1. health and fitness
2. disease

by Michael G. Walker, Ph.D
1
Copyright 2011
Michael G. Walker and Kim Walker
All rights reserved.
No part of this book may be reproduced or transmitted in any form or by any means
without prior written permission from the authors. Address inquiries to
[email protected]
This publication is designed to provide accurate and authoritative information but it is
sold with the understanding that the publisher does not offer medical advice or other
professional services.
Library of Congress Control Number: pending
Includes Index
ISBN Print: 978-0-9802205-2-0
ISBN Digital: 978-0-9802205-3-7
Curious Press
Toronto, Canada
2
TABLE OF CONTENTS
Consumer Warning Label ....................................................................................... 4
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WHAT’S HAPPENING tO MY BRAIN? ...................................................................7
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How Does My Brain Age? ......................................................................................... 7
How Do Molecules Change My Brain? ....................................................................11
How Do My Genes Change My Brain? ................................................................... 13
How Healthy is My Brain? ...................................................................................... 17
What Are My Chances? ........................................................................................... 21
Do I Have Alzheimer’s Genes? ...............................................................................22
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FOOD CHOICES ................................................................................................... 24
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Fats: The Good, The Bad and The Ugly .................................................................24
Carbohydrates .........................................................................................................39
Protein .....................................................................................................................42
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CALORIC RESTRICTION ..................................................................................... 44
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First Experiments in CR .........................................................................................45
How Much CR? .......................................................................................................45
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How Does CR Affect Your Brain? ...........................................................................47
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CR and Age-Related Disease ..................................................................................48
3 Keys Of Caloric Restriction ..................................................................................49
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ANTIOXIDANTS ................................................................................................... 54
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Do Antioxidants Extend Lifespan? ......................................................................... 55
Can Antioxidants Save Your Brain? .......................................................................56
Can Antioxidants Defeat Alzheimer's? ...................................................................58
Which Antioxidants To Choose? ............................................................................59
Supplements ........................................................................................................... 60
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STRESS .................................................................................................................. 69
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Cortisol ....................................................................................................................69
DHEA Supplements ................................................................................................ 71
Hormone Replacement Therapy ............................................................................ 73
Meditation, Mindfulness & Depression ................................................................. 74
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EXERCISE ..............................................................................................................77
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Exercise and Intelligence ........................................................................................78
Exercise for the Brain .............................................................................................78
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FUTURE TREATMENTS ...................................................................................... 84
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Personalized Medicine ............................................................................................84
The Search For an Anti-Aging Pill ..........................................................................85
Research To Slow Aging .........................................................................................87
Predicting Longevity in Humans ............................................................................89
Genes, Cognition And Aging In Humans ............................................................... 91
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REFERENCES ......................................................................................................104
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3
CONSUMER WARNING LABEL
0B
“A worm, with very few exceptions, is not a human being.”~ Mel Brook’s
Young Frankenstein
Some parts of this book are wrong. I just don't know which parts. Research
papers on aging and the brain are published every day and every time a new
experiment finds unexpected results our understanding changes. What we believe
to be true turns out to be false.
For almost everything you read here there are some researchers who disagree
with the conclusions. They may have done different experiments or they may
have different interpretations of the findings. I have tried to present information
that the majority of scientists understand and agree upon.
There are bound to be holes in our knowledge and occasional flaws in our
thinking that lead to inconsistent experimental results. After all, so much of what
we know about aging and the brain is based on studies of worms, snails, rats,
mice and monkeys - not humans. A treatment that works in a rat brain may not
work the same way in a human brain. For example, when your head hurts you
probably swallow an aspirin without hesitation but the same pill can be lethal to
other animals.
With these limitations in mind, do we actually know enough about the brain to
protect it from aging and disease? I think so. The best evidence we have that
certain treatments are safe and effective for humans comes from rigorous,
scientific studies called clinical trials.
Clinical trials are randomized, placebo-controlled, double-blinded studies that
compare the effects of a new treatment to a placebo or to a treatment that is a
recognized standard of care. Patients are randomly assigned to one of these
treatments and neither the patients nor their doctors know which treatment they
are given.
Ideally, clinical trials study diverse populations, male and female, young and old,
with or without an associated disease, whether or not they already take
medication. This requires the participation of multiple health centers operating
under rigid protocols to ensure that results remain consistent.
4
The purpose of such rigorous testing is to prevent human error or any form of
bias from skewing the experimental results. It may surprise you to know that
almost no supplements, vitamins or herbal remedies have been tested in this way.
In fact, only a few anti-aging and brain-enhancing compounds have ever
undergone clinical testing and we’ll look closely at these.
Keep in mind that a positive outcome from a clinical trial means that a treatment
works, on average, for some people, some of the time. You and I respond
differently to medications or supplements because of differences in our genes,
our environment, previous diseases or current medications. Later on we'll see an
example of a promising drug that improves memory in some people but has the
opposite effect on those with a slightly different version of the same gene.
Some of our knowledge of how things affect the brain is based on observation.
For example, researchers have observed a correlation between a diet high in
saturated fat and a growing risk of Alzheimer's disease. Does this mean that
eating saturated fat causes Alzheimer's?
No, it doesn’t. Other factors may be involved like a gene variant that leads to
cravings for high levels of saturated fat or a mutation that increases the chances
of developing the disease. In either case, reducing saturated fat in your diet might
not reduce your chances of Alzheimer's. Correlation is not causation.
Experimental results can differ widely depending on the type of memory or
cognitive ability assessed. When researchers experiment to see if foods, drugs,
supplements or exercise affect the brain they often get inconsistent results. It
may be that they measured only a few of the variables involved or that they tested
different types of memory located in different parts of the brain. Other factors,
such as the duration and intensity of the treatment or the health and comfort
levels of patients and volunteers at the start of an experiment, can skew the
findings.
When we are fortunate, inconsistent results teach us something we didn’t know.
They refine our understanding of what is happening, the type of memory affected,
in which people and at what dose.
A few studies have tried to determine if commercial supplements contain the
quantity of active compounds that advertisers claim. These tests are often
disappointing and their results vary significantly. The reason is that many
supplements, like tea and ginkgo, are plant products and the amount of active
ingredients depends on many things - the soil they grew in, how much sun, water
and fertilizer they received, which insects and parasites they were exposed to,
when they were harvested, how they
were processed, stored and shipped,
5
how they were packaged and how long they sit on the shelf.
Because of these variables, the quantity of active ingredients can vary
tremendously making it difficult to test their effects. This may explain why
clinical trials of herbal supplements often give inconsistent results. It’s even more
difficult to predict how any given batch will affect you personally.
Another cause for concern is that supplements can interact with any medicine
you are already taking. Supplements and drugs are usually broken down by your
liver and excreted in urine produced by your kidneys. As we age, our livers and
kidneys are likely to become less effective and we lose some ability to process and
excrete these compounds. When that happens, it is easier for toxic amounts of a
drug or supplement to accumulate. This increases the risks of side effects.
As consumers, we buy a lot of health products without good evidence that they
will actually work. It would be good to know for certain that those drugs,
supplements, vitamins and herbal remedies that we purchase are safe and
effective for each and everyone of us, but that’s not possible. Your brain is unique
and very complex. It’s unrealistic to expect one product to be safe and effective
for everyone.
The information presented here explains what we think we know about the aging
brain. We have good evidence that it is possible to maintain a sane mind in a
sound body well into old age, but results may vary. Find a health care
professional you can talk to and discuss what is best and safest for you.
~
6
WHAT’S HAPPENING TO MY BRAIN?
1B
"When I was younger, I could remember everything, whether it had
happened or not. Now my facilities are decaying, and soon I will remember
only the things that never happened." ~ Mark Twain
One thing is certain – your brain is changing. Some people will see little decline
in mental abilities as they get older. Others won’t be so lucky. Many factors
influence how your brain ages. Some of them are under your control. Some are
not. What can you do to save your aging brain?
Many experts suggest that love, laughter and learning are among the keys to a
happy, healthy brain. Who can argue with that? Unfortunately we can’t measure
these qualities or prescribe them in recommended doses. What’s needed is a
practical way to achieve brain health that anyone can follow. After all, aren’t
healthy brain cells as likely to produce good thoughts and positive behaviors as
the other way around?
Experimental evidence suggests that if you maintain the underlying molecular
machinery that is responsible for your mental performance, then you can keep
your brain in good working condition. After all, it’s the molecules of memory and
mind that make emotion and intelligence possible.
Keep reading and you’ll discover how to fine tune your brain for optimum
performance using methods that have strong supporting evidence based on
scientific testing. You will also learn how to determine your personal risks and
calculate just how old your brain really is. But first, let’s take a look inside that
head of yours and see what makes you tick.
HOW DOES MY BRAIN AGE?
9B
If you pop the lid and look inside your head you will see a uniform blob of
wrinkled gray matter about the size of a middling cauliflower. It seems to be
crammed into the skull so tightly that it folds in on itself like wet laundry in a
bucket. There is no indication of its purpose and no sign that it does anything but
keep your ears apart. Despite its looks, your brain really is spectacularly diverse.
It contains a range of different cell types in various specialized compartments
within a number of evolutionary layers.
7
Neurons and Memory
38B
The most famous of brain cells are the neurons. They come in different shapes
and sizes depending on where they are situated and what they do. There are
interneurons, motor neurons and spiny neurons. Some are large, some are
granular and some are shaped like triangles. Most often we think of neurons as
the most important cells in your brain but they are vastly outnumbered by other
kinds of cells and are dependent upon them for structural integrity, nutrition and
housekeeping.
Synapses
91B
The most significant thing about neurons is that they talk to each other. Neurons
transmit information through your body fast enough for you to respond to your
environment and they do this without being physically connected to each other.
Where they do almost touch, they use chemicals to carry signals across the gap.
These synaptic gaps are more than empty space, they are a vital channel of
information. Lose them and you lose your mind.
Wherever the axon terminals of one neuron meet the branching dendrites of
another, hundreds of synapses are formed. Tiny spines on the dendrites of one
neuron reach out to miniscule hillocks running along the axon terminals of the
next. Once they are close enough, they can exchange chemical signals like good
neighbours swapping recipes.
8
Plasticity
92B
With old age, illness or inactivity, synapses can weaken or disappear. A healthy
spine is usually shaped like a lollipop but old age or disease can wear it down to a
mushroom-shape or reduce it to a mere stub. Such destructive changes are not
always inevitable or irreversible for we now know that synapses wax and wane,
can die and be reborn, thus changing the connections between neurons. This is
the plasticity that gives your brain the ability to adapt, to create fresh memories
and learn new skills.
Neurotransmitters
39B
Brain-Derived Neurotrophic Factor
93B
Certain molecules help maintain brain plasticity and one of them is BDNF. This
neurotransmitter is expressed throughout the brain and stimulates the birth of
neurons, the growth of dendrites and the development of new synapses.1
BDNF elevates forebrain serotonin, which affects learning, memory and mood.2
It also protects against neurotoxins3 and prevents the death of cells that produce
dopamine.4 It is no exaggeration to say that BDNF can affect your long term
memory formation, your decision making and ultimately your personality.5
Serotonin, Dopamine, Acetocholine
94B
Some molecules affect mood and many people take drugs to control the levels of
serotonin, dopamine and acetylcholine in their synapses and the rest of the brain.
Drugs are not the only way to accomplish this. After all, these neurotransmitters
are made from molecules found in your food. Serotonin, for example, requires the
amino acid tryptophan that you can get by eating healthy protein like eggs,
poultry and fish. What you eat determines how quickly your brain cells
manufacture these messenger molecules and how they affect your mood and
brain power.
9
Prozac and Paxil are selective Serotonin Re-uptake Inhibitors (SSRI's) that
increase serotonin in the synapses.
Wellbutrin, also an anti-depressant, increases dopamine levels in the synapses.
Donepezil, a memory-saving drug used to treat Alzheimer's, increases
acetylcholine levels in the synapses.
DHA
95B
You have probably heard of omega-3s, but did you know that DHA
(docosahexaenoic acid) is one of these essential fatty acids? About 50% of the fat
in a neuron's membrane is made of DHA, an important point because this is
where synapses and dendritic spines are formed.6
DHA also makes up half of the membrane lipids of mitochondria, the organelles
inside neurons that produce energy. Like little factories, mitochondria convert
sugar into ATP (adenosine triphosphate), a molecular battery that stores energy
until the cell is ready to use it. Unfortunately, this manufacturing process emits
toxic waste in the form of oxygen free radicals, also known as ROS (reactive
oxygen species).
ROS & Mitochondria
96B
Your brain may be only 2% of your body weight but it consumes over 20% of your
energy. Neurons have many more mitochondria than other cells and produce
more toxic waste, which makes them even more vulnerable to damage from ROS.
Later on you will see the harm ROS does to your brain and what you can do about
it.
10
Protect your neurons if you want to stay healthy, happy and wise. They may be a
specialized type of cell but they contain DNA just like any other cell in your body.
Damage to DNA corrupts the synthesis of proteins and neurons with bad proteins
have many problems. They lose synapses and dendrites, fail to transmit essential
signals and when they die they produce toxic waste that can lead to cancer or cell
death in neighboring cells.
HOW DO MOLECULES CHANGE MY BRAIN?
10B
Neurogenesis
40B
Until very recently, we believed that the brain stopped making new neurons after
childhood. This thinking changed only recently, in 1998, when researchers found
neurons growing in an adult brain.7 Now it is accepted that the hippocampus,
where memories are formed, is able to grow new neurons throughout life.
The hippocampus may be a source of new neurons but it is also one of the first
brain areas to be damaged by old age and Alzheimer’s disease. In older brains,
newborn neurons are not always able to survive - for some reason they commit
suicide before becoming fully connected or functional.
Apoptosis
41B
You could have been born with webbed feet or a tail, but thanks to apoptosis that
didn’t happen. When you were an
embryo, certain cells died off according
11
to a schedule of programmed suicide. Later on, apoptosis triggers the death of
sick or wounded cells as part of regular housekeeping. As you age, the suicide rate
begins to outpace the rate of repair and replacement. At some point, your body
starts to look and feel its age and so does your brain.
Aging Effects
42B
How do we age? Let us count the ways. In the aging brain we typically see:
•
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loss of synapses
loss of dendrites
loss of neurons
reduced plasticity
loss of function in neurotransmitter systems
reduced cerebral blood flow
reduced cerebral oxygen and glucose metabolism
Inside aging neurons there is:
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increased damage to DNA
increased damage to proteins8,9
increased damage to lipids
increased oxidative stress10,11
increased production of free radicals
reduced mitochondrial function
reduced neurotransmitter levels
perturbed energy homeostasis12
lesions in nucleic acids13,14
All these changes have a knock-on effect that interrupts cellular processes,
corrupts the synthesis of important molecules and generally makes matters
worse:
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reduced BDNF
reduced dopamine
a reduction in NMDA receptors important to learning and plasticity
increased atrophy of gray and white brain matter15
shrinkage of brain tissue16
degeneration of dendritic branches and synapses17
altered neurotransmitter concentrations18
decreased cerebral oxygen and glucose metabolism19
12
How do you know if these changes are happening to your brain? As the strength
and plasticity of synaptic contacts decline so your cortex20,21 and hippocampus22
begin to atrophy. The loss of neurons in the motor cortex and especially the
dopamine-producing neurons in the substantia nigra means you will lose some
motor control and have trouble keeping your balance.
HOW DO MY GENES CHANGE MY BRAIN?
11B
Do your genes determine how fast your brain will age? Yes. A single variation in
one gene can influence your ability to remember where you left your car keys.
And it’s not the only one. Many genes affect human intelligence. Since we've
already discussed BDNF (brain-derived neurotrophic factor) let’s start there.
