peanuts. Campbell noticed that the children whose diets were being “enriched” with
donated U.S. surplus milk appeared to be at increased risk for this cancer; a subsequent
literature search turned up previous work by Indian scientists showing that a diet high in
milk protein boosted the ability of aflatoxin to induce liver cancers in rats.713
Although esophageal cancer is prominent in many relatively poor societies, it is also a
prominent type of cancer in the West, primarily because smoking combined with heavy
drinking (especially hard liquors with a high concentration of alcohol)716 greatly
increases risk for this cancer. As in the case of gastric cancer, a low intake of fruits,
vegetables, and vitamin C markedly increases esophageal cancer risk.703, 717, 718 In the
U.S., risk for the most common type of esophageal cancer – squamous cell cancer - is
concentrated in smokers of lower socioeconomic status who are prone to alcohol abuse
and whose diets are low in fruits, vegetables, and vitamins.719
The incidence of a sub-type of esophageal cancer – esophageal adenocarcinoma – has
been increasing rapidly over the last several decades, and, in the U.S., is now the type
most commonly seen in white males.720 It occurs in the lower part of the esophagus near
the junction with the stomach, and arises from tissue that has been repeatedly damaged
by acid reflux.721 Obesity increases risk for this cancer by about three-fold, which
explains some but not all of the recent increase in incidence. Smoking is also a risk
factor, but the impact of alcohol is less clear. Case-control studies show that people who
develop this cancer tend to eat diets that are low in fruits, vegetables and fiber; some but
not all studies incriminate dietary fat as a risk factor.722-725 One large recent case-control
study conducted in the U.S. squarely indicts diets rich in saturated fat, animal protein, and
cholesterol – whereas polyunsaturated fat intake was not associated with risk.726 There is
little published information regarding the possible role of IGF-I in the genesis of this
cancer. Staying lean with a low-fat, whole-food vegan diet rich in fruits and vegetables
appears quite likely to minimize your risk for esophageal adenocarcinoma. If you suffer
from chronic heartburn, you may be at increased risk for this cancer, and might be welladvised to consult your doctor on this issue.727 The only known cure for this cancer is
prompt surgical excision of the tumor at its earliest stage.
A Brief Overview
Our discussion thus far has touched on nearly all of the cancers that cause over 10,000
deaths annually in the U.S. – the exceptions being cancers arising in the oral cavity,
larynx, and brain, as well as the most lethal type of skin cancer, malignant melanoma.
Risk for cancers of the oral cavity or larynx are dramatically increased in people who
smoke, drink heavily, and have a low intake of fruits and vegetables728 – in other words,
these cancers are substantially preventable by a prudent diet and lifestyle, whether or not
modulation of IGF-I activity has a marked influence on their induction.
With respect to malignant melanoma – which arises from special pigment cells in the skin
known as melanocytes – it is known that IGF-I is a crucial growth factor for melanocytes,
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for the pre-cancerous “pigmented nevi” that can give rise to melanoma, and for a high
proportion of melanomas.729-734 Antibodies to the IGF-I receptor suppress the growth of
many but not all human melanomas in cell culture and in immunodeficient mice.732, 734
Treatment with human growth hormone – which boosts the liver’s production of IGF-I –
has been reported to stimulate the growth of pigmented nevi in children,735 and
researchers have noted that the tendency of pigmented nevi to appear during adolescence
may reflect the increase in effective IGF-I activity that occurs during puberty.733 Thus,
although the limited relevant epidemiology does not clearly implicate dietary factors in
the induction of melanoma, there are reasons to suspect that the lower IGF-I activity
associated with low-fat, whole-food vegan diets might confer a measure of protection
from this cancer. In any case, the most effective way to prevent this cancer is to avoid
bad sunburns, particularly during childhood.736
The chief theme that emerges from studies examining the dietary determinants of brain
cancer risk, is that frequent consumption of cured (nitrite-treated) meats such as bacon
may increase this risk, whereas fruit and vegetable consumption is protective;737-743 these
findings thus suggest that carcinogenic nitrosamines found in foods or produced in the
digestive tract may play an important role in the induction of many brain cancers.
Nonetheless, the current evidence indicting cured meats as a major risk factor for brain
cancer is by no means airtight – more definitive studies will be required to firm up this
association before it can be generally accepted.744 In any case, you don’t have to worry
about this if you avoid meat altogether!
My point in taking you through this possibly rather tedious laundry list of the most
prominent human cancers is to stress the fact that almost all cancers are substantially
preventable by a prudent diet and lifestyle. You can achieve this protection
- by keeping key growth factor activities relatively low with a vegan diet that is low in
fat and emphasizes lower-glycemic-index whole foods - complemented by regular
exercise that promotes insulin sensitivity and leanness;
- by increasing your intake of protective cancer-fighting phytochemicals with a high
intake of fruits and vegetables;
- by minimizing exposure to mutagens or mutagenic infectious agents by practicing
sound hygiene and safe sex, making appropriate use of refrigeration for food
preservation, avoiding foods that are heavily salted or nitrite-cured, avoiding charred
flesh foods that contain heterocyclic amines and fatty animal products that may
harbor environmental mutagens, avoiding sudden excessive sun exposure, keeping
alcohol intake moderate, and of course not smoking;
- by using nutritional supplements that can boost your daily intake of nutrients and
phytochemicals likely to decrease cancer risk - such as vitamin D, selenium, fish oil
omega-3 fats, green tea polyphenols, and soy isoflavones (I’ll touch on
supplementation in the final chapter);
- and by availing yourself of your doctor’s ability to detect cancerous or pre-cancerous
tissues when they are still in an early, surgically-curable stage.
Take another look at Figure 1. Those marked disparities is cancer mortality correspond
to a tremendous amount of potentially preventable human suffering. In my first year of
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medical school, my classmates and I were allowed to interview patients in the nearby
V.A. hospital. Just by chance, the first three patients I worked with were all wasting
away with terminal colon cancer – men who were not yet elderly, down to skin and
bones, and without any realistic hope for a cure. I was so traumatized by this experience
that I spent hours in the library studying this disease, and ran across the recently
published studies suggesting a link between dietary fat and colon cancer risk. I was
astounded to learn that many Third World cultures enjoyed a comparatively very low risk
for this cancer. In other words, the suffering I had just seen was probably unnecessary
and inadvertently self-inflicted – really not much different from the lung cancer afflicting
smokers. If you have seen a friend or loved one cope with cancer – or experienced
cancer yourself – I won’t need to tell you how crucial it is to prevent this disease or,
failing that, to snuff it out at an early curable stage. The good news is that we don’t have
to wait for some miraculous new pharmaceutical breakthrough to protect ourselves – it
seems more and more likely that, with a prudent diet and lifestyle, we can decrease our
risk for cancer dramatically right now. All that we need are knowledge and the will to
apply it.
A Role in Cancer Therapy?
Many though not all types of cancer are still responsive to the growth-promoting actions
of IGF-I and of sex hormones;447 moreover, IGF-I supports the growth of new blood
vessels (angiogenesis) that is critically important to the expansion of solid tumors and
development of metastases.745-750 It is thus logical to expect that dietary measures which
decrease the blood levels of these hormones, or that increase the level of proteins that
block their activities, will have utility for slowing the growth and spread of certain
cancers. In other words, it is logical to inquire whether a low-fat, whole-food vegan diet
can have a palliative role in cancer treatment.
As we have noted, the macrobiotic vegan diet is low in fat and relatively low in glycemic
index (owing to the fact that it bans wheat flour products and emphasizes whole foods);
thus, it very likely would decrease IGF-I and sex hormone activities in the blood. The
founder of macrobiotics, Michio Kushi, encouraged the use of his diet for managing
cancer. For this reason, the powers-that-be in the cancer establishment have been at pains
to stigmatize macrobiotics as an “unproven therapy” tantamount to quackery.751, 752 Yet
Dr. James Carter, who is quite interested in the health impacts of vegetarianism, decided
that it would be of interest to quantify the survival of patients with pancreatic or
metastatic prostate cancer who had decided to adopt a macrobiotic vegan diet as part of
their therapy; he then compared their survival statistics with those of “historical controls”
– cancer patients from the same area whose cancers were in comparable stages of
development, but who had not elected to become vegans. He found that, with respect to
both pancreatic and prostate cancer, the patients who became vegan were surviving
significantly longer.753 Even though historically-controlled studies of this sort are lessthan-definitive medical evidence, Carter’s observations are both provocative and
credible, and merit replication in studies that are more rigorously designed (prospective
controlled studies).
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Back in the 1960s, two clinical groups reported favorably on their experience with a lowprotein vegan diets in the treatment of childhood leukemias. Although this diet was not
curative, it did seem to prolong remissions.658, 659 Presumably, these observations were
forgotten as more effective chemotherapeutic regimens for childhood leukemias became
available. These reports accord well with more recent evidence that increased IGF-I
activity represents a risk factor for this cancer,754, 755 which is more common in children
who are tall and had a high birthweight.
The Pritikin Clinic has provided striking evidence of related interest.756-758 Dr. James
Barnard of UCLA obtained serum samples from 13 overweight men enrolling in the
Pritikin program, both prior to their entering the program, and again after they had been
on the diet/exercise regimen for only 11 days. He also obtained serum from 8 Pritikin
“veterans” who had been following the Pritikin lifestyle regimen for an average of 14
years. He then used this serum as the growth medium for a cell line derived from a
human prostate cancer, LNCaP; these cells are known to be responsive to both IGF-I and
testosterone. Barnard measured the growth rate of the LNCaP cells in the various sera;
as compared to cells grown with sera obtained prior to the Pritikin program, the cells
grown in the sera obtained after 11 days of the Pritikin program grew 30% less rapidly.
Furthermore, cell growth was depressed by 45% when sera from the long-term Pritikin
veterans was used. Conversely, the rate of spontaneous cell death (apoptosis) was
markedly higher when cells were incubated with the 11-day Pritikin serum or the serum
from Pritikin veterans.
Clearly, a low-fat, whole-food vegan diet, coupled with daily exercise, can have a marked
effect on the growth factor activity of the blood. Direct measurements showed that the
Pritikin regimen lowered IGF-I levels while boosting that of IGFBP-1 – thereby
decreasing effective IGF-I activity; in addition, free testosterone declined owing to an
increase in sex hormone-binding globulin. These findings nicely rationalize the impact
of the sera on the growth of the LNCaP cells. Furthermore, in conjunction with previous
reports from the Pritikin Institute,4, 759, 760 these findings confirm that a low-fat wholefood near-vegan diet, complemented by insulin-sensitizing exercise, can decrease blood
levels of insulin, free IGF-I and free sex hormones – as suggested above.
In light of the fact that insulin is a major determinant of the effective activities of IGF-I
and of sex hormones, and can function directly as a growth factor for some cells, a recent
study correlating fasting insulin levels with cancer recurrence and survival in early-stage
breast cancer patients is of great interest. When the researchers compared those women
whose insulin levels were in the bottom 25% with those whose insulin was in the top
25%, the latter group was twice as likely to experience a cancer recurrence, and three
times as likely to die from their cancer.761 This doesn’t necessarily mean that high insulin
makes breast cancer more lethal – arguably, high insulin levels might just be an indicator
of some other factor which is responsible for the poorer outcome – but it’s a reasonably
safe bet that insulin does indeed have some direct role in this regard. Since we have just
mentioned the Pritikin Institute, it is worth recalling that, in cardiac patients whose serum
insulin levels were initially relatively high, these insulin levels dropped by an average of
40% after only 3 weeks of the Pritikin diet-exercise regimen.4
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Dr. Dean Ornish is currently conducting a controlled study to determine whether a strictly
vegan version of his regimen, originally developed for heart patients, can favorably
influence the clinical course of patients with early-stage prostate cancer; the patients
recruited were in the so-called “watchful waiting” period, in which the tumor is confined
to the prostate and it is initially unclear whether surgical treatment or radiation therapy
will be warranted. His preliminary results indicate that, after one year, the prognostic
marker PSA fell by an average of 4% in patients using this lifestyle program, whereas it
rose by an average of 6% in the control group.762, 763 After two years, 13 of the 49
control patients had decided to go forward with definitive therapy (surgery or radiation),
while only 2 of the 43 patients in the lifestyle group had made this choice.764 Since
prostate cancer therapy itself can have undesirable complications, any strategy which can
decrease the need for such therapy is quite worthwhile. Hopefully this and other future
studies will further clarify the role of optimal diet in cancer management. So as not to
raise false hopes, it should be noted that nutritional measures are extremely unlikely to
have a curative impact on cancer, or to markedly reduce tumor size (objective remission).
The extent to which feasible dietary measures can modulate blood growth factor activities
is limited, and moreover many cancers are no longer dependent (or can be expected to
eventually achieve independence) from blood-borne growth factors. A more realistic
expectation is that an appropriate diet could slow the spread of many tumors to a useful
degree, such that patients could look forward to extra months or perhaps even years of
useful life. (The remarkable experience of Dr. Anthony Satillaro, recounted in his book
Recalled by Life, may represent one of those very rare incidences in which a macrobiotic
diet does indeed achieve marked sustained tumor regression.)
Perhaps a vegan diet might have a more definitive impact on survival when it is used in
conjunction with potentially curative measures such as surgery, radiation, or effective
chemotherapy; if these latter strategies succeed in eradicating visible tumors, it is
reasonable to hope that instituting a vegan diet might reduce the chance that small
remaining nests of cancer cells will survive to induce a recurrence of the cancer.
Furthermore, it is reasonable to expect that a vegan diet will prove to be a useful
complement to novel anti-angiogenic strategies as these become clinically available.
There is good reason to hope that the advent of measures for slowing or stopping the
tumor-evoked growth of new blood vessels will make metastatic cancer susceptible to
long-term control. (By way of analogy, the development of insulin injections turned type
1 diabetes into a chronic treatahle disorder, rather than the rapid death sentence it had
previously been.) Harvard scientists have recently reported that, in immunodeficient
mice injected with the LNCaP human prostate cancer, a soy protein diet resulted in a
suppression of angiogenesis (and of tumor growth) associated with - and possibly
mediated by - a reduction of circulating IGF-I levels.765 These same scientists had
previously shown that caloric restriction – which markedly suppresses IGF-I activity –
likewise inhibits angiogenesis in this tumor model.766 Whether IGF-I suppression can
impede cancer-evoked angiogenesis in only some tumors, or rather has broad general
efficacy in this regard, remains to be seen. IGF-I acts on some tumors to boost their
production of VEGF (vascular endothelial growth factor), a potent stimulus to
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angiogenesis,749, 750 and it also makes endothelial cells more responsive to this growth
factor;748 thus, tumors which rely on production of VEGF to promote development of the
new blood vessels required for sustained tumor growth may be particularly dependent on
IGF-I activity.
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VI. Preventing and Treating Autoimmune Disorders
Autoimmune disorders are diseases in which the body’s immune cells become
“confused” and cause inflammatory damage to the body’s own tissues. Some prominent
examples are rheumatoid arthritis, ulcerative colitis, lupus erythematosus, multiple
sclerosis, and type 1 diabetes (in which the insulin-producing beta cells are destroyed by
immune cells). Although these disorders are rarely thought of as “western” diseases or
diseases of civilization, Dr. Hugh Trowell has summarized a large number of reports
indicating that most of these disorders used to be remarkably rare among sub-Saharan
black Africans, but are now becoming more common among urbanized Africans who
have adopted a more westernized lifestyle.767 Furthermore, it is pertinent to note that the
incidence of these diseases in African-Americans is generally no lower than that in
American whites – the incidence of lupus is actually higher; thus, genetic factors cannot
account for the remarkable rarity of autoimmune syndromes among black Africans
during the first half of the twentieth century. With respect to rheumatoid arthritis, it was
noted that, not only was this disorder rare among Africans, but that when it occurred, it
was generally much less severe than the disorder encountered in the West.768 Working
on the opposite side of the continent, British physician Dr. B.M. Greenwood made very
similar observations regarding the rarity of the whole range of autoimmune disorders in
Nigerians, and the mildness of clinical rheumatoid arthritis.769, 770
As might be expected, the urbanization and westernization of segments of the black
African population over the last few decades has been associated with a substantial
increase in autoimmune disorders. A report on ulcerative colitis illustrates this point
nicely. Up until 1975, only 18 cases of this disorder had been diagnosed among blacks in
all of sub-Saharan Africa. In the next four years, 13 cases were diagnosed in a single
large hospital serving blacks near Soweto, South Africa. Notably, all 13 of the victims
were educated, urbanized, and ate a westernized diet rich in animal products.771
I have attempted to find pertinent comparable data from Asia, where many rural societies
are quasi-vegan. Unfortunately, Asia did not give rise to a Hugh Trowell, and
information on the incidence of autoimmune disorders in most parts of Asia is spotty at
best. However, I was able to find several intriguing reports from Thailand, which – at
least until recently – appears to have been one of the most vegan of societies, as assessed
by United Nations food disappearance data.523 (Incidentally, Hebert reported that the
age-adjusted death rate from prostate cancer in Thailand was one-sixtieth of that in the
U.S!) Thai physicians have reported that both rheumatoid arthritis and type 1 diabetes
are far rarer in Thailand than in Western countries, and that the disorder systemic
sclerosis, when it occurs, is much milder in its manifestations.772-774 Since we don’t
know what the incidence of these disorders is in Thai-Americans, these findings are not
too meaningful in themselves - we can’t rule out the possibility that genetic factors are
primarily responsible; however, viewed in the context of the data from Africa, these
reports are satisfyingly consistent with the thesis that a vegan diet may reduce risk for
autoimmunity.
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Of related interest are recent international epidemiological studies correlating typical
diets with risk for type 1 diabetes and multiple sclerosis. The incidence of type 1
diabetes in a country tends to correlate with the extent to which animal products are
included in the typical diet;775 with respect to multiple sclerosis, international studies
suggest a link to saturated fat or animal fat consumption.776-778 Shanghai is noted for a
remarkably low rate of type 1 diabetes – about only 2% as high as the incidence in
Finland; unfortunately, since there are no available data on the incidence of type 1
diabetes in Chinese-Americans, it is not clear to what extent environmental factors are
responsible for this low incidence. As of 1960, not a single case of multiple sclerosis had
been diagnosed in a black sub-Saharan African, and as of 1975 no cases had been
identified in the Bantu population of 15 million.768, 779 From 1932 to 1952, Trowell
worked in busy pediatric wards in East Africa without diagnosing or observing a single
case of type 1 diabetes; a handful of cases appeared during the late 1950s prior to his
retirement.780 Yet black Americans are by no means immune to these disorders.
A recent American study, utilizing data from the Nurses’ Health Study, has failed to find
any link between saturated fat intake and subsequent risk for multiple sclerosis.781 As we
have noted, since almost all Americans consume substantial amounts of animal products
during all or most of their lives – even American vegetarians, who typically are quite
fond of dairy products and eggs – this study cannot invalidate the thesis that lifelong
consumption of a vegan diet tend to prevent multiple sclerosis and other autoimmune
disorders.
Vegan diets may also have a role in the treatment of autoimmune disorders.
Scandinavian clinics have demonstrated that uncooked (“living food”) vegan diets –
preceded by a one-week juice fast - are genuinely beneficial in the management of
various autoimmune or inflammatory disorders, most notably rheumatoid arthritis;778, 782
the arthritis does not go into complete remission, but the symptoms and related laboratory
indices are substantially improved in a high proportion of patients. (These findings are a
bit hard to interpret owing to the fact that, after the fast, vegan foods are introduced
gradually, and any food that appears to provoke a flare-up in symptoms is thenceforth
excluded from the diet; in other words, the regimen incorporates efforts to deal with
specific food sensitivities. Nonetheless, since most authorities believe that food
hypersensitivity plays a role in, at best, only a small percentage of cases of rheumatoid
arthrititis,783 it is unlikely that food exclusion is primarily responsible for the clinical
benefits achieved by these protocols.) The utility of a low-fat vegan diet for controlling
symptoms in rheumatoid arthritis has also been confirmed by an American study.784
Another common disorder which appears to respond to these techniques is
fibromyalgia.785, 786
These results are paralleled by the experience of Dr. Roy Swank, who for half a century
has been treating multiple sclerosis with a diet that minimizes animal fat and saturated
fat, while increasing polyunsaturate intakes.787-790 He reports that, in his experience,
patients who adopt this regimen within two years of first appearance of symptoms have a
very favorable response – although the disease does not remit entirely, it generally fails to
progress, so that 20 or 30 years later they are alive and functioning at a relatively high
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level. In the great majority of cases, MS follows a relapsing but inexorable downward
course which eventually leaves the patients severely crippled and precipitates their
premature deaths. Swank claims that this slow downward spiral can be prevented
altogether in patients who are treated promptly, and considerably slowed in patients who
adopt his diet at a more advanced stage of the disease. It is unfortunate that other
neurologists haven’t taken up the challenge of replicating Swank’s work – until this
happens, Swank will no doubt be relegated to “crank” status in the neurological
community. (Perhaps after his death they will erect the requisite monuments!) It will be
of great importance to determine whether it is avoidance of saturated fat per se, or rather
of the animal products which supply this fat, that is responsible for the claimed benefit.
One other report merits mention. A young lady in Japan, afflicted with the potentially
lethal disorder systemic lupus erythematosus (SLE), decided – against the advice of her
physicians, but egged on by her parents – to discontinue her steroid therapy and instead
adopt a low-calorie fully vegan diet. Her disorder rapidly improved, and, at the time her
case was reported by her red-faced physicians, had been in total remission for 5 years.788
Perhaps this was merely a coincidence – and perhaps not!
In Search of a Mechanism
It is well accepted that fasting leads to rapid symptomatic improvement in patients with
rheumatoid arthritis.791 This isn’t necessarily of much practical significance, because
sooner or later a person needs to go back to eating normal amounts of calories – at which
point symptoms usually return with a vengeance (assuming the patient doesn’t adopt a
vegan diet). But it may be practical importance to understand why fasting has this antiinflammatory effect. The fact that fasting very markedly decreases blood IGF-I activity
may be an important clue. Blood white cell levels drop dramatically during a fast, and it
is known that IGF-I is a crucial growth factor for the body’s production of white cells.792,
793
These white cells are mediators of inflammation in many inflammatory disorders.
Less dramatic reductions in circulating white cells are seen when people adopt wholefood vegan diets.794, 795 Trowell commented on the fact that, in the African populations
in which autoimmunity was so rare, blood white cell levels typically were much lower
than in Europeans (though Africans could respond appropriately to infections with a rise
in white cell levels).768 These findings encourage the hypothesis that a whole-food vegan
diet helps to control inflammation by decreasing the levels and possibly the activity of
white cells that mediate inflammation – owing in part to a suppression of IGF-I activity.
However, this is not an adequate explanation for the former virtual absence of most
autoimmune disorders in sub-Saharan black Africans. This absence seems to imply that
the crucial mechanisms which prevent the body’s immune cells from becoming
“confused” and recognizing the body’s own tissues as “the enemy” simply work more
effectively in the context of a whole-food vegan diet. These mechanisms are highly
dependent on the process of apoptosis: during their early development in the thymus
gland, juvenile immune cells which are capable of attacking the body’s own tissues are
identified and then “instructed” to commit suicide by apoptosis.796
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Guess what can protect the body’s immune cells from apoptosis. Did anybody
say….IGF-I?! In fact, there is suggestive, though not yet definitive, evidence that high
IGF-I activity can interfere with the process whereby self-attacking immune cells are
“strangled in their cradle” via apoptosis.797-800 Indeed, some researchers have expressed
concern that therapeutic administration of IGF-I might increase “the potential for the
development of autoimmune disease or lymphoid malignancy by allowing self-reactive or
transformed lymphocytes to escape programmed cell death.”800 These considerations
might provide at least part of the explanation for the apparent rarity of autoimmunity in
certain quasi-vegan populations – relatively low IGF-I activity may aid the efficiency of
the process that eliminates rogue immune cells.801 Conversely, high rates of both cancer
and autoimmunity in Western society may reflect the fact that high growth factor
activities evoked by rich diets impair the efficiency of protective apoptosis – we simply
do a poor job of eliminating the deranged cells that can give rise to chronic inflammatory
damage or cancer.
Of course, alternative or adjunctive explanations can be entertained. Some scientists
believe that exposure to partially absorbable antigens derived from animal proteins (like
milk protein) play a role in triggering certain autoimmune reactions.802, 803 However, it is
not immediately obvious why animal proteins, and not plant proteins, would be offenders
in this regard. It is reasonable to imagine that a specific food protein might help to
induce a specific autoimmune disease – indeed, this phenomenon has been demonstrated
in animals,804, 805 and the thesis that milk protein helps to trigger type 1 diabetes has
generated a great deal of controversy806-809 - but it would seem unreasonable to suggest
that animal proteins are uniquely nefarious in this respect and thus are responsible for the
full range of autoimmune disorders in omnivore societies.
Taking another tack entirely, Dr. Greenwood suggested that chronic parasitic infections
were primarily responsible for low African rates of autoimmunity.770 While this is an
intriguing suggestion, I would be more likely to suspect that the antigenic exposures
entailed by chronic infection would increase risk for autoimmunity. Moreover, I doubt
that the prevalence of parasitic infections was so uniform throughout black Africa as to
make this a tenable explanation for the virtual absence of autoimmunity there.
Nonetheless, this view merits further exploration.
In any case, there is reason to suspect that autoimmune disorders are substantially
preventable, and that a whole-food vegan diet can make a worthwhile contribution in this
regard. There is less doubt that such diets have anti-inflammatory properties that are
useful for the management of rheumatoid arthritis, fibromyalgia, and possibly multiple
sclerosis.
A role for growth factor activities in autoimmune syndromes is also supported by reports
that chronic caloric restriction has a favorable impact on several autoimmune conditions
in genetically-susceptible rodents.810-813 Although this strategy may not be clinically
practical, fasting or restricting calories on alternative days is now being studied in
humans as a health-promoting regimen; compliance is reported to be good in well
motivated overweight subjects, and is said to be beneficial in rheumatoid arthritis.814
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Controlling Asthma
Allergy is a type of immune hypersensitivity that is fundamentally different from the
autoimmune disorders considered above, in that it reflects an excessive response to
foreign proteins – proteins not made by your body. Thus, it does not result from a failure
to eliminate autoreactive immune cells. Allergy occurs in people who, for unknown
reasons, make high amounts of IgE antibodies. This particular type of antibody is bound
to the surface of inflammatory cells known as mast cells; when this IgE binds to its target
foreign protein, the mast cells are stimulated to release histamine and other inflammatory
substances that can lead to the sneezing, wheezing, and itching characteristic of an
allergic response. I know of no evidence that a vegan diet influences your risk for
allergies one way or another – with one qualification.
One of the most serious manifestations of allergy is asthma, which results from spasm
and inflammatory congestion of the narrow breathing tubes of the lung (bronchioles); a
serious attack can be life threatening if not promptly controlled. Allergy attacks are often
triggered by allergic reactions in the lungs, but exercise can also trigger or exacerbate
attacks in some people. The same Swedish doctors who report success with whole-food
vegan diets in rheumatoid arthritis, report that their regimen is also often successful for
alleviating chronic asthma.794 If this is true (more study is obviously needed, as no
controlled clinical trials have been published on this), my best guess is that the diet is not
influencing the allergic activation of mast cells, but rather the lung’s response to this
chronic inflammatory insult. Repeated bouts of asthma often cause the linings of the
bronchioles to thicken – a phenomenon known as “airway remodelling”; this narrows the
air passages, much like atherosclerosis constricts blood flow by narrowing the lumen of
arteries. It is now known that IGF-I is an important growth factor for the bronchial cells
whose multiplication leads to this remodelling – epithelial cells, smooth muscle cells, and
fibroblasts.815-819 One the the main inflammatory mediators involved in asthma,
leukotriene D4, is now known to boost IGF-I activity in the bronchioles by inducing
smooth muscle cells to release an enzyme that breaks down an inhibitory IGF-I binding
protein made in the lung.815, 817 It is reasonable to expect that a decrease in blood-borne
IGF-I activity, achieved with a low-fat, whole-food vegan diet, could reduce the IGF-I
activity in the lung’s bronchioles and thus help to prevent or reverse airway remodelling.
While there is currently no experimental evidence supporting this view, I think that it
deserves consideration. In any case, it would be worthwhile for asthma researchers to
evaluate the impact of vegan diets on chronic asthma.
Alternate-day caloric restriction has recently been reported to benefit patients with
moderate asthma.820 Since this would be expected to induce an episodic reduction in
growth factor activities, the benefit observed here may be mechanistically related to that
achieved with vegan diets.
A low-salt diet may also be useful for controlling asthma. Doctors had noted that, when
African children migrated from their villages to cities, their susceptibility to
asthma.seemed to increase rapidly and dramatically. Yet this migration did not influence
their reactivity on allergy skin tests, suggesting that urbanization was making their
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airways more sensitive to the inflammatory compounds released during an asthma attack.
Dr. Peter Burney may have been the first to propose that salt was at the root of this
phenomenon.821, 822 Subsequent investigations have shown that, in asthmatic subjects –
particularly males – a high-salt diet does indeed make the airways more sensitive to
bronchoconstrictive agents, and worsens the clinical course; conversely, a low-salt diet is
protective in this regard.823-825 More recent evidence indicates that dietary salt also
influences the severity of exercise-induced asthma.826, 827
My suspicion is that the sodium pump inhibitors evoked by salted diets, that make blood
vessels more sensitive to vasoconstrictors, likewise can make the bronchioles more
sensitive to bronchoconstrictors; indeed, other researchers have recently raised this
possibility.828 There is conflicting evidence as to whether inhalation of the drug ouabain
– a drug that inhibits the sodium pump – sensitizes humans to bronchoconstrictors;829-831
however, this drug may conceivably be an inefficient inhibitor of the type of sodium
pump expressed in the lungs. One intriguing recent study assessed blood levels of the
circulating sodium pump inhibitor, and showed that these levels correlated directly with
lung responsiveness to a bronchoconstrictor – a finding quite consistent with my
proposal.831
Finally, it should be noted that supplemental fish oil may have some utility for
controlling asthma – presumably because it can inhibit production of the most active
forms of certain inflammatory mediators (the aforementioned leukotrienes) that promote
bronchoconstriction and airway remodelling in asthma.832, 833 A number of studies
examining this application have had negative outcomes,834 but this may simply reflect the
fact that the supplementation regimen used did not achieve an adequate enrichment of
omega-3 fats in body membranes. To achieve the best anti-inflammatory benefits of fish
oil, you need to take an ample dose of the fish oil omega-3s (at least 4 grams daily) for a
long period of time, in the context of a diet that is relatively low in total fat and especially
omega-6 fats. This has been illustrated nicely with respect to psoriasis: many
investigators have concluded that fish oil is of minimal or no benefit in this disorder, but
a study which administered an ample dose of omega-3 while asking the subjects to
minimize dietary fat found a very nice response.835 One insightful study has shown that
supplemental fish oil benefits asthma only in those subjects whose leukotriene
metabolism is significantly influenced.833 Since I recommend a very-low-fat diet
anyway, supplemental fish oil could be expected to be relatively effective within the
context of that recommendation. (I shouldn’t neglect to mention that the antiinflammatory activity of fish oil is useful for treating rheumatoid arthritis and various
other autoimmune disorders,836, 837 and thus would make a useful complement to a lowfat whole-food vegan diet in the treatment of these syndromes.)
In summary, there is reason to expect that a low-fat, low-salt vegan diet supplemented
with ample amounts of fish omega-3 fats could have a very favorable clinical impact on
asthma, attacking the problem from several angles simultaneously. Given the fact that
asthma seems to be reaching epidemic proportions, especially among inner-city children,
this possibility merits clinical evaluation.
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VI. Bones and Joints – Staying Intact
If you are planning and hoping to live to a ripe old age, it’s important to keep your bones
reasonably strong, and your joints functional. How would the diet that I suggest
influence the health of these connective tissues? With respect to maintenance of bone
density, the diet that I recommend has some definite advantages, but also potentially
some drawbacks.
Vegan diets tend to be lower in protein than omnivore diets. Protein is a source of sulfur
amino acids – methionine and cysteine – that are eventually metabolized by the body to
yield sulfuric acid (ouch!). The body can buffer this acidity by drawing on the phosphate
in bone mineral, breaking down the bone mineral in the process; some of the calcium
released in this process ends up in the urine rather than back in bone. On the other hand,
the acid generated by protein metabolism can be buffered by the carbonate generated
when certain negatively-charged organic compounds are metabolized – compounds like
citrate, for example. Generally, foods that are rich in potassium are a good source of
such compounds. Thus, a diet high in natural-food potassium tends to protect your bones
from the calcium-leaching potential of dietary protein – and a potassium-rich diet of
moderate protein content seems to be optimal for bone health, at least from the standpoint
of acid-base balance.838-842
(Vegetarian advocates are fond of stating that the sulfur content of animal protein has a
bone-leaching acidifying effect on the body. What they usually fail to state is that the
sulfur content of plant protein is virtually as high as that of animal proteins: plant
proteins tend to be lower in the sulfur amino acid methionine, but higher in the sulfur
amino acid cysteine. Thus, any inherent advantage of vegan diets in this regard stems
from the fact that they usually are lower in total protein than omnivore diets.)
It is ironic that the calcium-rich foods most recommended for preservation of bone health
– dairy products – are high in protein, and thus have a countervailing acidifying
metabolic effect that promotes bone breakdown. This is especially true for cheese – a
real disaster for bone health, regardless of propaganda to the contrary.843 On the other
hand, milk contains compounds that can be metabolized to carbonate, and thus has a
somewhat less unfavorable effect in this regard. But if your intent is to protect your
bones by increasing your calcium intake, it makes much better sense to take a supplement
such as calcium carbonate or calcium citrate, that not only provides calcium, but also
generates alkaline buffering power to protect your bones. (No, every body does not need
milk!) In fact, the Nurses’ Health Study revealed that women who ate the most dairy
products had the highest subsequent risk for fracture. For example, risk for hip fracture
was increased by 45% in women who drank two or more glasses of milk a day.844 Since
this wasn’t a randomized trial, it doesn’t constitute truly cogent evidence that high dairy
consumption is bad for your bones – but these results are consistent with this possibility,
and in any case they hardly support the heavily financed propaganda of the dairy
industry.
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A salty diet also has an adverse effect on bone health, owing to the fact that, for reasons
that remain obscure, salt promotes loss of calcium in the urine.293, 845 On the other hand,
a high intake of potassium helps to offset this adverse effect of salt, possibly because it
promotes urinary excretion of sodium chloride.846, 847 So a low-salt, potassium-rich diet
should help you to maintain your bone density.
However, there are several respects in which a vegan diet might not be absolutely ideal
for maintaining dense bones. For one thing, IGF-I has an anabolic effect on bone;848
dietary protein supplements have been shown to promote better fracture healing in the
elderly, possibly because they boost circulating levels of IGF-I.849 Some studies report
that circulating IGF-I levels are relatively low in fracture patients850-852 - though,
conceivably, the low IGF-I could just a marker for the low calorie intake associated with
feebleness. Furthermore, the fact that free estrogen levels tend to be lower in vegans
(both pre- and post-menopausally), while beneficial in regard to cancer risk, would not be
expected to promote optimal bone density.
Another problem is that vegan diets, lacking dairy products, often don’t supply truly
optimal intakes of calcium and vitamin D. (Vitamin D is an artificial additive to dairy
products – the only natural foods truly rich in this vitamin are fish liver and fish liver
oils.) When children are raised on a vegan diet without supplementation, I suspect that
relatively low intakes of calcium and vitamin D, in conjunction with reduced IGF-I
acitivity, will conspire to blunt the increase in bone density that children normally
achieve. There are some reports regarding children raised on macrobiotic diets which
support this supposition.853, 854 On the other hand, once people reach adulthood, I suspect
that a low-salt, potassium-rich vegan diet will tend to slow the gradual loss of bone
density that is a natural feature of aging. If vegan children are given calcium/vitamin D
supplements, it seems likely that this will enable them to achieve a higher bone mass in
their youth, and if they maintain their vegan diet throughout adulthood, this bone mass
might decline more gradually. Thus, a supplement-assisted diet of the sort recommended
here seems quite consistent with maintaining adequate bone density into old age.
An additional potential hazard of a vegan diet for bone health is the fact that a diet
exceptionally low in protein can somehow impair the efficiency of calcium absorption.855,
856
So if you choose the vegan approach, make sure that your regular diet features some
beans and/or soy products; any adverse impact of this protein on acid-base balance can be
offset by a high potassium intake - provided that your total protein intake remains
moderate (don’t make a fetish of soy protein products!) As we have seen, increased
intakes of “low-quality” plant protein seem unlikely to increase IGF-I levels or cancer
risk; lentils, which are very low in methionine, may be a smart choice for boosting the
protein content of a vegan diet.857 There is growing evidence t that soy isoflavones may
be beneficial to bone health – presumably owing to activation of beta-type estrogen
receptors in bone.858-861 .
Finally, the fact that vegans tend to be quite lean – an evident advantage with respect to
many health risks – will actually work against optimal bone density. People who are fat
tend to have denser bones, in part because weight-bearing exercise will put a greater
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mechanical stress on bones; this stress acts as a signal for bones to increase their density.
If you are a lean, light person – whether or not you are a vegan – you can compensate for
your lack of heft by simply doing more weight-bearing exercise – brisk walking or stair
climbing, for example.
What does epidemiology suggest about vegan diets and bone health? Two studies have
attempted to correlate the age-adjusted risk for hip fracture in various nations which their
characteristic food intakes; they each conclude that, the higher the intake of animal
products, the higher the risk of hip fracture.862, 863 Ironically, quasi-vegan societies with
relatively low calcium intakes are thus seen to have much lower risk for fractures than
countries such as ours which make a fetish of dairy calcium! Critics will be quick to cast
doubts on the significance of these findings by claiming that people in quasi-vegan
cultures do more physical labor, or may have distinctive genetic inheritances that play an
important role in their lower fracture risk. While such criticisms are not without merit
(Chinese, for example, appear to be at lower risk for hip fracture owing to a genetic
difference in hip structure), it is of interest that fracture rates are now climbing in Hong
Kong and other parts of the Orient as diets become more westernized.864
In any case, I believe that an overall survey of relevant findings is consistent with the
view that a low-salt, potassium-rich vegan diet, complemented by calcium/vitamin D
supplementation – particularly during youth, when bone mass is being built – and
adequate in protein content, is likely to increase your chances for maintaining adequate
bone density into old age. Regular exercise will further increase this protection.
I should comment briefly on the current controversy regarding the possible impact of
dietary calcium on prostate cancer risk. High-calcium diets tend to decrease your body’s
production of activated vitamin D (calcitriol) - a reflection of the fact that you don’t need
to absorb calcium as efficiently if your calcium intake is high. Pharmacological doses of
calcitriol have been shown to retard the growth of many prostate cancers, and some
epidemiology suggests that good sun exposure – which improves vitamin D status - is
associated with lower prostate cancer risk.865-867 These considerations have given rise to
the suspicion that high-calcium diets might increase risk for prostate cancer by
suppressing production of calcitriol.868 Several epidemiological studies support this
view,869-871 but others do not872-878 – or only do so after drastic statistical manipulations of
the data.879 (One of these studies reported significant protection associated with high
calcium intake!)873 I am somewhat skeptical of this thesis primarily because, in most
studies that have examined serum calcitriol levels in large numbers of men, a relatively
low calcitriol level has not been associated with a subsequent increase in prostate cancer
risk – a finding that doesn’t seem to support the proposition that blood-borne calcitriol
plays a physiological role in prostate cancer prevention.880-882 However, the prostate cells
which can give rise to cancer are capable of manufacturing their own calcitriol, and this
production is not influenced by dietary calcium.883 Perhaps the calcitriol circulating in
the blood only becomes truly relevant to prostate cancer prevention when the prostate’s
own capacity for making calcitriol is compromised by poor vitamin D status.884 If this is
the case, then any impact of calcium nutrition on prostate cancer risk should be
minimized by taking ample but safe doses of supplemental vitamin D. Furthermore,
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good vitamin D status replicates the beneficial impact of dietary calcium on bone health,
since both vitamin D and calcium support bone density by suppressing production of the
bone-dissolving parathyroid hormone. So perhaps the smartest approach when
supplementing is to take ample doses of vitamin D (e.g. 2,000-5,000 IU daily) and
moderate doses of calcium (500-1,000 mg). In the Physicians Health Study, greatest risk
for aggressive cancer was seen in men with estimated daily calcium intakes in excess of
1,500 mg;870 moderate calcium supplementation in the context of a vegan (i.e. dairy-free)
diet is unlikely to yield a daily calcium intake in excess of this limit. Those tempted to
minimize calcium intakes in an effort to reduce their prostate cancer risk should bear in
mind that good calcium status not only aids bone health, but may also reduce risk for
colorectal cancer.885, 886
Many vegan advocates tend to over-react to the propaganda of the dairy interests by
trying to minimize the importance of dietary calcium for bone health. In particular, they
point to the low risk of fractures in quasi-vegan societies where calcium intakes are low.
I would counter by noting that, whereas, at least under certain circumstances, a lowcalcium diet can be compatible with the maintenance of good bone health, this is not
inconsistent with the possibility that insuring an ample calcium intake will promote even
better bone health – especially if the calcium is provided as a nutritional supplement
(rather than in protein-rich dairy products) and is accompanied by vitamin D, another
nutrient with great potential for promoting maintenance of bone density.887, 888 However,
I will agree with the calcium critics that the importance of dietary calcium has been
somewhat overemphasized relative to other protective factors such as an appropriate
acid/base balance and a low salt intake. Furthermore, vitamin D and calcium aren’t the
only supplemental nutrients that might be protective in this regard; there is evidence that
supplemental vitamin K, as well as other minerals such as magnesium, zinc, manganese,
and copper – all of which play important roles in bone metabolism - can aid maintenance
of bone density.889-897 In particular, Japanese clinical studies suggest that high doses of
vitamin K may markedly reduce fracture risk, even though only a modest impact on bone
density is observed.898 For this reason, I believe that a well designed “nutritional
insurance formula” (as described below) may be particularly helpful for keeping your
bones healthy. Supplemental calcium alone, at least postmenopausally, provides rather
modest benefit – perhaps a 2% increase in bone density in the first year or so of
supplementation, after which steady loss of bone mineral resumes. This modest benefit
may be enough to postpone your date with a serious fracture – but don’t let the
advertising hype of calcium pushers lull you into thinking that calcium supplements alone
will provide definitive protection for your bones.
However, supplementation is not always favorable to bone health. Recent evidence
suggests that dietary intakes of pre-formed vitamin A (retinol, retinyl palmitate) –
whether from foods or supplements – may promote loss of bone density and increase
fracture risk.899-901 Even relatively modest intakes – barely higher than the amount long
regarded as the “recommended daily intake’ by the U.S. government – are associated
with increased risk of fracture. Apparently, this reflects the ability of retinol (or rather its
metabolic product retinoic acid) to increase the activity of osteoclasts, the bone cells that
dissolve bone mineral.902, 903 The good news is that beta-carotene, which the body can
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convert to retinol to provide adequate vitamin A activity, has not been linked to loss of
bone density; evidently, the amount of vitamin A activity derived from dietary beta
carotene is sufficiently high to promote adequate nutrition, but sufficiently low that it
represents no threat to bones. Food sources of pre-formed vitamin A include fish, fish
oils, liver, eggs, and certain dairy products and breakfast cereals that are “vitamin
fortified”; retinol does not occur naturally in any vegan foods. So you can avoid dietary
retinol altogether if you eat a vegan diet, avoid “enriched” breakfast cereals, and choose
supplements in which the vitamin A activity is provided entirely by beta carotene. Once
manufacturers have revised their products to exclude pre-formed retinol, vitamin-mineral
supplements should be exceptionally beneficial for bone health.
A Comment on Kidney Stones
Although kidney stones are rarely life-threatening these days (thanks to the availability of
good surgeons), they can be excruciatingly painful. Most such stones consist of calcium
salts (e.g. calcium oxalate), so an effective way to prevent them is to minimize the
amount of calcium that the kidneys allow to pass into the urine. We have already noted
that a salty diet, as well as a diet high in protein, promotes loss of calcium in the urine –
whereas the alkalinizing effect of a potassium-rich diet is protective in this regard.904-908
In other words, a low-salt whole-food vegan diet of moderate protein content (i.e. that
isn’t high in soy protein products) should be just about ideal for preventing kidney stones.
The other key ways to reduce your risk for kidney stones is to moderate your intake of
vegetables (such as spinach) that are rich in the compound oxalic acid, and to increase
your intake of fluids.904, 907 In susceptible individuals, very high supplemental intakes of
vitamin C may cause the body to make significant amounts of oxalic acid;909 however, in
most people this is not a significant concern.910, 911. (Earlier studies suggesting a more
general effect of vitamin C on urinary oxalate levels proved to be technically flawed.)
Conversely, supplemental vitamin B6 tends to decrease oxalic acid production in people
who make excessive amounts of this compound, and thus may be useful for reducing
kidney stone risk in such individuals.912-914 Ample intakes of magnesium – from whole
grains, beans, or supplements – also appear to reduce kidney stone risk.915
Surprisingly, unless your diet is exceptionally high in calcium (say, over 2,000 mg per
day), dietary calcium seems to have relatively little influence on the amount of calcium
that is excreted in the urine. An increase in dietary calcium acts to suppress the
production of certain hormones that induce calcium absorption – the net effect being that
net calcium absorption does not rise significantly; this protective mechanism is
overridden only when calcium intake becomes exceedingly high. Ironically,
supplemental calcium has actually been found to reduce kidney stone risk in some
individuals, owing to the fact that dietary calcium tends to form an insoluble precipitate
with dietary oxalic acid, such that the oxalic acid cannot be absorbed.916 Yet the
conventional medical wisdom for years has been to have kidney stone patients cut back
on calcium – which does little to prevent these stones, while putting bone health at risk!
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In one recent Italian clinical study, patients who previously had experienced kidney
stones were randomly assigned to either a low-calcium diet or a diet with a reduced
intake of salt and animal protein. During the next five years, recurrent kidney stones
were only half as common in those patients restricting salt and animal protein, as in those
restricting calcium.917 Hopefully this highly publicized study will help to change medical
practice for the better.
Keeping Your Joints Healthy
If you want to enjoy the health-promoting advantages of regular aerobic exercise into a
vigorous old age, is it also of great importance to keep your weight-bearing joints in good
shape. Staying lean and choosing aerobic exercises that are low impact – power walking,
stair climbing, elliptical gliding, or cycling in preference to running or bouncing aerobics
– will be beneficial in this regard. The weight loss achievable with a low-fat, whole-food
vegan diet accompanied by exercise may be of particular benefit to overweight people
who are starting to experience hip or knee problems.918 However, how such a diet will
influence cartilage health in other respects is not clear. There does not appear to be any
evidence that quasi-vegan societies enjoy special protection from osteoarthritis.
There is recent evidence from two 3-year controlled studies that the natural supplement
glucosamine – a biosynthetic precursor of the mucopolysaccharides that constitute a high
proportion of the dry weight of cartilage, and of the hyaluronic acid that lubricates your
joints – can slow or halt the loss of cartilage in people suffering from osteoarthritis of the
knee.919, 920 Moreover, when the participants in this study were followed up five years
later, those who had received glucosamine during the study were found to be 57% less
likely to have undergone a surgical knee replacement.921 There is considerable evidence
– albeit not entirely consistent922 - that glucosamine supplementation can provide
symptomatic benefit in osteoarthritis, easing pain and improving joint mobility – without
the potential toxicity associated with many anti-inflammatory drugs.923, 924 These
considerations suggest that, in people who still enjoy healthful joint function,
glucosamine supplementation might have utility for preventing the onset of osteoarthritis
and keeping your joints structurally intact. It will probably be many years before this
supposition is adequately evaluated in clinical studies, but I am following my instinct and
incorporating glucosamine into my supplementation program while my joints are still in
good shape.
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VIII. Coda – A Few Odds and Ends
To wrap up, I will address a few relevant topics that somehow didn’t make it into the
preceding discussions:
Prostates and Periods
Prostatic hyperplasia – as distinct from prostate cancer, which usually arises in a different
part of the prostate – rarely kills men, but it can make one’s “golden years” more
annoying than they ought to be. I have a strong suspicion that the reduction of growth
factor and sex-hormone activity associated with whole-food vegan diets may slow the
onset of this disorder.925 It is intriguing to note that symptomatic prostatic hyperplasia
used to be considered quite rare in China – but has become increasingly more common in
recent years.926-928 The fact that it is now more common in urban China than in rural
China is consistent with the possibility that quasi-vegan diets are indeed protective in this
regard. Furthermore, there are recent reports that increased serum levels of free IGF-I
and of insulin may be associated with increased risk for clinically significant BPH,
whereas the IGF antagonists IGFBP-1 and IGFBP-3 may be protective in this regard.929932
Regular exercise, as well as moderate alcohol consumption – both of which promote
improved insulin sensitivity, and thus tend to lower blood levels of insulin – have also
been linked to reduced risk for this disorder.933, 934 Thus, an overview of the admittedly
limited relevant evidence that is currently available encourages the view that the
relatively low growth factor activity (low blood levels of free IGF-I and of insulin)
associated with low-fat whole-food vegan diets would tend to prevent or postpone
symptomatic overgrowth of the prostate.