We know from studies of twins that genes contribute a lot to intelligence and
that the heritability of IQ is in the range of 50% to 80% .23
Genes also influence processing speed, short-term memory and working
memory with a heritability of 30% to 60%.24
BDNF Genetic Variants – Met & Val
43B
Humans have two variations of the BDNF gene - met and val - named for the
amino acids methionine and valine. You got one allele or copy of your BDNF gene
from your father and one from your mother so you have one of three possible
13
BDNF combinations:
•
both alleles are val (val/val)
•
both alleles are met (met/met)
•
one of each (val/met).
BDNF Variants & Processing Speed
97B
In 2006, researchers demonstrated that variations of BDNF do seem to affect
different kinds of memory in different people.25A follow-up study in 2008
determined that someone’s rate of cognitive decline in old age is related
specifically to the type of BDNF variant they have.26
They arrived at this conclusion after asking 53 healthy adults, averaging 75 years
of age, to play a card game. Each of the participants had already participated in a
similar study a decade earlier so it was simply a matter of comparing past and
present performance to gauge their rate of mental decline over the past ten years.
Play along if you like. Divide some flashcards into four boxes. Then print one
letter and one number (for example A3 or C2) in different boxes on each of the
flash cards so that they appear randomly in one of the upper or lower boxes.
This game requires rapid switching between two tasks. When a flashcard is
revealed, note the position of the printed characters and then make a quick
decision:
1. If the printing is on top, decide if the number is odd or even
2. If the printing is on the bottom, decide if the letter is a vowel or a
consonant.
Then switch the rules and start over. Two trials of one task are followed by two
trials of the other task and so on.
14
Correlating the response times to the BDNF variants showed that the
performance of val/val carriers had declined much more rapidly over 10 years
than met carriers. On average, their processing speed had dropped by 25% while
those with met showed little or no change.
BDNF Variants & Memory
98B
In 2003, a study of BDNF variants in 621 people found that a single variation in
the sequence of the BDNF gene impaired episodic memory, the ability to recall
what happened yesterday or half and hour ago.27 During the test, functional MRI
recordings focused on the hippocampus to reveal abnormally high activity in
val/met subjects while people with met/met had significantly less activity and
scored poorly on a memory test.
Tracking the molecular consequences of this variation in mice uses fluorescent
microscopy to highlight the secretion and location of met and val and may
explain memory loss in human met carriers. It seems that BDNFmet first fails to
be secreted and then fails to arrive at the synapses, results that have since been
confirmed and extended by other researchers.28,29
Dopamine Related Variants
44B
Other gene variant affects dopamine, which helps to record incoming information
and store it for future reference. Your brain cells manufacture dopamine but
ultimately it is broken down by an enzyme called COMT (catechol-O-methyl
transferase). How quickly dopamine dissolves in your synapses depends on your
version of COMT, which is either met (methionine) or val (valine) similar to
BDNF.
15
COMT Variants & Cognition
99B
Does lingering dopamine give some people a cognitive advantage? A review of
published research in 2006 turned up 18 studies where the met allele appeared to
improve performance on working memory and cognitive tasks.30 However, a
similar review reported insufficient evidence to prove a clear association between
COMT genetic variants and cognition.31 The controversy was finally settled in
2008 by yet another card game called the Wisconsin Card Sort.
In this test, the rules change without warning. Participants match their own card
to one of four displayed cards and then press a corresponding button within a
limited time. At first they may match cards by color, but after 10 consecutive
correct responses the rule changes to matching by shape or by number.
Participants only know if their response is right or wrong, so they must make a
mental shift based on this limited feedback alone.
Compared to younger people, older adults with COMTval made more mistakes.
Overall, results show that different COMT and BDNF variants do affect cognition
with age as people with two COMTval and at least one BDNFmet have much
slower response times.32
D2 Dopamine Receptors
100B
In time, our dopamine receptors also begin to influence brain function. Neurons
have several types of dopamine receptors and humans have genetic variants of at
least two of them. The dopamine receptor D2 is encoded by the DRD2 gene and
has variants A1 and A2. The DRD2 gene gets lazy and expression levels subside as
we age. This also contributes to mental decline and later on we'll see an
experiment that tests the effects of increasing DRD2 expression levels on memory
and learning.33
16
Serotonin Transporter Gene (SLC6A4)
45B
Serotonin, which is linked to mood and social intelligence among other things, is
another factor in brain aging. To access your neurons, serotonin relies on a
transporter protein supplied by a gene with three genetic variations. Tests of 750
elderly people given 15 years apart show that those with two copies of one allele
(VNTR2 12) were declining faster in fluid intelligence, semantic memory and
general cognition.34
Your cerebral resistance to aging depends, at least in part, on your personal
version of those genes responsible for BDNF, COMT, dopamine receptors and
dopamine transporters. Given how many genes and molecules are involved, their
influence may be minor, but they do make inviting targets for therapeutic
intervention.
HOW HEALTHY IS MY BRAIN?
12B
Statistically speaking, your chances of avoiding the big three aging diseases are
fairly good. Unfortunately, as you age you might still find yourself having
difficulty with things that you used to take for granted. Memory loss can often be
the first sign that you are ‘starting to lose it’ but this is difficult to measure
because there are several types of memory in different parts of the brain.
Declarative memory or explicit memory helps us remember facts, dates and
events and functions largely in the hippocampus and cortex.
Procedural memory or implicit memory helps us remember how to do things
like riding a bicycle and resides mostly in the basal ganglia (striatum) and
cerebellum.
Emotional memory informs much of our decision making and stems from the
amygdala.
17
You may also experience a decline in mental processing leading to confused
thoughts about things that you used to manage with ease. Once again, it can be
difficult to pinpoint exactly what’s happening not only because different skills are
centered in different locations within the brain but because they involve complex
interactions between various regions.
Humans are naturally scatterbrained. Alzheimer patients suffering decay in one
part of the brain may be unable to learn or remember ordinary facts, but thanks
to undamaged areas they can still learn and remember how to read complex
words in a mirror as well as anyone else. They simply can’t recall the training
session or having acquired the skill. Unless you look in the right place or ask the
right questions, you might not suspect that their brain had been injured.
In general, it can be a mistake to apply experimental findings to the whole brain
or to think that they apply to everyone who has one. Different studies examine
different aspects of memory and learning. This implies that they have studied
different parts of the brain. What researchers discover depends entirely on what
they are looking at.
18
Can I Measure Cognitive Decline?
46B
Many kinds of tests are available to assess cognitive decline. The longest, most
comprehensive study of brain aging is the Seattle Longitudinal Study of Adult
Intelligence begun in the late 1950's and ongoing today.35 Many research studies
use the same tests to evaluate the effects of aging on the brain, so it's worth
seeing how they define and measure memory and cognition.
Inductive reasoning is the ability to solve logical problems and recognize
patterns. It allows you to analyze previous experiences to find solutions, to
understand novel concepts and relationships, to make plans and foresee results.
For example:
•
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predict the next letter in this series - a x b c x d e f x g h i.
solve 30 problems in 6 minutes
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predict the next word in this series - January, March, May.
solve 30 problems in 6 minutes
•
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predicting the next number in this series - 6, 11, 15, 18, 20.
solve 20 problems in 4.5 minutes
Spatial orientation is your ability to recognize and mentally rotate objects,
images and maps. Good spatial orientation allows you to match a 2 or 3dimensional picture of an object to a rotated version or to visualize what an
object looks like when the pieces are disassembled. For example:
•
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match an image to one of six other images
solve 20 problems in 5 minutes
•
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decide which one of six rotated images matches an object
solve 20 problems in 5 minutes
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determine if two drawings are the same cube rotated in 3-D space
solve 20 problems in 5 minutes
Numeric facility helps you recognize numerical relationships and solve simple
number problems quickly. For example:
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determine if simple addition sums are correct or not
solve 60 problems in 6 minutes
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add three single-digit or two-digit numbers
solve 40 problems in 6 minutes
19
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solve a series of subtraction and multiplication problems.
solve 40 problems in 6 minutes
Verbal comprehension includes your vocabulary and ability to understand
the meaning of words. For example:
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given a word, identify which of four other words is a synonym
solve 50 problems in 4 minutes
•
•
•
•
Educational Testing Service standardized test
given a more difficult word,
identify which of five other words is a synonym
solve 18 problems in 4 minutes
Perceptual speed is your ability to find images or make visual comparisons
quickly. For example:
•
determine which of five shapes or pictures is identical to the model.
You have 1.5 solve 50 problems in 1.5 minutes
•
•
in a column of 40 words, find the 5 words that contain the letter a
you have 1.5 minutes
•
•
shown a pair of multi-digit numbers, decide if they are the same or not.
solve 40 problems.1.5 minutes
Verbal memory is your ability to memorize and recall words. The verbal
memory test is among the best predictors of who will get Alzheimer's disease. For
example:
•
•
•
memorize a list of 20 words
you have 3.5 minutes to recall as many words as you can
now try to recall the same list of 20 words after an hour of other tests
Are you exhausted just reading about these tests? There are many more and some
of them are available online for self-assessment. Just remember that it is unwise
to make sweeping generalizations based on a few tests. If you suspect that you
have symptoms of cognitive decline, talk to your doctor and have your test results
evaluated by a medical professional.
20
WHAT ARE MY CHANCES?
13B
Until we find a cure for stroke, Parkinson's and Alzheimer's, these illnesses will
continue to account for most of the rapid and extreme loss of brain power, severe
dementia and early death among the elderly. These diseases are age-related, so
the longer you live the greater the chance that your brain will succumb to one of
them.
Alzheimer’s
47B
The lifetime risk of Alzheimer’s disease is about 10% for men and 20% for
women. Perhaps this tells us something important about the origins of the
disease. Later on, we’ll see what you can do to reduce your risk of Alzheimer’s.
Parkinson's Disease
48B
Parkinson's disease is the second most common brain disorder. Although it
occurs in less than 1% of people aged 65 to 69 it rises to 3% among those aged 80
years and older.36 We’ll also be looking at ways to reduce your risk of this disease.
21
Stroke
49B
According to the US Center for Disease Control, in 2007 roughly 8% of
Americans over 65 reported having a stroke before they could get to a hospital.
Compared to Europeans, American men have a 61% greater risk of stroke and
American women almost 100% greater risk. Why? Partly because we have higher
rates of obesity, diabetes and smoking.37
In contrast, more people live to be over 100 years old in Okinawa, Japan, than
anywhere else and their stroke rate is among the lowest in the world.38 Intensive
studies of diet and lifestyle in Okinawa have identified certain factors that
promote longevity and health and we’ll take a look at those findings to see how
you too can control your risk of stroke.
As you age, you will experience moments when you forget birthdays, misplace
your glasses or occasionally lose your balance. That doesn’t mean that you are
sliding toward dementia. None of those diseases is inevitable. According to the
Alzheimer's Association, the lifetime risk of all dementias is about 15% in men
and 23% in women. So if you are a ‘glass half full’ kind of person, you have a 75%
to 85% chance of avoiding the most severe forms of memory loss and cognitive
decline as you age.
DO I HAVE ALZHEIMER’S GENES?
14B
You have a gene that makes a protein that transports cholesterol through your
bloodstream. Everybody does. It’s called the apolipoprotein or ApoE gene. There
are three common variations of this gene (E2, E3 and E4) and one of them is a
factor in late-onset Alzheimer’s disease. People with the ApoE4/ApoE4 allele
combination decline most rapidly.
How might ApoE4 damage your brain? ApoE is known to influence your
cholesterol levels and since high cholesterol increases your risk of Alzheimer’s,
ApoE4 is guilty by association. If you inherit a single ApoE4 gene, you have an
increased risk of Alzheimer’s disease at age 65 or older. Inherit two of them and
your risk is greater still. And yet, having one or two copies of ApoE4 in no way
guarantees that you will ever develop the disease.39
22
How Do I Discover My Genotype?
50B
Curious to know which versions of these genes you have? Then send a sample of
your cells to a commercial company such as Navigenics or 23andme (named for
the 23 pairs of human chromosomes). Here's how it works at 23andme.com.
1
2
3
4
Order a kit online.
Drop your saliva into the tube and send it to the lab.
Wait 2-4 weeks for the lab to analyze your DNA.
Log in and start exploring your genome.
If you find out that you have a genetic variant such as ApoE4, is there anything
you can do with that information? Yes. Get moving! Physical activity improves
cognitive abilities and slows the effects of Alzheimer's significantly more in
ApoE4 carriers than in non-carriers.40,41 Just remember this, genes don’t tell the
whole story - they only partially explain your risk of cognitive decline with age.
Now that you have an idea of the molecular changes taking place as you get older,
it’s time to look at some of the major risk factors you encounter everyday and
discover practical ways to save your aging brain.
~
23
FOOD CHOICES
2B
The two biggest sellers in bookstores are the cookbooks and the diet books.
The cookbooks tell you how to prepare the food and the diet books tell you
how not to eat any of it. ~ Andy Rooney
What you eat - and how much you eat - determine how fast your brain ages. Your
food choices really do influence the health of your brain now and into the future.
Suppose your favorite meal is a hamburger with fries washed down with a regular
soda. It’s delicious. It’s filling. It leaves you happy and feeling full. What’s the
problem?
Actually, there is more than one problem with a meal like that and to understand
why let’s take a look at what food is made of. The three major components in any
meal are fats, carbohydrates and proteins. There are lesser amounts of minerals,
vitamins and other ingredients but the big three make up the bulk of your food.
All these ingredients are absorbed by your intestines, passed through your liver
and sent into your blood stream. A good portion of them end up inside your
brain.
Fats contain lipids, cholesterol, triglycerides (mostly bad fats) and omega-3 fatty
acids (the good fats).
Carbohydrates contain starch, fiber and sugars like:
•
•
•
•
sucrose (table sugar)
glucose (blood sugar used by the brain)
fructose (from fruit)
lactose (from milk).
Proteins are made of amino acids, the molecular building blocks in all plants
and animal cells and a major component of meat.
FATS: THE GOOD, THE BAD AND THE UGLY
15B
Did you know that rats on a diet of 10% saturated fats have almost zero learning
ability? What’s the average of saturated fats in American diets? About 11%.
24
The type and amount of fat you eat determines who you are and how you think.
That’s a strong statement but it is supported by experimental evidence as you’ll
see in a moment. Consider first that your brain is mostly made of fat. Fat-like
molecules or lipids make up to 60% of your brain cells. These molecules control
the growth of dendrites and the formation of synapses in your neurons, which
directly affects your ability to learn and remember. They also influence the type
and quantity of neurotransmitters available to brain cells, which affects your
mental acuity and mood. Fats even play a role in your risk of stroke, Parkinson's
and Alzheimer's disease.
The Good
Good fats are omega-3 fatty acids found in fish, flaxseed and some nuts, not to
mention supplements and monounsaturated fats from olive oil, canola oil,
flaxseed oil and avocado.
The Bad
Bad fats include omega-6 fatty acids in most processed foods, corn oil,
sunflower oil and safflower oil added to most salad dressings and
hydrogenated vegetable oils and trans fats in margarine, mayonnaise, fried
and deep-fried foods like french-fries, donuts and fried chicken.
The Ugly
Saturated fats lurk in some of our favorite foods like whole milk, butter, cheese
and meat such as beef and pork.
Saturated or Unsaturated?
51B
Why is one fat good for your brain and one is not? The short answer is that we
don’t know exactly for even though the chemical properties of fats are well
understood, how they react to events inside your brain is stunningly complex.
If you look at an olive oil molecule you will see that it has a carbon backbone with
25
hydrogen atoms attached to most of the carbon atoms like bristles on a wire
brush. There are a couple of extra atoms, in this case oxygen, but this is the basic
structure of most fats, good or bad.
Did you notice that there is room for more hydrogen atoms in the center? That’s
why olive oil is considered to be "unsaturated". Look again and you’ll see a
double=bond joining two carbon atoms in the middle of the structure. With room
for more hydrogen and only a single double bond, olive oil is both “mono” and
“unsaturated”.
How Do Saturated Fats Hurt My Brain?
52B
In contrast, saturated fats do not have double bonds between carbons and since
they have no space for extra hydrogen they are said to be saturated - a molecular
arrangement with dire consequences for your brain.
The next time you have a choice to make for breakfast, lunch or dinner,
remember that saturated fats are not your friends. They limit your ability to learn
by stunting the growth of dendrites and synapses. Because they alter the type and
quantity of neurotransmitters they can alter your mood and lead to cognitive
decline at any age. They also increase your chances of suffering a stroke or
developing Parkinson's and Alzheimer's disease.
When Professor Carol Greenwood at the University of Toronto fed rats on a diet
containing up to 10% saturated fat she found that their ability to learn fell directly
with the amount of saturated fat in their food, a negative effect since confirmed
by others.1,2
So why do many of us over-indulge in saturated fats? Apart from turning us into
slow learners, they also seem to fool our brains into thinking that we are still
hungry. When rodents at the University of Texas Southwestern Medical Centre
ate food containing olive oil, they did not overeat. When they ate a saturated fat
like palm oil, they didn’t know when to stop eating.3 That’s because palm oil
interferes with messenger molecules like leptin and insulin that signal satiation
26
to the brain.
Saturated fats are also a major source of LDL cholesterol, the Lousy type of
cholesterol, which means that choosing the wrong type of fat is a double threat to
your brain.4 If you are in the habit of spreading butter, mayo or cream cheese on
bread and bagels here’s a tip - use avocado instead. It is high in good
monounsaturated fat, low in saturated fat and has fewer calories.
Omega-3 vs Omega-6
53B
Another type of fat to watch out for is omega-6. Omega-6 fatty acids are essential
and poly-unsaturated, just like omega-3’s but one difference between them is that
your body doesn't make omega-6 so you definitely need it in your diet. The
trouble is that you probably eat far more omega-6 than you really need and that’s
a problem because it both interferes with the synthesis of omega-3 and reduces
its benefits.
You need omega-6 because it increases the amount of arachidonic acid in your
system. This is an essential fatty acid required for cellular signaling, but too much
can contribute to inflammation and damaged blood vessels in your brain and
increases your risk of stroke and Alzheimer's disease.
Even if you eat a lot of salads, look out for those salad dressings! Too often they
are made with corn oil, sunflower oil or safflower oil, all high in omega-6 and
potentially harmful to your neurons. Use olive oil, canola oil or flaxseed oil
instead.
Why Omega-3?
54B
Omega-3 fatty acids have many double=bonds and the first double bond
occurring at the third carbon gives omega-3 its name. Double bonds have the
potential to attract many more hydrogen atoms than those already attached, so
while an omega-3 molecule looks full of hydrogen, it really isn’t.
27
There are three omega-3 unsaturated fatty acids that are nutritionally important.
ALA (alpha-linolenic), which your body does not produce, is obtained by eating
eat plants and nuts, for example flax, walnuts and Brazil nuts. This is important,
because you need enough ALA to combine with EPA (eicosapentaenoic acid) to
produce a third critical fatty acid called DHA (docosahexaenoic acid).
DHA
101B
Does it matter if you have enough DHA? You bet it does! DHA is essential for
healthy brain cells and low DHA levels are associated with mental decline and the
loss of neurons. Half the fat in the membranes of neurons and mitochondria is
made of DHA so you need it to keep your neurons working and supplied with
energy.
DHA is involved in building anti-inflammatory molecules, a process that breaks
down as you age, so getting enough in your diet is critical. The richest sources of
omega-3 DHA are fish like salmon, tuna and mackerel.
You are almost certainly getting too much omega-6 and too little DHA in your
diet. The ratio of omega-6 to omega-3s in a typical diet, which usually includes
hamburgers, pizza, fried foods and most salad dressings, is about 15 to 1. A
healthy ratio is 1 to 1.
DHA Supplements
102B
We know from animal studies that DHA supplements improve memory and
learning in both young and old rodents.5,6 DHA supplements have improved
performance in maze running tasks and in one study, improved the impaired
learning ability of rats from an impoverished environment.7 This experiment
demonstrates that it is never too late to start improving your brain so let’s take a
closer look.
28
The Morris water maze is designed to test how quickly an animal can find safety
using only its wits and memory. A large vat of water about 6 feet across has a tiny,
invisible platform submerged under the surface. As a rodent swims around the
pool, the distance it travels and the time it takes to reach the platform is
recorded. If a rat remembers visual cues placed around the vat and learns how to
use them, it should find the platform faster each time it does the test.
The average rodent is pretty smart, so even untreated rats improve their escape
times with each trial. However, they are no match for rats taking DHA
supplements. Even rats with little or no learning experience (thanks to an
unstimulating environment) improved their escape times right from the start
once their diets included DHA. After four weeks of training, DHA animals were
more than three times faster than untreated animals to remember clues and
locate the platform.
In rodents, DHA is known to promote the growth of neurites, the immature
outgrowths that become axons and dendrites that will form additional synapses.8
What’s more, gerbils and rats receiving DHA or EPA supplements create more
synapses, more synaptic proteins and more phosphatides, the fats required to
build the all important neural membranes.9
DHA also has a marked impact on neurons in the hippocampus where it spurs
the growth of membranes and dendritic spines .10,11,12 In rodents, oral
supplements of 100mg, 200mg and 300mg per day of DHA increase the density
29
of neurites in the hippocampus by 50% over a 4 week period.13,14
Raising the levels of omega-3 fatty acids in rodents has proven beneficial. Does it
work the same way in people? Yes it does. In human studies, higher levels of
omega-3 in oxygen-bearing red blood cells (erythrocytes) are shown to reduce the
risk of cognitive decline and dementia in middle and old age.15,16,17,18 As it turns
out, the key to raising levels of omega-3 is to keep omega-6 levels down.
Of 1300 males aged 64 to 84 who took part in the long-term Zutphen Elderly
Study in Holland, those with high omega-6 had 75% greater risk of memory loss
and reduced cognition compared to those with low omega-6.19 The same study
also measured the dietary intake of fatty acids and fish in relation to cognition in
1,613 people ranging from 45 to 70 years of age. Results show that cholesterol and
saturated fats increased the risk of impaired cognition in middle-age while fatty
fish and marine omega-3 reduced the risk.
Another group of 210 people aged 70-89 years took part in a study where fish
consumption and other data were collected for five years. Their cognitive decline
over that time was measured using the Mini-Mental State Examination (MMSE),
which includes questions on orientation in time and place, registration, attention,
calculation, recall, language and visual construction.20
Elderly fish eaters experienced only minor decline. Statistical analysis shows that
the total DHA plus EPA from all food sources was inversely related to cognitive
decline. In other words, elderly people who did not eat fish suffered greater
decline prior to the study and continued to decline 4 times faster than fish eaters
over the next 5 years.
30
In 2005, a study at the University of Siena in Italy, reported on the effects of
omega-3 supplements on the central nervous system of healthy humans. One
group took take 8 capsules (4g) of fish oil per day as a source of omega-3 and one
group took 8 capsules (4g) of olive oil per day. Those in the control group
swallowed a placebo.
The study was designed to challenge several areas of the brain and goes like this.
A stimulus appears on a computer screen and the participant responds as quickly
and accurately as they can to the visual clue by tapping a key on the keyboard.
Reaction times and errors are recorded during four tests involving different types
of mental attention.
The Alert test measures the reaction time to a stimulus requiring little mental
effort. When the letter ‘X’ appears on the screen, press a key as fast as possible.
The Go/No-Go test requires more mental effort and analyzes the ability to
repress unsuitable responses and to react only to some stimuli and not others.
One of five squares colored either red, green, yellow, blue or black appears at
random on the screen. The key is pressed only if red or green appear but not the
others.
The Choice test requires some analysis and assesses the ability to react to
different stimuli. As one of three colored squares appears on screen, the person
has to press one of three buttons.
The Sustained Attention test analyzes the ability to react to a complex
stimulus. As a series of objects appear, the person must recognize if it is equal to
the previous one in color, shape or size. If any of the criteria match, they press a
button that covers all combinations.
31
Omega-3 supplements did improve attention and response times, especially in
tests requiring complex cortical processing. Blood analyses confirmed that the
supplements created a healthier omega-3 to omega-6 ratio, telling us that striking
the right balance in your diet can have significant benefits. Interestingly, the
results suggest that even a healthy brain can improve its decision making and
reaction times with omega-3 supplements.
In other human studies, omega-3 supplements have been beneficial for children
with learning and behavioral problems. After taking supplements for 15 weeks,
troubled children were able to control their attention and to switch their focus
better than those on a placebo. Then, after the placebo group took omega-3
supplement for 15 weeks, they too experienced the same benefits.22,23
Omega-3 and Depression
103B
Does omega-3 have an antidepressant effect? It might. The elderly often suffer
from depression and as any one who as experienced it can tell you, it can
profoundly interfere with mental processing. The good news is that seafood is
high in omega-3 fatty acids and those countries with higher rates of seafood
consumption have lower rates of depression and other mood disorders.24,25
32
One study found that patients with mood disorders have lower levels of omega-3
than normal.27 Another study of omega-3 supplements reported that omega-3
significantly reduced anger, anxiety, fatigue, depression and confusion while
significantly increasing vigor.28
That’s promising, however one 6-month study of the effects of fish-oil
supplements in older adults found no significant cognitive benefit.29 Then in
2007, a review of ten placebo-controlled trials of omega-3 fatty acids to treat
depression found a number of experimental discrepancies. While there was
statistical support for an antidepressant effect, there was also evidence of
publication bias, the tendency to report only favorable results.30
33
How much confidence you can place in omega-3 as an antidepressant is still an
open question. Unexpected outcomes reminds us that supplements, like
pharmaceuticals, work for some people some of the time, not for everybody all of
the time.
Omega-3 versus Alzheimer's Disease
104B
What about Alzheimer’s? Is there any reason to believe that food choices can
influence the development of this disease? Yes, there is. As the disease
progresses, two noticeable changes occur in the brain. The first is an
accumulation of amyloid-beta and the second is changes to tau proteins.
Amyloid-beta are coarse clusters of otherwise useful proteins that now start to
interfere with normal processes. Amyloid-beta is linked to a number of diseases
where it forms a plaque that inhibits cell signaling, especially in mitochondria
where it causes an overproduction of toxic ROS (reactive oxygen species) and
eventual cell death.
Tau proteins are concentrated in axons where they normally contribute to
structural support and cellular processes. The trouble starts when tau is no longer
soluble and deforms into tangled mattes.
In mice, a dietary supplement of DHA from omega-3 reduces the build up of both
amyloid-beta and tau clusters. However, if their diet includes omega-6 fatty
acids, DHA becomes less effective.31 Over time, an excessive amount of omega-6
interferes with DHA leading to inflammation, neural breakdown and cell death.32
In Alzheimer mice, a diet high in omega-6 and saturated fats damages tau
proteins as well as the insulin producing protein (IRS-1). This triggers the
activation of protein kinases, enzymes that respond to cellular stress by changing
the structure and purpose of proteins by attaching a phosphate group
(phosphorylation). This is normally a good thing, but in this case, the kinases
become over-active and start changing proteins willy-nilly within the JNK
pathway that regulates stress induced cell death downstream from DAXX, the
gene encoding the Death Associated Protein6 in humans.
On a positive note, the same mice were able to repair the damage done by
rampaging kinases and improve their performance in the water maze test by
eating various combinations of fish oil and curcumin, a natural antioxidant in
ginger. Mice fed on this diet for just 1 month had the least kinase activity and the
best scores.33
34
Clearly, an unbalanced diet does not work in favor of older brains. What’s needed
is a way to reset the natural equilibrium. In 2008, while looking for such a
solution, researchers found an anti-inflammatory signaling molecule called NPD1
derived from DHA itself. This molecule is helpful in maintaining the internal
balance (homeostasis) of neurons. Unfortunately, it sometimes promotes the
build up of harmful amyloid-beta. We have yet to see if NPD1 can be tweaked to
tip the scales in favor of aging brains.34
Observational Studies of Omega-3 versus Alzheimer's Disease
105B
Alzheimer’s disease is the most severe form of mental decay, but many more of us
likely to experience some form of dementia ranging from mild eccentricity to
extreme forgetfulness. Most observational (epidemiological) studies of aging
populations agree that omega-3 fatty acids appear to stave off dementia and delay
mental decline. They also agree that omega-6 are unhelpful and appear to be
responsible for higher levels of inflammatory prostaglandins, messenger
molecules derived from fatty acids that are often, though not always, an immune
response to cellular stress.35
One study in particular underscored the importance of DHA. Among the 1178
volunteers, averaging 75 years of age, were individuals known to have Azheimer's
disease and lower than normal levels of DHA. Unknown at the time was that a
number of people in the control group who were considered to be healthy, also
had lower than normal DHA. Not only did these individuals score below average
on memory tests, but ten years later, their statistical chance of dementia had
increased by two thirds.
Clinical Trials of Omega-3 versus Alzheimer's Disease
106B
Clinical trials are more rigorous than observational studies and they too suggest
that omega-3 helps to prevent amyloid-beta formation. Significantly, omega-3
modifies the upregulation of APOE (Apolipoprotein E), which is predictive of
Alzheimer’s disease. In addition, twelve clinical trials show that omega-3 reduces
the risk of stroke.36
The delivery method used in many of those omega-3 experiments was fish oil and
results were mixed. Observational studies may have concluded that fish oil can
prevent or treat cognitive decline and Alzheimer's disease, but clinical trials are
less convincing. For example, promising results from a six month study in
Taiwan were offset by Swedish and Dutch trials that found no positive effects at
all.
35
Later analysis suggested that participants suffering cognitive decline or mild
forms of Alzheimer's disease did experience slight improvements, even though
the evidence is marginal. None the less, it opened the door to fish oil as a
supplemental therapy for certain individuals.37
Omega-3 and Longevity
107B
Does omega-3 affect your life expectancy? A Harvard School of Public Health
study published in 2009 states:
"The mortality-reducing effects of omega-3 fatty acids and of replacing
saturated fatty acids with polyunsaturated fatty acids have been confirmed in
randomized trials."38
In 2005, almost two and half million Americans died. About 200,000 or 9% were
due to obesity, lack of physical activity and high blood sugar, all causes associated
with diets low in omega-3 but high in trans fatty acids and salt. What was the
death rate for those who eat mostly polyunsaturated and omega-3? Only 15,000
or less than 1%.
Odds are you can have a longer, happier and healthier life if you have sufficient
omega-3 in your diet. So why not eat fish more often? Fish are a good source of
omega-3 fatty acids, it’s true, but thanks to pollution and over-fishing, they may
contain more than you bargain for. Let’s deal with that right now.
36
Omega-3, Mercury and PCB's In Fish
108B
Many of the fish we eat do contain toxic mercury and PCBs (poly-chlorinated
biphenyl). At the top of the food chain, large, predatory fish like swordfish, shark
and tuna usually have the highest levels of mercury including methylmercury, the
most toxic form for humans. But how much is too much?
The University of Alaska examined concentrations of mercury in 17 freshwater
species and 24 marine species only to find that most fish had muscle mercury
concentrations under 1 mg/kg, well within the FDA’s safety guidelines. Pacific
salmon had even lower concentrations at under 0.1 mg/kg.40
In contrast, a study published in the journal Science concluded that:
"Although the risk/benefit computation is complicated … consumption of
farmed Atlantic salmon may pose risks that detract from the beneficial
effects of fish consumption."41
This report generated hot dispute because more than 90 percent of fresh salmon
eaten in the USA is farmed. Even the FDA did not agree with this study's
recommendations for the reason that farmed fish are subject to much stricter
controls and far lower limits. For example, the allowed limit for PCB's in wild
salmon is 2000 parts per billion, about 50 times the level for farmed fish.