Women have their own set of problems – including the pre-menstrual tension syndrome,
menstrual cramping, and the side effects associated with onset of menopause. Since free
estrogen levels are lower on whole-food vegan diets, the hormonal shifts which
precipitate these syndromes are less dramatic in the context of such a diet. A recent
controlled study by Dr. Neal Barnard and colleagues has demonstrated that the annoying
symptoms often experienced premenstrually, as well as menstrual cramping, are less
severe when women are eating a low-fat, whole-food vegan diet.80 (In fact, the
symptomatic benefit was so substantial that it interfered with the experimental design –
the women who were supposed to switch back to an ordinary omnivore diet refused to do
so!) There is also an impression that in quasi-vegan societies like China, the hot flashes
and other symptoms associated with onset of menopause are less troubling; whether
vegan diets might have preventive or therapeutic benefit in this regard has not been
assessed in clinical studies.
Health Benefits of Fiber
Although the idea that dietary fiber lowers colon cancer risk may not hold water after all,
there are plenty of other respects in which an ample intake of dietary fiber – which you
will surely achieve with a low-fat, whole-food vegan diet – can aid your health. Aside
from the obvious fact that you will avoid constipation, the incidences of appendicitis,
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diverticulitis, hemorrhoids, varicose veins, hiatal hernia, and gallstones are anomalously
low in cultures whose traditional diets are high in fiber. Dr. Hugh Trowell and his
eminent colleague Dr. Denis Burkitt did much to document this point in their insightful
writings promoting fiber-rich whole-food diets.313, 768, 779 They popularized the motto:
“hard in, soft out” – meaning that, if you eat “hard” fiber-rich foods, you will have a soft
stool that will protect you from the many potential health problems associated with hard
stools. Hard stool can lead to impactions that promote both appendicitis and
diverticulitis; and the straining associated with the need to evacuate hard stools is a
suspected to be a factor in the origin of hemorrhoids, varicose veins, and hiatal hernia.
The impact of dietary fiber on risk for appendicitis is now however a bit less clear than
we formerly suspected. Studies in South Africa indicate that risk of appendicitis in black
South Africans is remaining quite low despite the fact that dietary fiber consumption has
declined quite substantially and is now not much higher than that of whites.935, 936
However, dietary fat intake – and thus presumably intake of animal products – remains
low in most black South Africans.937 So perhaps it is a low-fat or quasi-vegan diet that
mediates the protection from appendicitis. There is evidence that a vegan diet can have
an impact on the types of bacteria that populate the lower intestinal tract.938, 939
Furthermore, as we have seen, a vegan diet influences the rate of cell multiplication in the
colon lining. Conceivably, such factors could influence risk for appendicitis.
Epidemiology in Britain suggests that British vegetarians have only about half as high a
risk for this disorder as do omnivores.940
An association of high fiber intake with reduced risk for diverticulitis and hemorrhoids
appears to be more solid, inasmuch as high-fiber diets have shown utility for treating
these syndromes.941-944
The rarity of varicose veins in rural Africa was once quite extraordinary. I can quote Dr.
Denis Burkitt on this: “During 1958 in an area of Uganda where at that time western
culture had little impact, I specifically looked for varicose veins in over 4,000 adults
during an inspection of an entire community for trypanosomiasis. Only five cases were
found, an incidence of 0.12%, which is about one-hundredth of the incidence in Britain or
the U.S.A.”768 This rarity of varicose veins goes hand-in-hand with a rarity of deep
venous thrombosis, a frequent complication of surgery that can lead to fatal pulmonary
embolism. (This is what killed Andy Warhol, for example.) Several British surgeons
have claimed that the incidence of deep venous thrombosis has plummeted in their
practices after they started to give bran supplements to their patients;945 unfortunately, I
am not aware of any controlled clinical studies that have attempted to validate these
observations.
With respect to gallstones, dietary fiber, by speeding the transit of food through the
intestines, decreases the ability of gut bacteria to transform bile acids into less soluble
metabolites that are linked to increased gallstone risk, such as deoxycholate.946, 947 These
metabolites, after being reabsorbed, inhibit the liver’s production of an enzyme (7-alphahydroxylase) that converts cholesterol to bile acids;948, 949 as a result, bile tends to have an
excess of cholesterol that may crystallize out to form gallstones. This key liver enzyme is
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also suppressed by insulin950, 951 – implying that good insulin sensitivity and low-insulinresponse diets should be protective. Low-fat whole-food vegan diets are typically rich in
fiber, tend to promote leanness and insulin sensitivity, and provoke relatively low insulin
secretion – so they are ideal for preventing gallstones.
To show how effective this protection can be, I will quote gallstone expert Dr. Kenneth
Heaton: “Denis Burkitt recalls that in 17 years’ surgical practice in East Africa he
operated on only two patients with gallstones, one of whom was a queen. At the time of
writing, figures from replies to questionnaires received by D.B. amply confirm personal
impressions. Twelve hospitals in Uganda have supplied 109 monthly returns and have
not reported a single case of gallstones. The same is true for Malawi after 102 hospital
months. In Tanzania, 207 hospital months have yielded only two cases and in Kenya 67
hospital months have turned up just one case. In West Africa, 13 Nigerian hospitals have
seen only two patients with gallstones in a total of 109 months.”952
Contrast these figures with the estimate that, as of 1970, about one-third million
gallbladders were removed annually in the U.S.!953 And lest there be any be any
suspicion that blacks are at low genetic risk for gallstones, Heaton cites a survey in
Philadelphia noting that African-Americans accounted for 42% of all admissions for
treatment of cholesterol gallstones.
Native American women – and women with significant Native American genetic
heritage, such as mestizo Mexicans and Mexican-Americans – are at greatly increased
genetic risk for gallstones, and their risk for this disorder is extremely high if they grow
up eating the fatty, over-refined omnivore foods popular in the U.S. Although having
symptomatic gallstones usually only entails physical discomfort and the inconvenience of
undergoing surgery, it can also have a more sinister outcome; in about 2-3% of cases, a
surgically-removed gall bladder is found to harbor a gallbladder cancer – which is almost
invariably rapidly fatal if not completely removed by the initial surgery. Presumably, the
inflammation often induced by gallstones markedly increases the chance that a cancer
will arise in the gallbladder; gallbladder cancer is associated with gallstones in about 8090% of cases. A survey of the records of the New Mexico Tumor Registry during the
1970s indicated that gall bladder cancer was the third most common cancer diagnosed in
Native American women, trailing only cancers of the breast and uterine cervix.954 To the
extent that proper diet can minimize gallstone risk in Native Americans, adopting such a
diet may thus be expected to proportionately lower risk for one of their most prominent
killer cancers.
Evidently, if you want to minimize your need for the services of a surgeon and stay out of
the hospital (which is where the really bad antibiotic-resistant germs are!), a high-fiber
whole-food diet is a really smart idea.
While I am on the topic of fiber, I shouldn’t neglect to cite some recent intriguing
epidemiological studies, making use of the huge Nurses’ Health Study data base,
indicating that a relatively high consumption of whole grains (not grains per se) is
asssociated with significantly decreased risk for heart attack, stroke, and diabetes.955-957
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The authors of these studies used sophisticated statistical analyses to try to pin down the
components of whole grains that were primarily responsible for this protection, but the
protection appeared to be largely independent of fiber per se, or of specific nutrients such
as B vitamins, vitamin E, or magnesium. Nor is reduced glycemic index a likely
explanation: in an American population, whole wheat flour is the predominant whole
grain – and this has virtually as high a glycemic index as white flour. Thus, there appears
to be a “mystery factor” in whole grains that provides important and versatile health
protection. I would like to see the neglected trace mineral silicon examined in this
regard958, 959 – but that is a mere hunch. The “take-home lesson” is that at every
opportunity you should choose whole grains over refined grains if at all possible –
consistent with the advice to eat a whole-food diet. Whole-wheat pasta is a great way to
get your whole wheat, as is bulgur wheat (a dish popular in the Mediterranean);
“flourless” breads featuring sprouted grains or partially intact grain kernels are a better
choice than breads made from finely-ground flour. Macrobiotic vegans place great
emphasis on brown rice, which in any case is more flavorsome than white rice. Health
food stores usually offer a wide range of rather exotic whole grains.
.
Adverse Effects of Veganism?
It is common sense to suspect that the reduction in IGF-I activity associated with a vegan
diet will not be favorable to optimally efficient wound healing.960, 961 As noted above,
there is evidence that protein supplements can boost circulating IGF-I levels and
accelerate the healing of fractures in the elderly. Theoretically, a reduction in IGF-I
levels might also compromise the ability of the body’s immune cells to multiply
aggressively in response to invasion by pathogenic microorganisms.962 However, there
currently is little evidence that vegans have a compromised immune status or are at
increased risk for infection.963 If you are faced with a severe trauma or a persistent
infection and would like to boost your IGF-I activity temporarily, adding some low-fat
dairy products to your diet would be a rational strategy.
In regard to risk of infection, inadequately cooked flesh products are the most common
source of staphylococcal “food poisoning” and other food-borne infectious illnesses.
Presumably, this is because the infectious organisms that thrive in animals - including
humans - are fundamentally different that those that infest plants. The harm that arises
from eating microbially contaminated plant products generally results, not from infection,
but from ingestion of carcinogens or other toxins produced by the contaminating
organisms. (The recent episode of E. coli-contaminated spinach stemmed from water
polluted by livestock waste.) Yet even proper cooking doesn’t seem to deter transmission
of “mad cow disease”. (Fortunately for vegans, “mad broccoli disease” is unlikely to
make an appearance!) The popular furor over the European “mad cow” epidemic and the
occasionally lethal outcomes of food-borne E. coli infections in children have motivated
many people to take a more serious look at vegetarianism or veganism (though I’m a mite
perplexed that fear of heart disease, diabetes, or cancer hasn’t already provided sufficient
motivation!)
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There is some evidence that, in people who are hypertensive, a low intake of saturated fat
and of animal protein – as well as low blood cholesterol levels - may increase risk for
hemorrhagic stroke; this has been reported in Japan,428, 429, 964, 965 and, more recently, in
the U.S.966 Conceivably, the cerebral vasculature may be thinner and more prone to
rupture when growth factor activities are low; smooth muscle cells of the artery wall are
protected from apoptosis by IGF-I, which also promotes production of the protein
elastin.967, 968 This is a very minimal risk if your blood pressure is on the low side –
hemorrhagic stroke is quite rare even in Japanese when their systolic blood pressure is
under 120429 – and it should be noted that so-called ischemic stroke (the type resulting
from blood clots) is much more common in the U.S. Nonetheless, if your blood pressure
is very high (despite your best effort to control it with diet and drugs) and your doctor
thinks that hemorrhagic stroke may be a major risk for you, cutting the animal protein out
of your diet may not be a wise idea. Theoretically, fish oil, which I have often
recommended for a wide range of health-protective benefits, has the potential to increase
risk for hemorrhagic stroke owing to the fact that, much like aspirin, it can stabilize the
blood clotting cells (platelets); however, there is currently little direct evidence in support
of this concern, whereas there is good reason to believe that fish oil provides protection
from the much more common thrombotic type of stroke.969
The epidemiological correlations between low serum cholesterol and hemorrhagic stroke
risk are just one aspect of a broader phenomenon that has led many to question the
wisdom of striving for low cholesterol levels. Epidemiological studies have often found
that people with relatively low serum cholesterol are at increased risk for death from a
number of non-vascular disorders, including many types of cancer, respiratory diseases,
digestive diseases, cirrhosis, trauma, and suicide.970-973 It is important to note that, when
people in Western society have a low cholesterol level, this is hardly ever attributable to a
consumption of a quasi-vegan diet – their cholesterol is usually low despite consuming a
fatty, over-refined diet. Low cholesterol under these circumstances implies a peculiarity
of metabolism or lifestyle that in many cases may be harmful to health, or that reflects an
ongoing disease process. Thus, a low cholesterol may be a reflection of a low food
calorie intake in people who are depressed, demented, feeble, or addicted to drugs or
alcohol; such people are evidently at increased risk for death from a number of causes –
and serum cholesterol clearly has nothing to do with it. The reduction in calorie intake
may itself pose a risk by compromising the intake of protective vitamins, minerals, and
phytochemicals. Chronic inflammation also typically lowers cholesterol,973 and it has
been shown that cholesterol tends to decline in the 4-6 years prior to death from cancer –
a phenomenon that, in the opinion of many experts, largely accounts for correlations
between low cholesterol and cancer risk.971, 974, 975 Some cancer cells remove cholesterolrich LDL particles from the bloodstream, whereas others can lower cholesterol through
inflammatory mechanisms. No one has ever proposed a credible mechanism whereby
low serum cholesterol could increase cancer risk, or demonstrated that low cholesterol
increases cancer yields in rodent studies.975
Analyses that take these factors into account have concluded that, with the likely
exception of the low cholesterol/hemorrhagic stroke connection (which still lacks a clear
explanation, but emerges quite consistently in epidemiological studies), low cholesterol
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itself is unlikely to be the cause of the increased non-vascular mortality associated with
low cholesterol levels.971, 972 The most definitive analysis in this regard – by British
epidemiologist Dr. M.R. Law and colleagues - divided epidemiological studies into two
kinds: those in which the enrollees were employees of a large company, and so-called
community-based studies that enrolled a large cross-section of the general public. Law
reasoned that, in the employee-based surveys, the subjects were very likely to be healthy
at baseline (when blood samples were taken), whereas in community-based surveys a far
higher proportion of the subjects would have pre-existing medical conditions that could
lower cholesterol. Sure enough, Law found that none of the employee-based studies
linked low cholesterol to increased mortality from any cause, whereas all of the
community-based studies correlated low cholesterol with increased non-coronary
mortality. Law concluded that this was definitive evidence that low cholesterol was the
result, rather than the cause, of lethal diseases or of medical conditions that promote
lethal disease.976 (The studies in question did not specifically note the incidence of
hemorrhagic stroke, so they did not provide insight into its link to low cholesterol – but
on other grounds Law concluded that the link between low cholesterol and hemorrhagic
stroke was genuine.) Another insightful study showed that increased risk was seen only
in people whose cholesterol declined substantially; people whose cholesterol was steadily
low for a number of years were not at increased risk.977 The authors of this study
concluded that their “results add strength to the reverse-causality proposition that
catabolic diseases cause total cholesterol to decrease.” In other words, the reduction in
cholesterol is usually a marker of a dangerous health problem – rather than a mediator of
it.
This is borne out by studies looking at mortality risk in people who use cholesterollowering drugs – these studies show that cholesterol reduction has a dramatically
protective impact on vascular risk, without increasing risk of mortality from cancer or
any other major cause.978 With respect to dietary impacts on cholesterol, it is comforting
to note that in the Oxford Vegetarian Study – a long-term follow-up of the health status
of 6,000 British vegetarians (a significant proportion of whom are vegans) – the
vegetarians were at substantially and significantly lower risk for all-cause mortality, as
well as for death from heart disease or cancer specifically.979 You will also recall that, in
the China Health Project, the provinces in China that had the lowest cholesterol levels
were also those that had the lowest risk for cancer – presumably owing to the fact that, in
China, a low cholesterol is a marker for low animal product consumption.506, 980 Thus,
there is little reason to suspect that either low cholesterol, or a reduction in cholesterol,
acts to increase cancer risk. It bears repeating that the correlations noted in
epidemiological studies very frequently do not reflect causation; for example, the fact
that heart disease is more common in societies that have safe drinking water does not
imply that safe drinking water causes heart disease! Similar logic may apply to the
association between low cholesterol and non-vascular mortality.
A major problem with the hypothesis that low cholesterol tends to increase mortality is
that, by and large, no one has offered any credible mechanism whereby moderately low
cholesterol levels could exert dire effects. However, some scientists still suspect that a
correlation between impulsive or violent behavior and low cholesterol may in fact reflect
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some impact of circulating cholesterol levels on brain function;981, 982 a limited amount of
animal data appears to support this possibility, whereas other animal studies do not. Law
did not find any association between suicide or other violent death and low cholesterol in
the employee-based studies. Furthermore, he cites evidence that depression can lower
cholesterol levels – via anorexia or inflammatory mechanisms – whereas successful
treatment of depression is typically followed by an increase in serum cholesterol.976
Suffice it to say that there is presently no evidence that vegan diets render people more
violent or impulsive, nor has the world yet been terrorized by roving bands of hopped-up
vegans! Indeed, the relatively low intake of branched-chain amino acids and high intake
of carbohydrates that characterizes most vegan diets would be expected to promote brain
synthesis of the neurotransmitter serotonin – a deficit of which is often a factor in violent
behavior or depression.983 Nonetheless, it should be noted that many vegan diets are poor
sources of omega-3 fatty acids, and a low intake of these has recently been linked to
increased risk for depression.984, 985 This once again argues that vegans would be well
advised to supplement with fish oil – though plant sources of omega-3 such as flax oil are
also likely to be useful with respect to optimizing brain function.
Vegans are usually lean and thin. You should be aware that, if you want your son to
become a star linebacker, a vegan diet may make it harder for him to acquire the large
muscle mass required. It is a common belief among body builders that, no matter how
much soy protein a person consumes, a vegan diet is not consistent with achieving
maximal lean mass. This is probably just the flip side of the reduction of growth factor
activity that is so protective from a health standpoint. For vegans attempting to build a
larger muscle mass, supplemental creatine (about 3 grams daily) as an adjunct to vigorous
resistance training may be particularly helpful, as vegan diets contain no creatine at all,
and vegetarians typically have a slightly lower body pool of creatine.986, 987. Supplements
of the essential amino acid leucine – as well as of its natural metabolite beta-hydroxybeta-methylbutyrate (HMB) – have also demonstrated some potential for increasing
muscle protein synthesis and/or slowing the rate of muscle protein breakdown,988-990, 9901000
apparently without adverse effects;1001 there is no evidence that supplemental leucine
or HMB influence IGF-I activity. A simple way to look at this is that skeletal muscle
tries to maintain a relatively constant level of free leucine; when this level is low (as it
often is immediately after strenuous exercise or in certain diseases associated with loss of
lean mass) muscle fibers attempt to normalize this level by increasing the rate of protein
breakdown and slowing the rate of protein synthesis. Conversely, an increase in muscle
levels of free leucine has the opposite effect, inducing an increase in protein synthesis
coupled with a reduction in protein breakdown – precisely what you would want if you
are trying to increase your lean mass. Muscle may also monitor the level of the leucine
metabolite HMB as an index of free leucine levels, and the utility of HMB supplements
(3 grams daily) for slowing muscle breakdown and building lean mass is now well
documented; remarkably, there is also preliminary evidence that such supplementation
may even slightly lower serum cholesterol and blood pressure.1001 Thus, for vegans who
would like to beef up their muscle mass without having to resort to androgenic hormones
(anabolic steroids) or measures that increase blood-borne IGF-I activity, supplements of
creatine, leucine, and HMB, complemented by resistance training, may offer a safe and
effective alternative.
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A further proviso – if you wish to raise an infant on a vegan diet, by all means make sure
that he/she gets human breast milk (if at all possible) during the first months of life; there
is more and more evidence that breast feeding provides important health advantages. (In
other words, human milk should not be viewed as a health-destructive animal product at least in infants!) Once the infant is eating solid food, don’t go overboard on restricting
fat – growing infants require a fair amount of fat for proper formation of their central
nervous systems. And of course make sure that your child takes a supplement providing
vitamin B12 – this nutrient plays an important role in supporting tissue growth.
Supplements of calcium and vitamin D may also be advisable, albeit less crucial. It may
interest you to learn that, in the final edition of his classic book on child rearing, Dr.
Benjamin Spock advised that all children over the age of 2 be raised on a low-fat vegan
diet (much to the consternation of his publisher, I might add!). A vegan diet had saved
Dr. Spock from a severe health problem in his eighties; he went on to live another
decade, and became a staunch advocate of veganism in his later years.
The Paleolithic Persuasion
I would be remiss not to take at least a little time to address the increasingly popular
notion that humans are evolutionarily adapted to a high meat diet such as that which they
practiced in pre-agricultural times. Whatever the merits of this view, it has great appeal
to people who want to be told that the flesh products they like to eat are actually good for
them!
After the invention of stone tools and weapons, which made hunting much more
effective, and prior to the invention of agriculture, humans did indeed get a high
proportion of their calories from game animals. Foliage, fruit, wild tubers, and nuts
supplied the remainder of their calories – grain products and beans were not dietary
staples prior to agriculture.1002
Many aspects of this diet doubtless were laudatory. The plant foods were whole, rich in
potassium, fiber, and phytochemicals, and low in both glycemic index and caloric
density. Refined salt was not available. The meat of game animals was usually quite
lean – not at all like the marbled steaks that modern man enjoys – yet was comparatively
rich in protective omega-3 fats. Dairy products were unknown, and eggs were only an
occasional treat. Quite a lot of energy was expended in the pursuit of not that many
calories – implying that obesity was probably a rare problem (as is certainly the case with
the few remaining hunter-gatherer cultures).
However, I refuse to buy into the argument that the thousands of years that our paleolithic
ancestors spent as hunger-gatherers implies that we are adapted to require a high intake
of flesh products to maintain good health. Although certain useful nutrients such as
carnitine, creatine, and taurine are supplied primarily by flesh foods, humans did not lose
their capacity to synthesize these compounds during their paleolithic years (in stark
contrast to the fact that cats have become obligately dependent on flesh as a source of
taurine). Very small dietary intakes of animal products can meet the need for vitamin B12
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(which these days can be readily provided in supplements). There is no reason to believe
that high protein intakes are vitally important to health and, as we have seen, relatively
low protein vegan diets can protect us from a wide range of disorders.
Vegan advocates could counter (and often do) by claiming that, in the millions of years
prior to the development of stone weapons, our hominid ancestors were quasi-vegan, like
the current great apes – and that we thus are adapted to require a vegan diet; they note
that our dentition and digestive tracts are much more akin to those of herbivores than
carnivores. Or they could claim that thousands of years of reliance on agriculture have
made us dependent on grains for good health. Frankly, I think that these views are just as
specious as the contrary view that we are adapted to require lean meat. Throughout their
evolution, man’s ancestor have eaten whatever they could get their hands on to stave off
starvation. There is no compelling reason to believe that any particular pre-modern
dietary pattern guarantees an Edenic state of lifelong good health. The sober fact is that,
rather than falling back on a comfortable myth about an ideal bygone diet, we need to
resort to scientific analysis of a broad range of evidence in order to define the diets and
lifestyles that can best protect us from the degenerative disorders of aging. I applaud the
anthropologists who are helping us to better understand the dietary patterns of our
ancestors – their work serves to expand our awareness of the wide range of dietary
choices open to us – but I categorically reject the notion that their findings constitute a
blueprint for an ideal future diet.
Furthermore, trying to implement a “paleolithic” diet in the modern age – doing one’s
“hunting and gathering” in modern supermarkets, I suppose – is of questionable
practicality. Flesh foods that are truly low in fat have a very low net calorie yield, with
the result that, lacking grain products, you will need to eat huge amounts of flesh just to
avoid starvation. Consider that, during the Lewis and Clark expedition, the men
consumed an average of 8 pounds of meat a day! If you had access to a lot of fruit and
nuts, your dependence on massive amounts of flesh foods would be alleviated somewhat,
but most paleolithic people probably didn’t have this luxury. If modern-day people
pretending to be paleolithic get by on much lesser amounts of meat, it’s undoubtedly
because the meat they are eating is a lot higher in fat than is half-starved wild game - or
they are eating a lot more fruit and nuts than most paleolithic people had access to. (In
this regard, it is interesting to note that, when Plains Indians killed a buffalo, if the animal
was quite lean, they often wouldn’t even bother to butcher it – too much trouble for too
few calories!)
Advocates of the paleolithic diet are fond of recounting the remarkable study by Dr.
Kerin O’Dea, who convinced 10 diabetic Australian aborigines to return to their
traditional hunter-gatherer lifestyle for a period of 7 weeks.1003 Not surprisingly, their
diabetic control improved to a remarkable degree, and, on average, they lost 8 kilograms
of weight. What is often left unsaid is the fact that these people were consuming an
average of 1200 calories (kcals) per day – in other words, they were virtually starving.
As long has they had stored fat to burn, I presume that this was reasonably tolerable – but
if the study had gone on much longer, the participants would have started to lose lean
mass and would not have been happy campers! Despite the fact that they were getting
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64% of their calories from animal products, the wild game they were eating was so low in
fat that their total diet derived only 13% of its calories from fat – even Pritikin would
have been impressed! They were eating over a pound of flesh daily – and yet starving.
Good luck finding any farm flesh even approximately that lean in a supermarket – the
grain-fed farm animals you’ll find there have severalfold higher fat content. The
“leanest” beef is about 29% fat calories, and skinless white meat poultry about 23%. The
only flesh you’ll find that is paleolithically lean is wild fish. So unless you choose
pescovegetarianism, high flesh diets will be high fat diets – or at least higher in fat than is
optimal for insulin sensitivity.
There are also important political and ecological issues to address. Hunting and
gathering made a fair amount of sense as a lifestyle when there were no more than a few
million humans on the entire earth to share the wild game. It makes no sense whatever
when the human population – thanks to agriculture – has swollen to multiple billions. As
matters stand now, humans devote substantially more arable land to grazing livestock,
and to growing the feed for livestock, than they do to raising crops for human
consumption - in a world where millions of children starve to death every year!
Furthermore, the demand for land to graze cattle and other livestock is one of the chief
factors driving the progressive destruction of the world’s rain forests. One can just
imagine the consequences if pampered, rich Americans decided to give up grain products
and increase their flesh consumption severalfold!
Thus, while many aspects of the diets practiced by our paleolithic forebears may have
favorable health consequences and are worthy of emulation, the notion that modern man
should give up grains and get a high proportion of his daily calories from low-fat flesh
foods – not as a temporary strategy to achieve weight loss, but as a continuing lifestyle –
is impractical and, moreover, socially irresponsible. Furthermore, what would be the
consequences for long-term bone health of a diet so high in protein? Eskimos, whose
traditional diets are quite high in protein (and only rendered practical by the fact that they
consume large amounts of blubber), are noted for a very high incidence of early-onset
osteoporosis.1004
Paleolithic Vegans
A very different – and, to my mind , much more commendable – way of emulating our
Paleolithic forebears is to eat a vegan diet that features fruits, vegetables, tubers, and nuts,
and omits grains and legumes (which became part of our diet during the agricultural era).
A popular variant of this is the raw-food vegan diet; this likewise excludes grains and
legumes, which aren’t edible unless cooked. Diets of this type are exceptionally rich in
micronutrients and phytochemicals. They tend to be rather high in fat (as nuts are the
only really concentrated sources of calories in such diets), but any negative effects in this
regard on insulin sensitivity or body fat would likely be mitigated by the fact that such
diets tend to be of low caloric density overall. Indeed, overweight people typically lose
large amounts of weight on such diets.1005 Not surprisingly, IGF-I levels tend to be low
in raw-food vegans, as they are in other vegans.1006 A potential disadvantage of raw food
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diets to people who are highly physically active – and thus have high caloric
requirements – is that an inordinate amount of time would have to be spent in eating! So
I am not likely to abandon my whole grains and beans any time soon – but I will
acknowledge that the Paleolithic vegan strategy is likely to have a very favorable impact
on health (assuming that B12 is supplemented), and is compatible with a healthy planet
and a well-fed human species – so Paleolithic vegans have my blessing.
A Word on Alcohol
Although I didn’t include a mention of alcohol in the “6 dietary commandments” that
begin this essay, I was tempted to do so. It seems that every other week there is another
story about a new health benefit related to moderate alcohol consumption. (By moderate
I mean, in women, 1 drink daily and maximally 2; in men 1-2 drinks daily, maximally 3.
Note that women are more sensitive both to the beneficial and harmful effects of alcohol,
owing to the fact that they usually have lower body mass, and moreover tend to absorb
alcohol more efficiently; in men, a significant proportion of ingested alcohol is
metabolized by the stomach lining before it can reach the bloodstream.)
Studies suggest that regular moderate use of alcohol reduces risk for heart attack, stroke,
diabetes, osteoporosis, and – in women, though not men – weight gain and obesity.1007,
1008, 1008-1010
Moderate drinkers tend to be much more insulin sensitive than non-drinkers,
suggesting that alcohol somehow promotes the insulin sensitivity of muscle.1010-1013 The
ability of alcohol to increase protective HDL cholesterol has long been known. More
recent studies show that transient exposure of vascular endothelial cells to physiological
levels of alcohol greatly improves their ability to break down blood clots;1014-1016 “acute
phase” risk factors (such as C-reactive protein) are lower in moderate drinkers.1017 The
ability of alcohol to prevent heart attack appears to be especially dramatic in diabetics: in
a couple of recent reports, risk of heart attack was 60-80% lower in diabetics who drank
moderately!1018-1020
An insulin-sensitizing effect of alcohol may perhaps explain another intriguing and
surprisingly little known impact of moderate alcohol consumption – preventing weight
gain in women.1010 Analysis of data from the Nurses’ Health Study revealed that, at any
given height, women who drank moderately were, on average, 15% lighter than
teetotalers – despite the fact that they consumed slightly more calories!1021 Similar, in a
large British study, women who drank regularly were only half as likely to be obese as
non-drinkers.1022 One recent study suggests that moderate alcohol consumption is at least
as effective as regular exercise in preventing weight gain in women.1023 The analogous
observation in men is that men drinkers consume substantially more calories, and yet are
no heavier than men who don’t drink.1024 These strange observations are known as “the
alcohol paradox”, and have not yet received an adequate explanation. I suspect that
decreased daily insulin secretion in drinkers may play a role in mediating this effect.1010
This phenomenon is of much more than just cosmetic interest – it no doubt contributes to
the marked reduction of diabetes risk in women drinkers.1025 It is ironic that the impact of
alcohol on weight gain in women appears to be considerably greater than than of
smoking1021 – and yet many teenage girls now take up smoking to keep their weight
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down! Fortunately, 1-2 drinks daily appear to optimize this impact of alcohol, so there is
no need to resort to alcoholism.
There of course are some drawbacks. Even moderate alcohol use appears to be
associated with a very modest increase in risk for both breast and colon cancer.1026, 1027
More recent careful analyses suggest that this increased risk is seen only in people whose
folic acid nutrition is mediocre, giving rise to the hypothesis that alcohol increases the
risk of these cancers by interfering with folic acid metabolism; if this is the case, then
supplemental folate should eliminate this risk in moderate drinkers.1028-1032 In one study,
the lowest rate of breast cancer was seen in regular moderate drinkers who had excellent
folic acid status.1028 At more abusive levels of intake, alcohol – especially in the high
concentrations found in hard liquor – is associated with increased risk for esophageal
cancer, and can potentiate the ability of smoking to induce head and neck cancer. Frank
alcoholics are of course at high risk for liver failure and disorders of the pancreas, heart,
and other tissues. Thus, the relationship between alcohol intake and mortality is a Ushaped curve – for best health, you need just enough, but not too much.
We shouldn’t lose sight of the fact that beer and wine are whole foods which provide
nutrients and well as protective phytochemicals. Although resveratrol and other
polyphenols in wine come in for special attention,1008 the phytochemical content of beer
is not negligible, as it reflects the flavonoid content of the whole grains from which it is
manufactured.1033 I have a less charitable attitude toward distilled hard liquors, which I
consider refined foods analogous to refined sugars. Furthermore, hard liquors make it
easier to grossly overconsume ethanol (the kids who occasionally die of acute ethanol
poisoning at frat parties were not drinking beer!), and the high concentration of ethanol in
these products has greater potential to damage the upper digestive tract and promote
cancer. Nonetheless, the chief protective component of alcoholic beverages (in
moderation) is clearly ethanol per se. .
Most physicians and health experts appear to be loath to recommend alcohol; they
obviously don’t want to cause new cases of alcoholism, but I have a suspicion that they
are also often are afflicted by an excessive puritanism or a fear of lawsuits. The fact of
the matter is, most adults already have enough experience with alcohol to know whether
they can control it – or whether it controls them. If you are the type of person who can’t
have one drink without having six drinks – or if you’ve never used alcohol and have a
family history of alcoholism - then you had better stay away from alcohol altogether. But
if you know that you can handle alcohol, then in my opinion you’re missing a big
opportunity to protect your health if you don’t drink moderate amounts of alcohol on a
regular basis. The health benefits are too great and too versatile to pass up!
I have a personal anecdote that may be of interest. Back in the 1950s, my grandmother,
then in her fifties, had a serious heart attack. Her doctors were of the opinion that she
would be lucky to live another year. But her folksy Texas family physician had one
simple prescription: “Mrs. McCarty, every day I want you to drink three shots of alcohol.
Alcohol is a blood thinner.” I can testify by first-hand experience that she was faithful to
this prescription – and she lived another 30 years! (And the latest research on alcohol
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and endothelial cells shows that – alcohol is a blood thinner. Never underestimate the
wisdom of folksy Texas physicians.)
Health Benefits of Coffee
Another common drink worthy of comment is coffee. The “mental energizing” impact of
this beverage reflects the fact that, in physiological concentrations, caffeine can inhibit
brain receptors for the hormone-like compound adenosine. However, adenosine
receptors influence the function of cells throughout the body. In particular, they appear
to have a pro-inflammatory impact in various neurodegenerative disorders,1034-1038 and
also play a mediating role in the fibrotic response (leading to cirrhosis, liver failure, and
increased risk for liver cancer) that often complicates chronic hepatic disorders such as
hepatitis, fatty liver, or alcoholism.1039, 1040 This probably explains why recent studies
show that people who make heavy use of (caffeinated) coffee are at decidedly lower risk
for Parkinson’s disease, Alzheimer’s disease, cirrhosis, and hepatic cancer.1041-1050 In
particular, a Finnish study found that people who drank 3-5 cups of coffee daily during
midlife were over 60% less likely to develop dementia in later life than coffee nondrinkers.1050 Given the high prevalence and devastating impact of dementia among the
elderly, this finding – which is roughly consistent with that of previous smaller
studies1047, 1048 – is of extraordinary practical importance if borne out in future research.
Moreover, heavy users of coffee – caffeinated or decaffeinated - enjoy a much lower risk
for type 2 diabetes; men who drink about 6 cups a day appear to decrease their risk by
about 50%!1051-1053 Obviously, something in coffee beans other than caffeine is
responsible for this benefit. Suspicion now centers on chlorogenic acid; there is
fragmentary evidence that this compound can slow the absorption of ingested
carbohydrate and also boost intestinal production of a hormone that promotes the proper
function of pancreatic beta cells.1054-1056 Regardless of the mechanism involved, there is
no serious doubt that heavy use of coffee lowers diabetes risk.
Like beer and wine, coffee is rich in phytochemicals, some of which may have protective
potential. In particular, the compounds cafestol and kahweol can act as phase 2 inducers,
promoting the detoxification of certain carcinogens.1057, 1058 Perhaps this explains the
trend toward a modest reduction in risk for colorectal cancer observed in coffee
drinkers.1059
In people who haven’t ingested caffeine in the recent past, caffeine typically raises the
heart rate and the blood pressure. This has encouraged the common presumption that
caffeine usage should increase risk for heart attack or vascular disorders. But, in fact, the
acute cardiovascular response to caffeine tends to wear off over time in people who
ingest it regularly; in fact, after several weeks of steady use, caffeine usually fails to raise
heart rate or blood pressure.1060 That presumably explains why long-term use of
caffeinated beverages has been found to have little impact on cardiovascular risk.1061, 1062
There is also concern that coffee and other caffeinated beverages may have an adverse
effect on calcium absorption and bone density. In fact, the negative impact of caffeine on
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calcium absorption appears to be quite modest, and unlikely to be of physiological
significance in people who achieve the recommended intake of calcium.1063 Many
studies fail to observe any impact of coffee drinking habits on bone density or fracture
risk,1064-1068 and some studies which do find an effect conclude that it is only significant
in those whose calcium intakes are low.1069, 1070 So including calcium in your daily
supplementation program – which in any case is appropriate if you are concerned about
your bone health – would likely alleviate any potential adverse impact of coffee intake on
your bone density.
So heavy regular use of coffee can be expected to decrease our risk for type 2 diabetes,
hepatic fibrosis or cancer, and some common devastating neurodegenerative disorders –
without however increasing cardiovascular risk. And its favorable impact on alertness
may modestly improve intellectual performance. Unless caffeinated coffee unduly
impairs your capacity to get restful sleep, or makes you too anxious, enjoying it regularly
and frequently – 3 cups or more daily - may be a smart idea.
Tea, although not as potent a source as coffee, also supplies caffeine. Green tea has
occasioned particular interest owing to its high content of catechin polyphenols – most
notably EGCG – that can act as phase II inducers and prevent carcinogen-induced
cancers in rodents.1071-1073 Epidemiological studies suggest that regular drinkers of green
tea may be at lower risk for certain cancers, notably those of the breast, lung, and
prostate.1074-1078
These considerations thus suggest that ample intakes of coffee and green tea, coupled
with moderate regular use of wine or beer, can confer a diverse array of health benefits.
Also recommendable are (unsalted or lightly-salted) fruit or vegetable juices, as these are
excellent sources of potassium and antioxidant phytochemicals;1079, 1080 one intriguing
recent study reports a markedly lower risk for Alzheimer’s disease in JapaneseAmericans who drink juices regularly.1081 Although it may be preferable to eat fruits and
vegetables in their whole fiber-rich form, juicing makes it more convenient to achieve a
high volume of fruit/vegetable consumption. We have also cited the vascular protection
afforded by raw cocoa – albeit the commercial cocoa preparations currently available
tend to be low in protective flavanols.
Ancillary Strategies: Exercise/Supplementation/Early Detection
Choosing the proper foods certainly isn’t the only measure you’ll want to adopt to
preserve your health. Regular exercise – both aerobic and resistance – is astonishingly
versatile in the health protection it affords. In fact, almost all of the prominent
pathologies we have discussed are susceptible to prevention or control, at least to some
degree, by regular exercise. That includes coronary disease, obesity, diabetes,
hypertension, stroke, dementia, osteoporosis, and many prominent types of cancer.1082
Preferentially, your aerobic exercise should be done in a way that selectively burns body
fat (as discussed above – see the Appendix on the NutriGuard Learn to Burn Leanness
Program) so that you will get the best benefits with respect to weight control and insulin
sensitivity. And low-impact exercise is highly advisable if you plan – as you should – to
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still be exercising in your nineties. With respect to resistance training, there is growing
evidence that this can promote glucose tolerance and insulin sensitivity, just as aerobic
activity can.1083-1087 In the elderly, resistance exercise can have a really outstanding
impact both on strength and muscle mass.1088-1091 (The elderly often lose substantial
amounts of lean mass – this is known as “sarcopenia”, and it impairs insulin sensitivity,
control of body fat, and of course physical capacity.)1092, 1093 Arguably, resistance
training is much more important for 70-year-olds than for 20-year-olds - though you’d be
hard-pressed to guess this when you visit your local gym! Dr. William Evans, a pioneer
in this field, aptly remarks that “there is no pharmacological intervention that holds a
greater promise of improving health and promoting independence in the elderly than does
exercise.”1088
With respect to supplementation, I maintain that it is rather ridiculous for us to expect
that any natural diet, no matter how carefully and insightfully planned, can provide the
optimally health-protective amounts of all essential and non-essential nutrients,
phytochemicals, and food factors. For a few nutrients, optimal intakes simply cannot be
feasibly or reliably achieved from natural diets – vitamin D, for an example. For others,
while it may be possible to obtain an appropriate intake from natural foods, it may be a
bit rash to assume that your dietary choices invariably supply this amount – particularly
since the content and availability of soil minerals varies widely, and since our foods are
not always prepared in a way that best preserves nutrient content. And, as Dr. Roger
Williams liked to stress, biochemical individuality implies that, owing to genetic quirks
influencing absorption or transport, you may need a bit more of a certain nutrient than
other people might. With respect to protective phytochemicals, it really isn’t realistic to
expect that we will eat enough broccoli, tomatoes, spinach, green tea, etc. to insure a
consistently high intake of the key phytochemicals they provide – supplementation can
insure this consistency while increasing your total intake of these protective factors. For
all of these reasons, I maintain that a rational supplementation program should be a key
component of a health-protective lifestyle. If you want to maximize your chances for a
long, vigorous, healthy life, you need to eat right, exercise right – and supplement
right!
The foundation of your supplementation program should be a good “nutrition insurance
formula”, which provides at least adequate daily amounts of the essential vitamins and
minerals.1094 (A proviso is that, since excess iron stores may pose a health risk, it may be
wise to choose an iron-free supplement unless you are at risk for iron deficiency.) The
common one-per-day vitamin-mineral pill which many Americans take is an example of
such a formula. More elaborate multiple-tablet formulations can provide higher intakes
of certain crucial vitamins and minerals. It is appropriate to complement such a formula
with additional supplements providing protective nutrients and phytochemicals not
standardly provided in insurance formulas
Arguably, a low-fat, whole-food vegan diet gives you an excellent chance to achieve
ample intakes of most micronutrients – a much better chance than you would have with
the fatty, over-refined foods consumed by most Americans. Nonetheless, as we have
noted, a vegan diet is devoid of vitamin B12 and vitamin D, and possibly sub-optimal in
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calcium – nutrients which are readily supplied by an insurance formula. Since such a diet
lacks the long-chain omega-3 fats found in fish, an enriched fish oil supplement is
advisable for vegans. In regions of the world where soil selenium is low (such as in
many parts of Europe), a vegan diet tends to be a poorer source of this crucial nutrient
than omnivore diets are1095 – so vegans would be wise to obtain selenium from
supplements. A further consideration is that diets high in fiber and low in fat often do not
promote optimal absorption of certain minerals and fat-soluble nutrients – nutritional
supplementation can compensate for this problem.
(Lest I be accused of hypocrisy for questioning the ecological practicality of high-flesh
diets while recommending that everyone use fish oil omega-3s, I will note that it should
be technically feasible to derive these protective oils from unicellular sources – after all,
the omega-3 fats in fish derive ultimately from marine algae.1096 In fact, a commercial
source of unicellular DHA is currently available – although it is more expensive than fish
oil omega-3; perhaps further technical advances will make unicellular omega-3 a
practical alternative. Terrestrial sources of omega-3 should also be considered; although
the alpha-linolenic acid found bountifully in flaxseed has limited health benefit compared
to the longer-chain omega-3s found in fish oil, its metabolite stearidonic acid appears to
share many of the protective properties of fish oil,1097-1100 and is produced by a wild weed
known as Echium.1101 Theoretically, flax itself could produce ample amounts of
stearidonic acid if it were genetically modified to express the enzyme delta-6-desaturase,
the catalyst for the conversion of alpha-linolenic acid to stearidonic acid. Ecologicallyaware scientists should devote much further attention to these issues.)
Certain nutrients, supplied by many animal-derived foods but not plant products, play
physiologically-essential vitamin-like cofactor roles in metabolism, but are not
considered nutritionally essential since our own bodies can make them. Nonetheless,
tissue levels of these nutrients tend to be higher in omnivores than in vegetarians. These
nutrients, which have been dubbed “carninutrients”, include carnitine, creatine, and
taurine.1102 Sub-optimal taurine status may be responsible for the fact that the platelets
(clotting cells) of vegetarians tend to aggregate (clot) more readily than those of
omnivores – one of the few respects in which vegetarians don’t have an edge when it
comes to vascular health.1102 Since creatine promotes strength and neuroprotection,
carnitine is a catalyst for fat burning, and taurine has anti-inflammatory/antioxidant
effects, carninutrient supplementation may be appropriate for vegans who wish to
optimize their health and physiological capacities.
Recently, Oasis of Hope Hospital has developed a cutting-edge program of functional
foods and nutraceutical supplements intended to promote optimal health, and
emphasizing a comprehensive strategy known as “full-spectrum antioxidant therapy”.
This regimen, which includes ample intakes of spirulina and flavanol-rich cocoa powder,
is described in the new monograph The Oasis Executive Health Program - please refer to
this treatise for my current views regarding the potential benefits of supplemental
nutrition. The strategies suggested in this new book are completely consistent with the
dietary advice provided here. For more comprehensive information on nutritional
supplements, I refer the interested reader to what is now arguably the most credible and
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encyclopedic source of information on supplemental nutrition, the Physician’s Desk
Reference on Nutritional Supplements by Dr. Sheldon Hendler, now in its second edition.
Dr. Hendler is a remarkably diligent and insightful biomedical scholar whose analyses of
the nutrition literature are both scientifically critical and yet highly appreciative of the
health-protective potential of supplemental nutrition. (And I’d say these nice things
about him even if he weren’t a longtime close friend!)
Finally, you should be aware that, no matter how carefully you plan your lifestyle, there
is nothing that you can do (short of dying!) that will provide you with absolute protection
from cancer. We are all gradually accumulating mutations in our body’s cells, and, if we
live long enough, sooner or later an errant cell will survive to generate a cancer. (In this
respect, cancer can be differentiated from certain other disorders – such as coronary
disease and type 2 diabetes – which, except perhaps in a few individuals with really
horrible genes, are truly unnecessary in a properly fed population.) Fortunately, some of
the most common types of cancer are often susceptible to early detection, and, if caught
early enough, can often be cured surgically. So follow your doctor’s guidance in regard
to regular screening programs that can detect colon, prostate, breast, and uterine cancer,
and any other screening measures that might be warranted in your case.
There has been some consternation in the macrobiotic vegan community occasioned by
the fact that macrobiotics do in fact sometimes develop cancer; perhaps their guru had
left the impression that such a diet confers mystical protective powers – rather like the
“impenetrable shield” that certain toothpastes were alleged to provide in bygone TV
advertising. In fact, the best that any diet and lifestyle can hope to do is postpone the
onset of a major cancer (and even then, some unfortunates will experience cancer at a
relatively early age). The hope is that you can postpone your date with cancer to such an
advanced age that something else will almost certainly get you first; but there are no
guarantees. The key point is: don’t get complacent – avail yourself of your doctor’s
talent for spotting cancer at an early stage when it may still be curable.
Occasional monitoring of vascular or other risk factors is also advisable, just in case your
healthful lifestyle fails to cope adequately with an unfavorable genetic inheritance – or
you are less than completely compliant with your own best intentions. Your doctor can
keep you apprised of your blood pressure, blood sugar, and standard blood fat risk
factors.
Slowing the Aging Process
So far, I have had very little to say about aging per se, although I’ve had much to say
about the diseases that can make old age miserable and short. But rodent studies show
that it is at least theoretically feasible to slow the aging process itself. When rats are fed
30-40% fewer calories than they ordinarily would eat by choice, both their average and
maximal longevity increases. An increase in average longevity is not necessarily a major
achievement – preventing or slowing the onset of certain diseases can achieve that. But if
humans had a magic pill that – say – prevented all vascular disease and cancer, the
chances of their living beyond 120 years of age would still be negligible; in effect, 120 is
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the maximal lifespan of humans. As we pass the century mark, we simply become too
physiologically frail in too many ways to last much longer. So we won’t get past the 120
barrier unless we find a way to slow the aging process itself – which is what caloric
restriction does in rodents. At any given advanced age, calorically restricted rats are
simply more physiologically youthful – smarter, leaner, more active, more capable of
fending off infections – than rats of comparable age who have been “pigging out” all
their lives. The aging process, in which the maximal physiological capacity of the body’s
organs gradually but inexorably declines, is literally in slow motion in rats that are
underfed.
The catch is that underfed rats are hungry rats – and few humans would conciously
choose to go hungry all their lives, or would be capable of abstaining when ample food is
available. So caloric restriction is not likely to have much practical utility for slowing
human aging.
However, certain genetic mutations have also been shown to increase lifespan in mice –
by up to 60% - and these mutant mice may help us both to better understand how caloric
restriction promotes longevity, and how humans might practically prolong their lifespans.
These long-lived mutant mice are all characterized by reduced growth hormone (GH)
activity. In some of these strains, the pituitary’s production of GH is greatly
diminished;1103-1105 in another strain, the GH receptor doesn’t function right.1106, 1107 The
result, in all cases, is that the liver makes very subnormal amounts of our old friend IGFI. And perhaps you will recall that IGF-I activity is also substantially diminished by
caloric restriction.1108
There is another dietary trick that you can play on rodents to increase their lifespans –
feed them diets that are low in one specific essential amino acids. Feeding rats diets that
are low in either methionine or tryptophan, while allowing them as many calories as they
want, increases their maximal lifespan.1109-1112 Of course, a diet that is low in one or
more essential amino acids can markedly decrease the liver’s production of IGF-I.466
Vegan diets of moderate protein content tend to be rather low in methionine; perhaps a
methionine-restricted vegan diet may represent a practical strategy for modest life
prolongation in humans.1113
Another strategy which delays aging in rodents – and protects the brain from neurotoxins
– is alternate-day fasting, which has proved protective even when total calorie intake
doesn’t fall owing to compensatory overconsumption on feeding days.1114, 1115 It has
been suggested that the “mini-fast with exercise” strategy, recommended for weight
control,213, 215 might represent a practical avenue for achieving such protection in
humans.1116 Alternate-day caloric restriction is also being studied as a potentially
feasible life-extension techhique.1117-1119
Could IGF-I be a crucial pacesetter for the aging process? Breeds of dogs and strains of
rats have characteristic longevities that differ a good deal. In general, the larger the breed
of dog, the shorter its lifespan; the same thing holds for rat strains.1120-1123 Not
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surprisingly, the IGF-I levels of dog breeds or or rat strains tend to correlate directly with
their adult weight.1124, 1125 In other words, the lower the IGF-I level, the longer the
lifespan – precisely what one would expect if IGF-I regulates the pace of aging.