Besides, most of the contaminants are in the skin and the fat just beneath it,
which people don't usually eat.
Tuna is more problematic. Studies have found that the amount of mercury in
canned tuna varies widely. In some cases it exceeds the level at which the FDA
can remove the product from shelves. Consequently, some experts recommend
limiting tuna to one serving per week.
Omega-3 and Fish Oil
109B
If fish doesn’t appeal to you, then fish oil supplements may be the safer way to get
omega-3. Two studies by researchers at Harvard University examined 5 over-thecounter preparations of fish oil to determine the concentrations of mercury, PCB
and other organochlorines used in plastics, solvents and pesticides. They found
mercury levels in fish oil to be negligible and similar to that found in human
blood. PCB and other chemicals were undetectable.42,43
Consumer Labs (consumerlab.com) confirmed those results after testing 52 fish
oil and omega-3 supplements and concluded that:
37
"Every product fish oil or omega-3 supplement in this review and quality
rating guide was found to be free of mercury, PCBs and other contaminants
found in fish."
Without doubt, fish oils provide the benefits of omega-3 fatty acids without the
risk of toxicity inherent in eating fish.
Environmental Toxins In Fish Oil
Brand
Polychlorinated Biphenyls
Organochlorine
CVS
Kirkland
Natrol
Omega Brite
Sundown
None Detected
None Detected
None Detected
None Detected
None Detected
None Detected
None Detected
None Detected
None Detected
None Detected
Mercury Content In Fish Oil
Brand
CVS
Kirkland
Nordic Ultimate
Omega Brite
Sundown
Mercury Level mg/kg
10
<6
<6
12
<6
How Much Omega-3 Should I Take?
55B
Many experts suggest taking 1 to 2 grams of omega-3 every day. In two of the
studies we saw earlier, people taking about 4 grams per day improved their
memory scores.44,45 Their risk of death from stroke or heart disease declined as
omega-3 increased to 2.5 grams per day, but above that there was little gain with
respect to deaths from heart disease and stroke.46
What’s the best source of omega-3, fish or plants? There is disagreement on this
subject, but in a way it doesn’t really matter. Our bodies can only convert a small
fraction of ingested ALA into DHA because the enzyme that performs the
conversion is not very efficient and any omega-6 we have consumed makes the
conversion process even less effective. So why not take ready-made EPA and
DHA supplements? A 2008 study suggests that this “may be the best way to
ensure adequate provision for both sexes, especially in ageing." 47
38
CARBOHYDRATES
16B
If you still have an appetite for a burger and fries after learning what saturated
fats can do to your aging brain, let’s move on to the next major component of
food, carbohydrates containing starch, fiber and sugars.
Biochemists refer to carbohydrates as saccharides, a Greek word for sugar. There
is no doubt that your hamburger and soda pop contain sugar and lots of it. That is
why it tastes so good and leaves you feeling energized. In the right amount, sugar
in your blood improves your memory, mood and learning ability, but too much
sugar causes both short-term and long-term damage to your brain.
Thinking really is hard work. Your neurons need sugar just as much if not more
than your muscles and organs. Your brain is about 2% of your body weight but it
burns over 20% of your energy, mainly in the form of glucose, commonly called
blood sugar. The trick is to maintain blood sugar levels within an optimum range
so that your brain works well and steadily but avoids damage. Later on you’ll see
how to supply your brain with the right amount of sugar at the right time.
Sugar Versus Artificial Sweeteners
56B
Maybe you use artificial sweeteners instead of table sugar (sucros). They are
many times sweeter than sugar and achieve the same level of sweetness with far
less energy input in the form of calories. Some sweeteners are natural food
additives but most of them are synthetic and that usually raises the question of
safety. Many people believe that artificial sweeteners cause cancer. So let's get
that out of the way immediately. Here what the National Cancer Institute
has to say:
“Artificial sweeteners are regulated by the U.S. Food and Drug Administration.
Studies have been conducted on the safety of several artificial sweeteners,
including saccharin, aspartame, acesulfame potassium, sucralose, neotame,
and cyclamate. There is no clear evidence that the artificial sweeteners on the
market in the United States are related to cancer risk in humans.” 48
H
H
Why should you trust the National Cancer Institute and the U.S. Food and Drug
Administration? Both are agencies of the Department of Health and Human
Services. The FDA regulates food, drugs , medical devices, cosmetics, biologics
and radiation -emitting products. It is required to approve food additives,
including artificial sweeteners, before they can be available for sale in the U.S.
H
H
H
H
39
Artificial sweeteners are thoroughly investigated, but sugar itself is one of many
products that do not require FDA approval. Conveniently, current legislation
does not apply to products that are "generally recognized as safe."
Is there any association between artificial sweeteners and cancer? In the minds of
some people there is because during the early 1970s the news that cyclamate
might be linked to cancer in rats tainted the reputation of all sugar substitutes.
You should be confident that any sweeteners you use are harmless so let’s look at
them one at a time.
Saccharin
110B
Several studies linked saccharin to bladder cancer in laboratory rats. Congress
mandated further studies and required all foods containing saccharin to carry
this warning label:
"Use of this product may be hazardous to your health. This product contains
saccharin, which has been determined to cause cancer in laboratory animals."
Later studies showed an increased bladder cancer at high doses of saccharin,
especially in male rats. However, mechanistic studies that examine how a
substance works in the body have shown that these results apply only to rats and
are not relevant to humans.
H
H
The warning label requirement was removed when human epidemiology studies
of patterns, causes, and control of diseases in groups of people were unable to
provide any consistent evidence that saccharin is associated with bladder cancer
in people. For more information about the delisting of saccharin go online to
http://ntp.niehs.nih.gov/ntp/roc/eleventh/append/appb.pdf .
H
H
H
H
Aspartame
111B
Aspartame (Nutrasweet® and Equal®) was approved in 1981. Numerous tests
showed that it did not cause cancer or other adverse effects in lab animals. A 1996
report suggested that an increase in brain tumors between 1975 and 1992 might
be associated with the introduction of aspartame, however, statistical analysis
showed that the overall incidence of brain and central nervous system cancers
began to rise in 1973, 8 years prior to the approval of aspartame. Moreover,
increases in overall brain cancer incidence occurred primarily in people age 70
and older, a group not exposed to the highest doses of aspartame. Again, there is
no clear link between aspartame and brain tumors.
H
H
H
40
H
Recently, an experiment found that rats had more lymphomas and leukemias
when fed very high doses of aspartame.49 The cancers found in these rats were
not specific to aspartame and the number of cancer cases did not rise with
increasing amounts of aspartame. Still, if you drink from 8 to 2,083 cans of diet
soda every day of your life maybe you will have a problem.
H
H
H
H
A subsequent study of over half a million retirees concluded that increasing
consumption of beverages containing aspartame was not associated with the
development of lymphoma, leukemia, or brain cancer.50 For more information
about aspartame see the FDA Statement at
http://www.cfsan.fda.gov/~lrd/tpaspart.html .
H
H
Acesulfame Potassium, Sucralose and Neotame
112B
Acesulfame potassium (ACK, Sweet One®, and Sunett®) was approved in 1988
for certain foods and beverages and approved in 2002 as a general purpose
sweetener (except in meat and poultry). Sucralose (Splenda®) was approved as a
tabletop sweetener in 1998 and as a general purpose sweetener in 1999. Neotame,
which is similar to aspartame, was approved in 2002.
Before approving these sweeteners, the FDA reviewed more than 100 safety
studies conducted on each sweetener, including studies to assess cancer risk. The
results showed no evidence that these sweeteners cause cancer or pose any threat
to human health.
Cyclamate
113B
Early studies showed that cyclamate in combination with saccharin caused
bladder cancer in laboratory animal. Erring on the side of caution, the FDA
banned the use of cyclamate in 1969. After reviewing additional data, scientists
decided that cyclamate was not a carcinogen and that it did not enhances the
effect of cancer-causing substances. Later studies have failed to provide any clear
evidence of a link to cancer in humans. A food additive petition is currently on
file with FDA for the reapproval of cyclamate.
H
H
Okay, let's set aside all these studies for a moment. Let’s suppose that there is a
chance that sweeteners increase your risk of cancer. In that case, using no
sweeteners at all is definitely the safest course. But are you prepared to stop using
sugar? If not, then perhaps you should ask yourself if sugar is safer than
sweeteners!
41
Reducing calories can extend your lifespan and prevent many diseases, including
cancer, diabetes and heart disease. On average, sugar contributes about 10% of
your caloric intake so replacing sugar with sweeteners would immediately
provide a 10% caloric restriction. That alone would prevent or delay many
diseases including cancer. And it could extend your lifespan by 5% or 10%.
PROTEIN
17B
Protein is third major component of food and how protein affects your brain
depends on what else comes along for the ride. You can choose protein that
comes with saturated fats containing cholesterol or you can opt for omega-3 fatty
acids with far fewer calories. It’s not always easy to sort out healthy from
unhealthy protein, so here’s a simple guide.
Four legs: Beef and pork are high in saturated fats, cholesterol and calories.
Two legs: Chicken and turkey are moderate in saturated fats, cholesterol and
calories.
No legs: Fish are low in saturated fats and cholesterol with moderate calories
and often high in omega-3 fatty acids.
What are legs? Plant proteins are generally low in saturated fats, cholesterol
and calories.
Whatever you eat, you want to feel satisfied afterwards. Some foods satiate
hunger better than others, leave you feeling full and less likely to go in search of
unnecessary protein and all the fats and sugars that accompany them. Your gut
has stretch sensors and receptors that tell your brain when your stomach and
intestines are full, but if any of them are not engaged, they send a default message
to your brain that says, "I'm still hungry".
Glycemic index (GI)
57B
Foods that are low on the glycemic index satiate hunger best. The glycemic index
(GI) is a measure of how quickly food raises your blood sugar. The carbs in low GI
foods are broken down into glucose molecules more slowly and so they provide a
steadier supply of energy to your brain. The stabilization of blood sugar levels
really does improve the quality and
duration of intellectual performance.
42
Dietary fiber from low GI foods is associated with higher alertness and less stress
whereas poor blood sugar control is associated with lower scores on memory tests
in infants, adults and the elderly.51
High GI foods cause blood sugar to rise very quickly:
•
•
•
•
•
•
white bread
most breakfast cereals
most baked items (cookies, muffins)
most white rice
potatoes
watermelon
Low GI foods stabilize blood sugar and keep the supply steady:
•
•
•
•
most fruits and vegetables (except potatoes and watermelon)
dark fiber-rich whole wheat bread
brown rice
yoghurt
So smarten up! Eat more omega-3 and less omega-6, learn how to prepare
delicious sea foods and take out a little insurance with EPA and DHA
supplements. You don’t want to eliminate all fats and sugars from your diet
because a small amount of fat, protein and carbs slows absorptions, lowers the
glycemic index and leaves you feeling satisfied. A hamburger with fries and a cola
is the opposite of what you need. A tasty salad of assorted greens, a sprinkling of
tuna or crushed walnuts with a little olive oil is a neuron-friendly lunch that will
definitely help you save your aging brain.
~
43
CALORIC RESTRICTION
3B
"When the waitress asked if I wanted my pizza cut into four or eight slices,
I said, 'Four. I don’t think I can eat eight.'" ~ Yogi Berra
If what you eat determines how fast your brain ages, does how much you eat also affect
your brain? Yes it does. A burger with fries and a soft drink contains anywhere from
1000 to 2000 calories, sometimes more. Depending on your weight and sex, if you are
over 35 years old that single meal contain 60% to over 100% of your recommended
caloric intake for the entire day. And guess what! You’re going to be hungry again very
soon.
Wait a minute, we’ve already seen that healthy food choices reduce caloric intake! We’ve
already switched to fish and salads. Are we supposed to starve ourselves as well?
Actually, no. Caloric restriction may sound like a harsh regimen of near starvation, but in
practice it is fairly simple to achieve and it won’t leave you feeling hungry all the time.
Besides, if you can reduce your total daily caloric intake by 10 to 30 percent, indications
are that you can significantly slow down the aging of your brain and reduce your risk of
dementia and Alzheimer’s disease.
Caloric restriction (CR) in animal models extends lifespan by 10% to 50% and greatly
reduces the incidence of cancer, heart disease, stroke, diabetes and other diseases. In
people, CR directly affects the brain by improving memory, reaction times and balance. It
improves your ability to learn (Long-Term Potentiation), the growth of NMDA
neurotransmitter receptors (N-methyl D-aspartate), glucose production for brain energy
and resistance to neurodegeneration.
CR has been found to protect neurons by decreasing free radical production (oxidation)
and cell death by apoptosis (cell suicide) and toxins. It is associated with lower fasting
levels of blood sugar and insulin on one hand and with increased sensitivity to insulin on
the other. It lowers cholesterol, triglycerides and bad LDL while increasing good HDL.
Perhaps that is why it seems to reduce the risk of diabetes, cardiovascular disease and
stroke.
Nonetheless, CR is not for everyone. If you are young, pregnant, in ill health or suffering
from anorexia or bulimia, CR is not recommended. Extreme CR, more than 30% calorie
reduction, borders on starvation and poses a potential health risk to anyone.1,2 Moderate
CR up to 20% involves choosing low calorie options rather than going hungry. It requires
some knowledge and self-discipline but it is safe and do-able.
44
FIRST EXPERIMENTS IN CR
18B
Almost 100 years ago, Thomas Osborne found that two thirds of his rats died within 2 yrs
on a normal diet, but four female rats on a CR diet lived much longer. As other females
became menopausal, they continued to breed and gave birth to 3 to 6 litters each of
healthy pups all as lively as those of young mothers.
Osborne knew he couldn’t draw firm conclusions from an experiment with only four rats,
but he did think the observation was interesting enough to publish in the journal
“Science” founded a few years earlier by Thomas Edison. In his article, Osborne said, “it
appears as if the preliminary stunting period lengthened the total span of their life.” 3
In that same year, J. Northrop extended the lifespan of fruit flies by restricting their food
intake during the larval stage. Since then, CR results have been replicated in many other
species. On a CR diet, spiders average 50 to 100 days of life while those on CR average
90 to 139 days. Guppies on a normal diet live on average from 33 to 54 month but
average 46 to 59 months with CR. Rats extended their lifespan from an average 23 to 33
months to an average of 33 to 47 months.
Long term CR studies are still underway in rhesus monkeys with an average lifespan of
25 to 30 years. Results so far show improvements in several biomarkers of aging: lower
fasting glucose and insulin levels, lower body temperature, lower body fat and higher
levels of memory boosting DHEA (dehydroepiandrosterone).
It’s too soon to claim that CR has provided a survival advantage, but these monkeys have
also experienced a lower incidence of chronic diseases like cancer, cardiovascular
disease, diabetes, ulcers, cataracts and kidney failure.
HOW MUCH CR?
19B
In animal studies, every 2% reduction in total calories results in about a 1% to 2%
extension of lifespan. So theoretically, reducing calories by 20% offers a 10% to 20%
extension in lifespan. Obviously there are limits. A 100% reduction in calories drastically
reduces life expectancy to a few days. But at 50%, CR begins to extend lifespan. Even
more dramatically, CR starts to prevent diseases such as cancer, stroke, and heart disease.
In CR animals, these diseases occur at only a fraction of the rate found in control animals.
45
The Okinawa study
58B
There are very few long-term studies of the effects of caloric restriction in humans.
However, on the island of Okinawa, in southern Japan, one experiment has been
underway for many decades. In Okinawa, more people live beyond 100 years than
anywhere else. The rate of stroke, cancer, dementia and other age-associated diseases is
among the lowest in the world. Several factors may contribute, but caloric restriction
appears to be one of the most important.
Bradley Willcox and Craig Willcox published many scientific articles and two books
describing their study of Okinawa’s population.4 They also reviewed earlier studies from
the Japan National Nutrition Survey published in 1972 and cited these revealing statistics:
Okinawan school children consumed only 62% of the calories of other
Japanese school children.6
Okinawa’s adult population consumed only 83% of Japan’s average caloric
intake.