Although comparable findings aren’t yet available in humans, epidemiological analyses
do suggest that, barring malnutrition, people who are shorter and lighter tend to outlive
people who are taller and heavier.1126, 1127 And people who are taller and heavier tend to
have higher levels and/or activity of IGF-I – that’s why they are tall and heavy. I recall
hearing that the average lifespan of massive NFL players is about 55 years – I’m not sure
how accurate this is, but it doesn’t surprise me. So the take-home lesson is this: while the
large hunks may get the babes, skinny little wimps live longer!
A growing number of scientists who specialize in aging – gerontologists – are coming
around to the view that IGF-I activity may indeed be a determinant of the rate of the
aging process.1128-1131 In the section on breast cancer, we saw that IGF-I is a key signal
for the onset of sexual maturity in teenagers – which explains why girls usually don’t get
their periods until age 17 in rural quasi-vegan societies, while the overfed young ladies in
this country often reach that milestone by age 12! In effect, IGF-I is signalling that
enough calories, and protein and stored fat are available to support a healthy pregnancy.
If IGF-I has such a crucial role in regulating this important developmental milestone,
isn’t it reasonable to suspect that it could play a comparable role later in life?
We have already discussed how a low-fat, low-glycemic index vegan diet can lower
your risk for cancer and inflammatory disorders by keeping IGF-I activity relatively low.
It may well be that this strategy also modestly retards the aging process. Ancillary
strategies which can lower daily insulin secretion – such as exercise training,
supplemental chromium, or taking vinegar or glucomannan with meals – or that decrease
the liver’s production of IGF-I – such as flax lignans or oral estrogen replacement – may
have complementary value in this regard. With the exception of estrogen’s adverse
impact on risk for estrogen-responsive tumors, these measures are all commendable from
the standpoint of preventing major diseases. Wouldn’t it be a wonderful bonus if they
also retarded the aging process?
To better explain what I mean by slowing aging, let’s pretend that you have an identical
twin. Let’s further assume that you elect to follow a low-fat, whole-food vegan diet for
most or all of your life, and to avail yourself of exercise and other healthful measures that
keep IGF-I activity relatively low, whereas your twin becomes a slothful omnivore who
has a real prediliction for double cheeseburgers. And let’s assume that, despite your
twin’s questionable health habits, you both manage to make it to age 80 without
experiencing any major diseases. At that time, I predict that you would be leaner, more
mentally agile, more physically spry, and possibly even younger looking than your twin –
even though you were both putatively healthy. Of course, the greater likelihood is that,
by age 80, your twin’s physical status would have been compromised not only by the
aging process, but also by vascular disease or possibly cancer – if your twin were still
alive at all!
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So, if you want to be able to really enjoy life at 80, or 90, or even 100, a low IGF-I
lifestyle may be just what the doctor ordered!
Compressing Morbidity
There is not, and will never be, a diet that can repeal mortality. Which is a good thing –
we have a moral obligation to “shuffle off this moral coil” so that future generations will
have room!
In the preceding discussion, I have attempted to show that it should be theoretically
feasible, by lifelong use of an optimally health-protective diet, assisted at times by
various ancillary strategies, to virtually totally prevent coronary disease, obesity,
diabetes, hypertension, stroke, and possibly even senile dementia, and to substantially
postpone the onset of (if not outright prevent) most of the prominent types of cancer.
Under these circumstances, infection and trauma would likely become the chief causes of
death.
Such is the case in Kitava, where there is essentially no vascular disease or diabetes, and
apparently very little cancer. Infection and trauma cause most deaths; in some extremely
elderly people, death comes for no apparent reason (an arrhythmia in a worn-out heart?)
While Dr. Lindeberg was visiting Kitava, the only fatality was a 70-year-old man who
fell out of a palm tree! (Take-home lesson: do not climb trees after age 70. In further
illustration of which: noted vegan George Bernard Shaw died at age 94 – razor-sharp
until the end - after falling out of an apple tree he had climbed in pursuit of apples!)
If an aged person dies of infection or trauma (or dies in his sleep for no discernible
reason), he will probably do so fairly quickly. In other words, unless there are other
illnesses that precipitated the infection or trauma, he won’t be in the hospital or on
elaborate therapies for months or years prior to his death. If he has avoided vascular
disease and dementia, and kept his bones and joints in reasonably decent shape, chances
are that he will remain reasonably independent and mentally and physically active up
until his death. In other words, old age won’t be the chamber of horrors that it all too
often proves to be for less fortunate people. This strategy of remaining reasonably
healthy to a ripe old age and then dying quickly of infection, trauma, or “old age”, is
known as “compression of morbidity”. This is the type of life – and death – that sane
people should wish for. I maintain that by eating right, exercising right, supplementing
right, and taking advantage of your doctor’s ability to detect some illnesses at an early
curable stage, you have a reasonably good chance to achieve this outcome, using foods,
nutrients, and other resources that are available now.
Consider the alternatives: Being a cardiac cripple for years, unable to function normally,
repeatedly requiring surgery, and in constant fear of “the big one”. Suffering strokes that
leave you physically or mentally impaired – perhaps barely able to talk – during your last
sad years of life. Becoming demented and spending years totally dependent, while your
loved ones suffer emotional havoc and ruinous expense, or have to devote their lives to
your care. Developing cancer and fighting it for years with the trauma of chemotherapy,
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surgery, or radiation, until the cancer progresses and your body wastes away while you
cope with chronic pain. Becoming diabetic and eventually going blind, or needing
regular kidney dialysis, or suffering constant nerve pain, or requiring a below-kneeamputation because your leg circulation is shutting down and you’ve developed gangrene
– all as a prelude to your premature and ultimately fatal heart disease.
Have I convinced you that staying healthy is very, very smart?!
Striving to compress your morbidity is also patriotic. With medical costs continuing to
sky-rocket, particularly in the U.S., the growing number of elderly Americans who
require several decades of medical care for chronic metabolic ailments are imposing a
near-intolerable financial burden on our society – a burden that is likely only to get larger
and larger. Arguably, doing whatever you can to stay healthy for as long as you can is a
lot more meaningfully patriotic that waving a flag. (Furthermore, as we’ll discuss below,
choosing a vegan diet can also benefit our planet’s ecology, help to conserve finite
resources, and help alleviate world hunger. It’s the way to be a “global patriot”!)
An Overview of Dietary Options
Of course, people who are attempting to learn how to stay healthy may be hard-pressed to
retain their sanity amid the welter of mutually-contradictory dietary advice that the media
dish out. One day we are told that a high-carbohydraate, low-fat diet is the key to
cardiovascular health – the next, we are told that monounsaturated fat is the real key, and
that carbohydrates can be bad for you. Then the advocates of high-protein diets weigh in
with their advice – which is promptly denounced by both the olive oil advocates and the
Pritikinists. Meanwhile, the conventional wisdom that people should cut back on salt is
confounded by breathless media reports that low-salt diets may increase risk for heart
attack – which are swept back under the rug when the latest DASH study confirms the
utility of salt restriction for controlling blood pressure. What next? Is it any wonder that
a high proportion of Americans now state that they are sick of all this dietary advice, and
plan to eat whatever they like?
Part of the purpose of this essay has been to put these contending views in perspective.
By and large, the scientific advocates of these seemingly irreconcilable views are
honorable, intelligent scientists who can cite some rational arguments in support of their
positions. And, as contrasted to the self-destructive diets currently being practiced by
most Americans – or even the half-bright recommendations of American Heart
Association - the low-fat whole-food vegan, the high-monounsaturate, and the highprotein approaches all can produce demonstrable benefits. And a large part of the reason
for this is that all of these regimens lower daily insulin secretion. Which suggests to me
that keeping insulin secretion low must have major merit as a health strategy.
If you can keep insulin secretion low while simultaneously minimizing fat intake, you are
likely to achieve greater leanness and better insulin sensitivity. If you can keep insulin
secretion low while avoiding animal protein, you are likely to reduce your cancer risk. In
a nutshell, that’s why I prefer the very-low-fat vegan approach. Furthermore, the fact
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that much of the Third World has been – at least until lately – following a diet of this sort
gives us some very direct insight into its likely health consequences. In these cultures,
coronary disease, obesity, and diabetes are virtually absent, while the incidence of
“western” cancers and of many autoimmune disorders is substantially reduced. In those
cultures that, in addition, avoid salt, hypertension, stroke, and possibly even dementia are
rare. While high-monounsaturate and high-protein approaches may indeed have some
health advantages relative to current American diets, there is simply no reason to believe
that they could confer the full range of health benefits enjoyed by quasi-vegan cultures.
Thus, although I respect the many scientists who advocate alternative views, the low-fat
whole-food vegan strategy seems the most protective overall and is my current choice.
The burden of proof is on those who advocate high protein or high monounsaturate
intakes to demonstrate that their approaches have comparably versatile protective
activity. Nonetheless, I intend to keep an open mind on this issue and take careful note of
future relevant research. One thing that should be quite clear is that the impact of dietary
choices on health can be incredibly complex, and no one yet has all the answers!
All the same, I’m confident that your health will be well served by following the
recommendations offered above, even if future research proves them to be less than ideal
in some respects. As compared to the salty, fatty, high-glycemic-index omnivore diet
that most Americans now ingest, the diet which I recommend will doubtless give you a
far better chance to achieve a ripe old age in vigorous good health.
The Ecological and Ethical Consequences of Omnivore Diets
The intent of this book has been to define dietary patterns that are most conducive to your
own long-term health. In other words, I’ve focussed on showing you where your selfinterest lies; whether you choose to accept this advice, or anyone else’s advice, to protect
your own health, is – and by rights should be - entirely your own decision.
However, now that there are 6 billion other people inhabiting the planet, your food
choices also have ecological and ethical ramifications that are potentially profound - your
own health is by no means the only consideration at stake. The Western practice of
including animal products in nearly every meal – now being emulated by the emerging
middle classes throughout Asia and elsewhere – is incredibly wasteful of our limited
resources of fossil fuels, fresh water, and arable land. It is the chief factor behind the
progressive destruction of the world’s rain forests and the remarkably diverse species
which they shelter. It is directly responsible for the rape of our oceans, now being
overfished to the point of ecological devastation. The high energy cost of producing farm
animals contributes importantly to the carbon dioxide pollution that drives global
warming – and the methane produced by ruminant livestock (most notably cattle) also
makes a significant contribution in this regard. The massive quantities of waste
generated by modern factory farms represent a continual threat to the health and purity of
our rivers and water supplies. Overgrazing by ruminant livestock is stripping bare much
of the world’s grasslands – and the wildlife indigenous to these areas are often purposely
slaughtered, as they are viewed as threats to cattle (or, more bluntly, the profits of
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cattlemen). But, perhaps most importantly, a progressively higher percentage of the
world’s arable land is being devoted to growing crops intended to feed farm animals – at
a time when hunger-related disease kills approximately 25,000 children per day
worldwide. This situation is now being exacerbated by the fact that newly emerging
middle classes in China and India are choosing to emulate Westerners in their high
consumption of flesh foods – and by growing use of arable land for biofuels production.
This situation recently has triggered major jumps in grain prices that have led to food
riots and increased starvation throughout the Third World. In effect, livestock breeders
are now outbidding poor humans for the available grain supply. The dollars that you elect
to spend on hamburgers, steaks, fried chicken, eggs, and dairy products set in motion
economic forces which effectively insure that a higher and higher proportion of the
world’s poor will suffer from chronic malnutrition – or outright starvation.
If you’d like to read a devastating critique of the ecological and ethical consequences of
our omnivore diet, you can’t do better than to read Part III of John Robbins’ important
new book, The Food Revolution. Let me cite just a few of the eye-opening statistics
which the author has compiled: According to specialists at the University of California
Agriculture Extension, it takes 25 gallons of water to raise a pound of wheat, 49 gallons
to raise a pound of apples, and 5,214 gallons to raise a pound of beef; Robbins drives this
point home further by calculating that “you’d save more water by not eating a pound of
California beef than you would by not showering for an entire year”. Much of the water
required, directly or indirectly, for livestock production derives from non-renewable
aquifers that are now in danger of depletion – most notably the crucial Ogallala aquifer in
the central U.S.
The livestock industry is also immensely inefficient with respect to fuel consumption.
Producing 1 calorie of protein from soybeans or wheat requires the expenditure of 2-3
calories of fossil fuel – whereas producing a calorie of beef protein requires the use of 54
calories of fuel. The energy-intensity of livestock production entails not only a wastage
of limited energy resources, but also a considerable increase in carbon dioxide
production. The Union of Concerned Scientists has concluded that “the two most
damaging things residents of this country do to our climate are drive vehicles that get
poor gas mileage and eat beef.”
It takes about 12-16 pounds of grain to produce a pound of saleable beef. That’s why
70% of the grain grown in the U.S. is fed to livestock – an amount that would be
sufficient to feed 1.4 billion people. In Russia, 75% of the grain consumed is now
devoted to livestock; in Brazil – where about two-thirds of the population is said to suffer
from malnutrition – the figure is 50%. Over the last couple of decades, the proportion of
domestic grain fed to farm animals has risen from 8% to 26% in China, from 1% to 30%
in Thailand, and from 10% to 36% in Egypt. Many countries which formerly were selfsufficient or grain exporters, are now perilously dependent on grain imports; if U.S. grain
production fell suddenly owing to climactic conditions or aquifer depletion, devastating
worldwide famine could result. Throughout the Third World, the desire to reap greater
profits is motivating landowners to expel peasants from subsistence farms, so that the
land can be devoted to growing crops intended for livestock. Largely as a result, the
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number of landless peasants in Central America has risen fourfold since 1960. I’m not so
naïve as to believe that increased availability of arable land for human food production
would automatically end hunger in the Third World – social justice and control of
explosive polulation growth would also be required – but adequate land availability is a
sine qua non if there is to be any hope of attaining this goal.
Meanwhile, total grain production per capita has fallen worldwide since 1984, owing to
soil depletion and the exhaustion of aquifers – trends markedly accelerated by the
massive demands on crop production imposed by the livestock industry – as well as
continuing human population growth. Increasingly, push is coming to shove – it is
estimated that over 1 billion humans are now chronically malnourished. Indulgence in
animal product-rich diets by the world’s expanding middle class is not an extravagance
that humans can afford at this juncture in history.
Unfortunately, we can’t turn to the oceans for salvation. . The United Nations has
estimated that “11 of the 15 major oceanic fishing grounds had gone into serious decline
as a result of overfishing” – largely a result of sophisticated new trawling methods which
literally strip the oceans bare. Worldwide annually, 16 kg of fish are caught per person –
whereas 200 kg of other marine life netted along with the edible fish are simply
discarded. Half of the world’s fish catch is devoted to the feeding of livestock, and fish
farms are also consuming a growing proportion of this catch.
There are also ethical issues related to the care of farm animals. In the interests of
economic efficiency, a high proportion of the world’s farm animals are now being raised
in “factory farms”. These entail the confinement of animals in incredibly tight holding
pens throughout their entire lives. You can forget about carefree livestock frolicking in
verdant glades – modern “farm” animals often effectively spend their lives in fetid
straightjackets. John Robbins devotes Part II of his book to this grim story – I frankly
don’t have the stomach to read it. Whether or not you have moral qualms about the
slaughter of animals for food – bear in mind that most farm animals would never have
existed at all if it weren’t for human intervention – it is certainly morally indefensible to
raise animals in grossly inhumane circumstances just so that a pork chop will be a bit
cheaper.
So think about these issues next time you hear some pundit holding forth on the alleged
health benefits of high-protein or “paleolithic” diets. And remember that, when you
choose to indulge in a diet rich in animal products, you aren’t just making a private
decision that affects your health - you effectively are voting to starve children, to deplete
our limited water and energy resources, to ravage the planet’s oceans and grasslands, to
accelerate global warming, and to subject farm animals to unspeakable cruelty. Of
course, that wouldn’t be your intent – drunk drivers don’t intend to kill their victims – but
that would be the net consequence of your actions.
But let’s look at the positive side – isn’t it astonishingly fortunate that the type of plantbased diet that is most suited to preserve your longterm health, is also the type of diet that
is most consistent with a healthy environment, preservation of biodiversity, conservation
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of our limited resources, prevention of global warming, and food sufficiency for the
earth’s whole population?!
If you want to be ecologically and ethically responsible but you simply aren’t willing to
go all the way to veganism, then try cutting way back on animal product usage – make
much greater use of beans and soy products – and choose poultry (preferably free-range)
or wild fish rather than beef or other large livestock. Although the raising of chickens
places a far greater burden on limited resources than does growing crops for direct human
consumption, it is a lot less offensive in this regard than the beef industry. And the
poultry industry, while it poses some water pollution issues, at least can’t be blamed for
the destruction of the ecology of much of the American West, or the ongoing loss of
Amazonian rain forests. Above all, try to avoid beef and dairy products. There are about
1 billion cattle on the earth now, and they tend to be better fed than large segments of the
human population!
Finally, a word on the ethical aspects of veganism. People who are unwilling to promote
the death or abusive treatment of animals, are also unlikely to accept war or terrorism as
instruments of political policy. It is no accident that the one avowed vegan member of
the U.S. Congress, Dennis Kucinich, has proposed the formation of a Department of
Peace dedicated to the resolution of disputes, nationally and worldwide, in a non-violent
manner. The great Emperor Ashoka of India, who converted to Buddhism after
experiencing the carnage triggered by his own war of conquest, was noted not only for
espousing vegetarianism and establishing animal hospitals throughout his kingdom, but
also for promoting the concept of “ahimsa” (non-violence), banning the needless killing
of any living being, eliminating slavery, preaching universal religious tolerance and
conversion by rational argument only, working in many ways to promote the welfare of
his subjects and of people in neighboring lands, encouraging the development of herbal
medicine, planting trees throughout his empire, and turning former enemies into wellrespected allies. His era was remembered as a Golden Age in India’s history, and H.G.
Wells commented that, whereas most “exalted majesties” “have shone for a brief
moment, and as quickly disappeared…Ashoka shines and shines brightly like a bright
star, even unto this day.” Clearly, ethical veganism has the potential not only to promote
the welfare of animals, but of all humans as well. (All the more reason why the world
needs a bountiful plant-derived source of stearidonic acid – so that humans can enjoy
optimal omega-3 status without exploiting fish!)1132
For Further Reading
There are a number of well-written, informative books currently available that can give
you further information on the health benefits of diets that are vegan, low in glycemic
index, and/or low in salt. Many of these books provide recipes that, to a greater or lesser
degree, are compatible with the dietary advice I have offered; you can use your own
creativity to modify them when warranted.
There is a growing literature on the health impacts of veganism; I must confess that I
certainly haven’t looked at all of it. If you are looking for biomedical information that is
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both credible and meaty, the best books I’ve found are by Dr. Neal Barnard, who is the
President of the Physicians Committee for Responsible Medicine (PCRM), and a highly
articulate advocate for vegan diets and the ethical treatment of animals. Although he has
written a number of fine books, my personal favorite is Eat Right, Live Longer; a more
concise and more recent book along similar lines is Food for Life: How the New Four
Food Groups Can Save Your Life. His latest work is Dr. Neal Barnard's Program for
Reversing Diabetes: The Scientifically Proven System for Reversing Diabetes without
Drugs. Under Dr. Barnard’s leadership, the PCRM has distinguished itself by
promulgating the new four food groups: fruits, vegetables, legumes, and whole grains.
If you would like to explore the ethical and ecological aspects of veganism, you can’t do
better than the writings of John Robbins. His first book, Diet for a New America, is, by
common consent, the classic work of the American vegan movement; he has followed
that up with The Food Revolution, which provides even deeper insight into the
devastating global consequences of omnivore diets. His latest book, Healthy at 100,
focuses on centenarian cultures to explain how a vegan diet, complemented by regular
physical activity and a positive emotional outlook fostered by respect for the elderly, can
optimize healthspan. Robbins is a fascinating character; heir to the Baskin-Robbins ice
cream fortune, his growing intellectual and ethical conviction that animal-based diets
entail the needless suffering of our fellow creatures and are disastrous for both the
ecology and our health, led him to turn his back on his heritage and become an ardent and
poetic champion of veganism. Although Robbins doesn’t have the formal biomedical
training that some vegan advocates do, his discussion of pertinent scientific evidence is
usually surprisingly credible and scholarly. (However, I must confess that I don’t share
his fashionably negative view of genetic engineering.)
If weight loss is of particular interest to you, Dr. Dean Ornish’s Eat More, Weigh Less
and Dr. Barnard’s more recent Turn off the Fat Genes can give your further insight into
the weight loss benefits of low-fat, whole-food vegan diets. The Pritikin Clinics now
stress the advantages of low-caloric-density whole foods for achieving weight loss, as
outlined in Robert Pritikin’s The Pritikin Principle – The Calorie Density Solution.
If your interest is more focused on heart disease, Dr. Dean Ornish’s Program for
Reversing Heart Disease is an excellent choice. The amazing story of Dr. Caldwell
Esselstyn’s 12-year clinical study with diet-treated heart patients is described in his
Prevent and Reverse Heart Disease. On the diabetes front, Dr. Julian Whitaker, formerly
chief clinician at the Pritikin Clinics, and now director of the Whitaker Wellness Institute,
offers good advice in Reversing Diabetes.
If you would like to learn more about the health impacts of dietary glycemic index and
have access to extensive tabular information about the glycemic indices of specific foods,
your best bet is The Glucose Revolution, by Dr. Thomas Wolever and colleagues. The
authors of this book are highly credible health scientists who have done much of the
formal scientific work establishing the importance of the glycemic index concept. (Note
that many of the recipes in this book are not vegan and are a bit higher in fat or salt than I
would approve.)
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There are only a couple of recent books on health implications of dietary salt. Salt, Diet,
and Health, by British hypertension experts Drs. Graham MacGregor and Hugh
DeWardener, provides the deepest insight into the connection between salted diets and
high blood pressure, and also provides a history of man’s use of salt. The Salt Solution,
by Herb Boynton and colleagues, examines the broader health implications of salted diets
while placing more emphasis on the importance of potassium-rich foods. (Another mea
culpa: I am a co-author of this volume.)
Dr. John McDougall is a vegan practicing physician whose writings reflect the
considerable success he has had in treating heart disease and obesity with a diet-based
approach for over two decades. Although I can’t agree with his rather puritanical views
on alcohol and caffeine, in other respects his practical recommendations are very
concordant with mine. He has authored several worthy books outlining the rationale and
results of his vegan health program, but his greatest contribution may be the cookbooks
he has co-authored with his wife Mary – in particular, The New McDougall Cookbook,
currently available through amazon.com. The recipes have been honed over years of
practical experience, and many are delicious. All of them are vegan, virtually all are
quite low in fat (except for a few sauces to be used sparingly), and salt per se is never
added. High-salt condiments are occasionally called for – such as soy sauce; you can use
reduced-salt soy sauce and, if the total salt intake would still be higher than desirable, you
can cut back the amount or try doing without it. (Remember though that even the
Kitavans get some salt in their diets!) Almost all ingredients used qualify as whole foods,
although they aren’t always structurally intact – for example whole wheat flour, a highinsulin-response food, is used in a few recipes (albeit flours are called for far less
frequently than in the typical American diet). All in all, this is a masterful piece of work
of great practical value, and it is easy to modify some recipes slightly if you want to be
more stringent about salt.
Dr. Colin Campbell’s work – particularly his China Health Project - has had a major
impact on my thinking and on that of the vegan movement. He describes this project –
and its provocative practical conclusions - in his outstanding new book, The China Study:
Startling Implications for Diet, Weight Loss, and Long-term Health.
Dr. Ornish has also made a signal contribution to our understanding of the central role
which emotions play in health – see his book Survival and Love for a survey of the
relevant scientific literature on this often neglected topic. Negative emotions appear to
increase risk, in some cases quite markedly, for a wide range of adverse health outcomes.
Dr. Ornish has pioneered the inclusion of stress management techniques in the treatment
of heart disease and cancer.
I apologize to other worthy authors whose relevant works may have escaped my fallible
attention.
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References
(1) Foster-Powell K, Miller JB. International tables of glycemic index. Am J Clin Nutr 1995
October;62(4):871S-90S.
(2) Rosenthal MB, Barnard RJ, Rose DP, Inkeles S, Hall J, Pritikin N. Effects of a highcomplex-carbohydrate, low-fat, low-cholesterol diet on levels of serum lipids and
estradiol. Am J Med 1985 January;78(1):23-7.
(3) Barnard RJ. Effects of life-style modification on serum lipids. Arch Intern Med 1991
July;151(7):1389-94.
(4) Barnard RJ, Ugianskis EJ, Martin DA, Inkeles SB. Role of diet and exercise in the
management of hyperinsulinemia and associated atherosclerotic risk factors. Am J
Cardiol 1992 February 15;69(5):440-4.
(5) Mehrabian M, Peter JB, Barnard RJ, Lusis AJ. Dietary regulation of fibrinolytic
factors. Atherosclerosis 1990 September;84(1):25-32.
(6) Ornish D, Brown SE, Scherwitz LW, Billings JH, Armstrong WT, Ports TA,
McLanahan SM, Kirkeeide RL, Brand RJ, Gould KL. Can lifestyle changes reverse
coronary heart disease? The Lifestyle Heart Trial [see comments]. Lancet 1990 July
21;336(8708):129-33.
(7) Gould KL, Ornish D, Kirkeeide R, Brown S, Stuart Y, Buchi M, Billings J, Armstrong
W, Ports T, Scherwitz L. Improved stenosis geometry by quantitative coronary
arteriography after vigorous risk factor modification. Am J Cardiol 1992 April
1;69(9):845-53.
(8) Ornish D, Scherwitz LW, Billings JH, Gould KL, Merritt TA, Sparler S, Armstrong
WT, Ports TA, Kirkeeide RL, Hogeboom C, Brand RJ. Intensive lifestyle changes for
reversal of coronary heart disease. JAMA 1998 December 16;280(23):2001-7.
(9) Dietschy JM. Dietary fatty acids and the regulation of plasma low density lipoprotein
cholesterol concentrations. J Nutr 1998 February;128(2 Suppl):444S-8S.
(10) Hopkins PN. Effects of dietary cholesterol on serum cholesterol: a meta-analysis and
review. Am J Clin Nutr 1992 June;55(6):1060-70.
(11) McNamara DJ. The impact of egg limitations on coronary heart disease risk: do the
numbers add up? J Am Coll Nutr 2000 October;19(5 Suppl):540S-8S.
(12) Goff DCJ, Shekelle RB, Moye LA, Katan MB, Gotto AMJ, Stamler J. Does body fatness
modify the effect of dietary cholesterol on serum cholesterol? Results from the Chicago
Western Electric Study. Am J Epidemiol 1993 January 15;137(2):171-7.
(13) Kritchevsky SB, Kritchevsky D. Egg consumption and coronary heart disease: an
epidemiologic overview. J Am Coll Nutr 2000 October;19(5 Suppl):549S-55S.
(14) Carroll KK. Hypercholesterolemia and atherosclerosis: effects of dietary protein. Fed
Proc 1982 September;41(11):2792-6.
136
(15) Kurowska EM, Carroll KK. Effect of high levels of selected dietary essential amino
acids on hypercholesterolemia and down-regulation of hepatic LDL receptors in rabbits.
Biochim Biophys Acta 1992 June 22;1126(2):185-91.
(16) Sirtori CR, Agradi E, Conti F, Mantero O, Gatti E. Soybean-protein diet in the
treatment of type-II hyperlipoproteinaemia. Lancet 1977 February 5;1(8006):275-7.
(17) Descovich GC, Ceredi C, Gaddi A, Benassi MS, Mannino G, Colombo L, Cattin L,
Fontana G, Senin U, Mannarino E, Caruzzo C, Bertelli E, Fragiacomo C, Noseda G,
Sirtori M, Sirtori CR. Multicentre study of soybean protein diet for outpatient hypercholesterolaemic patients. Lancet 1980 October 4;2(8197):709-12.
(18) Anderson JW, Johnstone BM, Cook-Newell ME. Meta-analysis of the effects of soy
protein intake on serum lipids [see comments]. N Engl J Med 1995 August 3;333(5):27682.
(19) Sirtori CR, Gianazza E, Manzoni C, Lovati MR, Murphy PA. Role of isoflavones in the
cholesterol reduction by soy proteins in the clinic. Am J Clin Nutr 1997
January;65(1):166-7.
(20) Hubbard RW, Sanchez A. Dietary protein control of serum cholesterol by insulin and
glucagon. Monogr Atheroscler 1990;16:139-47.
(21) Sanchez A, Hubbard RW. Plasma amino acids and the insulin/glucagon ratio as an
explanation for the dietary protein modulation of atherosclerosis. Med Hypotheses 1991
September;36(1):27-32.
(22) McCarty MF. Vegan proteins may reduce risk of cancer, obesity, and cardiovascular
disease by promoting increased glucagon activity [In Process Citation]. Med Hypotheses
1999 December;53(6):459-85.
(23) Ness GC, Zhao Z, Wiggins L. Insulin and glucagon modulate hepatic 3-hydroxy-3methylglutaryl-coenzyme A reductase activity by affecting immunoreactive protein
levels. J Biol Chem 1994 November 18;269(46):29168-72.
(24) Easom RA, Zammit VA. Acute effects of starvation and treatment of rats with antiinsulin serum, glucagon and catecholamines on the state of phosphorylation of hepatic 3hydroxy-3-methylglutaryl-CoA reductase in vivo. Biochem J 1987 January 1;241(1):1838.
(25) Jenkins DJ, Wolever TM, Collier GR, Ocana A, Rao AV, Buckley G, Lam Y, Mayer A,
Thompson LU. Metabolic effects of a low-glycemic-index diet. Am J Clin Nutr 1987
December;46(6):968-75.
(26) Sacks FM, Castelli WP, Donner A, Kass EH. Plasma lipids and lipoproteins in
vegetarians and controls. N Engl J Med 1975 May 29;292(22):1148-51.
(27) Toohey ML, Harris MA, DeWitt W, Foster G, Schmidt WD, Melby CL. Cardiovascular
disease risk factors are lower in African-American vegans compared to lacto-ovovegetarians. J Am Coll Nutr 1998 October;17(5):425-34.
(28) Sanders TA, Ellis FR, Dickerson JW. Studies of vegans: the fatty acid composition of
plasma choline phosphoglycerides, erythrocytes, adipose tissue, and breast milk, and
some indicators of susceptibility to ischemic heart disease in vegans and omnivore
controls. Am J Clin Nutr 1978 May;31(5):805-13.
137
(29) Resnicow K, Barone J, Engle A, Miller S, Haley NJ, Fleming D, Wynder E. Diet and
serum lipids in vegan vegetarians: a model for risk reduction. J Am Diet Assoc 1991
April;91(4):447-53.
(30) Lamarche B, Tchernof A, Mauriege P, Cantin B, Dagenais GR, Lupien PJ, Despres JP.
Fasting insulin and apolipoprotein B levels and low-density lipoprotein particle size as
risk factors for ischemic heart disease [see comments]. JAMA 1998 June
24;279(24):1955-61.
(31) Boden G, Chen X, Ruiz J, White JV, Rossetti L. Mechanisms of fatty acid-induced
inhibition of glucose uptake. J Clin Invest 1994 June;93(6):2438-46.
(32) Boden G, Chen X. Effects of fat on glucose uptake and utilization in patients with noninsulin-dependent diabetes. J Clin Invest 1995 September;96(3):1261-8.
(33) Boden G. Role of fatty acids in the pathogenesis of insulin resistance and NIDDM
[published erratum appears in Diabetes 1997 Mar;46(3):536]. Diabetes 1997
January;46(1):3-10.
(34) Boden G. Free fatty acids, insulin resistance, and type 2 diabetes mellitus. Proc Assoc
Am Physicians 1999 May;111(3):241-8.
(35) Santomauro AT, Boden G, Silva ME, Rocha DM, Santos RF, Ursich MJ, Strassmann
PG, Wajchenberg BL. Overnight lowering of free fatty acids with Acipimox improves
insulin resistance and glucose tolerance in obese diabetic and nondiabetic subjects.
Diabetes 1999 September;48(9):1836-41.
(36) Unger RH. Lipotoxicity in the pathogenesis of obesity-dependent NIDDM. Genetic and
clinical implications. Diabetes 1995 August;44(8):863-70.
(37) Mason TM, Goh T, Tchipashvili V, Sandhu H, Gupta N, Lewis GF, Giacca A. Prolonged
elevation of plasma free fatty acids desensitizes the insulin secretory response to glucose
in vivo in rats. Diabetes 1999 March;48(3):524-30.
(38) Rebrin K, Steil GM, Mittelman SD, Bergman RN. Causal linkage between insulin
suppression of lipolysis and suppression of liver glucose output in dogs. J Clin Invest
1996 August 1;98(3):741-9.
(39) Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron AD.
Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the
syndrome of insulin resistance. J Clin Invest 1996 June 1;97(11):2601-10.
(40) Steinberg HO, Tarshoby M, Monestel R, Hook G, Cronin J, Johnson A, Bayazeed B,
Baron AD. Elevated circulating free fatty acid levels impair endothelium- dependent
vasodilation. J Clin Invest 1997 September 1;100(5):1230-9.
(41) Egan BM, Lu G, Greene EL. Vascular effects of non-esterified fatty acids: implications
for the cardiovascular risk factor cluster. Prostaglandins Leukot Essent Fatty Acids 1999
May;60(5-6):411-20.
(42) Steinberg HO, Paradisi G, Hook G, Crowder K, Cronin J, Baron AD. Free fatty acid
elevation impairs insulin-mediated vasodilation and nitric oxide production. Diabetes
2000 July;49(7):1231-8.
138
(43) Falholt K, Jensen I, Lindkaer JS, Mortensen H, Volund A, Heding LG, Noerskov PP,
Falholt W. Carbohydrate and lipid metabolism of skeletal muscle in type 2 diabetic
patients. Diabet Med 1988 January;5(1):27-31.
(44) Phillips DI, Caddy S, Ilic V, Fielding BA, Frayn KN, Borthwick AC, Taylor R.
Intramuscular triglyceride and muscle insulin sensitivity: evidence for a relationship in
nondiabetic subjects. Metabolism 1996 August;45(8):947-50.
(45) Pan DA, Lillioja S, Kriketos AD, Milner MR, Baur LA, Bogardus C, Jenkins AB,
Storlien LH. Skeletal muscle triglyceride levels are inversely related to insulin action.
Diabetes 1997 June;46(6):983-8.
(46) Goodpaster BH, Thaete FL, Simoneau JA, Kelley DE. Subcutaneous abdominal fat and
thigh muscle composition predict insulin sensitivity independently of visceral fat.
Diabetes 1997 October;46(10):1579-85.
(47) Jacob S, Machann J, Rett K, Brechtel K, Volk A, Renn W, Maerker E, Matthaei S,
Schick F, Claussen CD, Haring HU. Association of increased intramyocellular lipid
content with insulin resistance in lean nondiabetic offspring of type 2 diabetic subjects.
Diabetes 1999 May;48(5):1113-9.
(48) Tsunoda N, Ikemoto S, Takahashi M, Maruyama K, Watanabe H, Goto N, Ezaki O.
High-monounsaturated fat diet-induced obesity and diabetes in C57BL/6J mice.
Metabolism 1998 June;47(6):724-30.
(49) Storlien LH, Jenkins AB, Chisholm DJ, Pascoe WS, Khouri S, Kraegen EW. Influence
of dietary fat composition on development of insulin resistance in rats. Relationship to
muscle triglyceride and omega-3 fatty acids in muscle phospholipid. Diabetes 1991
February;40(2):280-9.
(50) Chavez JA, Summers SA. Characterizing the effects of saturated fatty acids on insulin
signaling and ceramide and diacylglycerol accumulation in 3T3-L1 adipocytes and
C2C12 myotubes. Arch Biochem Biophys 2003 November 15;419(2):101-9.
(51) Schmitz-Peiffer C, Craig DL, Biden TJ. Ceramide generation is sufficient to account for
the inhibition of the insulin-stimulated PKB pathway in C2C12 skeletal muscle cells
pretreated with palmitate. J Biol Chem 1999 August 20;274(34):24202-10.
(52) Sabin MA, Stewart CE, Crowne EC, Turner SJ, Hunt LP, Welsh GI, Grohmann MJ,
Holly JM, Shield JP. Fatty acid-induced defects in insulin signalling, in myotubes
derived from children, are related to ceramide production from palmitate rather than
the accumulation of intramyocellular lipid. J Cell Physiol 2007 April;211(1):244-52.
(53) Wu Y, Song P, Xu J, Zhang M, Zou MH. Activation of protein phosphatase 2A by
palmitate inhibits AMP-activated protein kinase. J Biol Chem 2007 March
30;282(13):9777-88.
(54) Zhang DX, Zou AP, Li PL. Ceramide-induced activation of NADPH oxidase and
endothelial dysfunction in small coronary arteries. Am J Physiol Heart Circ Physiol 2003
February;284(2):H605-H612.
(55) Maron DJ, Fair JM, Haskell WL. Saturated fat intake and insulin resistance in men
with coronary artery disease. The Stanford Coronary Risk Intervention Project
Investigators and Staff. Circulation 1991 November;84(5):2020-7.
139
(56) Parker DR, Weiss ST, Troisi R, Cassano PA, Vokonas PS, Landsberg L. Relationship of
dietary saturated fatty acids and body habitus to serum insulin concentrations: the
Normative Aging Study. Am J Clin Nutr 1993 August;58(2):129-36.
(57) Snowdon DA, Phillips RL. Does a vegetarian diet reduce the occurrence of diabetes? Am
J Public Health 1985 May;75(5):507-12.
(58) Ong PJ, Dean TS, Hayward CS, la Monica PL, Sanders TA, Collins P. Effect of fat and
carbohydrate consumption on endothelial function. Lancet 1999 December
18;354(9196):2134.
(59) Itani SI, Ruderman NB, Schmieder F, Boden G. Lipid-induced insulin resistance in
human muscle is associated with changes in diacylglycerol, protein kinase C, and
IkappaB-alpha. Diabetes 2002 July;51(7):2005-11.
(60) Pickersgill L, Litherland GJ, Greenberg AS, Walker M, Yeaman SJ. Key role for
ceramides in mediating insulin resistance in human muscle cells. J Biol Chem 2007 April
27;282(17):12583-9.
(61) Lee JS, Pinnamaneni SK, Eo SJ, Cho IH, Pyo JH, Kim CK, Sinclair AJ, Febbraio MA,
Watt MJ. Saturated, but not n-6 polyunsaturated, fatty acids induce insulin resistance:
role of intramuscular accumulation of lipid metabolites. J Appl Physiol 2006
May;100(5):1467-74.
(62) Toborek M, Lee YW, Garrido R, Kaiser S, Hennig B. Unsaturated fatty acids selectively
induce an inflammatory environment in human endothelial cells. Am J Clin Nutr 2002
January;75(1):119-25.
(63) Soriguer F, Esteva I, Rojo-Martinez G, Ruiz de Adana MS, Dobarganes MC, GarciaAlmeida JM, Tinahones F, Beltran M, Gonzalez-Romero S, Olveira G, GomezZumaquero JM. Oleic acid from cooking oils is associated with lower insulin resistance
in the general population (Pizarra study). Eur J Endocrinol 2004 January;150(1):33-9.
(64) Nicolosi RJ, Wilson TA, Handelman G, Foxall T, Keaney JF, Vita JA. Decreased aortic
early atherosclerosis in hypercholesterolemic hamsters fed oleic acid-rich TriSun oil
compared to linoleic acid-rich sunflower oil. J Nutr Biochem 2002 July;13(7):392-402.
(65) Lada AT, Rudel LL. Dietary monounsaturated versus polyunsaturated fatty acids:
which is really better for protection from coronary heart disease? Curr Opin Lipidol
2003 February;14(1):41-6.
(66) Perez-Jimenez F, varez de CG, Badimon L, Barja G, Battino M, Blanco A, Bonanome A,
Colomer R, Corella-Piquer D, Covas I, Chamorro-Quiros J, Escrich E, Gaforio JJ,
Garcia Luna PP, Hidalgo L, Kafatos A, Kris-Etherton PM, Lairon D, LamuelaRaventos R, Lopez-Miranda J, Lopez-Segura F, Martinez-Gonzalez MA, Mata P,
Mataix J, Ordovas J, Osada J, Pacheco-Reyes R, Perucho M, Pineda-Priego M, Quiles
JL, Ramirez-Tortosa MC, Ruiz-Gutierrez V, Sanchez-Rovira P, Solfrizzi V, SoriguerEscofet F, de lT-F, Trichopoulos A, Villalba-Montoro JM, Villar-Ortiz JR, Visioli F.
International conference on the healthy effect of virgin olive oil. Eur J Clin Invest 2005
July;35(7):421-4.
(67) Jenkins DJ, Kendall CW, Marchie A, Parker TL, Connelly PW, Qian W, Haight JS,
Faulkner D, Vidgen E, Lapsley KG, Spiller GA. Dose response of almonds on coronary
heart disease risk factors: blood lipids, oxidized low-density lipoproteins, lipoprotein(a),
140
homocysteine, and pulmonary nitric oxide: a randomized, controlled, crossover trial.
Circulation 2002 September 10;106(11):1327-32.
(68) Jenkins DJ, Kendall CW, Marchie A, Josse AR, Nguyen TH, Faulkner DA, Lapsley KG,
Singer W. Effect of almonds on insulin secretion and insulin resistance in nondiabetic
hyperlipidemic subjects: a randomized controlled crossover trial. Metabolism 2008
July;57(7):882-7.
(69) Keys A. Coronary heart disease in seven countries. 1970. Nutrition 1997
March;13(3):250-2.
(70) Anderson JW, Herman RH, Zakim D. Effect of high glucose and high sucrose diets on
glucose tolerance of normal men. Am J Clin Nutr 1973 June;26(6):600-7.
(71) Kolterman OG, Greenfield M, Reaven GM, Saekow M, Olefsky JM. Effect of a high
carbohydrate diet on insulin binding to adipocytes and on insulin action in vivo in man.
Diabetes 1979 August;28(8):731-6.
(72) Fukagawa NK, Anderson JW, Hageman G, Young VR, Minaker KL. Highcarbohydrate, high-fiber diets increase peripheral insulin sensitivity in healthy young
and old adults. Am J Clin Nutr 1990 September;52(3):524-8.
(73) Nicholson AS, Sklar M, Barnard ND, Gore S, Sullivan R, Browning S. Toward
improved management of NIDDM: A randomized, controlled, pilot intervention using a
lowfat, vegetarian diet. Prev Med 1999 August;29(2):87-91.
(74) Hardinge MG, Crooks H, Stare FJ. Nutritional studies of vegetarians. J Am Diet Assoc
1966 January;48(1):25-8.
(75) Campbell TC, Chen J. Energy balance: interpretation of data from rural China. Toxicol
Sci 1999 December;52(2 Suppl):87-94.
(76) McCarty MF. The origins of western obesity: a role for animal protein? Med Hypotheses
2000 March;54(3):488-94.
(77) Rabinowitz D, Merimee TJ, Maffezzoli R, Burgess JA. Patterns of hormonal release
after glucose, protein, and glucose plus protein. Lancet 1966 August 27;2(7461):454-6.
(78) Spiller GA, Jensen CD, Pattison TS, Chuck CS, Whittam JH, Scala J. Effect of protein
dose on serum glucose and insulin response to sugars. Am J Clin Nutr 1987
September;46(3):474-80.
(79) Remer T, Pietrzik K, Manz F. A moderate increase in daily protein intake causing an
enhanced endogenous insulin secretion does not alter circulating levels or urinary
excretion of dehydroepiandrosterone sulfate. Metabolism 1996 December;45(12):1483-6.
(80) Barnard ND, Scialli AR, Hurlock D, Bertron P. Diet and sex-hormone binding globulin,
dysmenorrhea, and premenstrual symptoms. Obstet Gynecol 2000 February;95(2):24550.
(81) Miller JB, Pang E, Bramall L. Rice: a high or low glycemic index food? Am J Clin Nutr
1992 December;56(6):1034-6.
(82) McCarty MF. The origins of western obesity: a role for animal protein? Med Hypotheses
2000 March;54(3):488-94.
141
(83) Slabber M, Barnard HC, Kuyl JM, Dannhauser A, Schall R. Effects of a low-insulinresponse, energy-restricted diet on weight loss and plasma insulin concentrations in
hyperinsulinemic obese females. Am J Clin Nutr 1994 July;60(1):48-53.
(84) Ludwig DS, Majzoub JA, Al-Zahrani A, Dallal GE, Blanco I, Roberts SB. High glycemic
index foods, overeating, and obesity. Pediatrics 1999 March;103(3):E26.
(85) Spieth LE, Harnish JD, Lenders CM, Raezer LB, Pereira MA, Hangen SJ, Ludwig DS.
A low-glycemic index diet in the treatment of pediatric obesity. Arch Pediatr Adolesc
Med 2000 September;154(9):947-51.
(86) Panagiotakos DB, Chrysohoou C, Pitsavos C, Stefanadis C. Association between the
prevalence of obesity and adherence to the Mediterranean diet: the ATTICA study.
Nutrition 2006 May;22(5):449-56.
(87) Schroder H, Marrugat J, Vila J, Covas MI, Elosua R. Adherence to the traditional
mediterranean diet is inversely associated with body mass index and obesity in a spanish
population. J Nutr 2004 December;134(12):3355-61.
(88) Moussavi N, Gavino V, Receveur O. Could the quality of dietary fat, and not just its
quantity, be related to risk of obesity? Obesity (Silver Spring) 2008 January;16(1):7-15.
(89) Schroder H. Protective mechanisms of the Mediterranean diet in obesity and type 2
diabetes. J Nutr Biochem 2007 March;18(3):149-60.
(90) Bergouignan A, Momken I, Schoeller DA, Simon C, Blanc S. Metabolic fate of saturated
and monounsaturated dietary fats: The Mediterranean diet revisited from
epidemiological evidence to cellular mechanisms. Prog Lipid Res 2009 March 9.
(91) Paniagua JA, de la Sacristana AG, Sanchez E, Romero I, Vidal-Puig A, Berral FJ,
Escribano A, Moyano MJ, Perez-Martinez P, Lopez-Miranda J, Perez-Jimenez F. A
MUFA-rich diet improves posprandial glucose, lipid and GLP-1 responses in insulinresistant subjects. J Am Coll Nutr 2007 October;26(5):434-44.
(92) McCarty MF. Favorable impact of a vegan diet with exercise on hemorheology implications for control of diabetic neuropathy. Medical Hypotheses 2001;56:in press.
(93) McCarty MF. A shift in myocardial substrate, improved endothelial function, and
diminished sympathetic activity may contribute to the anti-anginal impact of very-lowfat diets. Med Hypotheses 2004;62(1):62-71.
(94) Calvani M, Reda E, rrigoni-Martelli E. Regulation by carnitine of myocardial fatty acid
and carbohydrate metabolism under normal and pathological conditions. Basic Res
Cardiol 2000 April;95(2):75-83.
(95) Ferrari R, Merli E, Cicchitelli G, Mele D, Fucili A, Ceconi C. Therapeutic effects of Lcarnitine and propionyl-L-carnitine on cardiovascular diseases: a review. Ann N Y Acad
Sci 2004 November;1033:79-91.
(96) Esselstyn CB, Ellis SG, Medendorp SV, Crowe TD. A strategy to arrest and reverse
coronary artery disease: a 5-year longitudinal study of a single physician's practice. J
Fam Pract 1995 December;41(6):560-8.
142
(97) Esselstyn CB. Updating a 12-year experience with arrest and reversal therapy for
coronary heart disease (an overdue requiem for palliative cardiology). Am J Cardiol
1999 August 1;84(3):339-41, A8.
(98) Endres M, Laufs U. [HMG-CoA reductase inhibitor and risk of stroke]. Nervenarzt 1998
August;69(8):717-21.
(99) Laufs U, La F, V, Plutzky J, Liao JK. Upregulation of endothelial nitric oxide synthase
by HMG CoA reductase inhibitors. Circulation 1998 March 31;97(12):1129-35.
(100) Rosenson RS. Non-lipid-lowering effects of statins on atherosclerosis. Curr Cardiol Rep
1999 September;1(3):225-32.
(101) Davignon J, Laaksonen R. Low-density lipoprotein-independent effects of statins. Curr
Opin Lipidol 1999 December;10(6):543-59.
(102) Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM, Jr., Kastelein JJ, Koenig W,
Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT,
Glynn RJ. Rosuvastatin to prevent vascular events in men and women with elevated Creactive protein. N Engl J Med 2008 November 20;359(21):2195-207.
(103) Ndumele CE, Pradhan AD, Ridker PM. Interrelationships between inflammation, Creactive protein, and insulin resistance. J Cardiometab Syndr 2006;1(3):190-6.
(104) Qamirani E, Ren Y, Kuo L, Hein TW. C-reactive protein inhibits endotheliumdependent NO-mediated dilation in coronary arterioles by activating p38 kinase and
NAD(P)H oxidase. Arterioscler Thromb Vasc Biol 2005 May;25(5):995-1001.
(105) Singh U, Devaraj S, Vasquez-Vivar J, Jialal I. C-reactive protein decreases endothelial
nitric oxide synthase activity via uncoupling. J Mol Cell Cardiol 2007
December;43(6):780-91.
(106) Nagaoka T, Kuo L, Ren Y, Yoshida A, Hein TW. C-reactive protein inhibits
endothelium-dependent nitric oxide-mediated dilation of retinal arterioles via enhanced
superoxide production. Invest Ophthalmol Vis Sci 2008 May;49(5):2053-60.
(107) Heber D, Yip I, Ashley JM, Elashoff DA, Elashoff RM, Go VL. Cholesterol-lowering
effects of a proprietary Chinese red-yeast-rice dietary supplement. Am J Clin Nutr 1999
February;69(2):231-6.
(108) Levy HB, Kohlhaas HK. Considerations for supplementing with coenzyme Q10 during
statin therapy. Ann Pharmacother 2006 February;40(2):290-4.
(109) Littarru GP, Langsjoen P. Coenzyme Q10 and statins: biochemical and clinical
implications. Mitochondrion 2007 June;7 Suppl:S168-S174.
(110) Young JM, Florkowski CM, Molyneux SL, McEwan RG, Frampton CM, George PM,
Scott RS. Effect of coenzyme Q(10) supplementation on simvastatin-induced myalgia.
Am J Cardiol 2007 November 1;100(9):1400-3.
(111) Sinatra ST. Refractory congestive heart failure successfully managed with high dose
coenzyme Q10 administration. Mol Aspects Med 1997;18 Suppl:S299-S305.
143
(112) Molyneux SL, Florkowski CM, George PM, Pilbrow AP, Frampton CM, Lever M,
Richards AM. Coenzyme Q10: an independent predictor of mortality in chronic heart
failure. J Am Coll Cardiol 2008 October 28;52(18):1435-41.
(113) Rosenfeldt FL, Haas SJ, Krum H, Hadj A, Ng K, Leong JY, Watts GF. Coenzyme Q10
in the treatment of hypertension: a meta-analysis of the clinical trials. J Hum Hypertens
2007 April;21(4):297-306.
(114) Wang PS, Solomon DH, Mogun H, Avorn J. HMG-CoA reductase inhibitors and the
risk of hip fractures in elderly patients. JAMA 2000 June 28;283(24):3211-6.
(115) Chan KA, Andrade SE, Boles M, Buist DS, Chase GA, Donahue JG, Goodman MJ,
Gurwitz JH, LaCroix AZ, Platt R. Inhibitors of hydroxymethylglutaryl-coenzyme A
reductase and risk of fracture among older women. Lancet 2000 June
24;355(9222):2185-8.
(116) Edwards CJ, Hart DJ, Spector TD. Oral statins and increased bone-mineral density in
postmenopausal women. Lancet 2000 June 24;355(9222):2218-9.
(117) Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA. Statins and the risk of
dementia. Lancet 2000 November 11;356(9242):1627-31.
(118) Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G. Decreased prevalence of
Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase
inhibitors. Arch Neurol 2000 October;57(10):1439-43.
(119) Haag MD, Hofman A, Koudstaal PJ, Stricker BH, Breteler MM. Statins are associated
with a reduced risk of Alzheimer disease regardless of lipophilicity. The Rotterdam
Study. J Neurol Neurosurg Psychiatry 2009 January;80(1):13-7.
(120) Cicero AF, Rovati LC, Setnikar I. Eulipidemic effects of berberine administered alone
or in combination with other natural cholesterol-lowering agents. A single-blind clinical
investigation. Arzneimittelforschung 2007;57(1):26-30.
(121) Kong WJ, Wei J, Zuo ZY, Wang YM, Song DQ, You XF, Zhao LX, Pan HN, Jiang JD.
Combination of simvastatin with berberine improves the lipid-lowering efficacy.
Metabolism 2008 August;57(8):1029-37.
(122) Kong W, Wei J, Abidi P, Lin M, Inaba S, Li C, Wang Y, Wang Z, Si S, Pan H, Wang S,
Wu J, Wang Y, Li Z, Liu J, Jiang JD. Berberine is a novel cholesterol-lowering drug
working through a unique mechanism distinct from statins. Nat Med 2004
December;10(12):1344-51.
(123) Doggrell SA. Berberine--a novel approach to cholesterol lowering. Expert Opin Investig
Drugs 2005 May;14(5):683-5.
(124) Abidi P, Zhou Y, Jiang JD, Liu J. Extracellular signal-regulated kinase-dependent
stabilization of hepatic low-density lipoprotein receptor mRNA by herbal medicine
berberine. Arterioscler Thromb Vasc Biol 2005 October;25(10):2170-6.
(125) Yin J, Xing H, Ye J. Efficacy of berberine in patients with type 2 diabetes mellitus.
Metabolism 2008 May;57(5):712-7.
144
(126) Brusq JM, Ancellin N, Grondin P, Guillard R, Martin S, Saintillan Y, Issandou M.
Inhibition of lipid synthesis through activation of AMP kinase: an additional mechanism
for the hypolipidemic effects of berberine. J Lipid Res 2006 June;47(6):1281-8.
(127) Chen HL, Sheu WH, Tai TS, Liaw YP, Chen YC. Konjac supplement alleviated
hypercholesterolemia and hyperglycemia in type 2 diabetic subjects--a randomized
double-blind trial. J Am Coll Nutr 2003 February;22(1):36-42.
(128) Sood N, Baker WL, Coleman CI. Effect of glucomannan on plasma lipid and glucose
concentrations, body weight, and blood pressure: systematic review and meta-analysis.
Am J Clin Nutr 2008 October;88(4):1167-75.
(129) Demonty I, Ras RT, van der Knaap HC, Duchateau GS, Meijer L, Zock PL, Geleijnse
JM, Trautwein EA. Continuous Dose-Response Relationship of the LDL-CholesterolLowering Effect of Phytosterol Intake. J Nutr 2008 December 17.
(130) Brufau G, Canela MA, Rafecas M. Phytosterols: physiologic and metabolic aspects
related to cholesterol-lowering properties. Nutr Res 2008 April;28(4):217-25.
(131) Parker RA, Pearce BC, Clark RW, Gordon DA, Wright JJ. Tocotrienols regulate
cholesterol production in mammalian cells by post-transcriptional suppression of 3hydroxy-3-methylglutaryl-coenzyme A reductase. J Biol Chem 1993 May
25;268(15):11230-8.
(132) Tomeo AC, Geller M, Watkins TR, Gapor A, Bierenbaum ML. Antioxidant effects of
tocotrienols in patients with hyperlipidemia and carotid stenosis. Lipids 1995
December;30(12):1179-83.
(133) Qureshi AA, Bradlow BA, Brace L, Manganello J, Peterson DM, Pearce BC, Wright JJ,
Gapor A, Elson CE. Response of hypercholesterolemic subjects to administration of
tocotrienols. Lipids 1995 December;30(12):1171-7.
(134) Qureshi AA, Qureshi N, Wright JJ, Shen Z, Kramer G, Gapor A, Chong YH, DeWitt G,
Ong A, Peterson DM. Lowering of serum cholesterol in hypercholesterolemic humans
by tocotrienols (palmvitee). Am J Clin Nutr 1991 April;53(4 Suppl):1021S-6S.
(135) Black TM, Wang P, Maeda N, Coleman RA. Palm tocotrienols protect ApoE +/- mice
from diet-induced atheroma formation. J Nutr 2000 October;130(10):2420-6.
(136) Elson CE, Peffley DM, Hentosh P, Mo H. Isoprenoid-mediated inhibition of mevalonate
synthesis: potential application to cancer. Proc Soc Exp Biol Med 1999
September;221(4):294-311.
(137) Reaven GM. Do high carbohydrate diets prevent the development or attenuate the
manifestations (or both) of syndrome X? A viewpoint strongly against. Curr Opin Lipidol
1997 February;8(1):23-7.
(138) Jeppesen J, Schaaf P, Jones C, Zhou MY, Chen YD, Reaven GM. Effects of low-fat,
high-carbohydrate diets on risk factors for ischemic heart disease in postmenopausal
women. Am J Clin Nutr 1997 April;65(4):1027-33.
(139) Abbasi F, McLaughlin T, Lamendola C, Kim HS, Tanaka A, Wang T, Nakajima K,
Reaven GM. High carbohydrate diets, triglyceride-rich lipoproteins, and coronary heart
disease risk. Am J Cardiol 2000 January 1;85(1):45-8.
145
(140) Willett WC. Will high-carbohydrate/low-fat diets reduce the risk of coronary heart
disease? Proc Soc Exp Biol Med 2000 December;225(3):187-90.
(141) Garg A, Bantle JP, Henry RR, Coulston AM, Griver KA, Raatz SK, Brinkley L, Chen
YD, Grundy SM, Huet BA. Effects of varying carbohydrate content of diet in patients
with non-insulin-dependent diabetes mellitus. JAMA 1994 May 11;271(18):1421-8.
(142) Morgan SA, O'Dea K, Sinclair AJ. A low-fat diet supplemented with monounsaturated
fat results in less HDL-C lowering than a very-low-fat diet. J Am Diet Assoc 1997
February;97(2):151-6.
(143) Lithell H, Karlstrom B, Selinus I, Vessby B, Fellstrom B. Is muscle lipoprotein lipase
inactivated by ordinary amounts of dietary carbohydrates? Hum Nutr Clin Nutr 1985
July;39(4):289-95.
(144) Farese RV, Yost TJ, Eckel RH. Tissue-specific regulation of lipoprotein lipase activity
by insulin/glucose in normal-weight humans. Metabolism 1991 February;40(2):214-6.
(145) Laville M, Auboeuf D, Khalfallah Y, Vega N, Riou JP, Vidal H. Acute regulation by
insulin of phosphatidylinositol-3-kinase, Rad, Glut 4, and lipoprotein lipase mRNA
levels in human muscle. J Clin Invest 1996 July 1;98(1):43-9.
(146) Parks EJ, Krauss RM, Christiansen MP, Neese RA, Hellerstein MK. Effects of a low-fat,
high-carbohydrate diet on VLDL-triglyceride assembly, production, and clearance. J
Clin Invest 1999 October;104(8):1087-96.
(147) Parks EJ, Hellerstein MK. Carbohydrate-induced hypertriacylglycerolemia: historical
perspective and review of biological mechanisms. Am J Clin Nutr 2000
February;71(2):412-33.
(148) Roche HM, Gibney MJ. The impact of postprandial lipemia in accelerating
atherothrombosis. J Cardiovasc Risk 2000 October;7(5):317-24.
(149) Havel RJ. Remnant lipoproteins as therapeutic targets. Curr Opin Lipidol 2000
December;11(6):615-20.
(150) Anderson JW. Dietary fiber prevents carbohydrate-induced hypertriglyceridemia. Curr
Atheroscler Rep 2000 November;2(6):536-41.
(151) Harris WS, Connor WE, Inkeles SB, Illingworth DR. Dietary omega-3 fatty acids
prevent carbohydrate-induced hypertriglyceridemia. Metabolism 1984
November;33(11):1016-9.
(152) Richter EA, Turcotte L, Hespel P, Kiens B. Metabolic responses to exercise. Effects of
endurance training and implications for diabetes. Diabetes Care 1992
November;15(11):1767-76.
(153) Frayn KN. Non-esterified fatty acid metabolism and postprandial lipaemia.
Atherosclerosis 1998 December;141 Suppl 1:S41-S46.
(154) Vogel RA, Corretti MC, Plotnick GD. Effect of a single high-fat meal on endothelial
function in healthy subjects. Am J Cardiol 1997 February 1;79(3):350-4.
146
(155) Ong PJ, Dean TS, Hayward CS, Della MP, Sanders TA, Collins P. Effect of fat and
carbohydrate consumption on endothelial function. Lancet 1999 December
18;354(9196):2134.
(156) Vogel RA, Corretti MC, Plotnick GD. The postprandial effect of components of the
Mediterranean diet on endothelial function. J Am Coll Cardiol 2000 November
1;36(5):1455-60.
(157) Barnard RJ, Massey MR, Cherny S, O'Brien LT, Pritikin N. Long-term use of a highcomplex-carbohydrate, high-fiber, low-fat diet and exercise in the treatment of NIDDM
patients. Diabetes Care 1983 May;6(3):268-73.
(158) Ornish D. Serum lipids after a low-fat diet. JAMA 1998 May 6;279(17):1345-6.
(159) Connor WE, Cerqueira MT, Connor RW, Wallace RB, Malinow MR, Casdorph HR.
The plasma lipids, lipoproteins, and diet of the Tarahumara indians of Mexico. Am J
Clin Nutr 1978 July;31(7):1131-42.
(160) McCarty MF. An elevation of triglycerides reflecting decreased triglyceride clearance
may not be pathogenic -- relevance to high-carbohydrate diets. Med Hypotheses
2004;63(6):1065-73.
(161) Kenney JJ, Barnard RJ, Inkeles S. Very-low-fat diets do not necessarily promote small,
dense LDL particles. Am J Clin Nutr 1999 September;70(3):423-5.
(162) Marckmann P, Astrup A. Fatty diets are unhealthy--even those based on
monounsaturates. Am J Clin Nutr 2000 September;72(3):853-6.
(163) Berrino F, Bellati C, Secreto G, Camerini E, Pala V, Panico S, Allegro G, Kaaks R.
Reducing bioavailable sex hormones through a comprehensive change in diet: the diet
and androgens (DIANA) randomized trial. Cancer Epidemiol Biomarkers Prev 2001
January;10(1):25-33.
(164) Jenkins DJ, Kendall CW, Marchie A, Josse AR, Nguyen TH, Faulkner DA, Lapsley KG,
Blumberg J. Almonds reduce biomarkers of lipid peroxidation in older hyperlipidemic
subjects. J Nutr 2008 May;138(5):908-13.
(165) Fraser GE, Sabate J, Beeson WL, Strahan TM. A possible protective effect of nut
consumption on risk of coronary heart disease. The Adventist Health Study. Arch Intern
Med 1992 July;152(7):1416-24.
(166) Hu FB, Stampfer MJ, Manson JE, Rimm EB, Colditz GA, Rosner BA, Speizer FE,
Hennekens CH, Willett WC. Frequent nut consumption and risk of coronary heart
disease in women: prospective cohort study. BMJ 1998 November 14;317(7169):1341-5.
(167) Fraser GE. Nut consumption, lipids, and risk of a coronary event. Clin Cardiol 1999
July;22(7 Suppl):III11-III15.
(168) Hu FB, Stampfer MJ. Nut consumption and risk of coronary heart disease: a review of
epidemiologic evidence. Curr Atheroscler Rep 1999 November;1(3):204-9.
(169) Jiang R, Manson JE, Stampfer MJ, Liu S, Willett WC, Hu FB. Nut and peanut butter
consumption and risk of type 2 diabetes in women. JAMA 2002 November
27;288(20):2554-60.
147
(170) Lovejoy JC. The impact of nuts on diabetes and diabetes risk. Curr Diab Rep 2005
October;5(5):379-84.
(171) Rocca AS, LaGreca J, Kalitsky J, Brubaker PL. Monounsaturated fatty acid diets
improve glycemic tolerance through increased secretion of glucagon-like peptide-1.
Endocrinology 2001 March;142(3):1148-55.
(172) Jenkins DJ, Kendall CW, Josse AR, Salvatore S, Brighenti F, Augustin LS, Ellis PR,
Vidgen E, Rao AV. Almonds decrease postprandial glycemia, insulinemia, and oxidative
damage in healthy individuals. J Nutr 2006 December;136(12):2987-92.
(173) Jenkins DJ, Kendall CW, Marchie A, Josse AR, Nguyen TH, Faulkner DA, Lapsley KG,
Blumberg J. Almonds reduce biomarkers of lipid peroxidation in older hyperlipidemic
subjects. J Nutr 2008 May;138(5):908-13.
(174) Jenkins DJ, Kendall CW, Marchie A, Parker TL, Connelly PW, Qian W, Haight JS,
Faulkner D, Vidgen E, Lapsley KG, Spiller GA. Dose response of almonds on coronary
heart disease risk factors: blood lipids, oxidized low-density lipoproteins, lipoprotein(a),
homocysteine, and pulmonary nitric oxide: a randomized, controlled, crossover trial.
Circulation 2002 September 10;106(11):1327-32.
(175) Josse AR, Kendall CW, Augustin LS, Ellis PR, Jenkins DJ. Almonds and postprandial
glycemia--a dose-response study. Metabolism 2007 March;56(3):400-4.
(176) Vogel RA, Corretti MC, Plotnick GD. The postprandial effect of components of the
Mediterranean diet on endothelial function. J Am Coll Cardiol 2000 November
1;36(5):1455-60.
(177) Esselstyn CB. Prevent and reverse heart disease. New York: Avery; 2007.
(178) Rueckschloss U, Duerrschmidt N, Morawietz H. NADPH oxidase in endothelial cells:
impact on atherosclerosis. Antioxid Redox Signal 2003 April;5(2):171-80.
(179) Cai H, Griendling KK, Harrison DG. The vascular NAD(P)H oxidases as therapeutic
targets in cardiovascular diseases. Trends Pharmacol Sci 2003 September;24(9):471-8.
(180) Soccio M, Toniato E, Evangelista V, Carluccio M, De CR. Oxidative stress and
cardiovascular risk: the role of vascular NAD(P)H oxidase and its genetic variants. Eur
J Clin Invest 2005 May;35(5):305-14.
(181) Mital S, Liao JK. Statins and the myocardium. Semin Vasc Med 2004
November;4(4):377-84.
(182) Fortuno A, San JG, Moreno MU, Diez J, Zalba G. Oxidative stress and vascular
remodelling. Exp Physiol 2005 July;90(4):457-62.
(183) Murdoch CE, Grieve DJ, Cave AC, Looi YH, Shah AM. NADPH oxidase and heart
failure. Curr Opin Pharmacol 2006 April;6(2):148-53.
(184) Guzik TJ, Harrison DG. Vascular NADPH oxidases as drug targets for novel
antioxidant strategies. Drug Discov Today 2006 June;11(11-12):524-33.
(185) Cave AC, Brewer AC, Narayanapanicker A, Ray R, Grieve DJ, Walker S, Shah AM.
NADPH oxidases in cardiovascular health and disease. Antioxid Redox Signal 2006
May;8(5-6):691-728.
148
(186) McCormick ML, Gavrila D, Weintraub NL. Role of oxidative stress in the pathogenesis
of abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 2007 March;27(3):461-9.
(187) Paravicini TM, Touyz RM. NADPH oxidases, reactive oxygen species, and hypertension:
clinical implications and therapeutic possibilities. Diabetes Care 2008 February;31 Suppl
2:S170-S180.
(188) om-Ruiz SP, Anilkumar N, Shah AM. Reactive oxygen species and endothelial
activation. Antioxid Redox Signal 2008 June;10(6):1089-100.
(189) Delles C, Miller WH, Dominiczak AF. Targeting reactive oxygen species in
hypertension. Antioxid Redox Signal 2008 June;10(6):1061-77.
(190) Endres M, Laufs U. Effects of statins on endothelium and signaling mechanisms. Stroke
2004 November;35(11 Suppl 1):2708-11.
(191) Lanone S, Bloc S, Foresti R, Almolki A, Taille C, Callebert J, Conti M, Goven D, Aubier
M, Dureuil B, El-Benna J, Motterlini R, Boczkowski J. Bilirubin decreases nos2
expression via inhibition of NAD(P)H oxidase: implications for protection against
endotoxic shock in rats. FASEB J 2005 November;19(13):1890-2.
(192) Matsumoto H, Ishikawa K, Itabe H, Maruyama Y. Carbon monoxide and bilirubin from
heme oxygenase-1 suppresses reactive oxygen species generation and plasminogen
activator inhibitor-1 induction. Mol Cell Biochem 2006 October;291(1-2):21-8.
(193) Jiang F, Roberts SJ, Datla S, Dusting GJ. NO modulates NADPH oxidase function via
heme oxygenase-1 in human endothelial cells. Hypertension 2006 November;48(5):950-7.
(194) Datla SR, Dusting GJ, Mori TA, Taylor CJ, Croft KD, Jiang F. Induction of heme
oxygenase-1 in vivo suppresses NADPH oxidase derived oxidative stress. Hypertension
2007 October;50(4):636-42.
(195) Schwertner HA, Vitek L. Gilbert syndrome, UGT1A1*28 allele, and cardiovascular
disease risk: possible protective effects and therapeutic applications of bilirubin.
Atherosclerosis 2008 May;198(1):1-11.
(196) Lin JP, O'Donnell CJ, Schwaiger JP, Cupples LA, Lingenhel A, Hunt SC, Yang S,
Kronenberg F. Association between the UGT1A1*28 allele, bilirubin levels, and
coronary heart disease in the Framingham Heart Study. Circulation 2006 October
3;114(14):1476-81.
(197) Terry MJ, Maines MD, Lagarias JC. Inactivation of phytochrome- and
phycobiliprotein-chromophore precursors by rat liver biliverdin reductase. J Biol Chem
1993 December 15;268(35):26099-106.
(198) McCarty MF. Clinical potential of Spirulina as a source of phycocyanobilin. J Med Food
2007 December;10(4):566-70.
(199) Romay C, Gonzalez R, Ledon N, Remirez D, Rimbau V. C-phycocyanin: a biliprotein
with antioxidant, anti-inflammatory and neuroprotective effects. Curr Protein Pept Sci
2003 June;4(3):207-16.
(200) Riss J, Decorde K, Sutra T, Delage M, Baccou JC, Jouy N, Brune JP, Oreal H, Cristol
JP, Rouanet JM. Phycobiliprotein C-Phycocyanin from Spirulina platensis Is
Powerfully Responsible for Reducing Oxidative Stress and NADPH Oxidase Expression
149
Induced by an Atherogenic Diet in Hamsters. J Agric Food Chem 2007 September
19;55(19):7962-7.
(201) Chamorro G, Salazar M, Favila L, Bourges H. [Pharmacology and toxicology of
Spirulina alga]. Rev Invest Clin 1996 September;48(5):389-99.
(202) Torres-Duran PV, Ferreira-Hermosillo A, Juarez-Oropeza MA. Antihyperlipemic and
antihypertensive effects of Spirulina maxima in an open sample of mexican population:
a preliminary report. Lipids Health Dis 2007 November 26;6(1):33.
(203) McCarty MF. ''Iatrogenic Gilbert syndrome''--a strategy for reducing vascular and
cancer risk by increasing plasma unconjugated bilirubin. Med Hypotheses
2007;69(5):974-94.
(204) McGuire MT, Wing RR, Klem ML, Hill JO. Behavioral strategies of individuals who
have maintained long-term weight losses. Obes Res 1999 July;7(4):334-41.
(205) Flatt JP. Dietary fat, carbohydrate balance, and weight maintenance: effects of exercise.
Am J Clin Nutr 1987 January;45(1 Suppl):296-306.
(206) McCarty MF. Optimizing exercise for fat loss. Med Hypotheses 1995 May;44(5):325-30.
(207) Friedman MI. Obesity and the hepatic control of feeding behavior. Drug News Perspect
2007 November;20(9):573-8.
(208) Ji H, Friedman MI. Reduced capacity for fatty acid oxidation in rats with inherited
susceptibility to diet-induced obesity. Metabolism 2007 August;56(8):1124-30.
(209) Koeslag JH. Post-exercise ketosis and the hormone response to exercise: a review. Med
Sci Sports Exerc 1982;14(5):327-34.
(210) McCarty MF. Orthomolecular aids for dieting. Med Hypotheses 1982 March;8(3):26974.
(211) McCarty MF. Promotion of hepatic lipid oxidation and gluconeogenesis as a strategy for
appetite control. Med Hypotheses 1994 April;42(4):215-25.
(212) McCarty MF. Hepatothermic therapy of obesity: rationale and an inventory of
resources. Med Hypotheses 2001 September;57(3):324-36.
(213) Bahadori B, Pestemer-Lach I. Die 7 Stufen zum Gleichgewicht. 3rd ed. Graz, Austria:
Eigenverlag Bahadori; 2005.
(214) McCarty MF, Falahati-Nini A. Neuroprotective potential of the Bahadori leanness
program: a "mini-fast with exercise" strategy. Med Hypotheses 2007;68(5):935-40.
(215) McCarty MF, Barroso-Aranda J, Gustin JC, Contreras F. A "mini-fast with exercise"
protocol for fat loss. Medical Hypotheses 2009;accepted for publication.
(216) Goodyear LJ, Kahn BB. Exercise, glucose transport, and insulin sensitivity. Annu Rev
Med 1998;49:235-61.
(217) Holloszy JO. Exercise-induced increase in muscle insulin sensitivity. J Appl Physiol 2005
July;99(1):338-43.
150
(218) Poitout V, Robertson RP. Glucolipotoxicity: fuel excess and beta-cell dysfunction.
Endocr Rev 2008 May;29(3):351-66.
(219) El-Assaad W, Buteau J, Peyot ML, Nolan C, Roduit R, Hardy S, Joly E, Dbaibo G,
Rosenberg L, Prentki M. Saturated fatty acids synergize with elevated glucose to cause
pancreatic beta-cell death. Endocrinology 2003 September;144(9):4154-63.
(220) Schulze MB, Liu S, Rimm EB, Manson JE, Willett WC, Hu FB. Glycemic index,
glycemic load, and dietary fiber intake and incidence of type 2 diabetes in younger and
middle-aged women. Am J Clin Nutr 2004 August;80(2):348-56.
(221) Krishnan S, Rosenberg L, Singer M, Hu FB, Djousse L, Cupples LA, Palmer JR.
Glycemic index, glycemic load, and cereal fiber intake and risk of type 2 diabetes in US
black women. Arch Intern Med 2007 November 26;167(21):2304-9.
(222) Barclay AW, Petocz P, Millan-Price J, Flood VM, Prvan T, Mitchell P, Brand-Miller
JC. Glycemic index, glycemic load, and chronic disease risk--a meta-analysis of
observational studies. Am J Clin Nutr 2008 March;87(3):627-37.
(223) Van de Laar FA, Lucassen PL, Akkermans RP, Van de Lisdonk EH, De Grauw WJ.
Alpha-glucosidase inhibitors for people with impaired glucose tolerance or impaired
fasting blood glucose. Cochrane Database Syst Rev 2006;(4):CD005061.
(224) Barnard RJ, Jung T, Inkeles SB. Diet and exercise in the treatment of NIDDM. The
need for early emphasis. Diabetes Care 1994 December;17(12):1469-72.
(225) Kontessis P, Jones S, Dodds R, Trevisan R, Nosadini R, Fioretto P, Borsato M, Sacerdoti
D, Viberti G. Renal, metabolic and hormonal responses to ingestion of animal and
vegetable proteins. Kidney Int 1990 July;38(1):136-44.
(226) Soroka N, Silverberg DS, Greemland M, Birk Y, Blum M, Peer G, Iaina A. Comparison
of a vegetable-based (soya) and an animal-based low-protein diet in predialysis chronic
renal failure patients. Nephron 1998;79(2):173-80.
(227) Jibani MM, Bloodworth LL, Foden E, Griffiths KD, Galpin OP. Predominantly
vegetarian diet in patients with incipient and early clinical diabetic nephropathy: effects
on albumin excretion rate and nutritional status. Diabet Med 1991 December;8(10):94953.
(228) Crane MG, Sample C. Regression of diebetic neuropathy with total vegetarian (vegan)
diet. J Nutr Med 1994;4:431-9.
(229) DeRose D, Charles-Marcel Z. 1998.
Ref Type: Unpublished Work
(230) Howard BV, Robbins DC, Sievers ML, Lee ET, Rhoades D, Devereux RB, Cowan LD,
Gray RS, Welty TK, Go OT, Howard WJ. LDL cholesterol as a strong predictor of
coronary heart disease in diabetic individuals with insulin resistance and low LDL: The
Strong Heart Study. Arterioscler Thromb Vasc Biol 2000 March;20(3):830-5.
(231) Jenkins DJ, Wolever TM, Buckley G, Lam KY, Giudici S, Kalmusky J, Jenkins AL,
Patten RL, Bird J, Wong GS. Low-glycemic-index starchy foods in the diabetic diet. Am
J Clin Nutr 1988 August;48(2):248-54.
151
(232) Wolever TM, Jenkins DJ, Vuksan V, Jenkins AL, Wong GS, Josse RG. Beneficial effect
of low-glycemic index diet in overweight NIDDM subjects. Diabetes Care 1992
April;15(4):562-4.
(233) Miller JC. Importance of glycemic index in diabetes. Am J Clin Nutr 1994 March;59(3
Suppl):747S-52S.
(234) Coulston AM, Hollenbeck CB, Swislocki AL, Chen YD, Reaven GM. Deleterious
metabolic effects of high-carbohydrate, sucrose-containing diets in patients with noninsulin-dependent diabetes mellitus. Am J Med 1987 February;82(2):213-20.
(235) Chen YD, Coulston AM, Zhou MY, Hollenbeck CB, Reaven GM. Why do low-fat highcarbohydrate diets accentuate postprandial lipemia in patients with NIDDM? Diabetes
Care 1995 January;18(1):10-6.
(236) Pories WJ, MacDonald KG, Flickinger EG, Dohm GL, Sinha MK, Barakat HA, May
HJ, Khazanie P, Swanson MS, Morgan E. Is type II diabetes mellitus (NIDDM) a
surgical disease? Ann Surg 1992 June;215(6):633-42.
(237) Leahy JL, Bonner-Weir S, Weir GC. Beta-cell dysfunction induced by chronic
hyperglycemia. Current ideas on mechanism of impaired glucose-induced insulin
secretion. Diabetes Care 1992 March;15(3):442-55.
(238) Leahy JL, Cooper HE, Deal DA, Weir GC. Chronic hyperglycemia is associated with
impaired glucose influence on insulin secretion. A study in normal rats using chronic in
vivo glucose infusions. J Clin Invest 1986 March;77(3):908-15.
(239) Zangen DH, Bonner-Weir S, Lee CH, Latimer JB, Miller CP, Habener JF, Weir GC.
Reduced insulin, GLUT2, and IDX-1 in beta-cells after partial pancreatectomy. Diabetes
1997 February;46(2):258-64.
(240) McCarty MF. A preliminary fast may potentiate response to a subsequent low-salt, lowfat vegan diet in the management of hypertension - fasting as a strategy for breaking
metabolic vicious cycles. Med Hypotheses 2003 May;60(5):624-33.
(241) Gumbiner B, Polonsky KS, Beltz WF, Griver K, Wallace P, Brechtel G, Henry RR.
Effects of weight loss and reduced hyperglycemia on the kinetics of insulin secretion in
obese non-insulin dependent diabetes mellitus. J Clin Endocrinol Metab 1990
June;70(6):1594-602.
(242) Henry RR, Gumbiner B. Benefits and limitations of very-low-calorie diet therapy in
obese NIDDM. Diabetes Care 1991 September;14(9):802-23.
(243) Wing RR, Marcus MD, Salata R, Epstein LH, Miaskiewicz S, Blair EH. Effects of a
very-low-calorie diet on long-term glycemic control in obese type 2 diabetic subjects [see
comments]. Arch Intern Med 1991 July;151(7):1334-40.
(244) Wing RR, Blair EH, Bononi P, Marcus MD, Watanabe R, Bergman RN. Caloric
restriction per se is a significant factor in improvements in glycemic control and insulin
sensitivity during weight loss in obese NIDDM patients. Diabetes Care 1994
January;17(1):30-6.
(245) Fuhrman J. Fasting and eating for health. New York: St. Martin's Griffin; 1995.
(246) Allen FM. Prolonged fasting in diabetes. Am J Med Sci 1915;159(4):480-5.
152
(247) Wajchenberg BL. beta-cell failure in diabetes and preservation by clinical treatment.
Endocr Rev 2007 April;28(2):187-218.
(248) Inoguchi T, Nawata H. NAD(P)H oxidase activation: a potential target mechanism for
diabetic vascular complications, progressive beta-cell dysfunction and metabolic
syndrome. Curr Drug Targets 2005 June;6(4):495-501.
(249) Inoguchi T, Sasaki S, Kobayashi K, Takayanagi R, Yamada T. Relationship between
Gilbert syndrome and prevalence of vascular complications in patients with diabetes.
JAMA 2007 September 26;298(12):1398-400.
(250) Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, Nakayama
O, Makishima M, Matsuda M, Shimomura I. Increased oxidative stress in obesity and
its impact on metabolic syndrome. J Clin Invest 2004 December;114(12):1752-61.
(251) Guichard C, Moreau R, Pessayre D, Epperson TK, Krause KH. NOX family NADPH
oxidases in liver and in pancreatic islets: a role in the metabolic syndrome and diabetes?
Biochem Soc Trans 2008 October;36(Pt 5):920-9.
(252) Bistrian BR, Blackburn GL, Flatt JP, Sizer J, Scrimshaw NS, Sherman M. Nitrogen
metabolism and insulin requirements in obese diabetic adults on a protein-sparing
modified fast. Diabetes 1976 June;25(6):494-504.
(253) Fleming RM. The effect of high-protein diets on coronary blood flow. Angiology 2000
October;51(10):817-26.
(254) White AM, Johnston CS, Swan PD, Tjonn SL, Sears B. Blood ketones are directly
related to fatigue and perceived effort during exercise in overweight adults adhering to
low-carbohydrate diets for weight loss: a pilot study. J Am Diet Assoc 2007
October;107(10):1792-6.
(255) Skov AR, Toubro S, Ronn B, Holm L, Astrup A. Randomized trial on protein vs
carbohydrate in ad libitum fat reduced diet for the treatment of obesity. Int J Obes Relat
Metab Disord 1999 May;23(5):528-36.
(256) Hannah JS, Dubey AK, Hansen BC. Postingestional effects of a high-protein diet on the
regulation of food intake in monkeys. Am J Clin Nutr 1990 August;52(2):320-5.
(257) Barnard ND. The lipid-lowering effect of lean meat diets falls far short of that of
vegetarian diets. Arch Intern Med 2000 February 14;160(3):395-6.
(258) Knopman D, Boland LL, Mosley T, Howard G, Liao D, Szklo M, McGovern P, Folsom
AR. Cardiovascular risk factors and cognitive decline in middle-aged adults. Neurology
2001 January 9;56(1):42-8.
(259) Forette F, Seux ML, Staessen JA, Thijs L, Birkenhager WH, Babarskiene MR, Babeanu
S, Bossini A, Gil-Extremera B, Girerd X, Laks T, Lilov E, Moisseyev V, Tuomilehto J,
Vanhanen H, Webster J, Yodfat Y, Fagard R. Prevention of dementia in randomised
double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial.
Lancet 1998 October 24;352(9137):1347-51.
(260) Black SE, Patterson C, Feightner J. Preventing dementia. Can J Neurol Sci 2001
February;28 Suppl 1:S56-S66.
153
(261) Beilin LJ, Rouse IL, Armstrong BK, Margetts BM, Vandongen R. Vegetarian diet and
blood pressure levels: incidental or causal association? Am J Clin Nutr 1988
September;48(3 Suppl):806-10.
(262) Appel LJ, Moore TJ, Obarzanek E, Vollmer WM, Svetkey LP, Sacks FM, Bray GA,
Vogt TM, Cutler JA, Windhauser MM, Lin PH, Karanja N. A clinical trial of the effects
of dietary patterns on blood pressure. DASH Collaborative Research Group. N Engl J
Med 1997 April 17;336(16):1117-24.
(263) Sacks FM, Rosner B, Kass EH. Blood pressure in vegetarians. Am J Epidemiol 1974
November;100(5):390-8.
(264) Skott P, Vaag A, Bruun NE, Hother-Nielsen O, Gall MA, Beck-Nielsen H, Parving HH.
Effect of insulin on renal sodium handling in hyperinsulinaemic type 2 (non-insulindependent) diabetic patients with peripheral insulin resistance. Diabetologia 1991
April;34(4):275-81.
(265) Endre T, Mattiasson I, Berglund G, Hulthen UL. Insulin and renal sodium retention in
hypertension-prone men. Hypertension 1994 March;23(3):313-9.
(266) Reaven GM. The kidney: an unwilling accomplice in syndrome X. Am J Kidney Dis 1997
December;30(6):928-31.
(267) Reaven GM, Hoffman BB. A role for insulin in the aetiology and course of
hypertension? Lancet 1987 August 22;2(8556):435-7.
(268) Krieger DR, Landsberg L. Mechanisms in obesity-related hypertension: role of insulin
and catecholamines. Am J Hypertens 1988 January;1(1):84-90.
(269) O'Hare JA, Minaker KL, Meneilly GS, Rowe JW, Pallotta JA, Young JB. Effect of
insulin on plasma norepinephrine and 3,4-dihydroxyphenylalanine in obese men.
Metabolism 1989 April;38(4):322-9.
(270) Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron AD.
Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the
syndrome of insulin resistance. J Clin Invest 1996 June 1;97(11):2601-10.
(271) Cappuccio FP, MacGregor GA. Does potassium supplementation lower blood pressure?
A meta-analysis of published trials. J Hypertens 1991 May;9(5):465-73.
(272) Zhou MS, Nishida Y, Yoneyama H, Chen QH, Kosaka H. Potassium supplementation
increases sodium excretion and nitric oxide production in hypertensive Dahl rats. Clin
Exp Hypertens 1999 November;21(8):1397-411.
(273) Morris RC, Schmidlin O, Tanaka M, Forman A, Frassetto L, Sebastian A. Differing
effects of supplemental KCl and KHCO3: pathophysiological and clinical implications.
Semin Nephrol 1999 September;19(5):487-93.
(274) McCabe RD, Bakarich MA, Srivastava K, Young DB. Potassium inhibits free radical
formation. Hypertension 1994 July;24(1):77-82.
(275) McCarty MF. Endothelial membrane potential regulates production of both nitric oxide
and superoxide--a fundamental determinant of vascular health. Med Hypotheses 1999
October;53(4):277-89.
154
(276) Khaw KT, Barrett-Connor E. Dietary potassium and stroke-associated mortality. A 12year prospective population study. N Engl J Med 1987 January 29;316(5):235-40.
(277) Iso H, Stampfer MJ, Manson JE, Rexrode K, Hennekens CH, Colditz GA, Speizer FE,
Willett WC. Prospective study of calcium, potassium, and magnesium intake and risk of
stroke in women. Stroke 1999 September;30(9):1772-9.
(278) Ascherio A, Rimm EB, Hernan MA, Giovannucci EL, Kawachi I, Stampfer MJ, Willett
WC. Intake of potassium, magnesium, calcium, and fiber and risk of stroke among US
men. Circulation 1998 September 22;98(12):1198-204.
(279) Stamler J, Liu K, Ruth KJ, Pryer J, Greenland P. Eight-year blood pressure change in
middle-aged men: relationship to multiple nutrients. Hypertension 2002 May;39(5):10006.
(280) Stamler J, Caggiula AW, Grandits GA. Relation of body mass and alcohol, nutrient,
fiber, and caffeine intakes to blood pressure in the special intervention and usual care
groups in the Multiple Risk Factor Intervention Trial. Am J Clin Nutr 1997
January;65(1 Suppl):338S-65S.
(281) Stamler J, Elliott P, Kesteloot H, Nichols R, Claeys G, Dyer AR, Stamler R. Inverse
relation of dietary protein markers with blood pressure. Findings for 10,020 men and
women in the INTERSALT Study. INTERSALT Cooperative Research Group.
INTERnational study of SALT and blood pressure. Circulation 1996 October
1;94(7):1629-34.
(282) Liu L, Ikeda K, Sullivan DH, Ling W, Yamori Y. Epidemiological evidence of the
association between dietary protein intake and blood pressure: a meta-analysis of
published data. Hypertens Res 2002 September;25(5):689-95.
(283) Elliott P, Stamler J, Dyer AR, Appel L, Dennis B, Kesteloot H, Ueshima H, Okayama A,
Chan Q, Garside DB, Zhou B. Association between protein intake and blood pressure:
the INTERMAP Study. Arch Intern Med 2006 January 9;166(1):79-87.
(284) Wang YF, Yancy WS, Jr., Yu D, Champagne C, Appel LJ, Lin PH. The relationship
between dietary protein intake and blood pressure: results from the PREMIER study. J
Hum Hypertens 2008 November;22(11):745-54.
(285) Papanikolaou Y, Fulgoni VL, III. Bean consumption is associated with greater nutrient
intake, reduced systolic blood pressure, lower body weight, and a smaller waist
circumference in adults: results from the National Health and Nutrition Examination
Survey 1999-2002. J Am Coll Nutr 2008 October;27(5):569-76.
(286) Nagata C, Shimizu H, Takami R, Hayashi M, Takeda N, Yasuda K. Association of blood
pressure with intake of soy products and other food groups in Japanese men and
women. Prev Med 2003 June;36(6):692-7.
(287) Hasler CM. The cardiovascular effects of soy products. J Cardiovasc Nurs 2002
July;16(4):50-63.
(288) Djousse L, Rudich T, Gaziano JM. Nut consumption and risk of hypertension in US
male physicians. Clin Nutr 2008 September 30.
(289) Meneely GR, Battarbee HD. High sodium-low potassium environment and
hypertension. Am J Cardiol 1976 November 23;38(6):768-85.
155
(290) MacGregor GA, de Wardener HE. Salt, diet and health: Neptune's poisoned chalice: the
origins of high blood pressure. Cambridge: Cambridge University Press; 1998.
(291) Denton D, Weisinger R, Mundy NI, Wickings EJ, Dixson A, Moisson P, Pingard AM,
Shade R, Carey D, Ardaillou R. The effect of increased salt intake on blood pressure of
chimpanzees [see comments]. Nat Med 1995 October;1(10):1009-16.
(292) Perry IJ, Beevers DG. Salt intake and stroke: a possible direct effect. J Hum Hypertens
1992 February;6(1):23-5.
(293) Goulding A. Fasting urinary sodium/creatinine in relation to calcium/creatinine and
hydroxyproline/creatinine in a general population of women. N Z Med J 1981 May
13;93(683):294-7.
(294) Goulding A, McParland BE. Fasting and 24-h urinary sodium/creatinine values in
young and elderly women on low-salt and salt-supplemented regimens. J Cardiovasc
Pharmacol 1990;16 Suppl 7:S47-S49.
(295) MacGregor GA, Cappuccio FP. The kidney and essential hypertension: a link to
osteoporosis? J Hypertens 1993 August;11(8):781-5.
(296) Cirillo M, Laurenzi M, Panarelli W, Stamler J. Urinary sodium to potassium ratio and
urinary stone disease. The Gubbio Population Study Research Group. Kidney Int 1994
October;46(4):1133-9.
(297) Burney P. A diet rich in sodium may potentiate asthma. Epidemiologic evidence for a
new hypothesis. Chest 1987 June;91(6 Suppl):143S-8S.
(298) Carey OJ, Locke C, Cookson JB. Effect of alterations of dietary sodium on the severity
of asthma in men. Thorax 1993 July;48(7):714-8.
(299) Gotshall RW, Mickleborough TD, Cordain L. Dietary salt restriction improves
pulmonary function in exercise-induced asthma. Med Sci Sports Exerc 2000
November;32(11):1815-9.
(300) Joossens JV, Hill MJ, Elliott P, Stamler R, Lesaffre E, Dyer A, Nichols R, Kesteloot H.
Dietary salt, nitrate and stomach cancer mortality in 24 countries. European Cancer
Prevention (ECP) and the INTERSALT Cooperative Research Group. Int J Epidemiol
1996 June;25(3):494-504.
(301) Sonnenberg A. Dietary salt and gastric ulcer. Gut 1986 October;27(10):1138-42.
(302) Fox JG, Dangler CA, Taylor NS, King A, Koh TJ, Wang TC. High-salt diet induces
gastric epithelial hyperplasia and parietal cell loss, and enhances Helicobacter pylori
colonization in C57BL/6 mice. Cancer Res 1999 October 1;59(19):4823-8.
(303) MacGregor GA. Salt--more adverse effects [see comments]. Am J Hypertens 1997
May;10(5 Pt 2):37S-41S.
(304) de Wardener HE. Kidney, salt intake, and Na+,K(+)-ATPase inhibitors in hypertension.
1990 Corcoran Lecture. Hypertension 1991 June;17(6 Pt 2):830-6.
(305) Yuan C, Manunta P, Chen S, Hamlyn JM, Haddy FJ, Pamnani MB. Role of ouabainlike factors in hypertension: effects of ouabain and certain endogenous ouabain-like
factors in hypertension. J Cardiovasc Pharmacol 1993;22 Suppl 2:S10-S12.
156
(306) Dichtchekenian V, Gisiger S, Quental I, Santos SR, Marcondes M, Heimann JC. Higher
salt consumption, digoxin-like factor, and nifedipine response are associated with salt
sensitivity in essential hypertension. Am J Hypertens 1992 October;5(10):707-12.
(307) Oda M, Kurosawa M, Numazawa S, Tanaka S, Akizawa T, Ito K, Maeda M, Yoshida T.
Determination of bufalin-like immunoreactivity in serum of humans and rats by timeresolved fluoroimmunoassay for using a monoclonal antibody. Life Sci 2001 January
26;68(10):1107-17.
(308) Woolfson RG, Graves J, LaBella FS, Templeton JF, Poston L. Effect of bufalin and
pregnanes on vasoreactivity of human resistance arteries. Biochem Biophys Res
Commun 1992 July 15;186(1):1-7.
(309) McCarty MF. Up-regulation of endothelial nitric oxide activity as a central strategy for
prevention of ischemic stroke - just say NO to stroke! Med Hypotheses 2000
November;55(5):386-403.
(310) Lindeberg S, Lundh B. Apparent absence of stroke and ischaemic heart disease in a
traditional Melanesian island: a clinical study in Kitava. J Intern Med 1993
March;233(3):269-75.
(311) Lindeberg S. Apparent absence of cerebrovascular disease in Melanesians. Ph.D thesis.
Lund University, Sweden; 1994.
(312) Lindeberg S, Eliasson M, Lindahl B, Ahren B. Low serum insulin in traditional Pacific
Islanders--the Kitava Study. Metabolism 1999 October;48(10):1216-9.
(313) Trowell HC, Burkitt DP. Western Diseases: Their Emergence and Prevention.
Cambridge, MA: Harvard University Press; 1981.
(314) Stamler JS. Alzheimer's disease. A radical vascular connection. Nature 1996 March
14;380(6570):108-11.
(315) McCarty MF. Vascular nitric oxide may lessen Alzheimer's risk. Med Hypotheses 1998
December;51(6):465-76.
(316) McCarty MF. Vascular nitric oxide, sex hormone replacement, and fish oil may help to
prevent Alzheimer's disease by suppressing synthesis of acute-phase cytokines. Med
Hypotheses 1999 November;53(5):369-74.
(317) de la Torre JC. Cerebral hypoperfusion, capillary degeneration, and development of
Alzheimer disease. Alzheimer Dis Assoc Disord 2000;14 Suppl 1:S72-S81.
(318) Breteler MM. Vascular risk factors for Alzheimer's disease: an epidemiologic
perspective. Neurobiol Aging 2000 March;21(2):153-60.
(319) Kudo T, Imaizumi K, Tanimukai H, Katayama T, Sato N, Nakamura Y, Tanaka T,
Kashiwagi Y, Jinno Y, Tohyama M, Takeda M. Are cerebrovascular factors involved in
Alzheimer's disease? Neurobiol Aging 2000 March;21(2):215-24.
(320) Kalaria RN. The role of cerebral ischemia in Alzheimer's disease. Neurobiol Aging 2000
March;21(2):321-30.
(321) Skoog I. Vascular aspects in Alzheimer's disease. J Neural Transm Suppl 2000;59:37-43.
157
(322) Ogunniyi A, Baiyewu O, Gureje O, Hall KS, Unverzagt F, Siu SH, Gao S, Farlow M,
Oluwole OS, Komolafe O, Hendrie HC. Epidemiology of dementia in Nigeria: results
from the Indianapolis-Ibadan study. Eur J Neurol 2000 September;7(5):485-90.
(323) Endres M, Laufs U, Huang Z, Nakamura T, Huang P, Moskowitz MA, Liao JK. Stroke
protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated
by endothelial nitric oxide synthase. Proc Natl Acad Sci U S A 1998 July 21;95(15):88805.
(324) Zekry D, Epperson TK, Krause KH. A role for NOX NADPH oxidases in Alzheimer's
disease and other types of dementia? IUBMB Life 2003 June;55(6):307-13.
(325) Block ML. NADPH oxidase as a therapeutic target in Alzheimer's disease. BMC
Neurosci 2008;9 Suppl 2:S8.
(326) Huang BS, Veerasingham SJ, Leenen FH. Brain "ouabain," ANG II, and
sympathoexcitation by chronic central sodium loading in rats. Am J Physiol 1998
April;274(4 Pt 2):H1269-H1276.
(327) Huang BS, Cheung WJ, Wang H, Tan J, White RA, Leenen FH. Activation of brain
renin-angiotensin-aldosterone system by central sodium in Wistar rats. Am J Physiol
Heart Circ Physiol 2006 September;291(3):H1109-H1117.
(328) Van Huysse JW. Endogenous brain Na pumps, brain ouabain-like substance and the
alpha2 isoform in salt-dependent hypertension. Pathophysiology 2007 December;14(34):213-20.
(329) Miyoshi M, Miyano K, Moriyama N, Taniguchi M, Watanabe T. Angiotensin type 1
receptor antagonist inhibits lipopolysaccharide-induced stimulation of rat microglial
cells by suppressing nuclear factor kappaB and activator protein-1 activation. Eur J
Neurosci 2008 January;27(2):343-51.
(330) Rodriguez-Pallares J, Rey P, Parga JA, Munoz A, Guerra MJ, Labandeira-Garcia JL.
Brain angiotensin enhances dopaminergic cell death via microglial activation and
NADPH-derived ROS. Neurobiol Dis 2008 July;31(1):58-73.
(331) Skoog I, Gustafson D. Hypertension, hypertension-clustering factors and Alzheimer's
disease. Neurol Res 2003 September;25(6):675-80.
(332) Ohrui T, Matsui T, Yamaya M, Arai H, Ebihara S, Maruyama M, Sasaki H.