Death rates from heart disease, cancer and cerebral vascular disease were
only 60 to 70% of Japan’s average.
Mortality rate from all causes in 60 to 64 year olds was half that of other
Japanese.7
The dietary and phenotypic data for septuagenarians and centenarians
was consistent with CR.
They had an ‘energy deficit (fewer calories) for most of their lives right up
to the late 1960s.
They ate 11% fewer calories (approximately 1,785 calories per day) fewer
than recommended for maintenance of body weight.8
Their traditional diet of green leafy and yellow root vegetables, sweet potatoes and soy
with small amounts of fish and meat was full of nutrition and high in antioxidants and
vitamins. Those over 70 years of age who ate calorie restricted diets until at least middle
age had higher memory-boosting DHEA levels than age-matched Americans on a regular
diet.9,10,11,12
Relative Lifespans
1995
Okinawans
Average lifespan
83.8
Maximum lifespan
104.9
46
Japanese
82.3
101.1
Americans
78.9
101.3
In Okinawa, the mortality rate for age-related diseases is extremely low compared to
other Japanese or Americans.13,14 Even in old age, life expectancy in Okinawa is the
longest in Japan and possibly the world. Women from age 65 can expect to live another
24.1 years and men another 18.5 years. This compares to 22.5 and 17.6 years for aging
Japanese and 19.3 and 16.2 years for similarly aged Americans.15,16,17
Can you get the same benefits from CR? Bradley and Craig Willcox think so. According
to them, current studies of apes, who share over 95% of our genes, are looking positive.
They also point to 70 years of studies suggesting that CR is an “extremely ancient and
very important survival mechanism”. CR is strongly conserved from yeast to mammals
and “as such, it would be unusual if it did not work in some positive capacity in humans
as well.”
Many people have agreed to undergo CR for short and longer-term studies. They too
experience the dramatic changes in physiology and shifts in metabolism similar to other
animals. If the pattern holds, a 10 to 20% calorie reduction could lead to a surprising 10%
to 20% increase in lifespan for humans.
Remarkably, Okinawans consumed only 11% fewer calories than recommended for
people of their weight and activity levels (based on the Harris-Benedict equation). By
any measure, this is a mild CR regimen and yet older Okinawans gained an additional 6%
or 1.3 years survival time from age 65 versus other Japanese and an additional 20% or
3.6 years survival time versus Americans.
Most importantly, aging Okinawans not only lived longer, they lived healthier and were
largely free of disability and disease in old age.18 If you live in the USA and survive to 85
years of age, your risk of dementia is 25% to 30%. If you practiced CR like the
Okinawans, your risk would be about 15%. 19
HOW DOES CR AFFECT YOUR BRAIN?
Explaining exactly how CR slows down aging and protects against age-related disease is
difficult. Theories abound, but most of CR's beneficial effects seem to involve decreasing
the activity of ROS (reactive oxygen species) while increasing the production of
antioxidants. Many experiments are underway to help us understand the molecular
mechanics of CR and this brief review of recent experiments provides a tantalizing
glimpse of CR at work.20,21
CR in rats completely prevents age related deficits in long term potentiation, the
signal transmissions that are the basis of learning and memory.22
47
CR in rats and mice increases the number of newly generated neurons in the
dentate gyrus, an area in the hippocampus associated with new memories and
neurogenesis in humans.23,24
CR enhances neurogenesis and neurotrophin expression (growth and survival
factors) in the hippocampus of adult mice.25
CR promotes BDNF (brain-derived neurotrophic factor) synthesis required for
neurogenesis in the basal ganglia and hippocampus of adult mice.26
CR significantly counteracts DNA fragmentation, a specific marker of apoptosis
in the cerebral cortex of aging rats.27
CR promotes neuronal survival against naturally-occurring apoptosis by
restoring an enzyme critical to DNA repair.28
CR preserves the shape and density of dendritic spines on neurons, compared to
a 38% loss in controls.29
CR maintains both motor coordination and learning compared to
controls.30,31,32,33
CR in older rats improved motor learning correlated with improved
neurotransmitter function.34
CR AND AGE-RELATED DISEASE
20B
Caloric restriction may delay the normal aging of your brain, but can it protect you
against the most common neurodegenerative diseases like Alzheimer’s, Parkinson’s and
stroke? Here is a review of recent experiments that suggest that it can.35
CR And Alzheimer’s Disease
59B
•
In humans, CR reduces the risk of Alzheimer’s disease36 and may delay
and reduce symptoms.37
•
In mice, CR significantly protects against the damaging development of
amyloid plaques in the cortex and hippocampus caused by mutated
48
human amyloid-beta precursor protein (APP) in the short38 and longterm.39
•
CR gave greater protection to double transgenic mice with both a
mutated gene for the Alzheimer’s related protein presenilin-1 and the
gene for a beta-amyloid precursor protein.40
•
In triple transgenic mice (a mutation of APP, presenilin-1 and tau
protein) CR reduced the development of the Alzheimer markers for
amyloid-beta build up and tau protein phosphorylation. It also restored
some cognitive losses.41
CR And Parkinson’s Disease
60B
•
In a mouse model of Parkinson’s disease, CR reduced both the loss of
dopaminergic neurons and motor deficits.42
•
In a monkey model, CR gave similar neuroprotection and improved
motor activity.43
CR And Stroke
61B
•
CR has reduced brain damage and improved behavioral recovery in a
rat model of stroke.44 CR did not protect the neurons in the
hippocampus but afterwards, 3-months of CR did improve their
performance in spatial learning and memory while reducing stress
behavior.
•
CR rats, despite damage to hippocampal neurons from stroke, recover
better.45
3 KEYS OF CALORIC RESTRICTION
21B
Caloric restriction may seem like an effective way to live a longer and better life, but you
must be asking yourself how it’s possible to cut down on calories without feeling hungry
all the time. Besides, if you have to give up all your favorite treats, how will you ever be
able to enjoy your meals?
49
1 Food Substitution
62B
Actually, it’s not difficult to practice CR and enjoy your food too. The first key to a
sustained CR diet is food substitution. Let's assume you eat a typical diet of 2,000
calories per day and drink one Classic Coke per day. Consider this:
•
•
1 medium-size Classic Coke = 210 calories.
1 Diet Coke of any size = 0 calories.
Just switching to diet pop restricts your daily calorie intake by 10%.
If you change your preferences and buying habits you can generally achieve a 10%
caloric restriction across the board. Doing so will likely extend your lifespan by 5% to
10% and reduce your risk of cancer, heart disease, diabetes, stroke, dementia and many
other diseases. Burning off those same 210 calories by exercising would take about 40
minutes of cycling, 30 minutes of swimming or 20 minutes of running.
Low Calorie Food Substitutes
Regular food
Breakfast cereal, 30 g
Milk, 2%, 8 oz
Starbucks Grande
Vanilla Latte, 2% milk,
vanilla syrup
Hamburger, ¼ pound
(169 g)
Large French fries (154
g)
Classic Coke, medium,
McDonalds
Tortilla, flour, 62g
Cheese, cheddar, 1 oz
Apple pie, slice, 180
grams
Jell-O, regular, 3.5 oz
Total calories
Calories
100
130
250
410
500
210
160
114
420
70
2364
Substitution
Fiber One cereal, 30 g
Almond milk, 8 oz
unsweetened, Blue Diamond
Starbucks Grande Skinny
Vanilla Latte, non-fat milk,
sugar-free vanilla syrup
Salmon, wild, 3/4 cup (168 g)
Calories
60
40
Cottage cheese, non-fat, 1 cup
(145 grams)
Diet Coke
123
Tortilla, low-carb, 62g, La
Tortilla Factory
Cheese, cheddar, non-fat 1 oz
Apple, 1 medium 3" diameter,
180 grams
Jell-O, sugar-free, 3.5 oz
80
50
130
180
0
45
95
10
763
Here are some examples of easy ways to restrict calories by substitution. This doesn't
mean portion control - they are all the same amount of food. If you eat food in the left
column, you are likely gaining weight. If you eat the alternative food in the right hand
column, you can eat twice as much and still be caloric restricted!
2 Caloric Density
63B
The second key to a sustained CR diet is to understand caloric density. People need about
2 to 3 pounds of food every day to avoid feeling hungry. In America, those 2 or 3 pounds
are usually loaded with extra calories. The average American consumes far more calories
every day than is necessary: men 2,666 calories and women 1,877 calories.
If the average person cuts down their calorie intake to 2,000 calories per day, they can
achieve a 25% caloric restriction, but one difficulty that American shoppers encounter is
making sense of the information on food labels. The use of grams is scientifically
accurate but even a conscientious calorie counter can have trouble converting from metric
to pounds. Doing the conversion in your head can get confusing. There’s a simpler way
to reduce your calories and feel sated without doing the math.
Simply start with healthy food choices and the calories will take care of themselves. For
example, many of us are happy with 2 pounds of food, but if you need 3 pounds of food
to feel satisfied then make sure you buy food that contains about one calorie per gram,
which is roughly 1400 grams. Many foods have less than one calorie per gram and you
can eat as much of these foods as you want:
•
•
•
•
•
•
•
•
Vegetables (you have dozens of options here)
Fruits
Soups (clear broth not cream-based)
Cottage cheese
Tofu
Low-fat yoghurt
Most fish (baked, boiled, or stir fried. Not deep fried)
Sweet potato (yam) and purple yams.
If you eat 3 pounds of these foods every day you would consume about 1400 calories per
day and, believe me, you will feel stuffed. If you tried to eat 2000 calories worth of items
on this list you would have to eat around 4.5 pounds of food (2,000 grams x 2.2
pounds/gram = 4.4 pounds). That's way more what most people can eat.
It may take time for your taste buds to adjust, but there are ways to make new foods taste
good. Sprinkle fresh raspberries or sliced apple, some non-fat feta, a little olive oil or
some balsamic vinegar on a salad. Try a bowl of blueberries and cottage cheese as a
snack. Stir fry some veggies and tofu in
olive oil, throw in some green onion and
51
mushrooms and add some interesting spices. There are tasty yet healthy dips with a
caloric density around 1.0 that you can use to add extra flavor.
3 Glucose Delivery
64B
The third key to caloric restriction is glucose. You need glucose to make your brain
function effectively, but you want to deliver that glucose at a steady rate over several
hours, not minutes. Otherwise, high insulin levels in your blood cause the liver and other
tissues to remove sugar quickly and convert most of it to fat. That leaves you hungry
again within a couple of hours.
Poor food choices have a high caloric density – from 2.5 to 3 or higher calories per gram.
Foods that are white, like bread, rice, pasta, potatoes, simple sugars in soft drinks, bagels,
muffins, crackers, donuts and cookies deliver sugar too quickly and make your blood
sugar and insulin levels spike. Eat them in small amounts only when you need a shot of
glucose to get your brain working and even then, mix them with protein or a little healthy
oil to slow their absorption.
Instead, eat foods low in saturated fat but plenty of beneficial omega-3 fatty acids
are yams (sweet potatoes), brown rice, oatmeal, brown breads, non-white pasta,
salmon and tuna. Better choices like wheat bread, which has a caloric density of
1.1, break down more slowly than white versions. Salmon and tuna are a good
substitute for meats with a lower caloric density of around 1.8.
Caloric restriction does not have to be severe, tasteless or painful. I know from
personal experience that it can be a pleasant, tasty adventure. After awhile, the
idea of eating a burger with fries will make you shudder. You need a good brain to
make good choices. So cut back on the calories, eat right and save your aging
brain.
52
53
ANTIOXIDANTS
4B
If I'd known I was going to live so long, I'd have taken better care of myself. ~ Leon Eldred
Oxygen! It rusts your brain as surely as it rusts your car. In 1956, a famous and very
influential paper by Denham Harman first proposed that organisms age because of
damage caused by free radicals.1 In 1972, Harman extended his free radical theory of
aging by pointing to mitochondria as the critical source of the problem.2
Mitochondria are little factories – they combine oxygen with sugar to produce energy in
the form of ATP. Those ATP molecules (adenosine triphosphate) attach to proteins
(usually enzymes) like a battery pack and provide the energy to get things done.
Your body cycles through its own weight in ATP molecules everyday. The chemical
reactions responsible for this energy transfer (dephosphorylation and oxidativephosphorylation) are not always neat and tidy. Sometimes, electrons get lost in the
process and combine with other molecules such as oxygen. When they do, they create
free radicals like hydrogen peroxide and hydroxyl, which are linked to numerous
diseases.
If mitochondria are factories, then free radicals are toxic waste. Free radicals, also known
as reactive oxygen species or ROS for short, have at least one unpaired electron, which
makes them chemically unstable and highly reactive. That’s a problem because
mitochondrial DNA is located near the inner membrane where much of this chemical
activity takes place. What’s more, mitochondria have primitive DNA repair mechanisms
so they are highly susceptible to damage from ROS.
Damage to mitochondrial DNA can be the start of a vicious cycle leading to excessive
ROS and even more damage to proteins, membranes and DNA of both the mitochondria
and the cell’s nucleus. The oxidative stress caused by ROS appears to be a factor in
Parkinson's and Alzheimer's disease.3,4,5,6
Your cells try to protect themselves by producing antioxidant enzymes like superoxide
dismutase (SOD), catalase, alpha-lipoic acid and co-enzyme Q. These naturally occurring
proteins break apart free radicals and then try to build stable oxygen molecules out of the
pieces. Any left-over electrons are passed along from one antioxidant to another like a
hot potato - "I don't want it! Here, you take it."
Antioxidant supplements are growing in popularity and perhaps you already take
vitamins A, C and E. After all, if a few antioxidants are good, aren’t more likely to be
better? The answer is yes and no.
54
DO ANTIOXIDANTS EXTEND LIFESPAN?
22B
In experiments with yeast, worms, fruit flies and rodents, antioxidants have dramatically
extended lifespan. William Orr and Rajindar Sohal at the Southern Methodist University
in Dallas created transgenic fruit flies with three copies of both the superoxide dismutase
gene (SOD1) and the catalase gene.7 Compared to normal fruit flies they suffered less
oxidative damage, had a higher metabolic rate, were more physically fit in old age and
lived up to 30% longer.
Tony Parkes at the University of Guelph in Canada created transgenic fruit flies that
over-expressed SOD1 specifically in motor neurons. Compared to control flies, these
transgenic flies had greater resistance to oxidative stress and lived up to 40% longer.8
These findings have implications for people struggling with Lou Gehrig's Disease. ALS
(amyotrophic lateral sclerosis) is the same disease affecting the famous physicist Steven
Hawking. In humans, the cause is a mutation in the SOD1 gene linked to the lifeshortening loss of motor neurons in the brain.
Bernard Malfroy and Susan Doctrow at Eukarion in Bedford, Massachusetts, developed
drug-like molecules that mimic the action of SOD1 and catalase in collaboration with
Simon Melov at the Buck Institute for Age Research, in Novato, California.9,10 They
tested their Eukarion SOD mimetics on roundworms (C. elegans) and discovered that
they increased the average lifespan by 44% and restored the lifespan of prematurely
aging worms to normal, an increase of 67% in life expectancy.
These results are promising, but nobody is entirely sure if altering ROS with
supplemental antioxidants has unforeseen side effects. It may be that we need ROS since
it is involved in cell signaling, although most of the signals identified so far are part of a
feedback loop telling your cells to initiate ROS clean up. But that is not the only question
mark.
Remember passing the hot potato? If we speed up the hand off of free electrons during
one phase of the oxidation cascade, we alter just one step in a series of transfers without
increasing the coping capacity of later stages. That’s like building a six-lane highway that
suddenly empties into a two-lane street. At first, traffic moves quickly but then it comes
to a crashing halt at the bottleneck. The same thing could happen to electrons in free
radicals.