Angiotensin-converting enzyme inhibitors and incidence of Alzheimer's disease in
Japan. J Am Geriatr Soc 2004 April;52(4):649-50.
(333) Ohrui T, Tomita N, Sato-Nakagawa T, Matsui T, Maruyama M, Niwa K, Arai H, Sasaki
H. Effects of brain-penetrating ACE inhibitors on Alzheimer disease progression.
Neurology 2004 October 12;63(7):1324-5.
(334) Tzourio C, Anderson C, Chapman N, Woodward M, Neal B, MacMahon S, Chalmers J.
Effects of blood pressure lowering with perindopril and indapamide therapy on
dementia and cognitive decline in patients with cerebrovascular disease. Arch Intern
Med 2003 May 12;163(9):1069-75.
(335) Ellul J, Archer N, Foy CM, Poppe M, Boothby H, Nicholas H, Brown RG, Lovestone S.
The effects of commonly prescribed drugs in patients with Alzheimer's disease on the
rate of deterioration. J Neurol Neurosurg Psychiatry 2007 March;78(3):233-9.
158
(336) Takeda S, Sato N, Ogihara T, Morishita R. The renin-angiotensin system, hypertension
and cognitive dysfunction in Alzheimer's disease: new therapeutic potential. Front
Biosci 2008;13:2253-65.
(337) Hajjar I, Keown M, Frost B. Antihypertensive agents for aging patients who are at risk
for cognitive dysfunction. Curr Hypertens Rep 2005 December;7(6):466-73.
(338) Savaskan E. The role of the brain renin-angiotensin system in neurodegenerative
disorders. Curr Alzheimer Res 2005 January;2(1):29-35.
(339) Grant WB. Fish consumption, cancer, and Alzheimer disease. Am J Clin Nutr 2000
February;71(2):599-600.
(340) Graudal NA, Galloe AM, Garred P. Effects of sodium restriction on blood pressure,
renin, aldosterone, catecholamines, cholesterols, and triglyceride: a meta-analysis.
JAMA 1998 May 6;279(17):1383-91.
(341) Alderman MH, Madhavan S, Ooi WL, Cohen H, Sealey JE, Laragh JH. Association of
the renin-sodium profile with the risk of myocardial infarction in patients with
hypertension. N Engl J Med 1991 April 18;324(16):1098-104.
(342) Meade TW, Cooper JA, Peart WS. Plasma renin activity and ischemic heart disease. N
Engl J Med 1993 August 26;329(9):616-9.
(343) MacGregor GA. The importance of the response of the renin-angiotensin system in
determining blood pressure changes with sodium restriction. Br J Clin Pharmacol
1987;23 Suppl 1:21S-6S.
(344) He FJ, Markandu ND, Sagnella GA, MacGregor GA. Importance of the renin system in
determining blood pressure fall with salt restriction in black and white hypertensives.
Hypertension 1998 November;32(5):820-4.
(345) Geleijnse JM, Hofman A, Witteman JC, Hazebroek AA, Valkenburg HA, Grobbee DE.
Long-term effects of neonatal sodium restriction on blood pressure. Hypertension 1997
April;29(4):913-7.
(346) Egan BM, Weder AB, Petrin J, Hoffman RG. Neurohumoral and metabolic effects of
short-term dietary NaCl restriction in men. Relationship to salt-sensitivity status. Am J
Hypertens 1991 May;4(5 Pt 1):416-21.
(347) Egan BM, Stepniakowski K, Goodfriend TL. Renin and aldosterone are higher and the
hyperinsulinemic effect of salt restriction greater in subjects with risk factors clustering.
Am J Hypertens 1994 October;7(10 Pt 1):886-93.
(348) Meland E, Laerum E, Aakvaag A, Ulvik RJ. Salt restriction and increased insulin
production in hypertensive patients. Scand J Clin Lab Invest 1994 August;54(5):405-9.
(349) Fliser D, Fode P, Arnold U, Nowicki M, Kohl B, Ritz E. The effect of dietary salt on
insulin sensitivity. Eur J Clin Invest 1995 January;25(1):39-43.
(350) Prada P, Okamoto MM, Furukawa LN, Machado UF, Heimann JC, Dolnikoff MS.
High- or low-salt diet from weaning to adulthood: effect on insulin sensitivity in Wistar
rats. Hypertension 2000 January;35(1 Pt 2):424-9.
159
(351) Feldman RD, Schmidt ND. Moderate dietary salt restriction increases vascular and
systemic insulin resistance. Am J Hypertens 1999 June;12(6):643-7.
(352) Feldman RD, Logan AG, Schmidt ND. Dietary salt restriction increases vascular insulin
resistance. Clin Pharmacol Ther 1996 October;60(4):444-51.
(353) Grey A, Braatvedt G, Holdaway I. Moderate dietary salt restriction does not alter
insulin resistance or serum lipids in normal men. Am J Hypertens 1996 April;9(4 Pt
1):317-22.
(354) Meland E, Laerum E, Aakvaag A, Ulvik RJ, Hostmark AT. Salt restriction: effects on
lipids and insulin production in hypertensive patients. Scand J Clin Lab Invest 1997
October;57(6):501-5.
(355) Hilgenfeldt U, Puschner T, Riester U, Finsterle J, Hilgenfeldt J, Ritz E. Low-salt diet
downregulates plasma but not tissue kallikrein-kinin system. Am J Physiol 1998
July;275(1 Pt 2):F88-F93.
(356) Warren SE, Vieweg WV, O'Connor DT. Sympathetic nervous system activity during
sodium restriction in essential hypertension. Clin Cardiol 1980 October;3(5):348-51.
(357) Julius S, Jamerson K. Sympathetics, insulin resistance and coronary risk in
hypertension: the 'chicken-and-egg' question. J Hypertens 1994 May;12(5):495-502.
(358) Giorda C, Appendino M, Mason MG, Imperiale E, Pagano G. Alpha 1-blocker
doxazosin improves peripheral insulin sensitivity in diabetic hypertensive patients.
Metabolism 1995 May;44(5):673-6.
(359) Bataineh A, Raij L. Angiotensin II, nitric oxide, and end-organ damage in hypertension.
Kidney Int Suppl 1998 December;68:S14-S19.
(360) Alderman MH. Salt, blood pressure, and human health. Hypertension 2000
November;36(5):890-3.
(361) Alderman MH, Madhavan S, Cohen H, Sealey JE, Laragh JH. Low urinary sodium is
associated with greater risk of myocardial infarction among treated hypertensive men.
Hypertension 1995 June;25(6):1144-52.
(362) de Wardener H, MacGregor GA. Sodium intake and mortality. Lancet 1998 May
16;351(9114):1508-10.
(363) He J, Ogden LG, Vupputuri S, Bazzano LA, Loria C, Whelton PK. Dietary sodium
intake and subsequent risk of cardiovascular disease in overweight adults. JAMA 1999
December 1;282(21):2027-34.
(364) Alderman MH, Cohen H, Madhavan S. Dietary sodium intake and mortality: the
National Health and Nutrition Examination Survey (NHANES I). Lancet 1998 March
14;351(9105):781-5.
(365) MacGregor GA, Markandu ND, Singer DR, Cappuccio FP, Shore AC, Sagnella GA.
Moderate sodium restriction with angiotensin converting enzyme inhibitor in essential
hypertension: a double blind study. Br Med J (Clin Res Ed) 1987 February
28;294(6571):531-4.
160
(366) Egan BM, Stepniakowski K. Effects of enalapril on the hyperinsulinemic response to
severe salt restriction in obese young men with mild systemic hypertension. Am J Cardiol
1993 July 1;72(1):53-7.
(367) Hui R, St-Louis J, Falardeau P. Antihypertensive properties of linoleic acid and fish oil
omega-3 fatty acids independent of the prostaglandin system. Am J Hypertens 1989
August;2(8):610-7.
(368) Juan H, Sametz W. Vasoconstriction induced by noradrenaline and angiotensin II is
antagonized by eicosapentaenoic acid independent of formation of trienoic eicosanoids.
Naunyn Schmiedebergs Arch Pharmacol 1986 March;332(3):288-92.
(369) Yoshimura T, Matsui K, Ito M, Yunohara T, Kawasaki N, Nakamura T, Okamura H.
Effects of highly purified eicosapentaenoic acid on plasma beta thromboglobulin level
and vascular reactivity to angiotensin II. Artery 1987;14(5):295-303.
(370) Kenny D, Warltier DC, Pleuss JA, Hoffmann RG, Goodfriend TL, Egan BM. Effect of
omega-3 fatty acids on the vascular response to angiotensin in normotensive men. Am J
Cardiol 1992 November 15;70(15):1347-52.
(371) Chin JP, Gust AP, Nestel PJ, Dart AM. Marine oils dose-dependently inhibit
vasoconstriction of forearm resistance vessels in humans. Hypertension 1993
January;21(1):22-8.
(372) Adair CD, Sanchez-Ramos L, Briones DL, Ogburn P. The effect of high dietary n-3 fatty
acid supplementation on angiotensin II pressor response in human pregnancy. Am J
Obstet Gynecol 1996 September;175(3 Pt 1):688-91.
(373) Cobiac L, Nestel PJ, Wing LM, Howe PR. A low-sodium diet supplemented with fish oil
lowers blood pressure in the elderly. J Hypertens 1992 January;10(1):87-92.
(374) Karaki H, Doi K, Sugano S, Uchiwa H, Sugai R, Murakami U, Takemoto S.
Antihypertensive effect of tryptic hydrolysate of milk casein in spontaneously
hypertensive rats. Comp Biochem Physiol C 1990;96(2):367-71.
(375) Yokoyama K, Chiba H, Yoshikawa M. Peptide inhibitors for angiotensin I-converting
enzyme from thermolysin digest of dried bonito. Biosci Biotechnol Biochem 1992
October;56(10):1541-5.
(376) Matsufuji H, Matsui T, Seki E, Osajima K, Nakashima M, Osajima Y. Angiotensin Iconverting enzyme inhibitory peptides in an alkaline protease hydrolyzate derived from
sardine muscle. Biosci Biotechnol Biochem 1994 December;58(12):2244-5.
(377) Astawan M, Wahyuni M, Yasuhara T, Yamada K, Tadokoro T, Maekawa A. Effects of
angiotensin I-converting enzyme inhibitory substances derived from Indonesian driedsalted fish on blood pressure of rats. Biosci Biotechnol Biochem 1995 March;59(3):425-9.
(378) Fujita H, Yokoyama K, Yasumoto R, Yoshikawa M. Antihypertensive effect of
thermolysin digest of dried bonito in spontaneously hypertensive rat. Clin Exp
Pharmacol Physiol Suppl 1995;1:S304-S305.
(379) Matsui T, Li CH, Osajima Y. Preparation and characterization of novel bioactive
peptides responsible for angiotensin I-converting enzyme inhibition from wheat germ. J
Pept Sci 1999 July;5(7):289-97.
161
(380) Fujita H, Yoshikawa M. LKPNM: a prodrug-type ACE-inhibitory peptide derived from
fish protein. Immunopharmacology 1999 October 15;44(1-2):123-7.
(381) Pihlanto-Leppala A, Koskinen P, Piilola K, Tupasela T, Korhonen H. Angiotensin Iconverting enzyme inhibitory properties of whey protein digests: concentration and
characterization of active peptides. J Dairy Res 2000 February;67(1):53-64.
(382) Matsui T, Li CH, Tanaka T, Maki T, Osajima Y, Matsumoto K. Depressor effect of
wheat germ hydrolysate and its novel angiotensin I-converting enzyme inhibitory
peptide, Ile-Val-Tyr, and the metabolism in rat and human plasma. Biol Pharm Bull
2000 April;23(4):427-31.
(383) Fujita H, Yokoyama K, Yoshikawa M. Classification and antihypertensive activity oF
angiotensin I-converting enzyme inhibitory peptides derived from food proteins. J Food
Science 2000;65:564-9.
(384) Gobbetti M, Ferranti P, Smacchi E, Goffredi F, Addeo F. Production of angiotensin-Iconverting-enzyme-inhibitory peptides in fermented milks started by Lactobacillus
delbrueckii subsp. bulgaricus SS1 and Lactococcus lactis subsp. cremoris FT4. Appl
Environ Microbiol 2000 September;66(9):3898-904.
(385) FitzGerald RJ, Meisel H. Milk protein-derived peptide inhibitors of angiotensin-Iconverting enzyme. Br J Nutr 2000 November;84 Suppl 1:S33-S37.
(386) Wu J, Ding X. Hypotensive and physiological effect of angiotensin converting enzyme
inhibitory peptides derived from soy protein on spontaneously hypertensive rats. J Agric
Food Chem 2001 January;49(1):501-6.
(387) Fujita H, Yamagami T, Ohshima K. Effects of an ace-inhibitory agent, katsuobushi
oligopeptide, in the spontaneously hypertensive rat and in borderline and mildly
hypertensive subjects. Nutrition Research 2001;21:in press.
(388) Cheng JW, Ngo MN. Current perspective on the use of angiotensin-converting enzyme
inhibitors in the management of coronary (atherosclerotic) artery disease. Ann
Pharmacother 1997 December;31(12):1499-506.
(389) Gibbons GH. Vasculoprotective and cardioprotective mechanisms of angiotensinconverting enzyme inhibition: the homeostatic balance between angiotensin II and nitric
oxide. Clin Cardiol 1997 November;20(11 Suppl 2):II-25.
(390) Mombouli JV. ACE inhibition, endothelial function and coronary artery lesions. Role of
kinins and nitric oxide. Drugs 1997;54 Suppl 5:12-22.
(391) Hornig B, Drexler H. Endothelial function and bradykinin in humans. Drugs 1997;54
Suppl 5:42-7.
(392) Lee AF, Struthers AD. The impact of angiotensin converting enzyme inhibitors on the
arterial wall. Vasc Med 1996;1(2):109-13.
(393) Yusuf S, Gerstein H, Hoogwerf B, Pogue J, Bosch J, Wolffenbuttel BH, Zinman B.
Ramipril and the development of diabetes. JAMA 2001;286:1882-5.
(394) Goldman J, Pfister D, Vukmirovich R. Potentiation of insulin stimulation of hexose
transport by kallikrein and bradykinin in isolated rat adipocytes. Mol Cell Endocrinol
1987 April;50(3):183-91.
162
(395) Isami S, Kishikawa H, Araki E, Uehara M, Kaneko K, Shirotani T, Todaka M, Ura S,
Motoyoshi S, Matsumoto K, Miyamura N, Shichiri M. Bradykinin enhances GLUT4
translocation through the increase of insulin receptor tyrosine kinase in primary
adipocytes: evidence that bradykinin stimulates the insulin signalling pathway.
Diabetologia 1996 April;39(4):412-20.
(396) Miyata T, Taguchi T, Uehara M, Isami S, Kishikawa H, Kaneko K, Araki E, Shichiri M.
Bradykinin potentiates insulin-stimulated glucose uptake and enhances insulin signal
through the bradykinin B2 receptor in dog skeletal muscle and rat L6 myoblasts. Eur J
Endocrinol 1998 March;138(3):344-52.
(397) Caldiz CI, de Cingolani GE. Insulin resistance in adipocytes from spontaneously
hypertensive rats: effect of long-term treatment with enalapril and losartan. Metabolism
1999 August;48(8):1041-6.
(398) Motoshima H, Araki E, Nishiyama T, Taguchi T, Kaneko K, Hirashima Y, Yoshizato K,
Shirakami A, Sakai K, Kawashima J, Shirotani T, Kishikawa H, Shichiri M. Bradykinin
enhances insulin receptor tyrosine kinase in 32D cells reconstituted with bradykinin and
insulin signaling pathways. Diabetes Res Clin Pract 2000 June;48(3):155-70.
(399) Kowala MC, Valentine M, Recce R, Beyer S, Goller N, Durham S, Aberg G. Enhanced
reduction of atherosclerosis in hamsters treated with pravastatin and captopril: ACE in
atheromas provides cellular targets for captopril. J Cardiovasc Pharmacol 1998
July;32(1):29-38.
(400) Villa E, Rabano A, Albarran OG, Ruilope LM, Garcia-Robles R. Effects of chronic
combined treatment with captopril and pravastatin on the progression of insulin
resistance and cardiovascular alterations in an experimental model of obesity in dogs.
Am J Hypertens 1998 July;11(7):844-51.
(401) Nazzaro P, Manzari M, Merlo M, Triggiani R, Scarano A, Ciancio L, Pirrelli A. Distinct
and combined vascular effects of ACE blockade and HMG-CoA reductase inhibition in
hypertensive subjects. Hypertension 1999 February;33(2):719-25.
(402) Sposito AC, Mansur AP, Coelho OR, Nicolau JC, Ramires JA. Additional reduction in
blood pressure after cholesterol-lowering treatment by statins (lovastatin or pravastatin)
in hypercholesterolemic patients using angiotensin-converting enzyme inhibitors
(enalapril or lisinopril). Am J Cardiol 1999 May 15;83(10):1497-9, A8.
(403) Esper RJ, Machado R, Vilarino J, Cacharron JL, Ingino CA, Garcia GC, Bereziuk E,
Bolano AL, Suarez DH. Endothelium-dependent responses in patients with
hypercholesterolemic coronary artery disease under the effects of simvastatin and
enalapril, either separately or combined. Am Heart J 2000 October;140(4):684-9.
(404) Siani A, Pagano E, Iacone R, Iacoviello L, Scopacasa F, Strazzullo P. Blood pressure and
metabolic changes during dietary L-arginine supplementation in humans [In Process
Citation]. Am J Hypertens 2000 May;13(5 Pt 1):547-51.
(405) Kohashi N, Okabayashi T, Hama J, Katori R. Decreased urinary taurine in essential
hypertension. Prog Clin Biol Res 1983;125:73-87.
(406) Fujita T, Ando K, Noda H, Ito Y, Sato Y. Effects of increased adrenomedullary activity
and taurine in young patients with borderline hypertension. Circulation 1987
March;75(3):525-32.
163
(407) Digiesi V, Cantini F, Oradei A, Bisi G, Guarino GC, Brocchi A, Bellandi F, Mancini M,
Littarru GP. Coenzyme Q10 in essential hypertension. Mol Aspects Med 1994;15
Suppl:s257-s263.
(408) Singh RB, Niaz MA, Rastogi SS, Shukla PK, Thakur AS. Effect of hydrosoluble
coenzyme Q10 on blood pressures and insulin resistance in hypertensive patients with
coronary artery disease. J Hum Hypertens 1999 March;13(3):203-8.
(409) Grassi D, Necozione S, Lippi C, Croce G, Valeri L, Pasqualetti P, Desideri G, Blumberg
JB, Ferri C. Cocoa reduces blood pressure and insulin resistance and improves
endothelium-dependent vasodilation in hypertensives. Hypertension 2005
August;46(2):398-405.
(410) Grassi D, Desideri G, Necozione S, Lippi C, Casale R, Properzi G, Blumberg JB, Ferri
C. Blood pressure is reduced and insulin sensitivity increased in glucose-intolerant,
hypertensive subjects after 15 days of consuming high-polyphenol dark chocolate. J Nutr
2008 September;138(9):1671-6.
(411) Bayard V, Chamorro F, Motta J, Hollenberg NK. Does flavanol intake influence
mortality from nitric oxide-dependent processes? Ischemic heart disease, stroke,
diabetes mellitus, and cancer in Panama. Int J Med Sci 2007;4(1):53-8.
(412) McCullough ML, Chevaux K, Jackson L, Preston M, Martinez G, Schmitz HH, Coletti
C, Campos H, Hollenberg NK. Hypertension, the Kuna, and the epidemiology of
flavanols. J Cardiovasc Pharmacol 2006;47 Suppl 2:S103-S109.
(413) Schroeter H, Heiss C, Balzer J, Kleinbongard P, Keen CL, Hollenberg NK, Sies H,
Kwik-Uribe C, Schmitz HH, Kelm M. (-)-Epicatechin mediates beneficial effects of
flavanol-rich cocoa on vascular function in humans. Proc Natl Acad Sci U S A 2006
January 24;103(4):1024-9.
(414) Wilkinson BL, Landreth GE. The microglial NADPH oxidase complex as a source of
oxidative stress in Alzheimer's disease. J Neuroinflammation 2006;3:30.
(415) Qin B, Cartier L, Dubois-Dauphin M, Li B, Serrander L, Krause KH. A key role for the
microglial NADPH oxidase in APP-dependent killing of neurons. Neurobiol Aging 2006
November;27(11):1577-87.
(416) Jana A, Pahan K. Fibrillar amyloid-beta peptides kill human primary neurons via
NADPH oxidase-mediated activation of neutral sphingomyelinase. Implications for
Alzheimer's disease. J Biol Chem 2004 December 3;279(49):51451-9.
(417) Chamorro G, Perez-Albiter M, Serrano-Garcia N, Mares-Samano JJ, Rojas P. Spirulina
maxima pretreatment partially protects against 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine neurotoxicity. Nutr Neurosci 2006 October;9(5-6):207-12.
(418) Rimbau V, Camins A, Romay C, Gonzalez R, Pallas M. Protective effects of Cphycocyanin against kainic acid-induced neuronal damage in rat hippocampus. Neurosci
Lett 1999 December 3;276(2):75-8.
(419) Brown GC. Mechanisms of inflammatory neurodegeneration: iNOS and NADPH
oxidase. Biochem Soc Trans 2007 November;35(Pt 5):1119-21.
(420) Wu DC, Teismann P, Tieu K, Vila M, Jackson-Lewis V, Ischiropoulos H, Przedborski S.
NADPH oxidase mediates oxidative stress in the 1-methyl-4-phenyl-1,2,3,6-
164
tetrahydropyridine model of Parkinson's disease. Proc Natl Acad Sci U S A 2003 May
13;100(10):6145-50.
(421) Wu DC, Re DB, Nagai M, Ischiropoulos H, Przedborski S. The inflammatory NADPH
oxidase enzyme modulates motor neuron degeneration in amyotrophic lateral sclerosis
mice. Proc Natl Acad Sci U S A 2006 August 8;103(32):12132-7.
(422) Kotchen TA, Kotchen JM. Dietary sodium and blood pressure: interactions with other
nutrients. Am J Clin Nutr 1997 February;65(2 Suppl):708S-11S.
(423) Kurtz TW, Al-Bander HA, Morris RC. "Salt-sensitive" essential hypertension in men. Is
the sodium ion alone important? N Engl J Med 1987 October 22;317(17):1043-8.
(424) Sharma AM, Schattenfroh S, Thiede HM, Oelkers W, Distler A. Effects of sodium salts
on pressor reactivity in salt-sensitive men. Hypertension 1992 June;19(6 Pt 1):541-8.
(425) Kurtz TW, Morris RCJ. Dietary chloride as a determinant of "sodium-dependent"
hypertension. Science 1983 December 9;222(4628):1139-41.
(426) Sharma AM, Schattenfroh S, Thiede HM, Oelkers W, Distler A. Effects of sodium salts
on pressor reactivity in salt-sensitive men. Hypertension 1992 June;19(6 Pt 1):541-8.
(427) Imamura T, Doi Y, Arima H, Yonemoto K, Hata J, Kubo M, Tanizaki Y, Ibayashi S,
Iida M, Kiyohara Y. LDL Cholesterol and the Development of Stroke Subtypes and
Coronary Heart Disease in a General Japanese Population. The Hisayama Study. Stroke
2008 December 18.
(428) Puddey IB. Low serum cholesterol and the risk of cerebral haemorrhage. Atherosclerosis
1996 January 5;119(1):1-6.
(429) Tanaka H, Ueda Y, Hayashi M, Date C, Baba T, Yamashita H, Shoji H, Tanaka Y,
Owada K, Detels R. Risk factors for cerebral hemorrhage and cerebral infarction in a
Japanese rural community. Stroke 1982 January;13(1):62-73.
(430) Kuller L, Reisler DM. An explanation for variations in distribution of stroke and
arteriosclerotic heart disease among populations and racial groups. Am J Epidemiol
1971 January;93(1):1-9.
(431) He J, Klag MJ, Wu Z, Whelton PK. Stroke in the People's Republic of China. II. Metaanalysis of hypertension and risk of stroke. Stroke 1995 December;26(12):2228-32.
(432) Reed DM. The paradox of high risk of stroke in populations with low risk of coronary
heart disease. Am J Epidemiol 1990 April;131(4):579-88.
(433) Goldhamer A, Lisle D, Parpia B, Anderson SV, Campbell TC. Medically supervised
water-only fasting in the treatment of hypertension. J Manipulative Physiol Ther 2001
June;24(5):335-9.
(434) McCarty MF. A preliminary fast may potentiate response to a subsequent low-salt, lowfat vegan diet in the management of hypertension - fasting as a strategy for breaking
metabolic vicious cycles. Medical Hypotheses 2001;submitted for publication.
(435) Landau RL, Rochman H, Blix-Gruber P, Rubenstein AH. The protein-sparing action of
protein feeding: absence of relationship to insulin secretion. Am J Clin Nutr 1981
July;34(7):1300-4.
165
(436) Bistrian BR. Clinical use of a protein-sparing modified fast. JAMA 1978 November
17;240(21):2299-302.
(437) Bistrian BR, Blackburn GL, Flatt JP, Sizer J, Scrimshaw NS, Sherman M. Nitrogen
metabolism and insulin requirements in obese diabetic adults on a protein-sparing
modified fast. Diabetes 1976 June;25(6):494-504.
(438) Palgi A, Read JL, Greenberg I, Hoefer MA, Bistrian BR, Blackburn GL.
Multidisciplinary treatment of obesity with a protein-sparing modified fast: results in
668 outpatients. Am J Public Health 1985 October;75(10):1190-4.
(439) Schatzkin A, Lanza E, Corle D, Lance P, Iber F, Caan B, Shike M, Weissfeld J, Burt R,
Cooper MR, Kikendall JW, Cahill J. Lack of effect of a low-fat, high-fiber diet on the
recurrence of colorectal adenomas. Polyp Prevention Trial Study Group. N Engl J Med
2000 April 20;342(16):1149-55.
(440) Ornish D. High-fiber diet and colorectal adenomas. N Engl J Med 2000 September
7;343(10):736-8.
(441) Willett WC. Specific fatty acids and risks of breast and prostate cancer: dietary intake.
Am J Clin Nutr 1997 December;66(6 Suppl):1557S-63S.
(442) O'Keefe SJ, Kidd M, Espitalier-Noel G, Owira P. Rarity of colon cancer in Africans is
associated with low animal product consumption, not fiber. Am J Gastroenterol 1999
May;94(5):1373-80.
(443) Alberts DS, Martinez ME, Roe DJ, Guillen-Rodriguez JM, Marshall JR, van Leeuwen
JB, Reid ME, Ritenbaugh C, Vargas PA, Bhattacharyya AB, Earnest DL, Sampliner
RE. Lack of effect of a high-fiber cereal supplement on the recurrence of colorectal
adenomas. Phoenix Colon Cancer Prevention Physicians' Network. N Engl J Med 2000
April 20;342(16):1156-62.
(444) Schulte-Hermann R, Bursch W, Kraupp-Grasl B, Oberhammer F, Wagner A.
Programmed cell death and its protective role with particular reference to apoptosis.
Toxicol Lett 1992 December;64-65 Spec No:569-74.
(445) Schulte-Hermann R, Bursch W, Grasl-Kraupp B, Mullauer L, Ruttkay-Nedecky B.
Apoptosis and multistage carcinogenesis in rat liver. Mutat Res 1995 December;333(12):81-7.
(446) Wright SC, Zhong J, Larrick JW. Inhibition of apoptosis as a mechanism of tumor
promotion. FASEB J 1994 June;8(9):654-60.
(447) Werner H, LeRoith D. The role of the insulin-like growth factor system in human
cancer. Adv Cancer Res 1996;68:183-223.
(448) Resnicoff M, Abraham D, Yutanawiboonchai W, Rotman HL, Kajstura J, Rubin R,
Zoltick P, Baserga R. The insulin-like growth factor I receptor protects tumor cells from
apoptosis in vivo. Cancer Res 1995 June 1;55(11):2463-9.
(449) Parrizas M, Saltiel AR, LeRoith D. Insulin-like growth factor 1 inhibits apoptosis using
the phosphatidylinositol 3'-kinase and mitogen-activated protein kinase pathways. J Biol
Chem 1997 January 3;272(1):154-61.
166
(450) Werner H, Shalita-Chesner M, Abramovitch S, Idelman G, Shaharabani-Gargir L,
Glaser T. Regulation of the insulin-like growth factor-I receptor gene by oncogenes and
antioncogenes: implications in human cancer. Mol Genet Metab 2000 September;71(12):315-20.
(451) Maor SB, Abramovitch S, Erdos MR, Brody LC, Werner H. BRCA1 suppresses insulinlike growth factor-I receptor promoter activity: potential interaction between BRCA1
and Sp1. Mol Genet Metab 2000 February;69(2):130-6.
(452) Dunn SE, Kari FW, French J, Leininger JR, Travlos G, Wilson R, Barrett JC. Dietary
restriction reduces insulin-like growth factor I levels, which modulates apoptosis, cell
proliferation, and tumor progression in p53- deficient mice. Cancer Res 1997 November
1;57(21):4667-72.
(453) Kari FW, Dunn SE, French JE, Barrett JC. Roles for insulin-like growth factor-1 in
mediating the anti- carcinogenic effects of caloric restriction [In Process Citation]. J
Nutr Health Aging 1999;3(2):92-101.
(454) Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson P, Hennekens CH,
Pollak M. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective
study [see comments]. Science 1998 January 23;279(5350):563-6.
(455) Giovannucci E. Insulin-like growth factor-I and binding protein-3 and risk of cancer.
Horm Res 1999;51 Suppl 3:34-41.
(456) Pollak M. Insulin-like growth factor physiology and cancer risk. Eur J Cancer 2000
June;36(10):1224-8.
(457) Yu H, Rohan T. Role of the insulin-like growth factor family in cancer development and
progression. J Natl Cancer Inst 2000 September 20;92(18):1472-89.
(458) Chokkalingam AP, Pollak M, Fillmore CM, Gao YT, Stanczyk FZ, Deng J, Sesterhenn
IA, Mostofi FK, Fears TR, Madigan MP, Ziegler RG, Fraumeni JFJ, Hsing AW.
Insulin-like growth factors and prostate cancer: a population-based case-control study
in china. Cancer Epidemiol Biomarkers Prev 2001 May;10(5):421-7.
(459) Roddam AW, Allen NE, Appleby P, Key TJ, Ferrucci L, Carter HB, Metter EJ, Chen C,
Weiss NS, Fitzpatrick A, Hsing AW, Lacey JV, Jr., Helzlsouer K, Rinaldi S, Riboli E,
Kaaks R, Janssen JA, Wildhagen MF, Schroder FH, Platz EA, Pollak M, Giovannucci
E, Schaefer C, Quesenberry CP, Jr., Vogelman JH, Severi G, English DR, Giles GG,
Stattin P, Hallmans G, Johansson M, Chan JM, Gann P, Oliver SE, Holly JM, Donovan
J, Meyer F, Bairati I, Galan P. Insulin-like growth factors, their binding proteins, and
prostate cancer risk: analysis of individual patient data from 12 prospective studies. Ann
Intern Med 2008 October 7;149(7):461-8.
(460) Phillips LS, Goldstein S, Pao CI. Nutrition and somatomedin. XXVI. Molecular
regulation of IGF-I by insulin in cultured rat hepatocytes. Diabetes 1991
November;40(11):1525-30.
(461) Baxter RC. Insulin-like growth factor binding proteins in the human circulation: a
review. Horm Res 1994;42(4-5):140-4.
(462) Lewitt MS, Denyer GS, Cooney GJ, Baxter RC. Insulin-like growth factor-binding
protein-1 modulates blood glucose levels. Endocrinology 1991 October;129(4):2254-6.
167
(463) Frystyk J, Hussain M, Skjaerbaek C, Schmitz O, Christiansen JS, Froesch ER, Orskov
H. Serum free IGF-I during a hyperinsulinemic clamp following 3 days of
administration of IGF-I vs. saline. Am J Physiol 1997 September;273(3 Pt 1):E507-E513.
(464) Khaodhiar L, McCowen KC, Blackburn GL. Obesity and its comorbid conditions. Clin
Cornerstone 1999;2(3):17-31.
(465) McTiernan A, Ulrich C, Slate S, Potter J. Physical activity and cancer etiology:
associations and mechanisms. Cancer Causes Control 1998 October;9(5):487-509.
(466) Underwood LE, Thissen JP, Lemozy S, Ketelslegers JM, Clemmons DR. Hormonal and
nutritional regulation of IGF-I and its binding proteins. Horm Res 1994;42(4-5):145-51.
(467) Straus DS. Nutritional regulation of hormones and growth factors that control
mammalian growth. FASEB J 1994 January;8(1):6-12.
(468) Jousse C, Bruhat A, Ferrara M, Fafournoux P. Physiological concentration of amino
acids regulates insulin-like- growth-factor-binding protein 1 expression. Biochem J 1998
August 15;334 ( Pt 1):147-53.
(469) Appleton BS, Campbell TC. Inhibition of aflatoxin-initiated preneoplastic liver lesions
by low dietary protein. Nutr Cancer 1982;3(4):200-6.
(470) Schulsinger DA, Root MM, Campbell TC. Effect of dietary protein quality on
development of aflatoxin B1-induced hepatic preneoplastic lesions. J Natl Cancer Inst
1989 August 16;81(16):1241-5.
(471) Youngman LD, Campbell TC. The sustained development of preneoplastic lesions
depends on high protein intake. Nutr Cancer 1992;18(2):131-42.
(472) Youngman LD, Campbell TC. Attenuation of preneoplastic lesion development by
dietary protein intervention: apparent persistence and regression. Cancer Lett 1992
September 30;66(2):165-74.
(473) Hawrylewicz EJ, Zapata JJ, Blair WH. Soy and experimental cancer: animal studies. J
Nutr 1995 March;125(3 Suppl):698S-708S.
(474) Allen NE, Appleby PN, Davey GK, Key TJ. Hormones and diet: low insulin-like growth
factor-I but normal bioavailable androgens in vegan men. Br J Cancer 2000
July;83(1):95-7.
(475) Allen NE, Appleby PN, Davey GK, Kaaks R, Rinaldi S, Key TJ. The associations of diet
with serum insulin-like growth factor I and its main binding proteins in 292 women
meat-eaters, vegetarians, and vegans. Cancer Epidemiol Biomarkers Prev 2002
November;11(11):1441-8.
(476) Sanchez A, Hubbard RW. Plasma amino acids and the insulin/glucagon ratio as an
explanation for the dietary protein modulation of atherosclerosis. Med Hypotheses 1991
August;35(4):324-9.
(477) McCarty MF. Vegan proteins may reduce risk of cancer, obesity, and cardiovascular
disease by promoting increased glucagon activity. Med Hypotheses 1999
December;53(6):459-85.
168
(478) Krajcovicova-Kudlackova M, Babinska K, Valachovicova M. Health benefits and risks
of plant proteins. Bratisl Lek Listy 2005;106(6-7):231-4.
(479) Jacobs RL, Stead LM, Brosnan ME, Brosnan JT. Hyperglucagonemia in rats results in
decreased plasma homocysteine and increased flux through the transsulfuration
pathway in liver. J Biol Chem 2001 November 23;276(47):43740-7.
(480) Singh A, Hamilton-Fairley D, Koistinen R, Seppala M, James VH, Franks S, Reed MJ.
Effect of insulin-like growth factor-type I (IGF-I) and insulin on the secretion of sex
hormone binding globulin and IGF-I binding protein (IBP-I) by human hepatoma cells.
J Endocrinol 1990 February;124(2):R1-R3.
(481) Franks S, Kiddy DS, Hamilton-Fairley D, Bush A, Sharp PS, Reed MJ. The role of
nutrition and insulin in the regulation of sex hormone binding globulin. J Steroid
Biochem Mol Biol 1991 November;39(5B):835-8.
(482) Reis AF, Miranda WL, Chacra AR. Low levels of sex hormone-binding globulin and
hyperproinsulinemia as markers of increased pancreatic beta-cell demand in men. Braz
J Med Biol Res 1998 December;31(12):1545-51.
(483) Foster CM, Hashimoto N, Randolph JF, Beitins IZ. Comparison of growth hormone and
insulin-like growth factor-I regulation of estradiol and progesterone production in
human luteinized granulosa cells. Pediatr Res 1995 November;38(5):763-7.
(484) Bagga D, Ashley JM, Geffrey SP, Wang HJ, Barnard RJ, Korenman S, Heber D. Effects
of a very low fat, high fiber diet on serum hormones and menstrual function.
Implications for breast cancer prevention. Cancer 1995 December 15;76(12):2491-6.
(485) Key TJ, Chen J, Wang DY, Pike MC, Boreham J. Sex hormones in women in rural
China and in Britain. Br J Cancer 1990 October;62(4):631-6.
(486) Gorbach SL, Goldin BR. Diet and the excretion and enterohepatic cycling of estrogens.
Prev Med 1987 July;16(4):525-31.
(487) Tymchuk CN, Tessler SB, Aronson WJ, Barnard RJ. Effects of diet and exercise on
insulin, sex hormone-binding globulin, and prostate-specific antigen. Nutr Cancer
1998;31(2):127-31.
(488) Rosenthal MB, Barnard RJ, Rose DP, Inkeles S, Hall J, Pritikin N. Effects of a highcomplex-carbohydrate, low-fat, low-cholesterol diet on levels of serum lipids and
estradiol. Am J Med 1985 January;78(1):23-7.
(489) Belanger A, Locong A, Noel C, Cusan L, Dupont A, Prevost J, Caron S, Sevigny J.
Influence of diet on plasma steroids and sex hormone-binding globulin levels in adult
men. J Steroid Biochem 1989 June;32(6):829-33.
(490) Schmidt T, Wijga A, Von Zur M, Brabant G, Wagner TO. Changes in cardiovascular
risk factors and hormones during a comprehensive residential three month kriya yoga
training and vegetarian nutrition. Acta Physiol Scand Suppl 1997;640:158-62.
(491) Lookingbill DP, Demers LM, Wang C, Leung A, Rittmaster RS, Santen RJ. Clinical and
biochemical parameters of androgen action in normal healthy Caucasian versus Chinese
subjects. J Clin Endocrinol Metab 1991 June;72(6):1242-8.
169
(492) van der Burg B, Rutteman GR, Blankenstein MA, de Laat SW, van Zoelen EJ.
Mitogenic stimulation of human breast cancer cells in a growth factor-defined medium:
synergistic action of insulin and estrogen. J Cell Physiol 1988 January;134(1):101-8.
(493) Stewart AJ, Johnson MD, May FE, Westley BR. Role of insulin-like growth factors and
the type I insulin-like growth factor receptor in the estrogen-stimulated proliferation of
human breast cancer cells. J Biol Chem 1990 December 5;265(34):21172-8.
(494) Thorsen T, Lahooti H, Rasmussen M, Aakvaag A. Oestradiol treatment increases the
sensitivity of MCF-7 cells for the growth stimulatory effect of IGF-I. J Steroid Biochem
Mol Biol 1992 March;41(3-8):537-40.
(495) Molloy CA, May FE, Westley BR. Insulin receptor substrate-1 expression is regulated
by estrogen in the MCF-7 human breast cancer cell line. J Biol Chem 2000 April
28;275(17):12565-71.
(496) Surmacz E, Burgaud JL. Overexpression of insulin receptor substrate 1 (IRS-1) in the
human breast cancer cell line MCF-7 induces loss of estrogen requirements for growth
and transformation. Clin Cancer Res 1995 November;1(11):1429-36.
(497) Iwamura M, Sluss PM, Casamento JB, Cockett AT. Insulin-like growth factor I: action
and receptor characterization in human prostate cancer cell lines. Prostate
1993;22(3):243-52.
(498) Gapstur SM, Gann PH, Lowe W, Liu K, Colangelo L, Dyer A. Abnormal glucose
metabolism and pancreatic cancer mortality [In Process Citation]. JAMA 2000 May
17;283(19):2552-8.
(499) Fisher WE, Boros LG, Schirmer WJ. Insulin promotes pancreatic cancer: evidence for
endocrine influence on exocrine pancreatic tumors. J Surg Res 1996 June;63(1):310-3.
(500) Goalstone ML, Leitner JW, Wall K, Dolgonos L, Rother KI, Accili D, Draznin B. Effect
of insulin on farnesyltransferase. Specificity of insulin action and potentiation of nuclear
effects of insulin-like growth factor-1, epidermal growth factor, and platelet-derived
growth factor. J Biol Chem 1998 September 11;273(37):23892-6.
(501) Goalstone ML, Natarajan R, Standley PR, Walsh MF, Leitner JW, Carel K, Scott S,
Nadler J, Sowers JR, Draznin B. Insulin potentiates platelet-derived growth factor
action in vascular smooth muscle cells. Endocrinology 1998 October;139(10):4067-72.
(502) Nagase T, Kawata S, Nakajima H, Tamura S, Yamasaki E, Fukui K, Yamamoto K,
Miyagawa J, Matsumura I, Matsuda Y, Matsuzawa Y. Effect of farnesyltransferase
overexpression on cell growth and transformation. Int J Cancer 1999 January
5;80(1):126-33.
(503) Goalstone ML, Wall K, Leitner JW, Kurowski T, Ruderman N, Pan SJ, Ivy JL, Moller
DE, Draznin B. Increased amounts of farnesylated p21Ras in tissues of
hyperinsulinaemic animals. Diabetologia 1999 March;42(3):310-6.
(504) Giovannucci E. Metabolic syndrome, hyperinsulinemia, and colon cancer: a review. Am
J Clin Nutr 2007 September;86(3):s836-s842.
(505) Pisani P. Hyper-insulinaemia and cancer, meta-analyses of epidemiological studies. Arch
Physiol Biochem 2008 February;114(1):63-70.
170
(506) Campbell TC, Junshi C. Diet and chronic degenerative diseases: perspectives from
China. Am J Clin Nutr 1994 May;59(5 Suppl):1153S-61S.
(507) Armstrong B, Doll R. Environmental factors and cancer incidence and mortality in
different countries, with special reference to dietary practices. Int J Cancer 1975 April
15;15(4):617-31.
(508) Cunningham AS. Lymphomas and animal-protein consumption. Lancet 1976 November
27;2(7996):1184-6.
(509) Gray GE, Pike MC, Henderson BE. Breast-cancer incidence and mortality rates in
different countries in relation to known risk factors and dietary practices. Br J Cancer
1979 January;39(1):1-7.
(510) Rose DP, Boyar AP, Wynder EL. International comparisons of mortality rates for
cancer of the breast, ovary, prostate, and colon, and per capita food consumption.
Cancer 1986 December 1;58(11):2363-71.
(511) Parkin DM. Cancers of the breast, endometrium and ovary: geographic correlations.
Eur J Cancer Clin Oncol 1989 December;25(12):1917-25.
(512) Prentice RL, Sheppard L. Dietary fat and cancer: consistency of the epidemiologic data,
and disease prevention that may follow from a practical reduction in fat consumption
[published erratum appears in Cancer Causes Control 1990 Nov;1(3):253]. Cancer
Causes Control 1990 July;1(1):81-97.
(513) Hursting SD, Thornquist M, Henderson MM. Types of dietary fat and the incidence of
cancer at five sites. Prev Med 1990 May;19(3):242-53.
(514) Kesteloot H, Lesaffre E, Joossens JV. Dairy fat, saturated animal fat, and cancer risk.
Prev Med 1991 March;20(2):226-36.
(515) Ghadirian P, Thouez JP, PetitClerc C. International comparisons of nutrition and
mortality from pancreatic cancer. Cancer Detect Prev 1991;15(5):357-62.
(516) Hebert JR, Rosen A. Nutritional, socioeconomic, and reproductive factors in relation to
female breast cancer mortality: findings from a cross-national study. Cancer Detect Prev
1996;20(3):234-44.
(517) Kato I, Tominaga S, Kuroishi T. Relationship between westernization of dietary habits
and mortality from breast and ovarian cancers in Japan. Jpn J Cancer Res 1987
April;78(4):349-57.
(518) Koo LC, Mang OW, Ho JH. An ecological study of trends in cancer incidence and
dietary changes in Hong Kong. Nutr Cancer 1997;28(3):289-301.
(519) Serra-Majem L, La Vecchia C, Ribas-Barba L, Prieto-Ramos F, Lucchini F, Ramon JM,
Salleras L. Changes in diet and mortality from selected cancers in southern
Mediterranean countries, 1960-1989. Eur J Clin Nutr 1993 September;47 Suppl 1:S25S34.
(520) Devesa SS, Silverman DT. Cancer incidence and mortality trends in the United States:
1935-74. J Natl Cancer Inst 1978 March;60(3):545-71.
171
(521) McCarty MF. Mortality from "Western" cancers rose dramatically among AfricanAmericans during the twentieth century - are dietary animal products to blame?
Medical Hypotheses 2000;submitted for publication.
(522) Cook PJ, Burkitt DP. Cancer in Africa. Br Med Bull 1971 January;27(1):14-20.
(523) Hebert JR, Hurley TG, Olendzki BC, Teas J, Ma Y, Hampl JS. Nutritional and
socioeconomic factors in relation to prostate cancer mortality: a cross-national study
[see comments]. J Natl Cancer Inst 1998 November 4;90(21):1637-47.
(524) Shimizu H, Ross RK, Bernstein L, Yatani R, Henderson BE, Mack TM. Cancers of the
prostate and breast among Japanese and white immigrants in Los Angeles County. Br J
Cancer 1991 June;63(6):963-6.
(525) Kaizer L, Boyd NF, Kriukov V, Tritchler D. Fish consumption and breast cancer risk:
an ecological study. Nutr Cancer 1989;12(1):61-8.
(526) Rose DP, Connolly JM. Omega-3 fatty acids as cancer chemopreventive agents.
Pharmacol Ther 1999 September;83(3):217-44.
(527) Karmali R. n-3 fatty acids: biochemical actions in cancer. J Nutr Sci Vitaminol (Tokyo)
1992;Spec No:148-52.
(528) Stoll BA. Breast cancer and the western diet: role of fatty acids and antioxidant
vitamins. Eur J Cancer 1998 November;34(12):1852-6.
(529) Hiney JK, Srivastava V, Nyberg CL, Ojeda SR, Dees WL. Insulin-like growth factor I of
peripheral origin acts centrally to accelerate the initiation of female puberty.
Endocrinology 1996 September;137(9):3717-28.
(530) Sanchez A, Kissinger DG, Phillips RI. A hypothesis on the etiological role of diet on age
of menarche. Med Hypotheses 1981 November;7(11):1339-45.
(531) Mills PK, Beeson WL, Phillips RL, Fraser GE. Dietary habits and breast cancer
incidence among Seventh-day Adventists. Cancer 1989 August 1;64(3):582-90.
(532) Hu FB, Stampfer MJ, Manson JE, Rimm E, Colditz GA, Speizer FE, Hennekens CH,
Willett WC. Dietary protein and risk of ischemic heart disease in women [see
comments]. Am J Clin Nutr 1999 August;70(2):221-7.
(533) Bray GA. The underlying basis for obesity: relationship to cancer. J Nutr 2002
November;132(11 Suppl):3451S-5S.
(534) Hou WK, Xu YX, Yu T, Zhang L, Zhang WW, Fu CL, Sun Y, Wu Q, Chen L.
Adipocytokines and breast cancer risk. Chin Med J (Engl ) 2007 September
20;120(18):1592-6.
(535) Jarde T, Caldefie-Chezet F, Damez M, Mishellany F, Penault-Llorca F, Guillot J,
Vasson MP. Leptin and leptin receptor involvement in cancer development: a study on
human primary breast carcinoma. Oncol Rep 2008 April;19(4):905-11.
(536) Cirillo D, Rachiglio AM, la MR, Giordano A, Normanno N. Leptin signaling in breast
cancer: an overview. J Cell Biochem 2008 November 1;105(4):956-64.
172
(537) Rouyer-Fessard C, Gammeltoft S, Laburthe M. Expression of two types of receptor for
insulinlike growth factors in human colonic epithelium. Gastroenterology 1990
March;98(3):703-7.
(538) Cats A, Dullaart RP, Kleibeuker JH, Kuipers F, Sluiter WJ, Hardonk MJ, de Vries EG.
Increased epithelial cell proliferation in the colon of patients with acromegaly. Cancer
Res 1996 February 1;56(3):523-6.
(539) Ma J, Pollak MN, Giovannucci E, Chan JM, Tao Y, Hennekens CH, Stampfer MJ.
Prospective study of colorectal cancer risk in men and plasma levels of insulin-like
growth factor (IGF)-I and IGF-binding protein-3. J Natl Cancer Inst 1999 April
7;91(7):620-5.
(540) Giovannucci E, Pollak MN, Platz EA, Willett WC, Stampfer MJ, Majeed N, Colditz GA,
Speizer FE, Hankinson SE. A prospective study of plasma insulin-like growth factor-1
and binding protein-3 and risk of colorectal neoplasia in women. Cancer Epidemiol
Biomarkers Prev 2000 April;9(4):345-9.
(541) Jenkins PJ, Frajese V, Jones AM, Camacho-Hubner C, Lowe DG, Fairclough PD, Chew
SL, Grossman AB, Monson JP, Besser GM. Insulin-like growth factor I and the
development of colorectal neoplasia in acromegaly. J Clin Endocrinol Metab 2000
September;85(9):3218-21.