That may explain why increasing the levels of certain antioxidants have been harmful
rather than beneficial in some experiments. For example, increasing the levels of
antioxidant Q10 actually shortened the lifespan of some animals. Paradoxically, doing the
exact opposite and lowering the amount of the antioxidant superoxide dismutase
55
increased the lifespan of roundworms.11 So getting the right amount of antioxidants
seems to be very important.
In animal experiments, too much anti-oxidant can have adverse side effects that
overwhelm any benefits. When testing drugs on humans, finding a beneficial dosage that
minimizes side effects is a challenge often faced during clinical trials. Getting the right
balance matters.
CAN ANTIOXIDANTS SAVE YOUR BRAIN?
23B
Following Eukarion’s success at using antioxidants to mimic the small-molecule SOD to
extend the lifespan of worms, the company teamed with Ruolan and Ingrid Liu at the
University of Southern California to see if two new SOD mimetics (EUK-189 and EUK207) could reverse age-related learning disabilities in older mice.12
Mice experience a significant loss of memory and learning ability between 8 and 11
months of age. Untreated, their learning and memory deficits correlate with increased
oxidative damage to proteins, lipids and nucleic acids in the brain. When treated with
high doses of Eukarion’s mimetic antioxidants for 28 days they experience a near
reversal of learning and memory loss.
Unexpectedly, low doses had better results completely reversed protein oxidation and
reduced lipid peroxidation by 50%. They also significantly reduced the oxidization of
DNA and RNA. This is evidence that synthetic molecules of low molecular weight can
function like superoxide dismutase and catalase to improve cognitive performance and
decrease oxidative stress, albeit in middle-aged wild-type mice.
A follow-up study in 2008 by the Neuroscience Program at the University of Southern
California looked at the effects of these SOD mimetics in older mice, at lower doses and
for longer periods of time. Over the course of 6 months, aging control mice lost a
significant degree of learning and memory ability which correlated with increased
oxidative damage to proteins, lipids, and nucleic acids in the brain.
Meanwhile, old mice treated with SOD mimetics retained their learning and memory
capabilities. Again, the synthetic antioxidants significantly reduced damage to lipids,
DNA and RNA while reducing ROS.
56
Effects of EUK-189 or EUK-207 on ROS Concentration
Effects of EUK-189 or EUK-207 on Lipid Damage
Effects of EUK-189 or EUK-207 on Nucleic Acid Damage
These and other studies suggest that antioxidants not only provide an aging brain with
protection against decline, but can actually improve learning, memory, reaction time,
balance and coordination.
57
CAN ANTIOXIDANTS DEFEAT ALZHEIMER'S?
24B
Before you accept that antioxidants are an acceptable treatment for aging brain cells and
that they can fend off dementia, you might want to be certain that ROS really is at the
root of the problem.
In 1906, Alois Alzheimer autopsied a patient with severe memory loss and found the
entire brain filled with what looked like wads of old chewing gum inside the neurons and
matted hair between them. Those plaques and tangles were caused by two proteins that
dominate the brains of Alzheimer's patients - amyloid beta forms the plaques and tau
forms the tangles. Both contribute to the disease, but it's not clear if one or both are the
initial cause.
In 2004, Jeffrey Cummings summarized the current knowledge of amyloid beta and
Alzheimer’s for the New England Journal of Medicine:
•
•
•
•
•
Amyloid works in the synapse where the met32 version of amyloid beta
promotes ROS. An excess of one form of amyloid beta, called amyloid beta
42, is closely linked to Alzheimer's.
Mutations in the amyloid precursor protein lead to early-onset Alzheimer’s.
All known mutations in other genes associated with Alzheimer’s increase the
production of amyloid beta.
Transgenic mice that produce human amyloid precursor protein have learning
and memory deficits and their brains have plaques similar to Alzheimer’s.
The apolipoprotein E4 allele (a major risk factor for Alzheimer’s) accelerates
the deposition of amyloid.14
So what is the connection between amyloid beta and oxidative stress? Many studies of
Alzheimer’s disease link the activity of amyloid beta to the production of ROS. They also
show that increased oxidative damage in Alzheimer’s decreases polyunsaturated fatty
acids (omega 3) and promotes Advanced Glycation End products (AGE), aging factors
that affect every cell and molecule in your body.15,16,17
Oxidative damage appears to be one of the earliest signs preceding the formation of
plaques and tangles and it correlates with increased levels of amyloid beta in humans and
transgenic mice with the same clinical symptoms, disease progression and memory
impairment. In transgenic mice, the expression of both amyloid beta and presenilin 1
(required for memory) are down-regulated, the same memory-associated genes that are
down-regulated in the cortical tissue of Alzheimer’s patients.
In other studies, the levels of antioxidants are lower in patients with Alzheimer’s and
those with mild cognitive impairment. In some cases, ROS has caused neurons to
58
degenerate and die although immunization with antioxidants aimed at beta-amyloid has
removed plaques and restored memory.
It’s encouraging to note that epidemiologic studies searching for patterns among human
populations have linked antioxidants to a reduced risk of Alzheimer’s disease.18 In many
studies, antioxidants, especially Vitamin E, do protect against neurodegeneration. In
clinical trials, they even appear to be effective for treating Alzheimer’s.
A 1997 article in the New England Journal of Medicine describes a two year, doubleblinded, placebo-controlled, randomized, multi-center trial of Vitamin E in 341 patients
with moderate Alzheimer’s. The primary outcome or success rate was measured in days
until death, institutionalization, lost ability to perform basic activities or severe dementia.
The outcome for patients treated with Vitamin E was 670 days compared to 440 days for
the placebo group. After 2 years there was no significant difference in cognitive function
between the two groups but vitamin E seems to have slowed the progression of the
disease.19
A review of several clinical trials concerned with antioxidants and Alzheimer’s
concluded that dietary antioxidants are associated with a lower risk for Alzheimer's
disease and suggested that people at risk for Alzheimer's or already in it’s early stages,
may benefit from supplementary antioxidants like vitamin E.20,21
They also pointed out that no clinical studies to date prove that antioxidants protect
against Alzheimer's. At best, the evidence is hopeful but not conclusive. Studies of larger
populations over much longer periods of time are needed.
The evidence does, however, support the theory that oxidative stress is involved in the
development of Alzheimer's and on that basis, using antioxidants to slow the advance of
the disease makes sense.22 Initial studies of alpha lipoic acid also show promising results
in cases of mild dementia and Alzheimer’s, but larger studies will be necessary.23,24
WHICH ANTIOXIDANTS TO CHOOSE?
25B
Thousands of studies have examined anti-oxidant effects in-vitro and in-vivo, in both
animals and in humans. The fear that long-term use of antioxidants could be toxic
appears unfounded. In fact, sustained treatment with antioxidants has proven consistently
more beneficial than harmful. The question is which ones to choose and how much to
take.
59
Top 20 Antioxidants
Rank Food
Service Size
1
Small Red Bean
½ cup dried
2
Wild Blueberry
1 cup
3
Red Kidney Bean
½ cup dried
4
Pinto Bean
½ cup
5
Blueberry
1 cup cultivated
6
Cranberry
1 cup cultivated
7
Artichoke Hearts
1 cup cooked
8
Blackberry
1 cup
9
Prune
½ cup
10
Raspberry
1 cup
11
Strawberry
1 cup
12
Red Delicious Apple 1
13
Granny Smith Apple 1
14
Pecan
1 ounce
15
Sweet Cherry
1 cup
16
Black Plum
1
17
Russet Potato
1 cooked
18
Black Bean
½ cup dried
19
Plum
1
20
Gala Apple
1
(United States Department of Agriculture)
per Serving
13727
13427
13259
11864
9019
8983
7904
7701
7291
6058
5938
5900
5381
5095
4873
4844
4649
4181
4118
3903
The U.S. Department of Agriculture has published a top 20 list of foods that are rich in
antioxidants. More extensive lists are available online. In general, you should add beans
and berries and artichokes to your meals. That’s fine, but the amount of anti-oxidant you
can get from food is a tiny fraction of what you get by taking supplements. So which
supplements should you take?
SUPPLEMENTS
26B
The trouble with supplements is that they often contain less antioxidant that claimed.
Herbal supplements are very suspect because the amount of active ingredient in a plant
product depends on many factors:
•
•
the soil it grew in and the kinds of insects and parasites in the area
how much water, sun and fertilizer it had
60
•
•
•
when it was harvested
how it was processed, stored and shipped
how long it has been on the shelf.
It’s hard to know what you are buying. And it’s very difficult for researchers to make
evaluations in clinical trials.
The Lowdown on Ginkgo Biloba
65B
Today, the most widely-used herbal treatment for restoring memory, learning and
alertness is Ginkgo Biloba, a staple of traditional Chinese medicine for centuries. In
Germany, where it has been approved for dementia treatment, Schwabe Pharmaceuticals
manufactures an extract of Ginkgo called EGb 761. The typical dose used in many
experiments is 120 milligrams containing:
•
•
flavonoids - a large group of natural antioxidant plant products
terpenes - the active ingredients in catnip and marijuana.
Ginkgo and Animals
114B
Relatively few reports examine ginkgo in animals. In a 1991 study, young adult mice
trained to press a lever to receive food, were able to learn the task slightly more quickly
than control mice after four to eight weeks of treatment with ginkgo. Other reports found
that ginkgo reduced stress in lab rats, which may have influenced learning. One study
directly compared ginkgo in rats to other treatments and found the effects were about half
of that seen with other drugs.
Ginkgo and Humans
115B
In humans, dozens of clinical trials have examined the cognitive effects of ginkgo.
Unfortunately, there are several reasons why their results are unconvincing. Most of the
experiments involved people with only mild to moderate cognitive impairment. They
tested learning and memory but not attention, motivation or anxiety. Finally, most of the
people selected were tested long after they began using ginkgo, typically several months
later, so cognition prior to using ginkgo was unknown.
Any of these factors can introduce bias, especially if people with good cognitive abilities
are more likely to take ginkgo. For example, individuals with higher scores on memory
and learning tests may have read and understood more fully the articles suggesting that
ginkgo might help them. Then again, maybe they were simply better at remembering to
take the pill. Researchers need to give tests both before and after the use of ginkgo
61
otherwise their experimental results are suspect.
Barry Oken at Oregon Health Sciences University looked at more than 50 ginkgo trials
involving subjects with mental impairment. He found only four that met the basic criteria.
of sufficient characterization of Alzheimer's diagnosis, standardized ginkgo extract and
placebo controlled, double-blind study to avoid bias and data contamination.
All 50 of those studies showed that Alzheimer's patients taking ginkgo performed better
on various cognitive tests than patients on a placebo. Standardized tests of attention, short
term memory and reaction time show that ginkgo provided an average improvement of
10% to 20%. In some cases, ginkgo slowed cognitive decline. In others it actually
improved performance.
These results are similar to those of the drug donepezil, currently the most prescribed
treatment for Alzheimer's. Donepezil inhibits the breakdown of acetycholine, the
neurotransmitter that sustains attention and promotes neural plasticity in the central
nervous system.
In contrast, patients with mild or moderate dementia who took part in a recent, large and
well-controlled clinical trial sponsored by Schwabe, showed no "systematic and clinically
meaningful effect of ginkgo" on any of the cognitive tests used.25
Ginkgo Studies in Healthy Subjects
116B
Fewer studies still have examined the effects of ginkgo on healthy young adults. In a
small study during the mid-1980's, Ian Hindmarch from the University of Leeds, gave a
battery of tests to eight healthy people aged 25 to 40, after they took the ginkgo extract
EGb 761. The highest dose at 600 milligrams improved performance only in a short-term
memory test. Another study reported that people who took ginkgo performed better on
tasks involving attention than those taking a placebo. One study showed improvement in
memory among those aged 38 to 66 who were treated with a combination of ginkgo and
ginseng.
Is ginkgo as effective as glucose?
117B
Glucose is the main source of energy for your brain. A drop in blood sugar impairs your
self-control and decision making whereas a little extra sugar now and then gives you a
temporary psychological boost. In a short- term memory test given to young adults and
healthy seniors, glucose enhanced performance by 30% to 40%. In patients with
Alzheimer's, the improvement on similar tests was almost 100%.
62
Those results are much greater than the 10% to 20% improvement reported for ginkgo in
similar studies. It’s tempting to jump to conclusions based on such statistics but in reality
the design of those experiments was so different that comparisons are misleading. For
example, the experiments using glucose were short-term memory treatments whereas the
ginkgo tests were longer term. The glucose experiments also compared patients before
and after; ginkgo tests did not.
Is Ginkgo Safe?
118B
If you take 120 to 240 milligrams of ginkgo per day, health risks are considered minimal.
You should be aware that some people have suffered complications while taking ginkgo
such as blood clots between the skull and brain (subdural hematomas), gastrointestinal
problems, nausea and vomiting. Some experienced milder issues like increased
salivation, decreased appetite, headaches, dizziness, tinnitus and skin rash.
The truth is that ginkgo has an efficacy profile similar to most drugs. Take too little and
it’s ineffective. Take too much and it can be harmful. Drugs that improve memory have a
dose-response curve like an inverted U. “Only intermediate doses improve memory; low
doses are ineffective, and high doses may actually impair memory.” 26
Large doses of ginkgo may cause a sudden drop in blood pressure (orthostatic
hypotension) that leads to dizziness when you stand up too fast. That may not sound too
serious but it does indicate that ginkgo interferes with important biological mechanisms.
Still, the overall incidence of serious adverse reactions to ginkgo is relatively low. For all
we know, it is safe in moderation, but we have no idea at all how ginkgo reacts in
combination with other drugs or supplements.
Coenzyme Q
66B
Coenzyme Q (ubiquinone) is sold as an antioxidant to treat certain cardiac conditions
although many people buy it as a life-extension supplement. As with other supplements,
it is difficult to know for certain if Q10 is beneficial or harmful largely because it is
involved in so many complex biochemical interactions.
Coenzyme Q accepts electrons and transports them along the mitochondrial Electron
Transport Chain (ETC). This occurs inside the inner membrane, the factory area where
ATP is produced. Q is important because any electrons that escape from the electron
transport chain generate superoxide, a heavyweight among free radicals.
Q Mutants
119B
Different species tend to produce Q with a
side chain that varies in length from 6 to 10
63
subunits, hence Q6, Q7, Q8 in bacteria, Q9 in worms and Q10 in humans.
Worms have an enzyme responsible for the final step in the making of Q. Mutant worms
lacking the Clk-1 gene, which encodes for this enzyme, are unable to synthesize Q9. You
might expect the inability to produce this important antioxidant would have a devastating
effect on the health of these worms, but it doesn’t. In fact, Clk-1 mutants live twice as
long as wildtype worms.
In worms, there are at least 8 genes participating in Q9 biosynthesis and when the effects
of these genes were examined using RNA interference (RNAi), suppressed gene
expression resulted in:
•
•
•
•
lower Q9 levels
lower superoxide production in the electron transport chain
less damage to macromolecules in mitochondria
extended lifespan.27
Apparently Q9 is not very efficient. Its role in the electron chain results in an excess of
electrons that ultimately increases the number of negatively charged superoxide anions
by 30-50%. Worms might be better off without it.
What about humans? Is it wise to put more Q10 into your body? We don’t know. But
what we do know this - the superoxide produced by Q10 is eventually de-activated by
alpha lipoic acid. So taking Q10 as a supplement without increasing lipoic acid is likely
to increase damaging superoxide levels.
Alpha Lipoic Acid
67B
Alpha lipoic acid is an anti-oxidant with proven neuroprotective benefits in multiple
animal studies. It has reversed memory impairment and oxidative damage in aged mice.
It has also been effective in many double-blind, randomized, controlled clinical trials in
humans and has a very good safety profile with side effect rates similar to a placebo.