(542) Kaaks R, Toniolo P, Akhmedkhanov A, Lukanova A, Biessy C, Dechaud H, Rinaldi S,
Zeleniuch-Jacquotte A, Shore RE, Riboli E. Serum C-peptide, insulin-like growth factor
(IGF)-I, IGF-binding proteins, and colorectal cancer risk in women. J Natl Cancer Inst
2000 October 4;92(19):1592-600.
(543) Renehan AG, Painter JE, Atkin WS, Potten CS, Shalet SM, O'Dwyer ST. High-risk
colorectal adenomas and serum insulin-like growth factors. Br J Surg 2001
January;88(1):107-13.
(544) Lipkin M, Uehara K, Winawer S, Sanchez A, Bauer C, Phillips R, Lynch HT, Blattner
WA, Fraumeni JFJ. Seventh-Day Adventist vegetarians have a quiescent proliferative
activity in colonic mucosa. Cancer Lett 1985 March;26(2):139-44.
(545) Giovannucci E. Insulin and colon cancer. Cancer Causes Control 1995 March;6(2):16479.
(546) Kim YI. Diet, lifestyle, and colorectal cancer: is hyperinsulinemia the missing link? Nutr
Rev 1998 September;56(9):275-9.
(547) Bruce WR, Wolever TM, Giacca A. Mechanisms linking diet and colorectal cancer: the
possible role of insulin resistance. Nutr Cancer 2000;37(1):19-26.
(548) Nilsen TI, Vatten LJ. Prospective study of colorectal cancer risk and physical activity,
diabetes, blood glucose and BMI: exploring the hyperinsulinaemia hypothesis. Br J
Cancer 2001 February 2;84(3):417-22.
(549) Franceschi S, Dal Maso L, Augustin L, Negri E, Parpinel M, Boyle P, Jenkins DJ, La
Vecchia C. Dietary glycemic load and colorectal cancer risk. Ann Oncol 2001
February;12(2):173-8.
(550) Tran TT, Medline A, Bruce WR. Insulin promotion of colon tumors in rats. Cancer
Epidemiol Biomarkers Prev 1996 December;5(12):1013-5.
173
(551) Koohestani N, Tran TT, Lee W, Wolever TM, Bruce WR. Insulin resistance and
promotion of aberrant crypt foci in the colons of rats on a high-fat diet. Nutr Cancer
1997;29(1):69-76.
(552) Tatsuta M, Iishi H, Baba M, Taniguchi H. Enhancement of azoxymethane-induced colon
carcinogenesis in spontaneously hypertensive rats. Int J Cancer 1990 May 15;45(5):95760.
(553) Tatsuta M, Iishi H, Baba M, Taniguchi H. Inhibition of azoxymethane-induced
experimental colon carcinogenesis in Wistar rats by 6-hydroxydopamine. Int J Cancer
1992 January 21;50(2):298-301.
(554) Terry P, Ekbom A, Lichtenstein P, Feychting M, Wolk A. Long-term tobacco smoking
and colorectal cancer in a prospective cohort study. Int J Cancer 2001 February
15;91(4):585-7.
(555) Correa P. Epidemiological correlations between diet and cancer frequency. Cancer Res
1981 September;41(9 Pt 2):3685-90.
(556) Giovannucci E, Rimm EB, Stampfer MJ, Colditz GA, Ascherio A, Willett WC. Intake of
fat, meat, and fiber in relation to risk of colon cancer in men. Cancer Res 1994 May
1;54(9):2390-7.
(557) Pence BC. Role of calcium in colon cancer prevention: experimental and clinical studies.
Mutat Res 1993 November;290(1):87-95.
(558) Grau MV, Baron JA, Sandler RS, Wallace K, Haile RW, Church TR, Beck GJ,
Summers RW, Barry EL, Cole BF, Snover DC, Rothstein R, Mandel JS. Prolonged
effect of calcium supplementation on risk of colorectal adenomas in a randomized trial.
J Natl Cancer Inst 2007 January 17;99(2):129-36.
(559) Weingarten MA, Zalmanovici A, Yaphe J. Dietary calcium supplementation for
preventing colorectal cancer and adenomatous polyps. Cochrane Database Syst Rev
2008;(1):CD003548.
(560) Lapre JA, De Vries HT, Koeman JH, Van der Meer R. The antiproliferative effect of
dietary calcium on colonic epithelium is mediated by luminal surfactants and dependent
on the type of dietary fat. Cancer Res 1993 February 15;53(4):784-9.
(561) Govers MJ, Termont DS, Lapre JA, Kleibeuker JH, Vonk RJ, Van der Meer R.
Calcium in milk products precipitates intestinal fatty acids and secondary bile acids and
thus inhibits colonic cytotoxicity in humans. Cancer Res 1996 July 15;56(14):3270-5.
(562) Sesink AL, Termont DS, Kleibeuker JH, Van der Meer R. Red meat and colon cancer:
the cytotoxic and hyperproliferative effects of dietary heme. Cancer Res 1999 November
15;59(22):5704-9.
(563) Sesink AL, Termont DS, Kleibeuker JH, Van der MR. Red meat and colon cancer:
dietary haem-induced colonic cytotoxicity and epithelial hyperproliferation are inhibited
by calcium. Carcinogenesis 2001 October;22(10):1653-9.
(564) Cross AJ, Pollock JR, Bingham SA. Haem, not protein or inorganic iron, is responsible
for endogenous intestinal N-nitrosation arising from red meat. Cancer Res 2003 May
15;63(10):2358-60.
174
(565) Pierre F, Tache S, Petit CR, Van der MR, Corpet DE. Meat and cancer: haemoglobin
and haemin in a low-calcium diet promote colorectal carcinogenesis at the aberrant
crypt stage in rats. Carcinogenesis 2003 October;24(10):1683-90.
(566) Balder HF, Vogel J, Jansen MC, Weijenberg MP, van den Brandt PA, Westenbrink S,
Van der MR, Goldbohm RA. Heme and chlorophyll intake and risk of colorectal cancer
in the Netherlands cohort study. Cancer Epidemiol Biomarkers Prev 2006
April;15(4):717-25.
(567) Gates JR, Parpia B, Campbell TC, Junshi C. Association of dietary factors and selected
plasma variables with sex hormone-binding globulin in rural Chinese women. Am J Clin
Nutr 1996 January;63(1):22-31.
(568) McCarty MF. Dietary glycemic index may influence cancer risk by modulating IGF-I
activity: a hypothesis. J Medicinal Food 1998;1:123-40.
(569) Carroll KK, Khor HT. Dietary fat in relation to tumorigenesis. Prog Biochem Pharmacol
1975;10:308-53.
(570) Wynder EL, Hebert JR, Kabat GC. Association of dietary fat and lung cancer. J Natl
Cancer Inst 1987 October;79(4):631-7.
(571) Taioli E, Nicolosi A, Wynder EL. Possible role of diet as a host factor in the aetiology of
tobacco-induced lung cancer: an ecological study in southern and northern Italy. Int J
Epidemiol 1991 September;20(3):611-4.
(572) Xie JX, Lesaffre E, Kesteloot H. The relationship between animal fat intake, cigarette
smoking, and lung cancer. Cancer Causes Control 1991 March;2(2):79-83.
(573) Wynder EL, Taioli E, Fujita Y. Ecologic study of lung cancer risk factors in the U.S. and
Japan, with special reference to smoking and diet. Jpn J Cancer Res 1992
May;83(5):418-23.
(574) Wynder EL. The past, present, and future of the prevention of lung cancer. Cancer
Epidemiol Biomarkers Prev 1998 September;7(9):735-48.
(575) Ziegler RG, Mayne ST, Swanson CA. Nutrition and lung cancer. Cancer Causes Control
1996 January;7(1):157-77.
(576) Yu H, Spitz MR, Mistry J, Gu J, Hong WK, Wu X. Plasma levels of insulin-like growth
factor-I and lung cancer risk: a case-control analysis. J Natl Cancer Inst 1999 January
20;91(2):151-6.
(577) Wu X, Yu H, Amos CI, Hong WK, Spitz MR. Joint effect of insulin-like growth factors
and mutagen sensitivity in lung cancer risk. J Natl Cancer Inst 2000 May 3;92(9):737-43.
(578) Wakai K, Ito Y, Suzuki K, Tamakoshi A, Seki N, Ando M, Ozasa K, Watanabe Y,
Kondo T, Nishino Y, Ohno Y. Serum insulin-like growth factors, insulin-like growth
factor-binding protein-3, and risk of lung cancer death: a case-control study nested in
the Japan Collaborative Cohort (JACC) Study. Jpn J Cancer Res 2002
December;93(12):1279-86.
(579) Darby S, Whitley E, Doll R, Key T, Silcocks P. Diet, smoking and lung cancer: a casecontrol study of 1000 cases and 1500 controls in South-West England. Br J Cancer 2001
March 2;84(5):728-35.
175
(580) Veierod MB, Laake P, Thelle DS. Dietary fat intake and risk of lung cancer: a
prospective study of 51,452 Norwegian men and women. Eur J Cancer Prev 1997
December;6(6):540-9.
(581) Pierce RJ, Kune GA, Kune S, Watson LF, Field B, Merenstein D, Hayes A, Irving LB.
Dietary and alcohol intake, smoking pattern, occupational risk, and family history in
lung cancer patients: results of a case-control study in males. Nutr Cancer
1989;12(3):237-48.
(582) Zhang J, Temme EH, Kesteloot H. Fish consumption is inversely associated with male
lung cancer mortality in countries with high levels of cigarette smoking or animal fat
consumption. Int J Epidemiol 2000 August;29(4):615-21.
(583) Sharp DS, Rodriguez BL, Shahar E, Hwang LJ, Burchfiel CM. Fish consumption may
limit the damage of smoking on the lung. Am J Respir Crit Care Med 1994
October;150(4):983-7.
(584) Clark LC, Combs GFJ, Turnbull BW, Slate EH, Chalker DK, Chow J, Davis LS, Glover
RA, Graham GF, Gross EG, Krongrad A, Lesher JLJ, Park HK, Sanders BBJ, Smith
CL, Taylor JR. Effects of selenium supplementation for cancer prevention in patients
with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of
Cancer Study Group [see comments] [published erratum appears in JAMA 1997 May
21;277(19):1520]. JAMA 1996 December 25;276(24):1957-63.
(585) Knekt P, Marniemi J, Teppo L, Heliovaara M, Aromaa A. Is low selenium status a risk
factor for lung cancer? Am J Epidemiol 1998 November 15;148(10):975-82.
(586) van den Brandt PA, Goldbohm RA, van ', V, Bode P, Dorant E, Hermus RJ, Sturmans
F. A prospective cohort study on selenium status and the risk of lung cancer. Cancer Res
1993 October 15;53(20):4860-5.
(587) Noy A, Bilezikian JP. Clinical review 63: Diabetes and pancreatic cancer: clues to the
early diagnosis of pancreatic malignancy. J Clin Endocrinol Metab 1994
November;79(5):1223-31.
(588) Bell RHJ, McCullough PJ, Pour PM. Influence of diabetes on susceptibility to
experimental pancreatic cancer. Am J Surg 1988 January;155(1):159-64.
(589) Lin Y, Tamakoshi A, Wakai K, Kawamura T, Aoki R, Kojima M, Ohno Y. Descriptive
epidemiology of pancreatic cancer in Japan. J Epidemiol 1998 March;8(1):52-9.
(590) Hebert JR, Miller DR. A cross-national investigation of diet and bladder cancer. Eur J
Cancer 1994;30A(6):778-84.
(591) Steinmaus CM, Nunez S, Smith AH. Diet and bladder cancer: a meta-analysis of six
dietary variables. Am J Epidemiol 2000 April 1;151(7):693-702.
(592) Mills PK, Beeson WL, Phillips RL, Fraser GE. Bladder cancer in a low risk population:
results from the Adventist Health Study. Am J Epidemiol 1991 February 1;133(3):230-9.
(593) Zhao H, Grossman HB, Spitz MR, Lerner SP, Zhang K, Wu X. Plasma levels of insulinlike growth factor-1 and binding protein-3, and their association with bladder cancer
risk. J Urol 2003 February;169(2):714-7.
176
(594) Iwamura M, Ishibe M, Sluss PM, Cockett AT. Characterization of insulin-like growth
factor I binding sites in human bladder cancer cell lines. Urol Res 1993
January;21(1):27-32.
(595) Cooper MJ, Fischer M, Komitowski D, Shevelev A, Schulze E, Ariel I, Tykocinski ML,
Miron S, Ilan J, de Groot N, Hochberg A. Developmentally imprinted genes as markers
for bladder tumor progression. J Urol 1996 June;155(6):2120-7.
(596) Chow WH, Gridley G, McLaughlin JK, Mandel JS, Wacholder S, Blot WJ, Niwa S,
Fraumeni JF. Protein intake and risk of renal cell cancer. J Natl Cancer Inst 1994
August 3;86(15):1131-9.
(597) McLaughlin JK, Gao YT, Gao RN, Zheng W, Ji BT, Blot WJ, Fraumeni JF. Risk factors
for renal-cell cancer in Shanghai, China. Int J Cancer 1992 October 21;52(4):562-5.
(598) Maclure M, Willett W. A case-control study of diet and risk of renal adenocarcinoma.
Epidemiology 1990 November;1(6):430-40.
(599) Wolk A, Gridley G, Niwa S, Lindblad P, McCredie M, Mellemgaard A, Mandel JS,
Wahrendorf J, McLaughlin JK, Adami HO. International renal cell cancer study. VII.
Role of diet. Int J Cancer 1996 January 3;65(1):67-73.
(600) Kellerer M, von Eye C, Muhlhofer A, Capp E, Mosthaf L, Bock S, Petrides PE, Haring
HU. Insulin- and insulin-like growth-factor-I receptor tyrosine-kinase activities in
human renal carcinoma. Int J Cancer 1995 September 4;62(5):501-7.
(601) Gnarra JR, Glenn GM, Latif F, Anglard P, Lerman MI, Zbar B, Linehan WM.
Molecular genetic studies of sporadic and familial renal cell carcinoma. Urol Clin North
Am 1993 May;20(2):207-16.
(602) Rosendahl AH, Holly JM, Celander M, Forsberg G. Systemic IGF-I administration
stimulates the in vivo growth of early, but not advanced, renal cell carcinoma. Int J
Cancer 2008 September 15;123(6):1286-91.
(603) Parazzini F, Franceschi S, La Vecchia C, Fasoli M. The epidemiology of ovarian cancer.
Gynecol Oncol 1991 October;43(1):9-23.
(604) Serra-Majem L, La Vecchia C, Ribas-Barba L, Prieto-Ramos F, Lucchini F, Ramon JM,
Salleras L. Changes in diet and mortality from selected cancers in southern
Mediterranean countries, 1960-1989. Eur J Clin Nutr 1993 September;47 Suppl 1:S25S34.
(605) Berg JW. Can nutrition explain the pattern of international epidemiology of hormonedependent cancers? Cancer Res 1975 November;35(11 Pt. 2):3345-50.
(606) Parkin DM. Cancers of the breast, endometrium and ovary: geographic correlations.
Eur J Cancer Clin Oncol 1989 December;25(12):1917-25.
(607) La Vecchia C, Decarli A, Negri E, Parazzini F, Gentile A, Cecchetti G, Fasoli M,
Franceschi S. Dietary factors and the risk of epithelial ovarian cancer. J Natl Cancer Inst
1987 October;79(4):663-9.
(608) Shu XO, Gao YT, Yuan JM, Ziegler RG, Brinton LA. Dietary factors and epithelial
ovarian cancer. Br J Cancer 1989 January;59(1):92-6.
177
(609) Risch HA, Jain M, Marrett LD, Howe GR. Dietary fat intake and risk of epithelial
ovarian cancer. J Natl Cancer Inst 1994 September 21;86(18):1409-15.
(610) Risch HA. Hormonal etiology of epithelial ovarian cancer, with a hypothesis concerning
the role of androgens and progesterone. J Natl Cancer Inst 1998 December
2;90(23):1774-86.
(611) Peeters PH, Lukanova A, Allen N, Berrino F, Key T, Dossus L, Rinaldi S, van Gils CH,
Bueno-de-Mesquita HB, Boeing H, Schulz M, Chang-Claude J, Linseisen J, Panico S,
Sacerdote C, Palli D, Tumino R, Trichopoulou A, Trichopolos D, Bamia C, Larranaga
N, Ardanaz E, Pera G, Quiros JR, Martinez-Garcia C, Navarro C, Bingham SA, Khaw
KT, Clavel F, Tjonneland A, Olsen A, Overvad K, Tetsche MS, Lund E, Lundin E,
Berglund G, Riboli E, Kaaks R. Serum IGF-I, its major binding protein (IGFBP-3) and
epithelial ovarian cancer risk: the European Prospective Investigation into Cancer and
Nutrition (EPIC). Endocr Relat Cancer 2007 March;14(1):81-90.
(612) Tworoger SS, Lee IM, Buring JE, Pollak MN, Hankinson SE. Insulin-like growth
factors and ovarian cancer risk: a nested case-control study in three cohorts. Cancer
Epidemiol Biomarkers Prev 2007 August;16(8):1691-5.
(613) Brokaw J, Katsaros D, Wiley A, Lu L, Su D, Sochirca O, de lL, I, Mayne S, Risch H, Yu
H. IGF-I in epithelial ovarian cancer and its role in disease progression. Growth Factors
2007 October;25(5):346-54.
(614) Yee D, Morales FR, Hamilton TC, Von Hoff DD. Expression of insulin-like growth
factor I, its binding proteins, and its receptor in ovarian cancer. Cancer Res 1991
October 1;51(19):5107-12.
(615) Berns EM, Klijn JG, Henzen-Logmans SC, Rodenburg CJ, van der Burg ME, Foekens
JA. Receptors for hormones and growth factors and (onco)-gene amplification in human
ovarian cancer. Int J Cancer 1992 September 9;52(2):218-24.
(616) Resnicoff M, Ambrose D, Coppola D, Rubin R. Insulin-like growth factor-1 and its
receptor mediate the autocrine proliferation of human ovarian carcinoma cell lines. Lab
Invest 1993 December;69(6):756-60.
(617) Beck EP, Russo P, Gliozzo B, Jaeger W, Papa V, Wildt L, Pezzino V, Lang N.
Identification of insulin and insulin-like growth factor I (IGF I) receptors in ovarian
cancer tissue. Gynecol Oncol 1994 May;53(2):196-201.
(618) Muller M, Dietel M, Turzynski A, Wiechen K. Antisense phosphorothioate
oligodeoxynucleotide down-regulation of the insulin-like growth factor I receptor in
ovarian cancer cells. Int J Cancer 1998 August 12;77(4):567-71.
(619) Rodriguez C, Patel AV, Calle EE, Jacob EJ, Thun MJ. Estrogen replacement therapy
and ovarian cancer mortality in a large prospective study of US women. JAMA 2001
March 21;285(11):1460-5.
(620) Coughlin SS, Giustozzi A, Smith SJ, Lee NC. A meta-analysis of estrogen replacement
therapy and risk of epithelial ovarian cancer. J Clin Epidemiol 2000 April;53(4):367-75.
(621) Bai W, Oliveros-Saunders B, Wang Q, Acevedo-Duncan ME, Nicosia SV. Estrogen
stimulation of ovarian surface epithelial cell proliferation. In Vitro Cell Dev Biol Anim
2000 November;36(10):657-66.
178
(622) Ahonen MH, Zhuang YH, Aine R, Ylikomi T, Tuohimaa P. Androgen receptor and
vitamin D receptor in human ovarian cancer: growth stimulation and inhibition by
ligands. Int J Cancer 2000 April 1;86(1):40-6.
(623) Bergh C, Carlsson B, Olsson JH, Selleskog U, Hillensjo T. Regulation of androgen
production in cultured human thecal cells by insulin-like growth factor I and insulin.
Fertil Steril 1993 February;59(2):323-31.
(624) Bandyopadhyay S, Chakrabarti J, Banerjee S, Pal AK, Goswami SK, Chakravarty BN,
Kabir SN. Galactose toxicity in the rat as a model for premature ovarian failure: an
experimental approach readdressed. Hum Reprod 2003 October;18(10):2031-8.
(625) Kaufman FR, Donnell GN, Roe TF, Kogut MD. Gonadal function in patients with
galactosaemia. J Inherit Metab Dis 1986;9(2):140-6.
(626) Cramer DW, Harlow BL, Willett WC, Welch WR, Bell DA, Scully RE, Ng WG, Knapp
RC. Galactose consumption and metabolism in relation to the risk of ovarian cancer.
Lancet 1989 July 8;2(8654):66-71.
(627) Larsson SC, Orsini N, Wolk A. Milk, milk products and lactose intake and ovarian
cancer risk: a meta-analysis of epidemiological studies. Int J Cancer 2006 January
15;118(2):431-41.
(628) Genkinger JM, Hunter DJ, Spiegelman D, Anderson KE, Arslan A, Beeson WL, Buring
JE, Fraser GE, Freudenheim JL, Goldbohm RA, Hankinson SE, Jacobs DR, Jr.,
Koushik A, Lacey JV, Jr., Larsson SC, Leitzmann M, McCullough ML, Miller AB,
Rodriguez C, Rohan TE, Schouten LJ, Shore R, Smit E, Wolk A, Zhang SM, SmithWarner SA. Dairy products and ovarian cancer: a pooled analysis of 12 cohort studies.
Cancer Epidemiol Biomarkers Prev 2006 February;15(2):364-72.
(629) Goodman MT, Hankin JH, Wilkens LR, Lyu LC, McDuffie K, Liu LQ, Kolonel LN.
Diet, body size, physical activity, and the risk of endometrial cancer. Cancer Res 1997
November 15;57(22):5077-85.
(630) Parazzini F, La Vecchia C, Negri E, Riboldi GL, Surace M, Benzi G, Maina A,
Chiaffarino F. Diabetes and endometrial cancer: an Italian case-control study. Int J
Cancer 1999 May 17;81(4):539-42.
(631) La Vecchia C. Cancers associated with high-fat diets. J Natl Cancer Inst Monogr
1992;(12):79-85.
(632) Shu XO, Zheng W, Potischman N, Brinton LA, Hatch MC, Gao YT, Fraumeni JF. A
population-based case-control study of dietary factors and endometrial cancer in
Shanghai, People's Republic of China. Am J Epidemiol 1993 January 15;137(2):155-65.
(633) Levi F, Franceschi S, Negri E, La Vecchia C. Dietary factors and the risk of endometrial
cancer. Cancer 1993 June 1;71(11):3575-81.
(634) Rutanen EM. Insulin-like growth factors in endometrial function. Gynecol Endocrinol
1998 December;12(6):399-406.
(635) Kleinman D, Roberts CT, LeRoith D, Schally AV, Levy J, Sharoni Y. Regulation of
endometrial cancer cell growth by insulin-like growth factors and the luteinizing
hormone-releasing hormone antagonist SB-75. Regul Pept 1993 October 20;48(1-2):91-8.
179
(636) Bermont L, Fauconnet S, Lamielle F, Adessi GL. Cell-associated insulin-like growth
factor-binding proteins inhibit insulin-like growth factor-I-induced endometrial cancer
cell proliferation. Cell Mol Biol (Noisy-le-grand) 2000 November;46(7):1173-82.
(637) Ayabe T, Tsutsumi O, Sakai H, Yoshikawa H, Yano T, Kurimoto F, Taketani Y.
Increased circulating levels of insulin-like growth factor-I and decreased circulating
levels of insulin-like growth factor binding protein-1 in postmenopausal women with
endometrial cancer. Endocr J 1997 June;44(3):419-24.
(638) Kleinman D, Karas M, Roberts CT, LeRoith D, Phillip M, Segev Y, Levy J, Sharoni Y.
Modulation of insulin-like growth factor I (IGF-I) receptors and membrane-associated
IGF-binding proteins in endometrial cancer cells by estradiol. Endocrinology 1995
June;136(6):2531-7.
(639) Rutanen EM, Nyman T, Lehtovirta P, Ammala M, Pekonen F. Suppressed expression of
insulin-like growth factor binding protein-1 mRNA in the endometrium: a molecular
mechanism associating endometrial cancer with its risk factors. Int J Cancer 1994
November 1;59(3):307-12.
(640) Elkas J, Gray K, Howard L, Petit N, Pohl J, Armstrong A. The effects of tamoxifen on
endometrial insulin-like growth factor-1 expression. Obstet Gynecol 1998
January;91(1):45-50.
(641) Wynder EL, Fujita Y, Harris RE, Hirayama T, Hiyama T. Comparative epidemiology
of cancer between the United States and Japan. A second look. Cancer 1991 February
1;67(3):746-63.
(642) Merchav S. The haematopoietic effects of growth hormone and insulin-like growth
factor-I. J Pediatr Endocrinol Metab 1998 November;11(6):677-85.
(643) Estrov Z, Meir R, Barak Y, Zaizov R, Zadik Z. Human growth hormone and insulinlike growth factor-1 enhance the proliferation of human leukemic blasts. J Clin Oncol
1991 March;9(3):394-9.
(644) Hursting SD, Switzer BR, French JE, Kari FW. The growth hormone: insulin-like
growth factor 1 axis is a mediator of diet restriction-induced inhibition of mononuclear
cell leukemia in Fischer rats. Cancer Res 1993 June 15;53(12):2750-7.
(645) Yoshida K, Inoue T, Nojima K, Hirabayashi Y, Sado T. Calorie restriction reduces the
incidence of myeloid leukemia induced by a single whole-body radiation in C3H/He
mice. Proc Natl Acad Sci U S A 1997 March 18;94(6):2615-9.
(646) Huggins CB, Ueda N. Regression of myelocytic leukemia in rats after hypophysectomy.
Proc Natl Acad Sci U S A 1984 January;81(2):598-601.
(647) Bentley HP, Hughs ER, Peterson RD. Effect of hypophysectomy on a virus-induced Tcell leukemia. Nature 1974 December 20;252(5485):747-8.
(648) Albanes D. Energy balance, body size, and cancer. Crit Rev Oncol Hematol
1990;10(3):283-303.
(649) Ross JA, Perentesis JP, Robison LL, Davies SM. Big babies and infant leukemia: a role
for insulin-like growth factor-1? Cancer Causes Control 1996 September;7(5):553-9.
180
(650) Yeazel MW, Ross JA, Buckley JD, Woods WG, Ruccione K, Robison LL. High birth
weight and risk of specific childhood cancers: a report from the Children's Cancer
Group. J Pediatr 1997 November;131(5):671-7.
(651) Petridou E, Skalkidou A, Dessypris N, Moustaki M, Mantzoros C, Spanos E,
Trichopoulos D. Endogenous risk factors for childhood leukemia in relation to the IGF
system (Greece). The Childhood Haematologists-Oncologists Group. Cancer Causes
Control 2000 September;11(8):765-71.
(652) Petridou E, Dessypris N, Spanos E, Mantzoros C, Skalkidou A, Kalmanti M, Koliouskas
D, Kosmidis H, Panagiotou JP, Piperopoulou F, Tzortzatou F, Trichopoulos D. Insulinlike growth factor-I and binding protein-3 in relation to childhood leukaemia. Int J
Cancer 1999 February 9;80(4):494-6.
(653) Broomhall J, May R, Lilleyman JS, Milner RD. Height and lymphoblastic leukaemia.
Arch Dis Child 1983 April;58(4):300-1.
(654) Petridou E, Trichopoulos D, Kalapothaki V, Pourtsidis A, Kogevinas M, Kalmanti M,
Koliouskas D, Kosmidis H, Panagiotou JP, Piperopoulou F, Tzortzatou F. The risk
profile of childhood leukaemia in Greece: a nationwide case-control study. Br J Cancer
1997;76(9):1241-7.
(655) Ge NL, Rudikoff S. Insulin-like growth factor I is a dual effector of multiple myeloma
cell growth. Blood 2000 October 15;96(8):2856-61.
(656) Ferlin M, Noraz N, Hertogh C, Brochier J, Taylor N, Klein B. Insulin-like growth factor
induces the survival and proliferation of myeloma cells through an interleukin-6independent transduction pathway. Br J Haematol 2000 November;111(2):626-34.
(657) Ish-Shalom D, Tzivion G, Christoffersen CT, Urso B, De Meyts P, Naor D. Mitogenic
potential of insulin on lymphoma cells lacking IGF-1 receptor. Ann N Y Acad Sci 1995
September 7;766:409-15.
(658) Halikowski B, Armata J, Garwicz S. Low-protein purine-free diet in treatment of acute
leukaemia in children: preliminary communication. Br Med J 1966 February
26;5486:519-21.
(659) Hilson D. Low-protein diet in leukemia. BMJ 1966;i:979.
(660) Daling JR, Starzyk P, Olshan AF, Weiss NS. Birth weight and the incidence of childhood
cancer. J Natl Cancer Inst 1984 May;72(5):1039-41.
(661) Leisenring WM, Breslow NE, Evans IE, Beckwith JB, Coppes MJ, Grundy P. Increased
birth weights of National Wilms' Tumor Study patients suggest a growth factor excess.
Cancer Res 1994 September 1;54(17):4680-3.
(662) Yeazel MW, Ross JA, Buckley JD, Woods WG, Ruccione K, Robison LL. High birth
weight and risk of specific childhood cancers: a report from the Children's Cancer
Group. J Pediatr 1997 November;131(5):671-7.
(663) Kopelovich L, Fay JR, Sigman CC, Crowell JA. The mammalian target of rapamycin
pathway as a potential target for cancer chemoprevention. Cancer Epidemiol Biomarkers
Prev 2007 July;16(7):1330-40.
181
(664) Avruch J, Hara K, Lin Y, Liu M, Long X, Ortiz-Vega S, Yonezawa K. Insulin and
amino-acid regulation of mTOR signaling and kinase activity through the Rheb GTPase.
Oncogene 2006 October 16;25(48):6361-72.
(665) Felton JS, Malfatti MA, Knize MG, Salmon CP, Hopmans EC, Wu RW. Health risks of
heterocyclic amines. Mutat Res 1997 May 12;376(1-2):37-41.
(666) Nagao M. A new approach to risk estimation of food-borne carcinogens-- heterocyclic
amines--based on molecular information. Mutat Res 1999 December 16;431(1):3-12.
(667) DeBruin LS, Martos PA, Josephy PD. Detection of PhIP (2-amino-1-methyl-6phenylimidazo[4,5-b]pyridine) in the Milk of Healthy Women. Chem Res Toxicol 2001
November;14(11):1523-8.
(668) Esumi H, Ohgaki H, Kohzen E, Takayama S, Sugimura T. Induction of lymphoma in
CDF1 mice by the food mutagen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine.
Jpn J Cancer Res 1989 December;80(12):1176-8.
(669) Franceschi S, Serraino D, Carbone A, Talamini R, La Vecchia C. Dietary factors and
non-Hodgkin's lymphoma: a case-control study in the northeastern part of Italy. Nutr
Cancer 1989;12(4):333-41.
(670) Chiu BC, Cerhan JR, Folsom AR, Sellers TA, Kushi LH, Wallace RB, Zheng W, Potter
JD. Diet and risk of non-Hodgkin lymphoma in older women. JAMA 1996 May
1;275(17):1315-21.
(671) Zhang S, Hunter DJ, Rosner BA, Colditz GA, Fuchs CS, Speizer FE, Willett WC.
Dietary fat and protein in relation to risk of non-Hodgkin's lymphoma among women. J
Natl Cancer Inst 1999 October 20;91(20):1751-8.
(672) Weisenburger DD. Environmental epidemiology of non-Hodgkin's lymphoma in eastern
Nebraska. Am J Ind Med 1990;18(3):303-5.
(673) Zahm SH, Weisenburger DD, Saal RC, Vaught JB, Babbitt PA, Blair A. The role of
agricultural pesticide use in the development of non-Hodgkin's lymphoma in women.
Arch Environ Health 1993 September;48(5):353-8.
(674) Zahm SH, Blair A. Pesticides and non-Hodgkin's lymphoma. Cancer Res 1992 October
1;52(19 Suppl):5485s-8s.
(675) Persson B. Occupational exposure and malignant lymphoma. Int J Occup Med Environ
Health 1996;9(4):309-21.
(676) Schecter A, Brandt-Rauf P, Olson J. Meat intake and non-Hodgkin lymphoma. JAMA
1996 August 21;276(7):524-5.
(677) Hergenrather J, Hlady G, Wallace B, Savage E. Pollutants in breast milk of vegetarians.
N Engl J Med 1981 March 26;304(13):792.
(678) Dickman MD, Leung CK, Leong MK. Hong Kong male subfertility links to mercury in
human hair and fish. Sci Total Environ 1998 June 18;214:165-74.
(679) Wilson AK, Ball MJ. Nutrient intake and iron status of Australian male vegetarians.
Eur J Clin Nutr 1999 March;53(3):189-94.
182
(680) Ball MJ, Bartlett MA. Dietary intake and iron status of Australian vegetarian women.
Am J Clin Nutr 1999 September;70(3):353-8.
(681) Haddad EH, Berk LS, Kettering JD, Hubbard RW, Peters WR. Dietary intake and
biochemical, hematologic, and immune status of vegans compared with nonvegetarians.
Am J Clin Nutr 1999 September;70(3 Suppl):586S-93S.
(682) Hua NW, Stoohs RA, Facchini FS. Low iron status and enhanced insulin sensitivity in
lacto-ovo vegetarians. Br J Nutr 2001 October;86(4):515-9.
(683) Mello-Filho AC, Meneghini R. Iron is the intracellular metal involved in the production
of DNA damage by oxygen radicals. Mutat Res 1991 November;251(1):109-13.
(684) Nascimento AL, Meneghini R. Cells transfected with transferrin receptor cDNA lacking
the iron regulatory domain become more sensitive to the DNA-damaging action of
oxidative stress. Carcinogenesis 1995 June;16(6):1335-8.
(685) Stevens RG. Iron and the risk of cancer. Med Oncol Tumor Pharmacother 1990;7(23):177-81.
(686) Stevens RG, Graubard BI, Micozzi MS, Neriishi K, Blumberg BS. Moderate elevation of
body iron level and increased risk of cancer occurrence and death. Int J Cancer 1994
February 1;56(3):364-9.
(687) Guo WD, Chow WH, Zheng W, Li JY, Blot WJ. Diet, serum markers and breast cancer
mortality in China. Jpn J Cancer Res 1994 June;85(6):572-7.
(688) Edgren G, Reilly M, Hjalgrim H, Tran TN, Rostgaard K, Adami J, Titlestad K,
Shanwell A, Melbye M, Nyren O. Donation frequency, iron loss, and risk of cancer
among blood donors. J Natl Cancer Inst 2008 April 16;100(8):572-9.
(689) Zacharski LR, Chow BK, Howes PS, Shamayeva G, Baron JA, Dalman RL, Malenka
DJ, Ozaki CK, Lavori PW. Decreased cancer risk after iron reduction in patients with
peripheral arterial disease: results from a randomized trial. J Natl Cancer Inst 2008 July
16;100(14):996-1002.
(690) Kato J, Miyanishi K, Kobune M, Nakamura T, Takada K, Takimoto R, Kawano Y,
Takahashi S, Takahashi M, Sato Y, Takayama T, Niitsu Y. Long-term phlebotomy with
low-iron diet therapy lowers risk of development of hepatocellular carcinoma from
chronic hepatitis C. J Gastroenterol 2007 October;42(10):830-6.
(691) Block G, Patterson B, Subar A. Fruit, vegetables, and cancer prevention: a review of the
epidemiological evidence. Nutr Cancer 1992;18(1):1-29.
(692) Potter JD, Steinmetz K. Vegetables, fruit and phytoestrogens as preventive agents. IARC
Sci Publ 1996;(139):61-90.
(693) Talalay P, Fahey JW, Holtzclaw WD, Prestera T, Zhang Y. Chemoprotection against
cancer by phase 2 enzyme induction. Toxicol Lett 1995 December;82-83:173-9.
(694) Zhang Y, Talalay P. Anticarcinogenic activities of organic isothiocyanates: chemistry
and mechanisms. Cancer Res 1994 April 1;54(7 Suppl):1976s-81s.
(695) Vanchieri C. Cutting copper curbs angiogenesis, studies show. J Natl Cancer Inst 2000
August 2;92(15):1202-3.
183
(696) Giovannucci E. Tomatoes, tomato-based products, lycopene, and cancer: review of the
epidemiologic literature. J Natl Cancer Inst 1999 February 17;91(4):317-31.
(697) Dinkova-Kostova AT, Holtzclaw WD, Cole RN, Itoh K, Wakabayashi N, Katoh Y,
Yamamoto M, Talalay P. Direct evidence that sulfhydryl groups of Keap1 are the
sensors regulating induction of phase 2 enzymes that protect against carcinogens and
oxidants. Proc Natl Acad Sci U S A 2002 September 3;99(18):11908-13.
(698) Kuiper GG, Lemmen JG, Carlsson B, Corton JC, Safe SH, van der Saag PT, van Der
BB, Gustafsson JA. Interaction of estrogenic chemicals and phytoestrogens with
estrogen receptor beta. Endocrinology 1998 October;139(10):4252-63.
(699) McCarty MF. Isoflavones made simple - genistein's agonist activity for the beta-type
estrogen receptor mediates their health benefits. Med Hypotheses 2006;66(6):1093-114.
(700) Trichopoulou A, Katsouyanni K, Stuver S, Tzala L, Gnardellis C, Rimm E,
Trichopoulos D. Consumption of olive oil and specific food groups in relation to breast
cancer risk in Greece. J Natl Cancer Inst 1995 January 18;87(2):110-6.
(701) Lipworth L, Martinez ME, Angell J, Hsieh CC, Trichopoulos D. Olive oil and human
cancer: an assessment of the evidence. Prev Med 1997 March;26(2):181-90.
(702) Willett WC. Specific fatty acids and risks of breast and prostate cancer: dietary intake.
Am J Clin Nutr 1997 December;66(6 Suppl):1557S-63S.
(703) Bosetti C, La Vecchia C, Talamini R, Simonato L, Zambon P, Negri E, Trichopoulos D,
Lagiou P, Bardini R, Franceschi S. Food groups and risk of squamous cell esophageal
cancer in northern Italy. Int J Cancer 2000 July 15;87(2):289-94.
(704) Newmark HL. Squalene, olive oil, and cancer risk. Review and hypothesis. Ann N Y
Acad Sci 1999;889:193-203.
(705) Owen RW, Mier W, Giacosa A, Hull WE, Spiegelhalder B, Bartsch H. Phenolic
compounds and squalene in olive oils: the concentration and antioxidant potential of
total phenols, simple phenols, secoiridoids, lignansand squalene. Food Chem Toxicol
2000 August;38(8):647-59.
(706) Coggon D, Barker DJ, Cole RB, Nelson M. Stomach cancer and food storage. J Natl
Cancer Inst 1989 August 2;81(15):1178-82.
(707) La Vecchia C, Negri E, D'Avanzo B, Franceschi S. Electric refrigerator use and gastric
cancer risk. Br J Cancer 1990 July;62(1):136-7.
(708) Palli D. Gastric cancer and Helicobacter pylori: a critical evaluation of the
epidemiological evidence. Helicobacter 1997 July;2 Suppl 1:S50-S55.
(709) Mirvish SS. Inhibition by vitamins C and E of in vivo nitrosation and vitamin C
occurrence in the stomach. Eur J Cancer Prev 1996 September;5 Suppl 1:131-6.
(710) Correa P. Human gastric carcinogenesis: a multistep and multifactorial process--First
American Cancer Society Award Lecture on Cancer Epidemiology and Prevention.
Cancer Res 1992 December 15;52(24):6735-40.
(711) Kono S, Hirohata T. Nutrition and stomach cancer. Cancer Causes Control 1996
January;7(1):41-55.
184
(712) La Vecchia C, Franceschi S. Nutrition and gastric cancer. Can J Gastroenterol 2000
November;14 Suppl D:51D-4D.
(713) Madhavan TV, Gopalan C. The effect of dietary protein on carcinogenesis of aflatoxin.
Arch Pathol 1968 February;85(2):133-7.
(714) Cheng Z, Hu J, King J, Jay G, Campbell TC. Inhibition of hepatocellular carcinoma
development in hepatitis B virus transfected mice by low dietary casein. Hepatology 1997
November;26(5):1351-4.
(715) Hu JF, Cheng Z, Chisari FV, Vu TH, Hoffman AR, Campbell TC. Repression of
hepatitis B virus (HBV) transgene and HBV-induced liver injury by low protein diet.
Oncogene 1997 December 4;15(23):2795-801.
(716) Pottern LM, Morris LE, Blot WJ, Ziegler RG, Fraumeni JF. Esophageal cancer among
black men in Washington, D.C. I. Alcohol, tobacco, and other risk factors. J Natl Cancer
Inst 1981 October;67(4):777-83.
(717) Brown LM, Swanson CA, Gridley G, Swanson GM, Silverman DT, Greenberg RS,
Hayes RB, Schoenberg JB, Pottern LM, Schwartz AG, Liff JM, Hoover R, Fraumeni JF.
Dietary factors and the risk of squamous cell esophageal cancer among black and white
men in the United States. Cancer Causes Control 1998 October;9(5):467-74.
(718) Levi F, Pasche C, Lucchini F, Bosetti C, Franceschi S, Monnier P, La Vecchia C. Food
groups and oesophageal cancer risk in Vaud, Switzerland. Eur J Cancer Prev 2000
August;9(4):257-63.
(719) Brown LM, Hoover R, Silverman D, Baris D, Hayes R, Swanson GM, Schoenberg J,
Greenberg R, Liff J, Schwartz A, Dosemeci M, Pottern L, Fraumeni JF. Excess
incidence of squamous cell esophageal cancer among US Black men: role of social class
and other risk factors. Am J Epidemiol 2001 January 15;153(2):114-22.
(720) Blot WJ, McLaughlin JK. The changing epidemiology of esophageal cancer. Semin
Oncol 1999 October;26(5 Suppl 15):2-8.
(721) Kim R, Weissfeld JL, Reynolds JC, Kuller LH. Etiology of Barrett's metaplasia and
esophageal adenocarcinoma. Cancer Epidemiol Biomarkers Prev 1997 May;6(5):369-77.
(722) Kabat GC, Ng SK, Wynder EL. Tobacco, alcohol intake, and diet in relation to
adenocarcinoma of the esophagus and gastric cardia. Cancer Causes Control 1993
March;4(2):123-32.
(723) Brown LM, Swanson CA, Gridley G, Swanson GM, Schoenberg JB, Greenberg RS,
Silverman DT, Pottern LM, Hayes RB, Schwartz AG. Adenocarcinoma of the
esophagus: role of obesity and diet. J Natl Cancer Inst 1995 January 18;87(2):104-9.
(724) Zhang ZF, Kurtz RC, Yu GP, Sun M, Gargon N, Karpeh M, Fein JS, Harlap S.
Adenocarcinomas of the esophagus and gastric cardia: the role of diet. Nutr Cancer
1997;27(3):298-309.
(725) Cheng KK, Sharp L, McKinney PA, Logan RF, Chilvers CE, Cook-Mozaffari P, Ahmed
A, Day NE. A case-control study of oesophageal adenocarcinoma in women: a
preventable disease. Br J Cancer 2000 July;83(1):127-32.
185
(726) Mayne ST, Risch HA, Dubrow R, Chow WH, Gammon MD, Vaughan TL, Farrow DC,
Schoenberg JB, Stanford JL, Ahsan H, West AB, Rotterdam H, Blot WJ, Fraumeni JFJ.
Nutrient intake and risk of subtypes of esophageal and gastric cancer. Cancer Epidemiol
Biomarkers Prev 2001 October;10(10):1055-62.
(727) Reynolds JC, Waronker M, Pacquing MS, Yassin RR. Barrett's esophagus. Reducing
the risk of progression to adenocarcinoma. Gastroenterol Clin North Am 1999
December;28(4):917-45.
(728) La Vecchia C, Tavani A, Franceschi S, Levi F, Corrao G, Negri E. Epidemiology and
prevention of oral cancer. Oral Oncol 1997 September;33(5):302-12.
(729) Mancianti ML, Gyorfi T, Shih IM, Valyi-Nagy I, Levengood G, Menssen HD, Halpern
AC, Elder DE, Herlyn M. Growth regulation of cultured human nevus cells. J Invest
Dermatol 1993 March;100(3):281S-7S.
(730) Rodeck U, Herlyn M, Menssen HD, Furlanetto RW, Koprowsk H. Metastatic but not
primary melanoma cell lines grow in vitro independently of exogenous growth factors.
Int J Cancer 1987 November 15;40(5):687-90.
(731) Herlyn M, Kath R, Williams N, Valyi-Nagy I, Rodeck U. Growth-regulatory factors for
normal, premalignant, and malignant human cells in vitro. Adv Cancer Res 1990;54:21334.
(732) Furlanetto RW, Harwell SE, Baggs RB. Effects of insulin-like growth factor receptor
inhibition on human melanomas in culture and in athymic mice. Cancer Res 1993 June
1;53(11):2522-6.
(733) Hodak E, Gottlieb AB, Colen S, Anzilotti M, Krueger JG. In vivo expression of the
insulin-like growth factor-I (IGF-I) receptor in congenital pigmented nevi. J Cutan
Pathol 1996 February;23(1):19-24.
(734) Kanter-Lewensohn L, Dricu A, Wang M, Wejde J, Kiessling R, Larsson O. Expression
of the insulin-like growth factor-1 receptor and its anti-apoptotic effect in malignant
melanoma: a potential therapeutic target. Melanoma Res 1998 October;8(5):389-97.
(735) Bourguignon JP, Pierard GE, Ernould C, Heinrichs C, Craen M, Rochiccioli P, Arrese
JE, Franchimont C. Effects of human growth hormone therapy on melanocytic naevi.
Lancet 1993 June 12;341(8859):1505-6.
(736) Marks R. Epidemiology of melanoma. Clin Exp Dermatol 2000 September;25(6):459-63.
(737) Bunin GR, Kuijten RR, Boesel CP, Buckley JD, Meadows AT. Maternal diet and risk of
astrocytic glioma in children: a report from the Childrens Cancer Group (United States
and Canada). Cancer Causes Control 1994 March;5(2):177-87.
(738) Giles GG, McNeil JJ, Donnan G, Webley C, Staples MP, Ireland PD, Hurley SF,
Salzberg M. Dietary factors and the risk of glioma in adults: results of a case-control
study in Melbourne, Australia. Int J Cancer 1994 November 1;59(3):357-62.
(739) Preston-Martin S, Pogoda JM, Mueller BA, Holly EA, Lijinsky W, Davis RL. Maternal
consumption of cured meats and vitamins in relation to pediatric brain tumors. Cancer
Epidemiol Biomarkers Prev 1996 August;5(8):599-605.
186
(740) Blowers L, Preston-Martin S, Mack WJ. Dietary and other lifestyle factors of women
with brain gliomas in Los Angeles County (California, USA). Cancer Causes Control
1997 January;8(1):5-12.
(741) Lee M, Wrensch M, Miike R. Dietary and tobacco risk factors for adult onset glioma in
the San Francisco Bay Area (California, USA). Cancer Causes Control 1997
January;8(1):13-24.
(742) Kaplan S, Novikov I, Modan B. Nutritional factors in the etiology of brain tumors:
potential role of nitrosamines, fat, and cholesterol. Am J Epidemiol 1997 November
15;146(10):832-41.
(743) Bunin GR. Maternal diet during pregnancy and risk of brain tumors in children. Int J
Cancer Suppl 1998;11:23-5.
(744) Blot WJ, Henderson BE, Boice JDJ. Childhood cancer in relation to cured meat intake:
review of the epidemiological evidence. Nutr Cancer 1999;34(1):111-8.
(745) Nakao-Hayashi J, Ito H, Kanayasu T, Morita I, Murota S. Stimulatory effects of insulin
and insulin-like growth factor I on migration and tube formation by vascular
endothelial cells. Atherosclerosis 1992 February;92(2-3):141-9.
(746) Grant MB, Mames RN, Fitzgerald C, Ellis EA, Aboufriekha M, Guy J. Insulin-like
growth factor I acts as an angiogenic agent in rabbit cornea and retina: comparative
studies with basic fibroblast growth factor. Diabetologia 1993 April;36(4):282-91.
(747) Mukherjee P, Sotnikov AV, Mangian HJ, Zhou JR, Visek WJ, Clinton SK. Energy
intake and prostate tumor growth, angiogenesis, and vascular endothelial growth factor
expression. J Natl Cancer Inst 1999 March 17;91(6):512-23.
(748) Smith LE, Shen W, Perruzzi C, Soker S, Kinose F, Xu X, Robinson G, Driver S, Bischoff
J, Zhang B, Schaeffer JM, Senger DR. Regulation of vascular endothelial growth factordependent retinal neovascularization by insulin-like growth factor-1 receptor. Nat Med
1999 December;5(12):1390-5.
(749) Bermont L, Lamielle F, Fauconnet S, Esumi H, Weisz A, Adessi GL. Regulation of
vascular endothelial growth factor expression by insulin-like growth factor-I in
endometrial adenocarcinoma cells. Int J Cancer 2000 January 1;85(1):117-23.
(750) Dunn SE. Insulin-like growth factor I stimulates angiogenesis and the production of
vascular endothelial growth factor. Growth Horm IGF Res 2000 April;10 Suppl A:S41S42.
(751) Unproven methods of cancer management. Zen macrobiotic diet. CA Cancer J Clin 1972
November;22(6):372-5.
(752) Unproven methods of cancer managememt: macrobiotic diets. CA Cancer J Clin 1984
January;34(1):60-3.
(753) Carter JP, Saxe GP, Newbold V, Peres CE, Campeau RJ, Bernal-Green L. Hypothesis:
dietary management may improve survival from nutritionally linked cancers based on
analysis of representative cases. J Am Coll Nutr 1993 June;12(3):209-26.
(754) Ross JA, Perentesis JP, Robison LL, Davies SM. Big babies and infant leukemia: a role
for insulin-like growth factor-1? Cancer Causes Control 1996 September;7(5):553-9.
187
(755) Petridou E, Dessypris N, Spanos E, Mantzoros C, Skalkidou A, Kalmanti M, Koliouskas
D, Kosmidis H, Panagiotou JP, Piperopoulou F, Tzortzatou F, Trichopoulos D. Insulinlike growth factor-I and binding protein-3 in relation to childhood leukaemia. Int J
Cancer 1999 February 9;80(4):494-6.
(756) Barnard RJ. American Pysiological Society (website) 2000;September 20th.
(757) Ngo TH, Barnard RJ, Tymchuk CN, Cohen P, Aronson WJ. Effect of diet and exercise
on serum insulin, IGF-I, and IGFBP-1 levels and growth of LNCaP cells in vitro (United
States). Cancer Causes Control 2002 December;13(10):929-35.
(758) Barnard RJ. Prevention of Cancer Through Lifestyle Changes. Evid Based Complement
Alternat Med 2004 December;1(3):233-9.
(759) Bagga D, Ashley JM, Geffrey SP, Wang HJ, Barnard RJ, Korenman S, Heber D. Effects
of a very low fat, high fiber diet on serum hormones and menstrual function.
Implications for breast cancer prevention. Cancer 1995 December 15;76(12):2491-6.
(760) Heber D, Ashley JM, Leaf DA, Barnard RJ. Reduction of serum estradiol in
postmenopausal women given free access to low-fat high-carbohydrate diet. Nutrition
1991 March;7(2):137-9.
(761) Goodwin PJ, Ennis M, Pritchard KI, Trudeau ME, Koo J, Madarnas Y, Hartwick W,
Hoffman B, Hood N. Fasting insulin and outcome in early-stage breast cancer: results of
a prospective cohort study. J Clin Oncol JID - 8309333 2002 January 1;20(1):42-51.
(762) Ornish DM, Lee KL, Fair WR, Pettengill EB, Carroll PR. Dietary trial in prostate
cancer: Early experience and implications for clinical trial design. Urology 2001
April;57(4 Suppl 1):200-1.
(763) Ornish D, Weidner G, Fair WR, Marlin R, Pettengill EB, Raisin CJ, Dunn-Emke S,
Crutchfield L, Jacobs FN, Barnard RJ, Aronson WJ, McCormac P, McKnight DJ, Fein
JD, Dnistrian AM, Weinstein J, Ngo TH, Mendell NR, Carroll PR. Intensive lifestyle
changes may affect the progression of prostate cancer. J Urol 2005
September;174(3):1065-9.
(764) Frattaroli J, Weidner G, Dnistrian AM, Kemp C, Daubenmier JJ, Marlin RO,
Crutchfield L, Yglecias L, Carroll PR, Ornish D. Clinical events in prostate cancer
lifestyle trial: results from two years of follow-up. Urology 2008 December;72(6):131923.
(765) Zhou JR, Gugger ET, Tanaka T, Guo Y, Blackburn GL, Clinton SK. Soybean
phytochemicals inhibit the growth of transplantable human prostate carcinoma and
tumor angiogenesis in mice. J Nutr 1999 September;129(9):1628-35.
(766) Zhou JR, Mukherjee P, Gugger ET, Tanaka T, Blackburn GL, Clinton SK. Inhibition of
murine bladder tumorigenesis by soy isoflavones via alterations in the cell cycle,
apoptosis, and angiogenesis. Cancer Res 1998 November 15;58(22):5231-8.
(767) Trowell HC, Burkitt DP. Treatment and prevention: a note on autoimmune disease in
sub-Saharal Africans. In: Trowell HC, Burkitt DP, eds. Western Diseases: Their
Emergence and Prevention.Cambridge, MA: Harvard University Press; 1981. p. 436-43.
(768) Burkitt DP, Trowell HC. Refined Carbohydrate Foods and Disease. London: Academic
Press; 1975.
188
(769) Greenwood BM. Autoimmune diseases in Nigerians. Lancet 1968 September
7;2(7567):573.
(770) Greenwood BM. Autoimmune disease and parasitic infections in Nigerians. Lancet 1968
August 17;2(7564):380-2.
(771) Segal I, Tim LO, Hamilton DG, Walker AR. The rarity of ulcerative colitis in South
African blacks. Am J Gastroenterol 1980 October;74(4):332-6.
(772) Chaiamnuay P, Darmawan J, Muirden KD, Assawatanabodee P. Epidemiology of
rheumatic disease in rural Thailand: a WHO-ILAR COPCORD study. Community
Oriented Programme for the Control of Rheumatic Disease. J Rheumatol 1998
July;25(7):1382-7.
(773) Tuchinda C, Angsusingha K, Chaichanwalanakul K, Likitmaskul S, Vannasaeng S. The
epidemiology of insulin-dependent diabetes mellitus (IDDM): report from Thailand. J
Med Assoc Thai 1992 April;75(4):217-22.
(774) Panicheewa S, Chitrabamrung S, Verasertniyom O, Vanichaphantu M, Kraisit SO,
Chiewsilp P, Vatanasuk M. Diffuse systemic sclerosis and related diseases in Thailand.
Clin Rheumatol 1991 June;10(2):124-9.
(775) Muntoni S, Cocco P, Aru G, Cucca F. Nutritional factors and worldwide incidence of
childhood type 1 diabetes. Am J Clin Nutr 2000 June;71(6):1525-9.
(776) Esparza ML, Sasaki S, Kesteloot H. Nutrition, latitude, and multiple sclerosis mortality:
an ecologic study. Am J Epidemiol 1995 October 1;142(7):733-7.
(777) Alter M, Yamoor M, Harshe M. Multiple sclerosis and nutrition. Arch Neurol 1974
October;31(4):267-72.
(778) Agranoff BW, Goldberg D. Diet and the geographical distribution of multiple sclerosis.
Lancet 1974 November 2;2(7888):1061-6.
(779) Trowell HC. Non-Infectious Disease in Africa. London: Edward Arnold; 1960.
(780) Trowell HC. Causes of insulin dependent diabetes [letter]. Br Med J (Clin Res Ed) 1983
August 6;287(6389):430.
(781) Zhang SM, Willett WC, Hernan MA, Olek MJ, Ascherio A. Dietary fat in relation to
risk of multiple sclerosis among two large cohorts of women. Am J Epidemiol 2000
December 1;152(11):1056-64.
(782) Kjeldsen-Kragh J, Haugen M, Borchgrevink CF, Laerum E, Eek M, Mowinkel P, Hovi
K, Forre O. Controlled trial of fasting and one-year vegetarian diet in rheumatoid
arthritis [see comments]. Lancet 1991 October 12;338(8772):899-902.
(783) Panush RS. Food induced ("allergic") arthritis: clinical and serologic studies [see
comments]. J Rheumatol 1990 March;17(3):291-4.
(784) McDougall J, Bruce B, Spiller G, Westerdahl J, McDougall M. Effects of a very low-fat,
vegan diet in subjects with rheumatoid arthritis. J Altern Complement Med 2002
February;8(1):71-5.
189
(785) Kaartinen K, Lammi K, Hypen M, Nenonen M, Hanninen O, Rauma AL. Vegan diet
alleviates fibromyalgia symptoms. Scand J Rheumatol 2000;29(5):308-13.
(786) Hanninen, Kaartinen K, Rauma AL, Nenonen M, Torronen R, Hakkinen AS,
Adlercreutz H, Laakso J. Antioxidants in vegan diet and rheumatic disorders.
Toxicology 2000 November 30;155(1-3):45-53.
(787) Swank RL. Multiple sclerosis: twenty years on low fat diet. Arch Neurol 1970
November;23(5):460-74.
(788) Shigemasa C, Tanaka T, Mashiba H. Effect of vegetarian diet on systemic lupus
erythematosus [letter; comment]. Lancet 1992 May 9;339(8802):1177.
(789) Swank RL, Grimsgaard A. Multiple sclerosis: the lipid relationship. Am J Clin Nutr
1988 December;48(6):1387-93.
(790) Swank RL, Goodwin J. Review of MS patient survival on a Swank low saturated fat
diet. Nutrition 2003 February;19(2):161-2.
(791) Palmblad J, Hafstrom I, Ringertz B. Antirheumatic effects of fasting. Rheum Dis Clin
North Am 1991 May;17(2):351-62.
(792) Shimon I, Shpilberg O. The insulin-like growth factor system in regulation of normal
and malignant hematopoiesis. Leuk Res 1995 April;19(4):233-40.
(793) Kelley KW, Arkins S, Minshall C, Liu Q, Dantzer R. Growth hormone, growth factors
and hematopoiesis. Horm Res 1996;45(1-2):38-45.
(794) Lindahl O, Lindwall L, Spangberg A, Stenram A, Ockerman PA. Vegan regimen with
reduced medication in the treatment of bronchial asthma. J Asthma 1985;22(1):45-55.
(795) Lithell H, Bruce A, Gustafsson IB, Hoglund NJ, Karlstrom B, Ljunghall K, Sjolin K,
Venge P, Werner I, Vessby B. A fasting and vegetarian diet treatment trial on chronic
inflammatory disorders. Acta Derm Venereol 1983;63(5):397-403.
(796) Sprent J. Central tolerance of T cells. Int Rev Immunol 1995;13(2):95-105.
(797) Kooijman R, Scholtens LE, Rijkers GT, Zegers BJ. Type I insulin-like growth factor
receptor expression in different developmental stages of human thymocytes. J
Endocrinol 1995 November;147(2):203-9.
(798) Kooijman R, Lauf JJ, Kappers AC, Rijkers GT. Insulin-like growth factor induces
phosphorylation of immunoreactive insulin receptor substrate and its association with
phosphatidylinositol-3 kinase in human thymocytes. J Exp Med 1995 August
1;182(2):593-7.
(799) Verland S, Gammeltoft S. Functional receptors for insulin-like growth factors I and II
in rat thymocytes and mouse thymoma cells. Mol Cell Endocrinol 1989 December;67(23):207-16.
(800) Hinton PS, Peterson CA, Dahly EM, Ney DM. IGF-I alters lymphocyte survival and
regeneration in thymus and spleen after dexamethasone treatment. Am J Physiol 1998
April;274(4 Pt 2):R912-R920.
190
(801) McCarty MF. Up-regulation of lymphocyte apoptosis as a strategy for preventing and
treating autoimmune disorders: a role for whole-food vegan diets, fish oil, and dopamine
agonists. Medical Hypotheses 2001;56:in press.
(802) Kostraba JN. What can epidemiology tell us about the role of infant diet in the etiology
of IDDM? Diabetes Care 1994 January;17(1):87-91.
(803) Virtanen SM, Hypponen E, Laara E, Vahasalo P, Kulmala P, Savola K, Rasanen L, Aro
A, Knip M, Akerblom HK. Cow's milk consumption, disease-associated autoantibodies
and type 1 diabetes mellitus: a follow-up study in siblings of diabetic children.
Childhood Diabetes in Finland Study Group. Diabet Med 1998 September;15(9):730-8.
(804) Elliott RB, Martin JM. Dietary protein: a trigger of insulin-dependent diabetes in the
BB rat? Diabetologia 1984 April;26(4):297-9.
(805) Carr R, Forsyth S, Sadi D. Abnormal responses to ingested substances in murine
systemic lupus erythematosus: apparent effect of a casein-free diet on the development
of systemic lupus erythematosus in NZB/W mice. J Rheumatol 1987 June;14 Suppl
13:158-65.
(806) Scott FW. Cow milk and insulin-dependent diabetes mellitus: is there a relationship?
Am J Clin Nutr 1990 March;51(3):489-91.
(807) Norris JM, Scott FW. A meta-analysis of infant diet and insulin-dependent diabetes
mellitus: do biases play a role? Epidemiology 1996 January;7(1):87-92.
(808) Wasmuth HE, Kolb H. Cow's milk and immune-mediated diabetes. Proc Nutr Soc 2000
November;59(4):573-9.
(809) Virtanen SM, Laara E, Hypponen E, Reijonen H, Rasanen L, Aro A, Knip M, Ilonen J,
Akerblom HK. Cow's milk consumption, HLA-DQB1 genotype, and type 1 diabetes: a
nested case-control study of siblings of children with diabetes. Childhood diabetes in
Finland study group. Diabetes 2000 June;49(6):912-7.
(810) Esquifino AI, Cano P, Jimenez-Ortega V, Fernandez-Mateos MP, Cardinali DP.
Immune response after experimental allergic encephalomyelitis in rats subjected to
calorie restriction. J Neuroinflammation 2007;4:6.
(811) Sogawa H, Kubo C. Influence of short-term repeated fasting on the longevity of female
(NZB x NZW)F1 mice. Mech Ageing Dev 2000 May 18;115(1-2):61-71.
(812) Sun D, Krishnan A, Su J, Lawrence R, Zaman K, Fernandes G. Regulation of immune
function by calorie restriction and cyclophosphamide treatment in lupus-prone
NZB/NZW F1 mice. Cell Immunol 2004 March;228(1):54-65.
(813) Shibolet O, Alper R, Avraham Y, Berry EM, Ilan Y. Immunomodulation of
experimental colitis via caloric restriction: role of Nk1.1+ T cells. Clin Immunol 2002
October;105(1):48-56.
(814) Johnson JB, Laub DR, John S. The effect on health of alternate day calorie restriction:
eating less and more than needed on alternate days prolongs life. Med Hypotheses
2006;67(2):209-11.
191
(815) Cohen P, Noveral JP, Bhala A, Nunn SE, Herrick DJ, Grunstein MM. Leukotriene D4
facilitates airway smooth muscle cell proliferation via modulation of the IGF axis. Am J
Physiol 1995 August;269(2 Pt 1):L151-L157.
(816) Cambrey AD, Kwon OJ, Gray AJ, Harrison NK, Yacoub M, Barnes PJ, Laurent GJ,
Chung KF. Insulin-like growth factor I is a major fibroblast mitogen produced by
primary cultures of human airway epithelial cells. Clin Sci (Colch) 1995
December;89(6):611-7.
(817) Rajah R, Nunn SE, Herrick DJ, Grunstein MM, Cohen P. Leukotriene D4 induces
MMP-1, which functions as an IGFBP protease in human airway smooth muscle cells.
Am J Physiol 1996 December;271(6 Pt 1):L1014-L1022.
(818) Hoshino M, Nakamura Y, Sim JJ, Yamashiro Y, Uchida K, Hosaka K, Isogai S. Inhaled
corticosteroid reduced lamina reticularis of the basement membrane by modulation of
insulin-like growth factor (IGF)-I expression in bronchial asthma. Clin Exp Allergy 1998
May;28(5):568-77.
(819) Oyamada H, Kayaba H, Kamada Y, Kuwasaki T, Yamada Y, Kobayashi Y, Cui C,
Honda K, Saito N, Chihara J. An optimal condition of bronchial cell proliferation
stimulated by insulin-like growth factor-I. Int Arch Allergy Immunol 2000 May;122
Suppl 1:59-62.
(820) Johnson JB, Summer W, Cutler RG, Martin B, Hyun DH, Dixit VD, Pearson M, Nassar
M, Telljohann R, Maudsley S, Carlson O, John S, Laub DR, Mattson MP. Alternate day
calorie restriction improves clinical findings and reduces markers of oxidative stress and
inflammation in overweight adults with moderate asthma. Free Radic Biol Med 2007
March 1;42(5):665-74.
(821) Burney PG, Britton JR, Chinn S, Tattersfield AE, Platt HS, Papacosta AO, Kelson MC.
Response to inhaled histamine and 24 hour sodium excretion. Br Med J (Clin Res Ed)
1986 June 7;292(6534):1483-6.
(822) Burney P. A diet rich in sodium may potentiate asthma. Epidemiologic evidence for a
new hypothesis. Chest 1987 June;91(6 Suppl):143S-8S.
(823) Burney PG, Neild JE, Twort CH, Chinn S, Jones TD, Mitchell WD, Bateman C,
Cameron IR. Effect of changing dietary sodium on the airway response to histamine.
Thorax 1989 January;44(1):36-41.
(824) Carey OJ, Locke C, Cookson JB. Effect of alterations of dietary sodium on the severity
of asthma in men. Thorax 1993 July;48(7):714-8.
(825) Medici TC, Schmid AZ, Hacki M, Vetter W. Are asthmatics salt-sensitive? A
preliminary controlled study. Chest 1993 October;104(4):1138-43.
(826) Gotshall RW, Mickleborough TD, Cordain L. Dietary salt restriction improves
pulmonary function in exercise-induced asthma. Med Sci Sports Exerc 2000
November;32(11):1815-9.
(827) Mickleborough TD, Lindley MR, Ray S. Dietary salt, airway inflammation, and
diffusion capacity in exercise-induced asthma. Med Sci Sports Exerc 2005
June;37(6):904-14.
192
(828) Hirota SA, Janssen LJ. Sodium and asthma: something borrowed, something new? Am
J Physiol Lung Cell Mol Physiol 2007 December;293(6):L1369-L1373.
(829) Knox AJ, Tattersfield AE, Britton JR. The effect of inhaled ouabain on bronchial
reactivity to histamine in man. Br J Clin Pharmacol 1988 June;25(6):758-60.
(830) Hulks G, Patel KR. The effect of inhaled ouabain on bronchomotor tone and histamine
responsiveness in asthmatic patients. Pulm Pharmacol 1989;2(3):161-2.
(831) Gentile DA, Skoner DP. The relationship between airway hyperreactivity (AHR) and
sodium, potassium adenosine triphosphatase (Na+,K+ ATPase) enzyme inhibition. J
Allergy Clin Immunol 1997 March;99(3):367-73.
(832) Arm JP, Thien FC, Lee TH. Leukotrienes, fish-oil, and asthma. Allergy Proc 1994
May;15(3):129-34.
(833) Broughton KS, Johnson CS, Pace BK, Liebman M, Kleppinger KM. Reduced asthma
symptoms with n-3 fatty acid ingestion are related to 5-series leukotriene production.
Am J Clin Nutr 1997 April;65(4):1011-7.
(834) Woods RK, Thien FC, Abramson MJ. Dietary marine fatty acids (fish oil) for asthma
(Cochrane Review). Cochrane Database Syst Rev 2000;(4):CD001283.
(835) Kragballe K, Fogh K. A low-fat diet supplemented with dietary fish oil (Max-EPA)
results in improvement of psoriasis and in formation of leukotriene B5. Acta Derm
Venereol 1989;69(1):23-8.
(836) Kremer JM. n-3 fatty acid supplements in rheumatoid arthritis. Am J Clin Nutr 2000
January;71(1 Suppl):349S-51S.
(837) Ross E. The role of marine fish oils in the treatment of ulcerative colitis. Nutr Rev 1993
February;51(2):47-9.
(838) Sebastian A, Harris ST, Ottaway JH, Todd KM, Morris RC. Improved mineral balance
and skeletal metabolism in postmenopausal women treated with potassium bicarbonate.
N Engl J Med 1994 June 23;330(25):1776-81.
(839) Tucker KL, Hannan MT, Chen H, Cupples LA, Wilson PW, Kiel DP. Potassium,
magnesium, and fruit and vegetable intakes are associated with greater bone mineral
density in elderly men and women. Am J Clin Nutr 1999 April;69(4):727-36.
(840) New SA, Robins SP, Campbell MK, Martin JC, Garton MJ, Bolton-Smith C, Grubb
DA, Lee SJ, Reid DM. Dietary influences on bone mass and bone metabolism: further
evidence of a positive link between fruit and vegetable consumption and bone health?
Am J Clin Nutr 2000 January;71(1):142-51.
(841) Jones G, Riley MD, Whiting S. Association between urinary potassium, urinary sodium,
current diet, and bone density in prepubertal children. Am J Clin Nutr 2001
April;73(4):839-44.
(842) Lemann J. Relationship between urinary calcium and net acid excretion as determined
by dietary protein and potassium: a review. Nephron 1999;81 Suppl 1:18-25.
(843) Remer T, Manz F. Potential renal acid load of foods and its influence on urine pH. J Am
Diet Assoc 1995 July;95(7):791-7.
193
(844) Feskanich D, Willett WC, Stampfer MJ, Colditz GA. Milk, dietary calcium, and bone
fractures in women: a 12-year prospective study. Am J Public Health 1997
June;87(6):992-7.
(845) McParland BE, Goulding A, Campbell AJ. Dietary salt affects biochemical markers of
resorption and formation of bone in elderly women. BMJ 1989 September
30;299(6703):834-5.
(846) Lemann JJ, Gray RW, Pleuss JA. Potassium bicarbonate, but not sodium bicarbonate,
reduces urinary calcium excretion and improves calcium balance in healthy men. Kidney
Int 1989 February;35(2):688-95.
(847) Lemann JJ, Pleuss JA, Gray RW. Potassium causes calcium retention in healthy adults.
J Nutr 1993 September;123(9):1623-6.
(848) Trippel SB. Potential role of insulinlike growth factors in fracture healing. Clin Orthop
1998 October;(355 Suppl):S301-S313.
(849) Schurch MA, Rizzoli R, Slosman D, Vadas L, Vergnaud P, Bonjour JP. Protein
supplements increase serum insulin-like growth factor-I levels and attenuate proximal
femur bone loss in patients with recent hip fracture. A randomized, double-blind,
placebo-controlled trial. Ann Intern Med 1998 May 15;128(10):801-9.
(850) Gamero P, Sornay-Rendu E, Delmas PD. Low serum IGF-1 and occurrence of
osteoporotic fractures in postmenopausal women. Lancet 2000 March 11;355(9207):8989.
(851) Hedstrom M, Saaf M, Dalen N. Low IGF-I levels in hip fracture patients. A comparison
of 20 coxarthrotic and 23 hip fracture patients. Acta Orthop Scand 1999 April;70(2):1458.
(852) Boonen S, Mohan S, Dequeker J, Aerssens J, Vanderschueren D, Verbeke G, Broos P,
Bouillon R, Baylink DJ. Down-regulation of the serum stimulatory components of the
insulin-like growth factor (IGF) system (IGF-I, IGF-II, IGF binding protein [BP]-3, and
IGFBP-5) in age-related (type II) femoral neck osteoporosis. J Bone Miner Res 1999
December;14(12):2150-8.
(853) Dagnelie PC, Vergote FJ, van Staveren WA, van den Berg H, Dingjan PG, Hautvast JG.
High prevalence of rickets in infants on macrobiotic diets. Am J Clin Nutr 1990
February;51(2):202-8.
(854) Parsons TJ, van Dusseldorp M, Van d, V, van de Werken K, Schaafsma G, van Staveren
WA. Reduced bone mass in Dutch adolescents fed a macrobiotic diet in early life. J Bone
Miner Res 1997 September;12(9):1486-94.
(855) Kerstetter JE, Caseria DM, Mitnick ME, Ellison AF, Gay LF, Liskov TA, Carpenter
TO, Insogna KL. Increased circulating concentrations of parathyroid hormone in
healthy, young women consuming a protein-restricted diet. Am J Clin Nutr 1997
November;66(5):1188-96.
(856) Kerstetter JE, Svastisalee CM, Caseria DM, Mitnick ME, Insogna KL. A threshold for
low-protein-diet-induced elevations in parathyroid hormone. Am J Clin Nutr 2000
July;72(1):168-73.
194
(857) McCarty MF, Barroso-Aranda J, Contreras F. The low-methionine content of vegan
diets may make methionine restriction feasible as a life extension strategy. Med
Hypotheses 2008 September 11.
(858) Messina M, Messina V. Soyfoods, soybean isoflavones, and bone health: a brief
overview. J Ren Nutr 2000 April;10(2):63-8.
(859) Marini H, Minutoli L, Polito F, Bitto A, Altavilla D, Atteritano M, Gaudio A,
Mazzaferro S, Frisina A, Frisina N, Lubrano C, Bonaiuto M, D'Anna R, Cannata ML,
Corrado F, Adamo EB, Wilson S, Squadrito F. Effects of the phytoestrogen genistein on
bone metabolism in osteopenic postmenopausal women: a randomized trial. Ann Intern
Med 2007 June 19;146(12):839-47.
(860) Ma DF, Qin LQ, Wang PY, Katoh R. Soy isoflavone intake increases bone mineral
density in the spine of menopausal women: meta-analysis of randomized controlled
trials. Clin Nutr 2008 February;27(1):57-64.
(861) Atmaca A, Kleerekoper M, Bayraktar M, Kucuk O. Soy isoflavones in the management
of postmenopausal osteoporosis. Menopause 2008 July;15(4 Pt 1):748-57.
(862) Abelow BJ, Holford TR, Insogna KL. Cross-cultural association between dietary animal
protein and hip fracture: a hypothesis. Calcif Tissue Int 1992 January;50(1):14-8.
(863) Frassetto LA, Todd KM, Morris RC, Sebastian A. Worldwide incidence of hip fracture
in elderly women: relation to consumption of animal and vegetable foods. J Gerontol A
Biol Sci Med Sci 2000 October;55(10):M585-M592.
(864) Lau EM, Cooper C. The epidemiology of osteoporosis. The oriental perspective in a
world context. Clin Orthop 1996 February;(323):65-74.
(865) Schwartz GG, Hulka BS. Is vitamin D deficiency a risk factor for prostate cancer?
(Hypothesis). Anticancer Res JID - 8102988 1990 September;10(5A):1307-11.
(866) Luscombe CJ, Fryer AA, French ME, Liu S, Saxby MF, Jones PW, Strange RC.
Exposure to ultraviolet radiation: association with susceptibility and age at presentation
with prostate cancer. Lancet 2001 August 25;358(9282):641-2.
(867) Colli JL, Grant WB. Solar ultraviolet B radiation compared with prostate cancer
incidence and mortality rates in United States. Urology 2008 March;71(3):531-5.
(868) Giovannucci E. Dietary influences of 1,25(OH)2 vitamin D in relation to prostate cancer:
a hypothesis. Cancer Causes Control 1998 December;9(6):567-82.
(869) Giovannucci E, Rimm EB, Wolk A, Ascherio A, Stampfer MJ, Colditz GA, Willett WC.
Calcium and fructose intake in relation to risk of prostate cancer. Cancer Res 1998
February 1;58(3):442-7.
(870) Giovannucci E, Liu Y, Stampfer MJ, Willett WC. A prospective study of calcium intake
and incident and fatal prostate cancer. Cancer Epidemiol Biomarkers Prev 2006
February;15(2):203-10.
(871) Kesse E, Bertrais S, Astorg P, Jaouen A, Arnault N, Galan P, Hercberg S. Dairy
products, calcium and phosphorus intake, and the risk of prostate cancer: results of the
French prospective SU.VI.MAX (Supplementation en Vitamines et Mineraux
Antioxydants) study. Br J Nutr 2006 March;95(3):539-45.
195
(872) Ohno Y, Yoshida O, Oishi K, Okada K, Yamabe H, Schroeder FH. Dietary betacarotene and cancer of the prostate: a case-control study in Kyoto, Japan. Cancer Res
1988 March 1;48(5):1331-6.
(873) Vlajinac HD, Marinkovic JM, Ilic MD, Kocev NI. Diet and prostate cancer: a casecontrol study. Eur J Cancer 1997 January;33(1):101-7.
(874) Hayes RB, Ziegler RG, Gridley G, Swanson C, Greenberg RS, Swanson GM,
Schoenberg JB, Silverman DT, Brown LM, Pottern LM, Liff J, Schwartz AG, Fraumeni
JF, Hoover RN. Dietary factors and risks for prostate cancer among blacks and whites
in the United States. Cancer Epidemiol Biomarkers Prev 1999 January;8(1):25-34.
(875) Schuurman AG, van den Brandt PA, Dorant E, Goldbohm RA. Animal products,
calcium and protein and prostate cancer risk in The Netherlands Cohort Study. Br J
Cancer 1999 June;80(7):1107-13.
(876) Chan JM, Pietinen P, Virtanen M, Malila N, Tangrea J, Albanes D, Virtamo J. Diet and
prostate cancer risk in a cohort of smokers, with a specific focus on calcium and
phosphorus (Finland). Cancer Causes Control 2000 October;11(9):859-67.
(877) Park Y, Mitrou PN, Kipnis V, Hollenbeck A, Schatzkin A, Leitzmann MF. Calcium,
dairy foods, and risk of incident and fatal prostate cancer: the NIH-AARP Diet and
Health Study. Am J Epidemiol 2007 December 1;166(11):1270-9.
(878) Koh KA, Sesso HD, Paffenbarger RS, Jr., Lee IM. Dairy products, calcium and prostate
cancer risk. Br J Cancer 2006 December 4;95(11):1582-5.
(879) Chan JM, Giovannucci E, Andersson SO, Yuen J, Adami HO, Wolk A. Dairy products,
calcium, phosphorous, vitamin D, and risk of prostate cancer (Sweden). Cancer Causes
Control 1998 December;9(6):559-66.
(880) Braun MM, Helzlsouer KJ, Hollis BW, Comstock GW. Prostate cancer and
prediagnostic levels of serum vitamin D metabolites (Maryland, United States). Cancer
Causes Control 1995 May;6(3):235-9.
(881) Gann PH, Ma J, Hennekens CH, Hollis BW, Haddad JG, Stampfer MJ. Circulating
vitamin D metabolites in relation to subsequent development of prostate cancer. Cancer
Epidemiol Biomarkers Prev 1996 February;5(2):121-6.
(882) Nomura AM, Stemmermann GN, Lee J, Kolonel LN, Chen TC, Turner A, Holick MF.
Serum vitamin D metabolite levels and the subsequent development of prostate cancer
(Hawaii, United States). Cancer Causes Control 1998 August;9(4):425-32.
(883) Schwartz GG, Whitlatch LW, Chen TC, Lokeshwar BL, Holick MF. Human prostate
cells synthesize 1,25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3. Cancer
Epidemiol Biomarkers Prev 1998 May;7(5):391-5.
(884) Vieth R. Dairy products, calcium, and prostate cancer risk in the Physicians' Health
Study. Am J Clin Nutr 2002 August;76(2):490-1.
(885) Kampman E, Slattery ML, Caan B, Potter JD. Calcium, vitamin D, sunshine exposure,
dairy products and colon cancer risk (United States). Cancer Causes Control 2000
May;11(5):459-66.
196
(886) Larsson SC, Bergkvist L, Rutegard J, Giovannucci E, Wolk A. Calcium and dairy food
intakes are inversely associated with colorectal cancer risk in the Cohort of Swedish
Men. Am J Clin Nutr 2006 March;83(3):667-73.
(887) Reid IR. The roles of calcium and vitamin D in the prevention of osteoporosis.
Endocrinol Metab Clin North Am 1998 June;27(2):389-98.
(888) Meunier PJ. Calcium, vitamin D and vitamin K in the prevention of fractures due to
osteoporosis. Osteoporos Int 1999;9 Suppl 2:S48-S52.
(889) Booth SL, Tucker KL, Chen H, Hannan MT, Gagnon DR, Cupples LA, Wilson PW,
Ordovas J, Schaefer EJ, Dawson-Hughes B, Kiel DP. Dietary vitamin K intakes are
associated with hip fracture but not with bone mineral density in elderly men and
women. Am J Clin Nutr 2000 May;71(5):1201-8.
(890) Shearer MJ. Role of vitamin K and Gla proteins in the pathophysiology of osteoporosis
and vascular calcification. Curr Opin Clin Nutr Metab Care 2000 November;3(6):433-8.
(891) Craciun AM, Wolf J, Knapen MH, Brouns F, Vermeer C. Improved bone metabolism in
female elite athletes after vitamin K supplementation. Int J Sports Med 1998
October;19(7):479-84.
(892) Vermeer C, Gijsbers BL, Craciun AM, Groenen-van Dooren MM, Knapen MH. Effects
of vitamin K on bone mass and bone metabolism. J Nutr 1996 April;126(4 Suppl):1187S91S.
(893) Knapen MH, Hamulyak K, Vermeer C. The effect of vitamin K supplementation on
circulating osteocalcin (bone Gla protein) and urinary calcium excretion. Ann Intern
Med 1989 December 15;111(12):1001-5.
(894) Toba Y, Kajita Y, Masuyama R, Takada Y, Suzuki K, Aoe S. Dietary magnesium
supplementation affects bone metabolism and dynamic strength of bone in
ovariectomized rats. J Nutr 2000 February;130(2):216-20.
(895) Sojka JE, Weaver CM. Magnesium supplementation and osteoporosis. Nutr Rev 1995
March;53(3):71-4.
(896) Strause L, Saltman P, Smith KT, Bracker M, Andon MB. Spinal bone loss in
postmenopausal women supplemented with calcium and trace minerals. J Nutr 1994
July;124(7):1060-4.
(897) Saltman PD, Strause LG. The role of trace minerals in osteoporosis. J Am Coll Nutr 1993
August;12(4):384-9.
(898) Cockayne S, Adamson J, Lanham-New S, Shearer MJ, Gilbody S, Torgerson DJ.
Vitamin K and the prevention of fractures: systematic review and meta-analysis of
randomized controlled trials. Arch Intern Med 2006 June 26;166(12):1256-61.
(899) Melhus H, Michaelsson K, Kindmark A, Bergstrom R, Holmberg L, Mallmin H, Wolk
A, Ljunghall S. Excessive dietary intake of vitamin A is associated with reduced bone
mineral density and increased risk for hip fracture. Ann Intern Med JID - 0372351 1998
November 15;129(10):770-8.
(900) Whiting SJ, Lemke B. Excess retinol intake may explain the high incidence of
osteoporosis in northern Europe. Nutr Rev JID - 0376405 1999 June;57(6):192-5.
197
(901) Feskanich D, Singh V, Willett WC, Colditz GA. Vitamin A intake and hip fractures
among postmenopausal women. JAMA JID - 7501160 2002 January 2;287(1):47-54.
(902) Kaji H, Sugimoto T, Kanatani M, Fukase M, Kumegawa M, Chihara K. Retinoic acid
induces osteoclast-like cell formation by directly acting on hemopoietic blast cells and
stimulates osteopontin mRNA expression in isolated osteoclasts. Life Sci JID - 0375521
1995;56(22):1903-13.
(903) Saneshige S, Mano H, Tezuka K, Kakudo S, Mori Y, Honda Y, Itabashi A, Yamada T,
Miyata K, Hakeda Y. Retinoic acid directly stimulates osteoclastic bone resorption and
gene expression of cathepsin K/OC-2. Biochem J JID - 2984726R 1995 August 1;309 ( Pt
3):721-4.
(904) Jaeger P. Prevention of recurrent calcium stones: diet versus drugs. Miner Electrolyte
Metab JID - 7802196 1994;20(6):410-3.
(905) Sakhaee K, Harvey JA, Padalino PK, Whitson P, Pak CY. The potential role of salt
abuse on the risk for kidney stone formation. J Urol JID - 0376374 1993 August;150(2 Pt
1):310-2.
(906) Massey LK, Whiting SJ. Dietary salt, urinary calcium, and kidney stone risk. Nutr Rev
JID - 0376405 1995 May;53(5):131-9.
(907) Goldfarb DS, Coe FL. Prevention of recurrent nephrolithiasis. Am Fam Physician JID 1272646 1999 November 15;60(8):2269-76.
(908) Cappuccio FP, Kalaitzidis R, Duneclift S, Eastwood JB. Unravelling the links between
calcium excretion, salt intake, hypertension, kidney stones and bone metabolism. J
Nephrol JID - 9012268 2000 May;13(3):169-77.
(909) Auer BL, Auer D, Rodgers AL. Relative hyperoxaluria, crystalluria and haematuria
after megadose ingestion of vitamin C. Eur J Clin Invest JID - 0245331 1998
September;28(9):695-700.
(910) Gerster H. No contribution of ascorbic acid to renal calcium oxalate stones. Ann Nutr
Metab JID - 8105511 1997;41(5):269-82.
(911) Auer BL, Auer D, Rodgers AL. The effect of ascorbic acid ingestion on the biochemical
and physicochemical risk factors associated with calcium oxalate kidney stone
formation. Clin Chem Lab Med JID - 9806306 1998 March;36(3):143-7.
(912) Balcke P, Schmidt P, Zazgornik J, Kopsa H, Minar E. Pyridoxine therapy in patients
with renal calcium oxalate calculi. Proc Eur Dial Transplant Assoc JID - 0355210
1983;20:417-21.
(913) Yendt ER, Cohanim M. Response to a physiologic dose of pyridoxine in type I primary
hyperoxaluria. N Engl J Med JID - 0255562 1985 April 11;312(15):953-7.
(914) Curhan GC, Willett WC, Speizer FE, Stampfer MJ. Intake of vitamins B6 and C and
the risk of kidney stones in women. J Am Soc Nephrol JID - 9013836 1999
April;10(4):840-5.
(915) Taylor EN, Stampfer MJ, Curhan GC. Dietary factors and the risk of incident kidney
stones in men: new insights after 14 years of follow-up. J Am Soc Nephrol 2004
December;15(12):3225-32.
198
(916) Takei K, Ito H, Masai M, Kotake T. Oral calcium supplement decreases urinary oxalate
excretion in patients with enteric hyperoxaluria. Urol Int JID - 0417373 1998;61(3):1925.
(917) Borghi L, Schianchi T, Meschi T, Guerra A, Allegri F, Maggiore U, Novarini A.
Comparison of two diets for the prevention of recurrent stones in idiopathic
hypercalciuria. N Engl J Med JID - 0255562 2002 January 10;346(2):77-84.
(918) Messier SP, Loeser RF, Mitchell MN, Valle G, Morgan TP, Rejeski WJ, Ettinger WH.
Exercise and weight loss in obese older adults with knee osteoarthritis: a preliminary
study. J Am Geriatr Soc 2000 September;48(9):1062-72.
(919) Reginster JY, Deroisy R, Rovati LC, Lee RL, Lejeune E, Bruyere O, Giacovelli G,
Henrotin Y, Dacre JE, Gossett C. Long-term effects of glucosamine sulphate on
osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet 2001
January 27;357(9252):251-6.
(920) Bruyere O, Pavelka K, Rovati LC, Deroisy R, Olejarova M, Gatterova J, Giacovelli G,
Reginster JY. Glucosamine sulfate reduces osteoarthritis progression in postmenopausal
women with knee osteoarthritis: evidence from two 3-year studies. Menopause 2004
March;11(2):138-43.
(921) Bruyere O, Pavelka K, Rovati LC, Gatterova J, Giacovelli G, Olejarova M, Deroisy R,
Reginster JY. Total joint replacement after glucosamine sulphate treatment in knee
osteoarthritis: results of a mean 8-year observation of patients from two previous 3-year,
randomised, placebo-controlled trials. Osteoarthritis Cartilage 2008 February;16(2):25460.
(922) Clegg DO, Reda DJ, Harris CL, Klein MA, O'Dell JR, Hooper MM, Bradley JD,
Bingham CO, III, Weisman MH, Jackson CG, Lane NE, Cush JJ, Moreland LW,
Schumacher HR, Jr., Oddis CV, Wolfe F, Molitor JA, Yocum DE, Schnitzer TJ, Furst
DE, Sawitzke AD, Shi H, Brandt KD, Moskowitz RW, Williams HJ. Glucosamine,
chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J
Med 2006 February 23;354(8):795-808.
(923) McCarty MF. The neglect of glucosamine as a treatment for osteoarthritis--a personal
perspective. Med Hypotheses 1994 May;42(5):323-7.
(924) Towheed TE, Maxwell L, Anastassiades TP, Shea B, Houpt J, Robinson V, Hochberg
MC, Wells G. Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst
Rev 2005;(2):CD002946.
(925) McCarty MF. Up-regulation of hepatic IGFBP-1 production as a strategy for preventing
benign prostatic hyperplasia. Med Hypotheses 2001 January;56(1):1-4.
(926) Gu FL, Xia TL, Kong XT. Preliminary study of the frequency of benign prostatic
hyperplasia and prostatic cancer in China. Urology 1994 November;44(5):688-91.
(927) Gu F. Changes in the prevalence of benign prostatic hyperplasia in China. Chin Med J
(Engl) 1997 March;110(3):163-6.
(928) Gu F. Epidemiological survey of benign prostatic hyperplasia and prostatic cancer in
China. Chin Med J (Engl ) 2000 April;113(4):299-302.
199
(929) Stattin P, Kaaks R, Riboli E, Ferrari P, Dechaud H, Hallmans G. Circulating insulinlike growth factor-I and benign prostatic hyperplasia--a prospective study. Scand J Urol
Nephrol 2001 April;35(2):122-6.
(930) Hammarsten J, Hogstedt B. Hyperinsulinaemia as a risk factor for developing benign
prostatic hyperplasia. Eur Urol 2001 February;39(2):151-8.
(931) Chokkalingam AP, Gao YT, Deng J, Stanczyk FZ, Sesterhenn IA, Mostofi FK,
Fraumeni JF, Jr., Hsing AW. Insulin-like growth factors and risk of benign prostatic
hyperplasia. Prostate 2002 July 1;52(2):98-105.
(932) Neuhouser ML, Schenk J, Song YJ, Tangen CM, Goodman PJ, Pollak M, Penson DF,
Thompson IM, Kristal AR. Insulin-like growth factor-I, insulin-like growth factor
binding protein-3 and risk of benign prostate hyperplasia in the prostate cancer
prevention trial. Prostate 2008 September 15;68(13):1477-86.
(933) Platz EA, Kawachi I, Rimm EB, Colditz GA, Stampfer MJ, Willett WC, Giovannucci E.
Physical activity and benign prostatic hyperplasia. Arch Intern Med 1998 November
23;158(21):2349-56.
(934) Platz EA, Rimm EB, Kawachi I, Colditz GA, Stampfer MJ, Willett WC, Giovannucci E.
Alcohol consumption, cigarette smoking, and risk of benign prostatic hyperplasia. Am J
Epidemiol 1999 January 15;149(2):106-15.
(935) Walker AR, Shipton E, Walker BF, Manetsi B, Van Rensburg PS, Vorster HH.
Appendicectomy incidence in black and white children aged 0 to 14 years with a
discussion on the disease's causation. Trop Gastroenterol 1989 April;10(2):96-101.
(936) Naaeder SB, Archampong EQ. Acute appendicitis and dietary fibre intake. West Afr J
Med 1998 October;17(4):264-7.
(937) Walker AR, Walker BF. Appendectomy in South African inter-ethnic school pupils. Am
J Gastroenterol 1987 March;82(3):219-22.
(938) van Faassen A, Bol J, van Dokkum W, Pikaar NA, Ockhuizen T, Hermus RJ. Bile acids,
neutral steroids, and bacteria in feces as affected by a mixed, a lacto-ovovegetarian, and
a vegan diet. Am J Clin Nutr 1987 December;46(6):962-7.
(939) Peltonen R, Nenonen M, Helve T, Hanninen O, Toivanen P, Eerola E. Faecal microbial
flora and disease activity in rheumatoid arthritis during a vegan diet. Br J Rheumatol
1997 January;36(1):64-8.
(940) Appleby P, Thorogood M, McPherson K, Mann J. Emergency appendicectomy and
meat consumption in the UK. J Epidemiol Community Health 1995 December;49(6):5946.
(941) Klurfeld DM. The role of dietary fiber in gastrointestinal disease. J Am Diet Assoc 1987
September;87(9):1172-7.
(942) Gray DS. The clinical uses of dietary fiber. Am Fam Physician 1995 February
1;51(2):419-26.
(943) Perez-Miranda M, Gomez-Cedenilla A, Leon-Colombo T, Pajares J, Mate-Jimenez J.
Effect of fiber supplements on internal bleeding hemorrhoids. Hepatogastroenterology
1996 November;43(12):1504-7.
200
(944) Moesgaard F, Nielsen ML, Hansen JB, Knudsen JT. High-fiber diet reduces bleeding
and pain in patients with hemorrhoids: a double-blind trial of Vi-Siblin. Dis Colon
Rectum 1982 July;25(5):454-6.
(945) Latto C. Postoperative deep vein thrombosis in Nigerians on high-fibre diets. Br Med J
1979 January 20;1(6157):199.
(946) Wicks AC, Yeates J, Heaton KW. Bran and bile: time-course of changes in normal
young men given a standard dose. Scand J Gastroenterol 1978;13(3):289-92.
(947) VanBerge-Henegouwen GP, Portincasa P, van Erpecum KJ. Effect of lactulose and
fiber-rich diets on bile in relation to gallstone disease: an update. Scand J Gastroenterol
Suppl 1997;222:68-71.
(948) Bertolotti M, Abate N, Loria P, Concari M, Guicciardi ME, Dilengite MA, Bozzoli M,
Carubbi F, Carulli N. Regulation of bile acid synthesis in humans: studies on cholesterol
7 alpha-hydroxylation in vivo. Ital J Gastroenterol 1995 October;27(8):446-9.
(949) Stroup D, Crestani M, Chiang JY. Identification of a bile acid response element in the
cholesterol 7 alpha-hydroxylase gene CYP7A. Am J Physiol 1997 August;273(2 Pt
1):G508-G517.
(950) Twisk J, Hoekman MF, Lehmann EM, Meijer P, Mager WH, Princen HM. Insulin
suppresses bile acid synthesis in cultured rat hepatocytes by down-regulation of
cholesterol 7 alpha-hydroxylase and sterol 27-hydroxylase gene transcription.
Hepatology 1995 February;21(2):501-10.
(951) Wang DP, Stroup D, Marrapodi M, Crestani M, Galli G, Chiang JY. Transcriptional
regulation of the human cholesterol 7 alpha-hydroxylase gene (CYP7A) in HepG2 cells.
J Lipid Res 1996 September;37(9):1831-41.
(952) Heaton KW. Gallstones and cholecystitis. In: Burkitt DP, Trowell HC, eds. Refined
carbohydrate foods and disease.London: Academic Press; 1975. p. 173-94.
(953) Glenn F. Calculous biliary tract disease an increasing burden on surgical facilities. Ann
Surg 1970 January;171(1):163-4.
(954) Black WC, Key CR, Carmany TB, Herman D. Carcinoma of the gallbladder in a
population of Southwestern American Indians. Cancer 1977 March;39(3):1267-79.
(955) Liu S, Stampfer MJ, Hu FB, Giovannucci E, Rimm E, Manson JE, Hennekens CH,
Willett WC. Whole-grain consumption and risk of coronary heart disease: results from
the Nurses' Health Study. Am J Clin Nutr 1999 September;70(3):412-9.
(956) Liu S, Manson JE, Stampfer MJ, Rexrode KM, Hu FB, Rimm EB, Willett WC. Whole
grain consumption and risk of ischemic stroke in women: A prospective study. JAMA
2000 September 27;284(12):1534-40.
(957) Liu S, Manson JE, Stampfer MJ, Hu FB, Giovannucci E, Colditz GA, Hennekens CH,
Willett WC. A prospective study of whole-grain intake and risk of type 2 diabetes
mellitus in US women. Am J Public Health 2000 September;90(9):1409-15.
(958) Schwarz K. Silicon, fibre, and atherosclerosis. Lancet 1977 February 26;1(8009):454-7.
201
(959) McCarty MF. Reported antiatherosclerotic activity of silicon may reflect increased
endothelial synthesis of heparan sulfate proteoglycans. Med Hypotheses 1997
August;49(2):175-6.
(960) Jyung RW, Mustoe JA, Busby WH, Clemmons DR. Increased wound-breaking strength
induced by insulin-like growth factor I in combination with insulin-like growth factor
binding protein-1. Surgery 1994 February;115(2):233-9.
(961) Bitar MS. Insulin-like growth factor-1 reverses diabetes-induced wound healing
impairment in rats. Horm Metab Res 1997 August;29(8):383-6.
(962) Clark R. The somatogenic hormones and insulin-like growth factor-1: stimulators of
lymphopoiesis and immune function. Endocr Rev 1997 April;18(2):157-79.
(963) Haddad EH, Berk LS, Kettering JD, Hubbard RW, Peters WR. Dietary intake and
biochemical, hematologic, and immune status of vegans compared with nonvegetarians.
Am J Clin Nutr 1999 September;70(3 Suppl):586S-93S.
(964) Yamori Y, Kihara M, Fujikawa J, Soh Y, Nara Y, Ohtaka M, Horie R, Tsunematsu T,
Note S, Fukase M. Dietary risk factors of stroke and hypertension in Japan -- Part 3:
Comparative study on risk factors between farming and fishing villages in japan. Jpn
Circ J 1982 September;46(9):944-7.
(965) Reed DM. The paradox of high risk of stroke in populations with low risk of coronary
heart disease. Am J Epidemiol 1990 April;131(4):579-88.
(966) Iso H, Stampfer MJ, Manson JE, Rexrode K, Hu F, Hennekens CH, Colditz GA, Speizer
FE, Willett WC. Prospective study of fat and protein intake and risk of
intraparenchymal hemorrhage in women. Circulation 2001 February 13;103(6):856-63.
(967) Bennett MR, Evan GI, Schwartz SM. Apoptosis of human vascular smooth muscle cells
derived from normal vessels and coronary atherosclerotic plaques. J Clin Invest 1995
May;95(5):2266-74.
(968) Conn KJ, Rich CB, Jensen DE, Fontanilla MR, Bashir MM, Rosenbloom J, Foster JA.
Insulin-like growth factor-I regulates transcription of the elastin gene through a
putative retinoblastoma control element. A role for Sp3 acting as a repressor of elastin
gene transcription. J Biol Chem 1996 November 15;271(46):28853-60.