Because it is soluble in both fat and water, it reaches all parts of the neuron and
mitochondria where it re-activates other antioxidants like vitamins A and C and coenzyme Q.
One criticism of Alpha lipoic acid is that it has a relatively short half-life, which means it
clears out of your body fairly quickly. Okay, its stay may be brief, but that doesn't mean
it’s not effective. After all, garbage collectors visit your house for only a few minutes
each week, but you are still glad they came by.
64
ACES
68B
In the 1980’s, ACES was a popularized combination of vitamins A, C and E plus
Selenium. In trace amounts, each of these is essential to good health, but they can be
toxic at higher levels. They are antioxidants in the sense that they play a part in redox
reactions where molecules gain or lose electrons, but their specific role in protecting
neurons needs more study. Vitamin E, as we have seen, is known to prevent ROS where
fat is oxidized, so it might also protect your cell membranes and sensitive mitochondria.
Folic Acid
69B
While we are on the subject of supplements, let’s look at folic acid, one of the most
popular anti-aging supplements on the market. Folic acid is not an antioxidant, in fact it’s
not even biologically active, but it is essential for forming new cells. Folic acid occurs
naturally in your body but only at minimal levels. A deficiency of folic acid can hamper
DNA synthesis and cell division, which is why the FDA approved folic acid as a
fortifying additive in bread, cereals and pasta more than ten years ago to prevent fetal
deformities and childhood diseases.
The findings of a 3-year trial published in The Lancet in 2007 noted that double the daily
recommended dose (800 micrograms) of folic acid improved short-term memory, mental
agility and verbal fluency among people over 50.28 Another study cautiously agreed that
long-term use of folic acid seems to have cognitive benefits for healthy seniors.29 These
studies were not focused on folic acid specifically and are by no means conclusive.
Some studies suggest that it’s too easy to overdose on folic acid, which could
compromise your health if you take folic acid supplements unnecessarily. Other studies
indicate that a little extra folic acid seems to be helpful in treating heart disease, stroke,
cancer and other conditions, but the findings are only preliminary.
Caffeine
70B
Caffeine is the most heavily used psychoactive drug in the world. The volume of caffeine
consumed in one day is said to be the equivalent of 1½ cups of coffee (150mg of
caffeine) for every man, woman and child on the planet. Americans average about 4½
cups of coffee each. You use this drug every time you have a sip of coffee, tea or soda
pop. Considering that the ritual and habitual consumption of caffeine as a daily
supplement has been a part of human culture for at least two thousand years, it’s amazing
how little we know about it.
Caffeine is not an antioxidant, but it does
have a knack of waking up your brain cells
65
and instilling a sense of revitalization. How does it do this? Scientists have long
hypothesized that cells accumulate some kind of ‘sleep substance’ during the day that
eventually reaches a level that triggers fatigue and slumber. This sleep substance could be
a by-product of energy production - the more energy your cells generate, the more sleep
substance is produced and the sleepier you get.
Adenosine
120B
In the search for a “sleep substance”, the most likely suspect so far is adenosine.
Adenosine is the A in ATP (adenosine tri-phosphate), the molecule your body uses to
store energy. When your cells need energy, they break the chemical bonds of ATP,
release captured phosphate molecules and reuse the energy that held them in place.
What’s left over is adenosine, which is known to block neuronal activity in the basal
forebrain. A microinjection of adenosine into this area of a rat’s brain induces sleep while
injecting an antagonist to block adenosine results in wakefulness.
All day long, while you are physically and mentally active, you consume energy from
ATP and pump out adenosine. Cells all over your body have receptors for adenosine.
Nerve cells have lots of adenosine receptors too. As adenosine levels rise, neural
signaling wanes because adenosine is a powerful inhibitor of neural transmission.
Eventually it’s time to recharge your ATP batteries and because adenosine acts like a
super-regulator overriding all other neurotransmitters, it shuts down your systems one by
one until you fall asleep.
When you are sleep-deprived, your brain grows additional adenosine receptors to make
you more sensitive to adenosine and therefore more likely to nod off. Those extra
receptors might be the molecular basis of ‘sleep deficit’ because as you become more
sensitive to lower levels of adenosine, you begin to sleep in longer than usual. What we
know for certain is that adenosine slows things down and caffeine speed them up.
Somehow, they are linked.
There are two types of adenosine receptors in your brain that operate in different areas
and produce different effects.
A1 adenosine receptors are abundant in your:
•
•
•
•
cortex, the area for solving problems, planning and complex memory
hippocampus, where memories form
cerebellum, responsible for coordinated movement
hypothalamus, the super-regulator of internal body functions.
A2 adenosine receptors are in the basal ganglia, the home of voluntary motor control.
66
When adenosine binds to A1 receptors on a neuron, it prevents signaling. At the
molecular level an A1 receptor opens potassium channels while closing calcium channels
and the membrane becomes hyperpolarized, which inhibits firing.
At least, that seems to be what happens. Neurons that have adenosine receptors can
themselves produce various neurotransmitters. It’s not always easy to determine if these
effects are due directly to adenosine or to the modulated release of dopamine, serotonin,
adrenaline, noradrenaline, glutamate or GABA (Gamma-AminoButyric Acid).
As for caffeine, it also binds to A1 receptors and, as far as we can tell, has the opposite
effect. It prevents adenosine from binding to A1 receptors and deactivates the A1
receptors by closing potassium channels and opening calcium channels. Now that the
membrane is less polarized it is easier for neurons to transmit signals. Thanks to caffeine,
the nerves in your thinking and memory areas, the cortex and hippocampus, keep on
firing.
Caffeine and Parkinson’s
121B
When adenosine binds to the A2A receptors in the basal ganglia it reduces motor activity.
Normally, dopamine binds to A2A receptors to stimulate movement, but people with
Parkinson’s have insufficient dopamine in this part of their brain. They need to be treated
with the drug L-Dopa, a pre-cursor to dopamine, which you may remember from the film
‘Awakenings’ with Robin Williams. About 2 percent of people over age 65 have
Parkinson’s disease, although it affects much younger people, including the actor
Michael J. Fox.
Caffeine also binds to A2A receptors and when it does it makes you want to stand up and
get moving. The Honolulu Heart Program, which studied Japanese-American men for 30
years beginning in 1965, showed that men who were not coffee-drinkers at the start of the
study were five times more likely to get Parkinson’s disease than men who drank large
amounts of coffee. Drinkers of moderate amounts of coffee were at lesser risk. The
results were replicated in two other studies (Nurses Health study and Health Professionals
Study) confirming that caffeine protects against Parkinson’s.
This evidence spurred the search for antagonists that bind selectively to adenosine A2A
receptors, but not to the more widespread A1 receptors leading to the development of
new drugs that improve symptoms of Parkinson’s in animals. Human clinical trials are
already underway.
Caffeine and Alzheimer’s
122B
Caffeine obviously has nootropic effects – it changes memory and learning. Not all of
theses changes are positive. Studies with
mice have found that long-term caffeine
67
consumption reduces neurogenesis in hippocampal neurons. In other words, it interferes
with long term memory and hippocampus-dependent learning.
Lab mice that take regular coffee breaks reduce their ability to learn and to form
memories.30 That’s surprising because caffeine injected directly into rat hippocampal
neurons in a test tube stimulates the growth of dendritic spines, which ought to improve
neural connections and memory. The effect is, however, short-lived.31
Caffeine, like most drugs, can seem helpful or not, depending on what you are looking at.
A 2002 review of epidemiological studies of caffeine and Alzheimer’s disease reached
the same conclusion. Overall, coffee intake seems to lower the risk of Alzheimer’s, but as
for memory and cognition, studies are few and results are inconsistent.32
In humans, one study shows that 100 mg of caffeine increases brain activity in the frontal
lobe (working memory) and the anterior cingulate cortex (attention) leading to higher
scores on memory tests. A different study found that caffeine impaired short-term
memory and made it difficult for people to recall familiar things that remained on the ‘tip
of the tongue’. These findings appear to conflict, but they are actually looking at different
kinds of memory. The first study tested the ability to stay focused. The second dealt with
unrelated memories that require some thought.33
As recently as 2009, caffeine reversed cognitive impairment and reduced amyloid-beta
deposits in aging Alzheimer's mice.34 Another study found that caffeine protects neurons
by binding to adenosine receptors, but the author notes that adenosine receptors are so
widespread and have an impact on so many cellular processes that acute treatment can
‘often produce diametrically opposite effects’.35
Are antioxidants and supplements worth the money you pay considering that you can't
know for sure that they work? It depends. After all, the cost of a little insurance seems
minor compared to the $100 billion spent annually to treat and care for American
Alzheimer's patients. Ask yourself how much you would pay to reverse Alzheimer's if
you were diagnosed with the disease tomorrow. Then think about the real cost of a
hamburger with fries and a cola.
If you want to stay younger and healthier and reduce your risk of dementia, skip the fast
food. Walk to your nearest farmers market and pick up some fresh vegetables and fruit to
go along with salmon for dinner. Maybe have a cup of coffee on the way, but get moving,
get thinking and save your aging brain. ~
68
STRESS
5B
Old age is no place for sissies. ~ Bette Davis
Stress can be stimulating. The stress you get from exercise or from encountering a novel
situation provides a healthy kind of tension that is good for your brain. The trouble is that
your brain is not built to cope with prolonged bouts of anxiety or depression. If your life
is full of stress then your brain will wear out and age faster.
Three hormones have a major impact on how fast your brain ages. The first is cortisol, a
response to stress that suppresses your immune system and increases blood sugar levels.
The second is DHEA (DeHydroEpiAndrosterone), a neurosteroid that regulates gene
expression, especially in males. The third is estrogen, the female sex hormone that turns
on a wide range of genes including those involved with sexual desire.
CORTISOL
27B
When our ancestors on the plains of Africa went down to the local watering hole only to
be surprised by a hungry lion, they would have experienced some stress. Even before
they were consciously aware of the situation, their senses would have informed the brain
of the danger and stress hormones would have triggered a cascade of emergency
signaling.
Everything essential to escape instantly sped up. Cortisol and adrenaline coursed through
their bodies. Heart rate and blood pressure shot up. Glucose and oxygen pumped into the
blood stream scrambling to reach muscles. Vision and hearing became acute. Memory
and recall sharpened “Did this happen before? How did I escape?” Learning improved
“Remember where this happened so I'm ready next time”. Anything not essential to
immediate survival stopped. The immune and reproductive systems quit and the bowels
let go as the digestive system shuts down.
This stress response can save your life - as long as it turns off afterwards. Unfortunately,
we have found ways to stress ourselves repeatedly with debilitating consequences.
Perpetual worry - about the boss, the mortgage, relationships, status, being late, our kids,
our parents, the guy who just cut in front of us – leads to a constant, stress-induced state
of "red alert". It’s not healthy and it does all sorts of damage to your brain.
In the short-term, a small dose of cortisol improves memory by increasing the levels of
69
glutamate, a neurotransmitter that activates neurons in your hippocampus where
memories are consolidated. In the long-term, too much glutamate over-excites your brain
cells and burns them out. For instance, it is excess glutamate that causes brain damage
after a stroke. It kills neurons.
Robert Sapolsky, my colleague at Stanford, wrote "Why Zebras Don't Get Ulcers", an
outstanding book on stress and stress-related diseases.1 Sapolsky did his graduate work
with Bruce McEwen at Rockefeller University who showed that cortisol floods into the
hippocampus, an area with a rich supply of cortisol receptors for rapid activation in times
of stress.2
Beginning in the 1980's, Sapolsky contributed to a series of critical discoveries with a
series of experiments on cortisol. He found that it accelerated aging of the hippocampus
even in young rats. Rats and monkeys with a poorly functioning hippocampus are less
able to switch off the stress response because the hippocampus is part of the feed-back
system that regulates and shuts it down. Older animals are more likely to have a poorly
functioning hippocampus, which traps them in a vicious cycle of extended stress and
rising levels of harmful cortisol.
It’s a mammalian thing. Aging rats, baboons and humans all have trouble turning off the
stress response. They also have higher levels of stress hormones in their blood, even
when nothing stressful is happening. Humans in their 70's and 80's often have increased
circulating stress hormones for no obvious reason, which probably contributes to high
blood pressure.
Many studies have shown that stress-level cortisol or stress itself accelerates damage to
the hippocampus of aging animals. In a test tube, depriving brain cells of oxygen triggers
a stroke and adding cortisol causes more neurons to die but removing cortisol allows
more neurons to survive. Cortisol has the same effect in rats after a stroke, more cortisol
kills neurons in the hippocampus while less cortisol allows more neurons survive.
So what’s happening? As Sapolsky sees it, everything relates to sugar and mitochondria.
We know that low blood sugar (hypoglycemia) drains the sugar supply away from
mitochondria. We also know that stroke and cardiac arrest cut off sugar and oxygen to
mitochondria. Uncontrolled firing of neurons, as in an epileptic seizure, also burns up
sugar needed by mitochondria.
Clearly cortisol diverts glucose away from fat cells and less essential cells and channels it
into muscle cells to help you escape from lions. At the same time, cortisol interferes with
glucose transport to neurons in the hippocampus, which makes the damage done by
stroke or cardiac arrest even worse.
Damage to the hippocampus is often the first sign of Alzheimer's disease and if you live
with constant stress the disease may occur sooner or get worse. A life of stress kills your
70
memory in two ways: by over-producing toxic glutamate and by inhibiting glucose
uptake by mitochondria. The neurons in your hippocampus are being poisoned and they
lack the energy to save themselves.
In their books, Sapolsky and McEwen suggest several ways to reduce stress. Many
books, websites, TV shows and magazine articles do the same. With plenty of
information available on the subject elsewhere, I’ll make only two observations.
First, the stress response evolved to support intense physical activity - fight or flight. It
makes sense that a good way to relieve stress would involve intense physical activity.
Beat up a pillow, hit a punching bag, go for a run - this is what the stress response intends
you to do. Why not do it?
Second, exercise protects your aging brain by stimulating the production of neurotrophins
like NGF (nerve growth factor) and BDNF (brain derived neurotrophic factor). Both
improve neuron survival and neurogenesis in the hippocampus. Simply going for a walk
induces these changes so if you are feeling stressed, just get moving.
DHEA SUPPLEMENTS
28B
DHEA and cortisol are steroid hormones produced by the adrenal gland.
Whereas cortisol suppresses the immune system, DHEA stimulates it. DHEA is
also a normally occurring ingredient necessary for making testosterone and
estrogen. Knowing only that much, you could easily assume that DHEA is a
natural foil for cortisol, which may explain why it has become such a widely-used
supplement.
Does it make sense to take a DHEA supplements? Sorry, there is no good answer to that
question. The use of DHEA as a supplement is controversial and despite marketing
claims is not supported by any rigorous evidence. On the other hand, a review of the few,
small clinical trials of DHEA concluded that supplements are neither beneficial nor
harmful to middle aged or elderly people.3
In the absence of large, long-term placebo-controlled trials, what do we really know
about DHEA? We know DHEA is a biomarker of aging as its production declines with
age.4 Shortly after puberty it begins to diminish and may drop to 5% of its original levels
in old age5 due to progressive atrophy within the adrenal gland.6 In contrast to cortisol,
which remains high and increases with age, DHEA becomes scarce causing an imbalance
between the two stress hormones.
71
In the Okinawa study of the world’s longest-lived people, both men and women had
higher levels of DHEA, testosterone and estrogen than Americans of the same age. As
Willcox puts it, "Measuring DHEA levels in people may be akin to counting tree rings
for trees".7 Show me your DHEA level and I can tell how old you are.
Many people take DHEA supplements to counter the effects of cortisol, but there is some
concern that as a precursor of estrogen it might increase the risk of breast cancer.
Fortunately, maintaining your DHEA levels with supplements is not your only option.