(969) Iso H, Rexrode KM, Stampfer MJ, Manson JE, Colditz GA, Speizer FE, Hennekens CH,
Willett WC. Intake of fish and omega-3 fatty acids and risk of stroke in women. JAMA
2001 January 17;285(3):304-12.
(970) Jacobs D, Blackburn H, Higgins M, Reed D, Iso H, McMillan G, Neaton J, Nelson J,
Potter J, Rifkind B. Report of the Conference on Low Blood Cholesterol: Mortality
Associations. Circulation 1992 September;86(3):1046-60.
(971) Wannamethee G, Shaper AG, Whincup PH, Walker M. Low serum total cholesterol
concentrations and mortality in middle aged British men. BMJ 1995 August
12;311(7002):409-13.
(972) Fagot-Campagna A, Hanson RL, Narayan KM, Sievers ML, Pettitt DJ, Nelson RG,
Knowler WC. Serum cholesterol and mortality rates in a Native American population
with low cholesterol concentrations: a U-shaped association. Circulation 1997 September
2;96(5):1408-15.
202
(973) Jacobs DR, Iribarren C. Invited commentary: low cholesterol and nonartherosclerotic
disease risk: a persistently perplexing question. Am J Epidemiol 2000 April
15;151(8):748-51.
(974) Sharp SJ, Pocock SJ. Time trends in serum cholesterol before cancer death.
Epidemiology 1997 March;8(2):132-6.
(975) Kritz H, Zielinski C, Sinzinger H. Low cholesterol and cancer. J Clin Oncol 1996
November;14(11):3043-8.
(976) Law MR, Thompson SG, Wald NJ. Assessing possible hazards of reducing serum
cholesterol. BMJ 1994 February 5;308(6925):373-9.
(977) Iribarren C, Reed DM, Chen R, Yano K, Dwyer JH. Low serum cholesterol and
mortality. Which is the cause and which is the effect? Circulation 1995 November
1;92(9):2396-403.
(978) Hebert PR, Gaziano JM, Chan KS, Hennekens CH. Cholesterol lowering with statin
drugs, risk of stroke, and total mortality. An overview of randomized trials. JAMA 1997
July 23;278(4):313-21.
(979) Appleby PN, Thorogood M, Mann JI, Key TJ. The Oxford Vegetarian Study: an
overview. Am J Clin Nutr 1999 September;70(3 Suppl):525S-31S.
(980) Peto R, Boreham J, Chen J, Li J, Campbell TC, Brun T. Plasma cholesterol, coronary
heart disease, and cancer. BMJ 1989 May 6;298(6682):1249.
(981) Kaplan JR, Muldoon MF, Manuck SB, Mann JJ. Assessing the observed relationship
between low cholesterol and violence-related mortality. Implications for suicide risk.
Ann N Y Acad Sci 1997 December 29;836:57-80.
(982) Alvarez JC, Cremniter D, Gluck N, Quintin P, Leboyer M, Berlin I, Therond P, SpreuxVaroquaux O. Low serum cholesterol in violent but not in non-violent suicide
attempters. Psychiatry Res 2000 August 21;95(2):103-8.
(983) Fernstrom JD. Dietary effects on brain serotonin synthesis: relationship to appetite
regulation. Am J Clin Nutr 1985 November;42(5 Suppl):1072-82.
(984) Hibbeln JR. Fish consumption and major depression. Lancet 1998 April
18;351(9110):1213.
(985) Tanskanen A, Hibbeln JR, Tuomilehto J, Uutela A, Haukkala A, Viinamaki H,
Lehtonen J, Vartiainen E. Fish consumption and depressive symptoms in the general
population in finland. Psychiatr Serv 2001 April;52(4):529-31.
(986) Delanghe J, De Slypere JP, De Buyzere M, Robbrecht J, Wieme R, Vermeulen A.
Normal reference values for creatine, creatinine, and carnitine are lower in vegetarians.
Clin Chem 1989 August;35(8):1802-3.
(987) Shomrat A, Weinstein Y, Katz A. Effect of creatine feeding on maximal exercise
performance in vegetarians. Eur J Appl Physiol 2000 July;82(4):321-5.
(988) Mero A. Leucine supplementation and intensive training. Sports Med 1999
June;27(6):347-58.
203
(989) Anthony JC, Anthony TG, Layman DK. Leucine supplementation enhances skeletal
muscle recovery in rats following exercise. J Nutr 1999 June;129(6):1102-6.
(990) Anthony JC, Anthony TG, Kimball SR, Vary TC, Jefferson LS. Orally administered
leucine stimulates protein synthesis in skeletal muscle of postabsorptive rats in
association with increased eIF4F formation. J Nutr 2000 February;130(2):139-45.
(991) Anthony JC, Yoshizawa F, Anthony TG, Vary TC, Jefferson LS, Kimball SR. Leucine
stimulates translation initiation in skeletal muscle of postabsorptive rats via a
rapamycin-sensitive pathway. J Nutr 2000 October;130(10):2413-9.
(992) Busquets S, Alvarez B, Llovera M, Agell N, Lopez-Soriano FJ, Argiles JM. Branchedchain amino acids inhibit proteolysis in rat skeletal muscle: mechanisms involved. J Cell
Physiol 2000 September;184(3):380-4.
(993) Lynch CJ. Role of leucine in the regulation of mTOR by amino acids: revelations from
structure-activity studies. J Nutr 2001 March;131(3):861S-5S.
(994) Liu Z, Jahn LA, Long W, Fryburg DA, Wei L, Barrett EJ. Branched chain amino acids
activate messenger ribonucleic acid translation regulatory proteins in human skeletal
muscle, and glucocorticoids blunt this action. J Clin Endocrinol Metab 2001
May;86(5):2136-43.
(995) Nissen S, Sharp R, Ray M, Rathmacher JA, Rice D, Fuller JCJ, Connelly AS, Abumrad
N. Effect of leucine metabolite beta-hydroxy-beta-methylbutyrate on muscle metabolism
during resistance-exercise training. J Appl Physiol 1996 November;81(5):2095-104.
(996) Slater GJ, Jenkins D. Beta-hydroxy-beta-methylbutyrate (HMB) supplementation and
the promotion of muscle growth and strength. Sports Med 2000 August;30(2):105-16.
(997) Panton LB, Rathmacher JA, Baier S, Nissen S. Nutritional supplementation of the
leucine metabolite beta-hydroxy-beta-methylbutyrate (hmb) during resistance training.
Nutrition 2000 September;16(9):734-9.
(998) Knitter AE, Panton L, Rathmacher JA, Petersen A, Sharp R. Effects of beta-hydroxybeta-methylbutyrate on muscle damage after a prolonged run. J Appl Physiol 2000
October;89(4):1340-4.
(999) Gallagher PM, Carrithers JA, Godard MP, Schulze KE, Trappe SW. Beta-hydroxybeta-methylbutyrate ingestion, Part I: effects on strength and fat free mass. Med Sci
Sports Exerc 2000 December;32(12):2109-15.
(1000) Vukovich MD, Stubbs NB, Bohlken RM. Body Composition in 70-Year-Old Adults
Responds to Dietary beta-Hydroxy-beta-Methylbutyrate Similarly to That of Young
Adults. J Nutr 2001 July;131(7):2049-52.
(1001) Nissen S, Sharp RL, Panton L, Vukovich M, Trappe S, Fuller JCJ. beta-hydroxy-betamethylbutyrate (HMB) supplementation in humans is safe and may decrease
cardiovascular risk factors. J Nutr 2000 August;130(8):1937-45.
(1002) Eaton SB. Paleolithic vs. modern diets--selected pathophysiological implications. Eur J
Nutr 2000 April;39(2):67-70.
204
(1003) O'Dea K. Marked improvement in carbohydrate and lipid metabolism in diabetic
Australian aborigines after temporary reversion to traditional lifestyle. Diabetes 1984
June;33(6):596-603.
(1004) Jeppesen BB, Harvald B. Serum calcium in Greenland Eskimos. Acta Med Scand
1983;214(2):99-101.
(1005) Sarter B, Campbell TC, Fuhrman J. Effect of a high nutrient density diet on long-term
weight loss: a retrospective chart review. Altern Ther Health Med 2008 May;14(3):48-53.
(1006) Fontana L, Shew JL, Holloszy JO, Villareal DT. Low bone mass in subjects on a longterm raw vegetarian diet. Arch Intern Med 2005 March 28;165(6):684-9.
(1007) Goldberg DM, Soleas GJ, Levesque M. Moderate alcohol consumption: the gentle face
of Janus. Clin Biochem 1999 October;32(7):505-18.
(1008) German JB, Walzem RL. The health benefits of wine. Annu Rev Nutr 2000;20:561-93.
(1009) Feskanich D, Korrick SA, Greenspan SL, Rosen HN, Colditz GA. Moderate alcohol
consumption and bone density among postmenopausal women. J Womens Health 1999
January;8(1):65-73.
(1010) McCarty MF. The insulin-sensitizing activity of moderate alcohol consumption may
promote leanness in women. Med Hypotheses 2000 May;54(5):794-7.
(1011) Facchini F, Chen YD, Reaven GM. Light-to-moderate alcohol intake is associated with
enhanced insulin sensitivity. Diabetes Care 1994 February;17(2):115-9.
(1012) Kiechl S, Willeit J, Poewe W, Egger G, Oberhollenzer F, Muggeo M, Bonora E. Insulin
sensitivity and regular alcohol consumption: large, prospective, cross sectional
population study (Bruneck study) [see comments]. BMJ 1996 October
26;313(7064):1040-4.
(1013) Lazarus R, Sparrow D, Weiss ST. Alcohol intake and insulin levels. The Normative
Aging Study. Am J Epidemiol 1997 May 15;145(10):909-16.
(1014) Aikens ML, Benza RL, Grenett HE, Tabengwa EM, Davis GC, Demissie S, Booyse FM.
Ethanol increases surface-localized fibrinolytic activity in cultured endothelial cells.
Alcohol Clin Exp Res 1997 November;21(8):1471-8.
(1015) Grenett HE, Aikens ML, Torres JA, Demissie S, Tabengwa EM, Davis GC, Booyse FM.
Ethanol transcriptionally upregulates t-PA and u-PA gene expression in cultured human
endothelial cells. Alcohol Clin Exp Res 1998 June;22(4):849-53.
(1016) Grenett HE, Aikens ML, Tabengwa EM, Davis GC, Booyse FM. Ethanol downregulates
transcription of the PAI-1 gene in cultured human endothelial cells. Thromb Res 2000
February 15;97(4):247-55.
(1017) Imhof A, Froehlich M, Brenner H, Boeing H, Pepys MB, Koenig W. Effect of alcohol
consumption on systemic markers of inflammation. Lancet 2001 March
10;357(9258):763-7.
(1018) Valmadrid CT, Klein R, Moss SE, Klein BE, Cruickshanks KJ. Alcohol intake and the
risk of coronary heart disease mortality in persons with older-onset diabetes mellitus.
JAMA 1999 July 21;282(3):239-46.
205
(1019) Solomon CG, Hu FB, Stampfer MJ, Colditz GA, Speizer FE, Rimm EB, Willett WC,
Manson JE. Moderate alcohol consumption and risk of coronary heart disease among
women with type 2 diabetes mellitus. Circulation 2000 August 1;102(5):494-9.
(1020) Ajani UA, Gaziano JM, Lotufo PA, Liu S, Hennekens CH, Buring JE, Manson JE.
Alcohol consumption and risk of coronary heart disease by diabetes status. Circulation
2000 August 1;102(5):500-5.
(1021) Colditz GA, Giovannucci E, Rimm EB, Stampfer MJ, Rosner B, Speizer FE, Gordis E,
Willett WC. Alcohol intake in relation to diet and obesity in women and men [see
comments]. Am J Clin Nutr 1991 July;54(1):49-55.
(1022) Prentice AM. Alcohol and obesity. Int J Obes Relat Metab Disord 1995 November;19
Suppl 5:S44-S50.
(1023) Martikainen PT, Marmot MG. Socioeconomic differences in weight gain and
determinants and consequences of coronary risk factors. Am J Clin Nutr 1999
April;69(4):719-26.
(1024) Jequier E. Alcohol intake and body weight: a paradox [letter] [In Process Citation]. Am
J Clin Nutr 1999 February;69(2):173-4.
(1025) Stampfer MJ, Colditz GA, Willett WC, Manson JE, Arky RA, Hennekens CH, Speizer
FE. A prospective study of moderate alcohol drinking and risk of diabetes in women.
Am J Epidemiol 1988 September;128(3):549-58.
(1026) Smith-Warner SA, Spiegelman D, Yaun SS, van den Brandt PA, Folsom AR, Goldbohm
RA, Graham S, Holmberg L, Howe GR, Marshall JR, Miller AB, Potter JD, Speizer FE,
Willett WC, Wolk A, Hunter DJ. Alcohol and breast cancer in women: a pooled analysis
of cohort studies [see comments]. JAMA 1998 February 18;279(7):535-40.
(1027) Potter JD. Nutrition and colorectal cancer. Cancer Causes Control 1996
January;7(1):127-46.
(1028) Zhang S, Hunter DJ, Hankinson SE, Giovannucci EL, Rosner BA, Colditz GA, Speizer
FE, Willett WC. A prospective study of folate intake and the risk of breast cancer.
JAMA 1999 May 5;281(17):1632-7.
(1029) Giovannucci E, Stampfer MJ, Colditz GA, Rimm EB, Trichopoulos D, Rosner BA,
Speizer FE, Willett WC. Folate, methionine, and alcohol intake and risk of colorectal
adenoma. J Natl Cancer Inst 1993 June 2;85(11):875-84.
(1030) Boutron-Ruault MC, Senesse P, Faivre J, Couillault C, Belghiti C. Folate and alcohol
intakes: related or independent roles in the adenoma-carcinoma sequence? Nutr Cancer
1996;26(3):337-46.
(1031) Homann N, Tillonen J, Salaspuro M. Microbially produced acetaldehyde from ethanol
may increase the risk of colon cancer via folate deficiency. Int J Cancer 2000 April
15;86(2):169-73.
(1032) Larsson SC, Giovannucci E, Wolk A. Folate and risk of breast cancer: a meta-analysis. J
Natl Cancer Inst 2007 January 3;99(1):64-76.
(1033) Denke MA. Nutritional and health benefits of beer. Am J Med Sci 2000
November;320(5):320-6.
206
(1034) Chen JF, Pedata F. Modulation of ischemic brain injury and neuroinflammation by
adenosine A2A receptors. Curr Pharm Des 2008;14(15):1490-9.
(1035) Chen JF, Xu K, Petzer JP, Staal R, Xu YH, Beilstein M, Sonsalla PK, Castagnoli K,
Castagnoli N, Jr., Schwarzschild MA. Neuroprotection by caffeine and A(2A) adenosine
receptor inactivation in a model of Parkinson's disease. J Neurosci 2001 May
15;21(10):RC143.
(1036) Boison D. Adenosine as a neuromodulator in neurological diseases. Curr Opin
Pharmacol 2008 February;8(1):2-7.
(1037) Dall'Igna OP, Fett P, Gomes MW, Souza DO, Cunha RA, Lara DR. Caffeine and
adenosine A(2a) receptor antagonists prevent beta-amyloid (25-35)-induced cognitive
deficits in mice. Exp Neurol 2007 January;203(1):241-5.
(1038) Arendash GW, Schleif W, Rezai-Zadeh K, Jackson EK, Zacharia LC, Cracchiolo JR,
Shippy D, Tan J. Caffeine protects Alzheimer's mice against cognitive impairment and
reduces brain beta-amyloid production. Neuroscience 2006 November 3;142(4):941-52.
(1039) Che J, Chan ES, Cronstein BN. Adenosine A2A receptor occupancy stimulates collagen
expression by hepatic stellate cells via pathways involving protein kinase A, Src, and
extracellular signal-regulated kinases 1/2 signaling cascade or p38 mitogen-activated
protein kinase signaling pathway. Mol Pharmacol 2007 December;72(6):1626-36.
(1040) Peng Z, Fernandez P, Wilder T, Yee H, Chiriboga L, Chan ES, Cronstein BN. Ecto-5'nucleotidase (CD73) -mediated extracellular adenosine production plays a critical role in
hepatic fibrosis. FASEB J 2008 July;22(7):2263-72.
(1041) Hernan MA, Takkouche B, Caamano-Isorna F, Gestal-Otero JJ. A meta-analysis of
coffee drinking, cigarette smoking, and the risk of Parkinson's disease. Ann Neurol 2002
September;52(3):276-84.
(1042) Gallus S, Tavani A, Negri E, La VC. Does coffee protect against liver cirrhosis? Ann
Epidemiol 2002 April;12(3):202-5.
(1043) Tverdal A, Skurtveit S. Coffee intake and mortality from liver cirrhosis. Ann Epidemiol
2003 July;13(6):419-23.
(1044) Ruhl CE, Everhart JE. Coffee and tea consumption are associated with a lower
incidence of chronic liver disease in the United States. Gastroenterology 2005
December;129(6):1928-36.
(1045) Tanaka K, hara M, Sakamoto T, Higaki Y, Mizuta T, Eguchi Y, Yasutake T, Ozaki I,
Yamamoto K, Onohara S, Kawazoe S, Shigematsu H, Koizumi S. Inverse association
between coffee drinking and the risk of hepatocellular carcinoma: a case-control study
in Japan. Cancer Sci 2007 February;98(2):214-8.
(1046) Cadden IS, Partovi N, Yoshida EM. Review article: possible beneficial effects of coffee
on liver disease and function. Aliment Pharmacol Ther 2007 July 1;26(1):1-8.
(1047) Barranco Quintana JL, Allam MF, Serrano Del CA, Fernandez-Crehuet NR.
Alzheimer's disease and coffee: a quantitative review. Neurol Res 2007
January;29(1):91-5.
207
(1048) Maia L, de MA. Does caffeine intake protect from Alzheimer's disease? Eur J Neurol
2002 July;9(4):377-82.
(1049) Ascherio A, Zhang SM, Hernan MA, Kawachi I, Colditz GA, Speizer FE, Willett WC.
Prospective study of caffeine consumption and risk of Parkinson's disease in men and
women. Ann Neurol 2001 July;50(1):56-63.
(1050) Eskelinen MH, Ngandu T, Tuomilehto J, Soininen H, Kivipelto M. Midlife Coffee and
Tea Drinking and the Risk of Late-Life Dementia: A Population-Based CAIDE Study. J
Alzheimers Dis 2009 January;16(1):85-91.
(1051) Salazar-Martinez E, Willett WC, Ascherio A, Manson JE, Leitzmann MF, Stampfer
MJ, Hu FB. Coffee consumption and risk for type 2 diabetes mellitus. Ann Intern Med
2004 January 6;140(1):1-8.
(1052) van Dam RM, Willett WC, Manson JE, Hu FB. Coffee, caffeine, and risk of type 2
diabetes: a prospective cohort study in younger and middle-aged U.S. women. Diabetes
Care 2006 February;29(2):398-403.
(1053) van Dam RM. Coffee and type 2 diabetes: from beans to beta-cells. Nutr Metab
Cardiovasc Dis 2006 January;16(1):69-77.
(1054) Johnston KL, Clifford MN, Morgan LM. Coffee acutely modifies gastrointestinal
hormone secretion and glucose tolerance in humans: glycemic effects of chlorogenic acid
and caffeine. Am J Clin Nutr 2003 October;78(4):728-33.
(1055) McCarty MF. A chlorogenic acid-induced increase in GLP-1 production may mediate
the impact of heavy coffee consumption on diabetes risk. Med Hypotheses
2005;64(4):848-53.
(1056) Thom E. The effect of chlorogenic acid enriched coffee on glucose absorption in healthy
volunteers and its effect on body mass when used long-term in overweight and obese
people. J Int Med Res 2007 November;35(6):900-8.
(1057) Cavin C, Holzhaeuser D, Scharf G, Constable A, Huber WW, Schilter B. Cafestol and
kahweol, two coffee specific diterpenes with anticarcinogenic activity. Food Chem
Toxicol 2002 August;40(8):1155-63.
(1058) Tao KS, Wang W, Wang L, Cao DY, Li YQ, Wu SX, Dou KF. The multifaceted
mechanisms for coffee's anti-tumorigenic effect on liver. Med Hypotheses 2008
November;71(5):730-6.
(1059) Je Y, Liu W, Giovannucci E. Coffee consumption and risk of colorectal cancer: A
systematic review and meta-analysis of prospective cohort studies. Int J Cancer 2008
October 30.
(1060) Ammon HP. Biochemical mechanism of caffeine tolerance. Arch Pharm (Weinheim) 1991
May;324(5):261-7.
(1061) Higdon JV, Frei B. Coffee and health: a review of recent human research. Crit Rev Food
Sci Nutr 2006;46(2):101-23.
(1062) Wu JN, Ho SC, Zhou C, Ling WH, Chen WQ, Wang CL, Chen YM. Coffee
consumption and risk of coronary heart diseases: A meta-analysis of 21 prospective
cohort studies. Int J Cardiol 2008 August 14.
208
(1063) Heaney RP. Effects of caffeine on bone and the calcium economy. Food Chem Toxicol
2002 September;40(9):1263-70.
(1064) Johansson C, Mellstrom D, Lerner U, Osterberg T. Coffee drinking: a minor risk factor
for bone loss and fractures. Age Ageing 1992 January;21(1):20-6.
(1065) Lloyd T, Rollings N, Eggli DF, Kieselhorst K, Chinchilli VM. Dietary caffeine intake and
bone status of postmenopausal women. Am J Clin Nutr 1997 June;65(6):1826-30.
(1066) Conlisk AJ, Galuska DA. Is caffeine associated with bone mineral density in young adult
women? Prev Med 2000 November;31(5):562-8.
(1067) Rico H, Canal ML, Manas P, Lavado JM, Costa C, Pedrera JD. Effects of caffeine,
vitamin D, and other nutrients on quantitative phalangeal bone ultrasound in
postmenopausal women. Nutrition 2002 February;18(2):189-93.
(1068) Demirbag D, Ozdemir F, Ture M. Effects of coffee consumption and smoking habit on
bone mineral density. Rheumatol Int 2006 April;26(6):530-5.
(1069) Barrett-Connor E, Chang JC, Edelstein SL. Coffee-associated osteoporosis offset by
daily milk consumption. The Rancho Bernardo Study. JAMA 1994 January
26;271(4):280-3.
(1070) Harris SS, wson-Hughes B. Caffeine and bone loss in healthy postmenopausal women.
Am J Clin Nutr 1994 October;60(4):573-8.
(1071) Stoner GD, Mukhtar H. Polyphenols as cancer chemopreventive agents. J Cell Biochem
Suppl 1995;22:169-80.
(1072) Fujiki H, Yoshizawa S, Horiuchi T, Suganuma M, Yatsunami J, Nishiwaki S, Okabe S,
Nishiwaki-Matsushima R, Okuda T, Sugimura T. Anticarcinogenic effects of (-)epigallocatechin gallate. Prev Med 1992 July;21(4):503-9.
(1073) Dashwood RH, Xu M, Hernaez JF, Hasaniya N, Youn K, Razzuk A. Cancer
chemopreventive mechanisms of tea against heterocyclic amine mutagens from cooked
meat. Proc Soc Exp Biol Med 1999 April;220(4):239-43.
(1074) Seely D, Mills EJ, Wu P, Verma S, Guyatt GH. The effects of green tea consumption on
incidence of breast cancer and recurrence of breast cancer: a systematic review and
meta-analysis. Integr Cancer Ther 2005 June;4(2):144-55.
(1075) Sun CL, Yuan JM, Koh WP, Yu MC. Green tea, black tea and breast cancer risk: a
meta-analysis of epidemiological studies. Carcinogenesis 2006 July;27(7):1310-5.
(1076) Tang N, Wu Y, Zhou B, Wang B, Yu R. Green tea, black tea consumption and risk of
lung cancer: A meta-analysis. Lung Cancer 2009 January 5.
(1077) Kurahashi N, Sasazuki S, Iwasaki M, Inoue M, Tsugane S. Green tea consumption and
prostate cancer risk in Japanese men: a prospective study. Am J Epidemiol 2008
January 1;167(1):71-7.
(1078) Jian L, Lee AH, Binns CW. Tea and lycopene protect against prostate cancer. Asia Pac J
Clin Nutr 2007;16 Suppl 1:453-7.
209
(1079) Lichtenthaler R, Marx F. Total oxidant scavenging capacities of common European
fruit and vegetable juices. J Agric Food Chem 2005 January 12;53(1):103-10.
(1080) Ruxton CH, Gardner EJ, Walker D. Can pure fruit and vegetable juices protect against
cancer and cardiovascular disease too? A review of the evidence. Int J Food Sci Nutr
2006 May;57(3-4):249-72.
(1081) Dai Q, Borenstein AR, Wu Y, Jackson JC, Larson EB. Fruit and vegetable juices and
Alzheimer's disease: the Kame Project. Am J Med 2006 September;119(9):751-9.
(1082) Lee IM, Paffenbarger RS, Hennekens CH. Physical activity, physical fitness and
longevity. Aging (Milano) 1997 February;9(1-2):2-11.
(1083) Ryan AS, Pratley RE, Goldberg AP, Elahi D. Resistive training increases insulin action
in postmenopausal women. J Gerontol A Biol Sci Med Sci 1996 September;51(5):M199M205.
(1084) Eriksson J, Tuominen J, Valle T, Sundberg S, Sovijarvi A, Lindholm H, Tuomilehto J,
Koivisto V. Aerobic endurance exercise or circuit-type resistance training for
individuals with impaired glucose tolerance? Horm Metab Res 1998 January;30(1):3741.
(1085) Fujitani J, Higaki Y, Kagawa T, Sakamoto M, Kiyonaga A, Shindo M, Taniguchi A,
Nakai Y, Tokuyama K, Tanaka H. Intravenous glucose tolerance test-derived glucose
effectiveness in strength-trained humans. Metabolism 1998 July;47(7):874-7.
(1086) Ishii T, Yamakita T, Sato T, Tanaka S, Fujii S. Resistance training improves insulin
sensitivity in NIDDM subjects without altering maximal oxygen uptake. Diabetes Care
1998 August;21(8):1353-5.
(1087) Eriksson JG. Exercise and the treatment of type 2 diabetes mellitus. An update. Sports
Med 1999 June;27(6):381-91.
(1088) Evans WJ, Campbell WW. Sarcopenia and age-related changes in body composition
and functional capacity. J Nutr 1993 February;123(2 Suppl):465-8.
(1089) Evans WJ. Reversing sarcopenia: how weight training can build strength and vitality.
Geriatrics 1996 May;51(5):46-3.
(1090) Singh MA, Ding W, Manfredi TJ, Solares GS, O'Neill EF, Clements KM, Ryan ND,
Kehayias JJ, Fielding RA, Evans WJ. Insulin-like growth factor I in skeletal muscle
after weight-lifting exercise in frail elders. Am J Physiol 1999 July;277(1 Pt 1):E135E143.
(1091) Foster-Burns SB. Sarcopenia and decreased muscle strength in the elderly woman:
resistance training as a safe and effective intervention. J Women Aging 1999;11(4):75-85.
(1092) Evans W. Functional and metabolic consequences of sarcopenia. J Nutr 1997 May;127(5
Suppl):998S-1003S.
(1093) Roubenoff R. Sarcopenia: a major modifiable cause of frailty in the elderly. J Nutr
Health Aging 2000;4(3):140-2.
(1094) McCarty MF. Point of view--a role for "nutritional insurance" supplementation in
preventive medicine. Med Hypotheses 1981 February;7(2):171-85.
210
(1095) Judd PA, Long A, Butcher M, Caygill CP, Diplock AT. Vegetarians and vegans may be
most at risk from low selenium intakes. BMJ 1997 June 21;314(7097):1834.
(1096) Sukenik A, Takahashi H, Mokady S. Dietary lipids from marine unicellular algae
enhance the amount of liver and blood omega-3 fatty acids in rats. Ann Nutr Metab
1994;38(2):85-96.
(1097) Yamazaki K, Fujikawa M, Hamazaki T, Yano S, Shono T. Comparison of the
conversion rates of alpha-linolenic acid (18:3(n - 3)) and stearidonic acid (18:4(n - 3)) to
longer polyunsaturated fatty acids in rats. Biochim Biophys Acta 1992 January
3;1123(1):18-26.
(1098) Petrik MB, McEntee MF, Johnson BT, Obukowicz MG, Whelan J. Highly unsaturated
(n-3) fatty acids, but not alpha-linolenic, conjugated linoleic or gamma-linolenic acids,
reduce tumorigenesis in Apc(Min/+) mice. J Nutr 2000 October;130(10):2434-43.
(1099) Kockmann V, Spielmann D, Traitler H, Lagarde M. Inhibitory effect of stearidonic acid
(18:4 n-3) on platelet aggregation and arachidonate oxygenation. Lipids 1989
December;24(12):1004-7.
(1100) Guichardant M, Traitler H, Spielmann D, Sprecher H, Finot PA. Stearidonic acid, an
inhibitor of the 5-lipoxygenase pathway. A comparison with timnodonic and
dihomogammalinolenic acid. Lipids 1993 April;28(4):321-4.
(1101) Guil-Guerrero JL, Gomez-Mercado F, Garcia-Maroto F, Campra-Madrid P.
Occurrence and characterization of oils rich in gamma-linolenic acid Part I: Echium
seeds from Macaronesia. Phytochemistry 2000 February;53(4):451-6.
(1102) McCarty MF. Sub-optimal taurine status may promote platelet hyperaggregability in
vegetarians. Med Hypotheses 2004;63(3):426-33.
(1103) Bartke A, Coschigano K, Kopchick J, Chandrashekar V, Mattison J, Kinney B, Hauck
S. Genes that prolong life: relationships of growth hormone and growth to aging and life
span. J Gerontol A Biol Sci Med Sci 2001 August;56(8):B340-B349.
(1104) Kinney BA, Meliska CJ, Steger RW, Bartke A. Evidence that Ames dwarf mice age
differently from their normal siblings in behavioral and learning and memory
parameters. Horm Behav 2001 June;39(4):277-84.
(1105) Flurkey K, Papaconstantinou J, Miller RA, Harrison DE. Lifespan extension and
delayed immune and collagen aging in mutant mice with defects in growth hormone
production. Proc Natl Acad Sci U S A 2001 June 5;98(12):6736-41.
(1106) Coschigano KT, Clemmons D, Bellush LL, Kopchick JJ. Assessment of growth
parameters and life span of GHR/BP gene-disrupted mice. Endocrinology 2000
July;141(7):2608-13.
(1107) Kinney BA, Coschigano KT, Kopchick JJ, Steger RW, Bartke A. Evidence that ageinduced decline in memory retention is delayed in growth hormone resistant GH-R-KO
(Laron) mice. Physiol Behav 2001 April;72(5):653-60.
(1108) Dunn SE, Kari FW, French J, Leininger JR, Travlos G, Wilson R, Barrett JC. Dietary
restriction reduces insulin-like growth factor I levels, which modulates apoptosis, cell
proliferation, and tumor progression in p53-deficient mice. Cancer Res 1997 November
1;57(21):4667-72.
211
(1109) Orentreich N, Matias JR, DeFelice A, Zimmerman JA. Low methionine ingestion by
rats extends life span. J Nutr 1993 February;123(2):269-74.
(1110) Richie JPJ, Leutzinger Y, Parthasarathy S, Malloy V, Orentreich N, Zimmerman JA.
Methionine restriction increases blood glutathione and longevity in F344 rats. FASEB J
1994 December;8(15):1302-7.
(1111) Segall PE, Timiras PS. Patho-physiologic findings after chronic tryptophan deficiency in
rats: a model for delayed growth and aging. Mech Ageing Dev 1976 March;5(2):109-24.
(1112) Ooka H, Segall PE, Timiras PS. Histology and survival in age-delayed low-tryptophanfed rats. Mech Ageing Dev 1988 April;43(1):79-98.
(1113) McCarty MF, Barroso-Aranda J, Contreras F. The low-methionine content of vegan
diets may make methionine restriction feasible as a life extension strategy. Med
Hypotheses 2008 September 11.
(1114) Anson RM, Guo Z, de CR, Iyun T, Rios M, Hagepanos A, Ingram DK, Lane MA,
Mattson MP. Intermittent fasting dissociates beneficial effects of dietary restriction on
glucose metabolism and neuronal resistance to injury from calorie intake. Proc Natl
Acad Sci U S A 2003 May 13;100(10):6216-20.
(1115) Varady KA, Hellerstein MK. Alternate-day fasting and chronic disease prevention: a
review of human and animal trials. Am J Clin Nutr 2007 July;86(1):7-13.
(1116) McCarty MF, Falahati-Nini A. Neuroprotective potential of the Bahadori leanness
program: a "mini-fast with exercise" strategy. Med Hypotheses 2007;68(5):935-40.
(1117) Varady KA, Roohk DJ, Evoy-Hein BK, Gaylinn BD, Thorner MO, Hellerstein MK.
Modified alternate-day fasting regimens reduce cell proliferation rates to a similar
extent as daily calorie restriction in mice. FASEB J 2008 June;22(6):2090-6.
(1118) Johnson JB, Summer W, Cutler RG, Martin B, Hyun DH, Dixit VD, Pearson M, Nassar
M, Telljohann R, Maudsley S, Carlson O, John S, Laub DR, Mattson MP. Alternate day
calorie restriction improves clinical findings and reduces markers of oxidative stress and
inflammation in overweight adults with moderate asthma. Free Radic Biol Med 2007
March 1;42(5):665-74.
(1119) Johnson JB, Laub DR, John S. The effect on health of alternate day calorie restriction:
eating less and more than needed on alternate days prolongs life. Med Hypotheses
2006;67(2):209-11.
(1120) Patronek GJ, Waters DJ, Glickman LT. Comparative longevity of pet dogs and
humans: implications for gerontology research. J Gerontol A Biol Sci Med Sci 1997
May;52(3):B171-B178.
(1121) Michell AR. Longevity of British breeds of dog and its relationships with sex, size,
cardiovascular variables and disease. Vet Rec 1999 November 27;145(22):625-9.
(1122) Eklund J, Bradford GE. Longeveity and lifetime body weight in mice selected for rapid
growth. Nature 1977 January 6;265(5589):48-9.
(1123) Miller RA, Chrisp C, Atchley W. Differential longevity in mouse stocks selected for
early life growth trajectory. J Gerontol A Biol Sci Med Sci 2000 September;55(9):B455B461.
212
(1124) Eigenmann JE, Patterson DF, Zapf J, Froesch ER. Insulin-like growth factor I in the
dog: a study in different dog breeds and in dogs with growth hormone elevation. Acta
Endocrinol (Copenh) 1984 March;105(3):294-301.
(1125) Eigenmann JE, Patterson DF, Froesch ER. Body size parallels insulin-like growth factor
I levels but not growth hormone secretory capacity. Acta Endocrinol (Copenh) 1984
August;106(4):448-53.
(1126) Samaras TT, Storms LH. Impact of height and weight on life span. Bull World Health
Organ 1992;70(2):259-67.
(1127) Samaras TT, Elrick H, Storms LH. Is attainment of greater height and body size really
desirable? J Natl Med Assoc 1999 June;91(6):317-21.
(1128) Kenyon C. A conserved regulatory system for aging. Cell 2001 April 20;105(2):165-8.
(1129) Gems D, Partridge L. Insulin/IGF signalling and ageing: seeing the bigger picture. Curr
Opin Genet Dev 2001 June;11(3):287-92.
(1130) Bartke A. Mutations prolong life in flies; implications for aging in mammals. Trends
Endocrinol Metab 2001 August;12(6):233-4.
(1131) Parr T. Insulin exposure controls the rate of mammalian aging. Mech Ageing Dev 1996
July 5;88(1-2):75-82.
(1132) Whelan J. Dietary stearidonic acid is a long chain (n-3) polyunsaturated fatty acid with
potential health benefits. J Nutr 2009 January;139(1):5-10.
The NutriGuard Learn to Burn Leanness Program
A Rational Strategy for Achieving and Maintaining Leanness
The basic “game plan” of the Learn to Burn leanness program is to maximize the rate at which your body
burns stored fat, while consuming a diet that is low in fat. Unlike rodents, cows, and many
other animals, humans rarely synthesize meaningful amounts of fat. There are exceptions
– gorging on food for days at a time, in great excess of caloric requirements, will evoke
fat synthesis, and chronic consumption of a fat-free diet will also lead to adaptive
increase in fat production. But, under ordinary circumstances, the fat in our bodies
derives primarily from dietary fat. This implies that if we boost our daily rate of fat
burning, while keeping our dietary fat intake low, we should gradually drain our body’s
fat stores until we gradually equilibrate at a much leaner physique. (Obviously, we can’t
continue losing fat indefinitely, as our rate of fat burning will decline as our fat stores are
depleted, until it equals our rate of fat ingestion and equilibrium is achieved.)
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Weight control experts unanimously endorse regular aerobic exercise as a crucial key to
achieving and maintaining leanness. This evidently reflects the fact that sustained
exercise of moderate intensity promotes fat burning. However, relatively little attention
has been paid to the metabolic context in which exercise is done – which can have a
major impact on the rate of fat burning that is achieved. The most novel aspect of the
Learn to Burn program is that it maximizes exercise-induced fat burning by nesting it
within a daily “mini-fast”; exercising in fasting metabolism – when insulin levels are low
- promotes selective use of stored fat, and fasting for several hours after the exercise
prolongs the exercise-induced fat burn. When you do subsequently eat, low-fat, carb-rich
food choices, moderate in glycemic index, promote satiety by re-filling your glycogen
stores and promoting even blood glucose levels – but they won’t replace the fat you have
just burned. This evidently implies a daily negative fat balance that over weeks and
months will make you much leaner – and you’ll stay leaner as long as you stick with the
program. This “mini-fast with exercise” strategy was first introduced by nutritional
scientist Mark McCarty – now a consultant at Oasis of Hope Hospital – who has used it
himself for over ten years, was generalized by Austrian physician Dr. Babak Bahadori in
his “7 Step Program” for weight control, that has become popular in central Europe.
The Learn to Burn program provides sound advice on healthful low-fat food choices that
will help you control your appetite and burn fat throughout the day. Low-glycemic-index
carbohydrate foods are recommended, as they tend to promote moderate and even insulin
levels. High insulin levels evoked by high-glycemic-index carbs bring fat burning to a
screeching halt, and the wild swings of blood sugar often triggered by such foods can
induce rebound hunger. So the Learn to Burn program stresses food choices that are both
low in fat and glycemic index.
Rapid fat oxidation in the liver sends satiety signals to the brain, and also generates
ketone bodies that can be used by the central nervous system as fuel. This mechanism is
largely responsible for the hunger suppression that is typically achieved after days of
fasting or severe carbohydrate restriction. But ordinarily it takes several days for the
liver to adapt to rapid fat burning. That’s why the Learn to Burn program makes use of
special dietary supplements that are intended to accelerate the liver’s adaptation to fasting
metabolism, so that the daily mini-fasts are readily tolerated.
Now that you understand the simple and logical concepts that underlie the Learn to Burn
leanness program, here’s how to do it:
1. Aerobic Exercise during a “Mini-Fast”
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Pick the time of day that is convenient and most congenial for you to exercise:
in the morning, mid-day, or evening.
If you choose to exercise in the morning, you should skip breakfast – no meals or
snacks in the morning until lunch.
If you choose to exercise in mid-day, you should skip lunch – no meals or snacks
between breakfast and dinner. (Some call this the “Ramadan option”, since during
the month of Ramadan, Moslems fast between sun-up and sun-down.)
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If you choose to exercise in the evening, you should eat a very early dinner – by
five, or as soon as you can get home from work. You should avoid any meals or
snacks in the evening after your dinner. Your exercise should be done at least 2
hours after dinner, when your insulin levels have returned to a fasting level.
You can drink plenty of non-caloric fluids during your mini-fasts; this will keep
you hydrated for successful exercise, while also aiding hunger control.
You will be surprised by how well you feel during these mini-fasts. When you
exercise in line with this strategy, you will be in vigorous fat-burning metabolism
for about 12 hours per day. This accelerated fat metabolism will enable you to feel
energetic and hunger-free during your mini-fasts – particularly if you use the
supplements, described below, that help the liver adapt rapidly to fasting
metabolism. Think of it this way: you aren’t starving yourself - by burning stored
fat, you are finally “eating” food calories that you ingested weeks or months ago.
You can be flexible in your choice of time for exercise. For example, if you prefer
to exercise in the evening during weekdays, but would prefer to go out to dinner
and evening entertainment on the weekend, you can switch your weekend exercise
to mid-day. Or if you ordinarily exercise at noon, but one day you wish to attend a
luncheon, you can use the morning exercise option that day.
For your exercise, do a moderate intensity workout (50-60% VO2max),
preferably one in which you support your own weight (i.e. brisk walking, jogwalking, stair-climbing, elliptical gliders); if knee problems make this difficult, use
a stationary bike. If you are exercising at the right moderate intensity, you should
be able to carry on a normal conversation at the same time; high intensity exercise
burns primarily stored carbohydrate rather than fat.
After you’ve had a chance to improve your muscle tone and cardiovascular fitness,
gradually increase the length of your exercise to at least 40 minutes per session.
However, if you are very out of shape, it is prudent to start with a short duration that
is comfortable for you, and then gradually increase it as your body adapts to
exercise. Don’t overdo it and injure or severely exhaust yourself – the point is
to establish a regimen that you can maintain on a regular basis.
Try to work out at least five times weekly. (Once you reach your target weight,
you may be able to reduce your exercise frequency a bit, but don’t exercise less
than three times a week.) On your non-exercise days, eat whenever you desire – but
try to follow the food guidelines outlined below.
Prolonged moderate-intensity exercise suppresses insulin, boosts glucagon,
mobilizes fat, and thus is ideal for fat burning; increased capacity for fat burning
will persist for several hours after exercise if you don’t raise insulin by ingesting
carbohydrate during this time.
The people who get the best and most rapid results with HT are usually those who
do the most exercise! Exercise is crucial to achieving optimal benefit from HT.
2. Proper Food Choices: Low Fat/Low Glycemic Index
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Food choices in HT are intended to keep daily insulin secretion relatively low and
support glucagon production (aiding fat burning), while minimizing fat intake.
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Avoid fatty foods - fat should be no more than 15% of daily calories. No fatty
meats, dairy products, or egg yolks. Minimize the use of oils in cooking, scan the
labels of convenience foods for fat content, and be very sparing in your
consumption of avocados and olives.
A moderate daily intake of nuts or nut butters (no more than one ounce daily) is
permissible, in light of evidence that these foods are markedly protective for
vascular health. (Avoid nut butters that have added hydrogenated oils.)
A very-low-fat diet, especially if accompanied by regular exercise, tends to
decrease your daily insulin production by improving your body’s sensitivity to
insulin – and of course also puts less new fat in your fat cells.
The starchy foods in your regular diet should have a relatively low glycemic index
(that is, they should increase blood sugar gradually and moderately, to avoid
excessive insulin secretion or – in diabetics – hyperglycemia.)
Pasta, rice (preferably brown, long-grain and parboiled), beans, corn (whole corn or
popcorn), bulgur wheat, barley, “old-fashioned” (not instant) oatmeal, and whole
fruit are recommendable. Avoid wheat flour products (excepting pasta,
sourdough and whole-wheat pita bread), baked or mashed potatoes (boiled are
better), and sugar-loaded soft drinks (diet sodas are fine).
Beans – particularly home-cooked beans – have an especially low glycemic index
and are great for weight control. Eat beans frequently.
Eat foods in a physically intact natural form when feasible – the glycemic index
of whole-kernel grains is lower than that of flours. “Flourless” breads made from
sprouted grains (e.g. “Ezekiel”) or intact grain kernels are far preferable to other
breads.
A table of glycemic indices – such as you can find in the popular book The Glucose
Revolution - can help you choose appropriate starchy foods.
Vegetables, vegetable juices, and whole fruit are strongly recommended – they are
great for your long-term health as well as for weight control. Try to eat at least one
large salad every day. Whole fruit is the best dessert or snack. These foods are rich
in potassium - crucial for the health of your vasculature and bones – as well as
protective phytonutrients.
With respect to protein intake, certain strategies in this regard can help you to
minimize your insulin secretion and/or better control appetite. Both protein-rich
diets and moderate-protein vegan diets can work well with the Learn to Burn
program. Long-term vegans tend to be leaner than either lacto-ovo vegetarians or
omnivores - possibly because their diet is quite low in the saturated fat palmitate,
which may adversely affect fat burning. Vegans typically are at low risk for
coronary heart disease, diabetes, and certain cancers, and vegan diets are highly
desirable from an ecological standpoint. On the other hand, high-protein diets often
also work well for weight control, presumably because they aid hunger control and
keep daily insulin levels fairly low. If you choose a high-protein approach, make
sure to choose foods that are relatively low in fat – especially saturated fat – and eat
plenty of fruits and vegetables to offset the metabolic acidifying effect of a high
protein intake (bad for your bones) .
Vinegar can lower the glycemic index of a meal. Use vinegar as a salad dressing.
You can also make a tasty “vinegar cocktail” by mixing a tablespoon of apple cider
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vinegar with about 2/3 cup of water, and adding a packet of artificial sweetener;
take this just prior to or with your meal.
Alcoholic beverages, in moderation (1 or 2 drinks daily), are permissible, and
indeed may benefit your health if you can drink responsibly. However, alcohol in
excess will bring fat burning to a halt, so never ingest alcohol during your minifasts. Remarkably, studies show that women who drink moderately but regularly
are less likely to gain weight than are non-drinkers. (Sorry guys – this doesn’t work
for you!)
Eat enough to satisfy your hunger – no calorie counting! Make sure that you eat
enough carbohydrate so that you have adequate fuel for your subsequent aerobic
exercise. But use your common sense and your self-restraint – gluttony will
sabotage any weight-loss program!
3. Supplementation for Easy Fasting
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To make the daily mini-fasts more comfortable, the Learn to Burn program offers supplements
featuring the following food factors and metabolites:
The availability of carnitine is rate-limiting for fat burning in the liver, and the liver gradually
accumulates carnitine during the first days of a fast to boost its capacity for fat burning. By
supplementing with carnitine, this adaptation can be achieved much more quickly.
The natural fruit acid hydroxycitrate, by inhibiting the enzyme citrate lyase, helps
to boost the activity of another enzyme, carnitine palmitoyltransferase, that works
with carnitine to promote hepatic fat burning.
The natural metabolite pyruvate, perhaps because it boosts the production of Krebs
cycle intermediates required for complete fat oxidation, appears to enhance the rate
of fat loss achievable with carnitine/hydroxycitrate supplementation. In rodents
studies, supplemental pyruvate has induced a marked thermogenic effect – enabling
fat to be converted efficiently to CO2 and heat.
A recent study shows that chromium picolinate promotes appetite control in
people who have carbohydrate cravings.
The supplements Brindall Trim, Lipidox, and Lipidox Powder can be used with
the Learn to Burn program. Brindall Trim features carnitine, hydroxycitrate, and
chromium picolinate; Lipidox and Lipidox Powder provide these nutrients as well
as an ample dose of pyruvate.
Take a full dose of the supplement of your choice prior to exercise; you can take a
further dose during the post-exercise fasting phase if you wish.
Note that these supplements do not involve drugs or even herbs – just nutrients,
natural metabolites and food factors, all of which appear to be health-protective.
This supplementation is not recommended for pregnant women, who in any case
should not attempt to lose weight except as instructed by their doctors.
Does it Work? During a twelve-week open trial of the Learn to Burn program,
overweight volunteers from the staff of Oasis of Hope Hospital lost an average of 25% of
their initial fat mass. One gung-ho participant lost 46 pounds of fat in this time, while
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eating two meals a day and not counting calories – and even ladies in their forties or
fifties, doing walking exercise, achieved substantial fat losses.
You don’t need to do everything right all the time! If you can manage to
exercise right, eat right, and supplement right the majority of the time, you can expect
good results.
Fat Loss vs.Weight Loss: Note that in the first few weeks of the Learn to Burn
program, lean mass often increases while body fat decreases. That means that body fat
will decrease faster than body weight, so that your initial rate of weight loss may not be
too impressive. After a month or more of the program, lean mass begins to decline as
well, and weight loss tends to catch up with fat loss. So don’t obsess about your scale
weight when beginning this program. To evaluate your progress, it is best to have your
body composition assessed periodically (by a personal trainer or physician) so that you
can quantify your fat loss.
A caution to diabetics: When using the Learn to Burn program, monitor your blood
sugar control as instructed by your doctor, and modify your medication usage as needed,
with your doctor’s assistance. If injectible insulin or sulfonylurea drugs are active during
a mini-fast and exercise, a hypoglycemic reaction could result – so work out a proper
medication schedule with your doctor. Physician supervision is mandatory for
diabetics!
That’s all there is to it! No drugs, no prolonged starvation, no calorie counting, no
avoidance of health-promoting carb-rich foods. Nothing but fat-burning exercise, healthprotective food choices, and safe, natural supplements. Remember:
The Learn to Burn program is a healthful, sustainable lifestyle –
not a quick-fix gimmick
Resources: Brindall Trim, Lipidox, and Lipidox Powder, priced at a moderate markup over cost, are available by mail-order from: NutriGuard Research, 1051 Hermes
Ave., Encinitas, CA. Call (800)433-2402; outside the U.S. or Canada, you can call 760942-3223. Or order via the web: nutriguard.com.
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