You have two alternatives: caloric restriction, which dramatically slows the rate of
DHEA loss, and exercise, which naturally increases DHEAS levels.8,9
In 2008, a Baylor University research team published a review of several studies
involving interactions between cortisol and DHEA and how they affect the immune
system in aging people. They concluded that DHEA supplements might be beneficial but
the most effective way to improve the balance of cortisol to DHEA is stress management
and acute exercise.10
In 2008, Maninger11 and colleagues summarized their finding of the neurobiological and
neuropsychiatric effects of DHEA by quoting the original report published sixty years
earlier:
‘‘Whether diandrone [DHEA] turns out to be of therapeutic value in psychiatric practice
remains to be seen. However, we appear to have at our disposal a chemical agent that
can exert a direct and prolonged action on the mental state” 12
The National Institute of Health recognizes that more research is needed and has
sponsored new studies of DHEA.
72
HORMONE REPLACEMENT THERAPY
29B
“The effects of estrogen are complicated and diverse and sometimes opposite...”13
Clinical trials demonstrate that estrogen protects the brain and promotes neurogenesis by
decreasing the risk and delaying the onset and progression of Alzheimer's disease. It may
even enhance recovery from stroke.14,15,16,17 In addition, there are animal studies showing
that estrogen improves neurogenesis, synaptic transmission and axonal sprouting, which
translates into better cell survival after stroke and better regeneration after injury.
The problem is this. Other animal studies, clinical trials and epidemiological studies have
reached the opposite conclusions by demonstrating that estrogen increases the risk of
dementia and cognitive decline.
A 2001 report describing the effects of hormone replacement therapy on cognitive
decline during the Baltimore Longitudinal Study of Aging found that it reduced the risk
of Alzheimer’s disease and protected against cognitive aging in postmenopausal women.
However, hormone replacement appeared to benefit only a few specific memory
processes. For instance, it protects against age-associated decline in figural memory and
is associated with better encoding, retrieval, and recognition of verbal material.
These findings agree with many other studies where hormone therapy improved verbal
recall and the ability to put names to faces. They are also in line with the only other study
of longitudinal memory where the previous use of hormone therapy helped maintain
verbal memory.18
Then, in 2009, an upset occurred when a randomized, double blind, placebo-controlled
clinical trial called WHISCA (Women’s Health Initiative Study of Cognitive Aging)
suggested that hormone therapy provides no cognitive benefits and may even do some
harm. 19
WHISCA was intended to measure the effects of a daily dose of 0.625 mg of conjugated
equine estrogens (CEE) on cognitive function on 886 non-demented, postmenopausal
women aged 65 yr and up who had previously undergone a hysterectomy. After 3 years
of hormone treatment these women had lower spatial rotational ability (mental pairing of
3D objects) and experienced no significant affect on other cognitive functions.
As it happens, these same women had already participated in WHIMS, a much larger
Women's Health Initiative Memory Study ending in 2004. This too was a rigorously
executed clinical trial primarily designed to see if estrogen replacement protects against
coronary heart disease in 7500 postmenopausal women aged 65 years or older. This study
was terminated abruptly when it became clear that women receiving hormone
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replacements were increasingly at risk for stroke. Results also showed that hormone
replacement increased the risks of dementia and cognitive decline.20
Case closed? Not yet. A recent re-analysis of WHIMS points out that the participants had
a mean age of 63 and that they were, on average, 12 years post-menopausal. This implies
that they were not representative of all women, never mind the general population. In
contrast, estrogen did prove beneficial in observational studies where participants
averaged 51 years of age and had begun hormone therapy before menopause. Clearly, the
timing of estrogen therapy is important.21
Does hormone replacement therapy affect brain aging or doesn’t it? Results vary
depending on the delivery route, the concentration, the ingredients and the treatment
sequence and, of course, the general health, sex and age of the patient.
Does estrogen have an impact on stress and the damage stress does to the brain? Almost
certainly, for it modulates your immune system and affects cellular inflammation. More
specifically, estrogen protects against cell death and stimulates the growth of new
neurons.
Many researchers believe that estrogen is neuroprotective despite apparently
contradictory evidence. Much of the confusion seems to be a result of comparing apples
to oranges in a well-intentioned search for meaningful patterns. Whether you are in favor
of estrogen therapy or not, you can find evidence to support your view.
MEDITATION, MINDFULNESS & DEPRESSION
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“…there is nothing either good or bad, but thinking makes it so.” Shakespeare’s Hamlet
Is stress all in your mind? Reports from cognitive therapists suggest that it is. We know
that aging brains are less able to cope with stress and are more prone to depression.
Prolonged stress and depression are closely related and both coincide with braindamaging levels of cortisol. Still, the idea that you can consciously turn off your
hormonal taps invites skepticism.
Practitioners of Mindfulness-Based Cognitive Therapy (MBCT) teach people who suffer
from bouts of depression to recognize and weed out negative thought patterns and
consciously establish positive thought patterns.
For best results, the process requires professional guidance and regular practice,
preferably over the course of a lifetime. So keep in mind that studies of MBCT in
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aging populations involve people who are new to the technique and whose brains are well
past their ‘best by date’.
A clinical trial ending in 2000 set out to teach 145 repeatedly depressed (but recovering)
patients to disengage from negative thoughts that contribute to anxiety and depression.
Patients were divided randomly into those who would continue to have treatment as usual
or treatment as usual plus MBCT training.
The study found that MBCT significantly reduced the risk of depression in patients with
3 or more previous episodes of depression (77% of the sample).22 Odd as it seems, it did
not help those with only 2 previous episodes, a result replicated by several other
researchers.23,24,25 Apparently three’s the charm.
Here’s something else to consider. MBCT trials provided measurable results that
depended on self-reporting - a subjective rather than an objective evaluation. Obviously,
more studies are needed. In the meantime, where is the harm in being more aware of the
impact of your thoughts and feelings?
John Teasdale, a co-developer of MBCT points out that understanding that your 'mental
events’ are not always a reflection of reality may help to derail the flight or fight process
and avoid its consequences.27 Helen Ma, a leading researcher says it best:
“Instead of reacting automatically and unconsciously to disquieting thoughts and
unwanted feelings you respond to them in a deliberate and skillful way.”28
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Mindfulness may or may not give you control of your stress levels, but that is also true of
supplements and hormone replacement therapies. Besides, self-meditation is unlikely to
have the same negative side effects as self-medication and if it helps you to cope with
stress it might just save your aging brain.
~
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EXERCISE
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If it weren't for the fact that the TV set and the refrigerator are so far
apart, some of us wouldn't get any exercise at all. ~ Joey Adams
There is a theory that running made our brains bigger. About 2 million years ago when
Homo Erectus arrived in Africa, they stood up to six feet tall, much taller than previous
human ancestors. Their bones have been found in regions that were hot, dry grasslands at
the time, suggesting that they may have been the first naked ape – losing hair but gaining
sweat glands over their entire bodies.
Why was that an advantage? Animals living in grasslands have a very limited ability to
dissipate body heat so they rest when the sun is hottest. Hunter-gatherers with no hair and
abundant sweat glands were able to chase their prey all afternoon until the animal
dropped from heat exhaustion.
According to this theory physical and mental effort evolved side by side. Chasing dinner
over open ground under the watchful eyes of hungry predators would have been a
stimulating exercise and no doubt it provided every incentive for Homo Erectus to plan
his strategies, design weapons and develop organized team work. Such heavy thinking
required a lot of energy and it’s possible that adding substantial amounts of meat to the
diet fueled the growth of larger brains, not to mention stronger legs.
It’s an interesting theory and there are good reasons to believe it is true. You usually
move around without much conscious effort but at the molecular level your brain is most
active when your body is moving. In fact, the mere notion of motion stimulates and
excites your brain.
Like Homo Erectus, we are designed to use physical and cognitive skills to hunt for food,
to recognize and predict danger, to learn where the lions are hiding and to find the safest
route home. We may be more mobile today, but we are far less active and it’s important
to remember that physical activity is a stimulus, not only for the parts of your brain that
control movement, but for every other part of it. Just standing up and walking around gets
your whole brain working.
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EXERCISE AND INTELLIGENCE
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Physical activity affects your mental ability in several ways.1 It speeds up learning and
information processing and improves spatial memory, reaction times and performance on
neuropsychological tests. At the same time it slows the rate of memory loss and reduces
the risk of cognitive decline and dementia.2,3,4,5
In studies of other mammals like rats and mice, exercise improves performance in
hippocampus-dependent tasks that require spatial memory, solving mazes and novel
object recognition.6,7 It also improves learning in aged rats as they figure out how to
escape the Morris water maze.8,9
Many human studies have examined the effects of physical activity on cognition in
healthy but sedentary elderly people. These tests varied in duration, intensity and type of
exercise over several days, months and years yet they consistently show that physical
activity improves cognition.10,11,12 Imaging studies support these finding and show
neurons waking up throughout the brain as exercise commences.13
By running on a treadmill, rats protect themselves against brain damage from stroke 14
and ensure that they recovery faster after brain injury.15 In mice, exercise improves
learning and memory even if it begins late in life or after the onset of disease.
Transgenic mice that start exercising before Alzheimer’s disease develops learn faster
and reduce beta-amyloid plaques in the hippocampus and cortex 16 while old mutant mice
with Alzheimer’s improved their working memory and reference memory once they
started exercising.17
EXERCISE FOR THE BRAIN
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So get out your dancing shoes! You have every reason to believe that exercise can protect
and restore your brain. Research shows that even a mild form of aerobic activity
increases your levels of vascular endothelial growth factor (VEGF), which promotes
capillary growth for better oxygen and glucose flow to the brain. It also stimulates the
expression of genes required for plasticity, the promotion of neuron growth and long term
potentiation (LTP) for learning.
Working up a little perspiration actually helps you to learn faster, remember better and
feel happier. That’s because mowing the lawn, vacuuming the house or dancing around
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the living room all prompt your muscles to produce Insulin Growth Factor-1 used to
make BDNF (Brain-Derived Neurotrophic Factor), which in turn elevates forebrain
serotonin. You will also stimulate the production of NMDA (N-Methyl-D-aspartate)
important to learning and plasticity.18,19,20
As you age, cerebral blood flow begins to ebb.21 People with Alzheimer's disease or
senile dementia have restricted blood flow 22 and less blood sugar compared with healthy
people of the same age.23 Low blood flow and low glucose utilization 24 correlate with
poor scores on cognition tests, especially for tasks that involve information processing
speed.25
Exercise gets your blood moving and helps to slow or reverse that trend. A four-year
study found that physically active seniors (62 to 70 years) maintained their resting
cerebral blood flow and scores significantly higher in cognitive tests than non-active,
sedentary people of the same age.26
Exercise is also an antidepressant.27,28,29 In 58 randomized trials involving almost 3000
people, those who exercise have significantly lower depression scores than people who
don’t.30
Brain Exercise
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Lawrence Katz, a Professor of Neurobiology at Duke University, wrote a fun book
entitled "Keep Your Brain Alive", which presents 83 "neurobic" exercises to stimulate
your brain. Here are a few examples.
1
Use your opposite hand to do routine tasks such as brushing your teeth,
combing your hair or pouring milk.
2 Close your eyes when getting dressed, finding things in the bathroom or
eating a meal.
3 Turn your clock, the pictures on your desk or your calendar upside down.
These seemingly trivial actions excite your brain and force it to process unexpected
information and adapt to changing circumstances. It pays to play games with your brain
and almost any simple challenge will do.
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Novelty
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Your brain thrives on novelty. It is stimulated by the unexpected and always alert for
something interesting to do. This trait may well be the root of human curiosity and
inventiveness, but it is shared by many other creatures that seem to enjoy a good
challenge. Even rats would rather work for their food than get it for free.31
A famous and influential series of experiments performed at Berkeley in the 1960's 32
measured the effect of novelty on the brain by raising rats in three different
environments. The standard laboratory cage usually contains several rats with adequate
food and water. An impoverished environment has food, water for one lonely rat. An
enriched environment has six to eight rats in a large cage, food and water plus a variety
of toys that are changed every day.
At the end of the experiment, rats in the stimulating environment had larger synapses, a
thicker and heavier cerebral cortex, wider blood vessels for increased oxygen and glucose
flow and increased RNA for protein synthesis. These experiments have been replicated
and extended many times in many other species.
A Balanced Brain
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Keeping your balance is a major brain exercise that involves your motor regions and
cerebellum. Here's a test you can do to evaluate your balance. It's also a good indicator of
your "biological" age.
1 Stand on one foot.
2 Close your eyes.
3 Time how many seconds you can stand on one foot.
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Training your brain to maintain balance can have a big impact on your health and
longevity because your sense of balance declines with age, making falls much more
likely. The Centers for Disease Control and Prevention reported that more than one-third
of adults ages 65 years and older (about 12 million people) fall each year in the United
States. More than 1.6 million older people were treated in emergency departments for
fall-related injuries and 388,000 were hospitalized. In 2002, over 12,900 older adults died
as a result of falls, the leading cause of fatal injuries in the elderly.33
Hip fractures are especially serious. More than 300,000 people over age 65 will fracture a
hip in the United States this year. Between 18% and 33% of them will die within 1 year.
Most survivors of hip fracture lose their mobility and are unable to function
independently. In the year after their fracture many of them who were independent before
the fracture will not be able to walk without help or regain their previous level of
independence.34
One way to prevent falls and broken bones is to practice keeping your balance. As long
as you do it safely, you will reduce your risk of falling and probably improve your brain
at the same time.
Rats, encouraged to tackle increasingly difficult acrobatic tasks with gentle physical
encouragement and bits of chocolate, overcame their fear of traversing wide stable
platforms and managed to progress to balance beams, see-saws, rope bridges, and other
obstacles. By the end of the experiment, the most acrobatic rats passed easily over
difficult obstacles like pencil-wide dowels and loosely suspended ropes and chains. They
also had more synapses per neuron in the cerebellum than less active animals.35
It is not necessary for you to walk across a rope ladder, but it is OK to pretend that you
are as long as you do it safely. Depending on how well you can keep your balance, you
might want to try some physical activities that both improve balance and stimulate your
brain such as dancing, tai chi and yoga. Balancing your body gives your brain a work out
that not only reduces your risk of falling but stimulates the growth of new synapses to
improve your attention span and visual perception. Moderate weight lifting in addition to
mild aerobics is helpful because it increases your bone density, minimizing your risk of
hip fracture if you do fall.
Personally, I enjoy virtual skiing using the Nintendo Wii Balance Board. Standing in line
at Starbucks I sometimes balance on one leg. If it’s a long wait, I occasionally try it with
my eyes closed. I’m surprised more people don’t try it since others obviously find my
efforts entertaining.
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Speaking of Video Games
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Is physical activity too taxing for you? Is your range of movement limited? Is it possible
that playing computer games can exercise your brain and improve your memory without
physically moving your body? A group of researchers at the Mayo Clinic have asked that
very question.
To find out, they enrolled healthy seniors over 64 years old in a computer-based training
program. The 245 people in the control group had to watch educational videos on art,
history and literature and then take a quiz. The 242 members of the therapy group worked
at home for 1hour a day, five days a week for eight weeks on computer-based activities
designed to improve the speed and accuracy of brain processing.36
The computer tasks consisted of six auditory exercises designed to improve the speed and
accuracy of cerebral processing. For example, one test required differentiating between
similar-sounding words like pop and pot. Another required distinguishing between high
and low pitched sounds. At first the sounds were slow and distinct but eventually sped up
to mere clicks over time. When the players achieved an 85 percent accuracy rate they
graduated to the next level.
At the end of eight weeks, playing computer games achieved twice the improvement in
certain aspects of memory as passively watching educational videos. Changes in
cognition and memory were measured using a standardized tool called the Repeatable
Battery for the Assessment of Neuropsychological Status, a commercially available
program developed by Posit Science, the San Francisco company that financed the
research. It should be noted that the researchers had no financial ties to this business.
"We found that the improvement in these skills was significantly greater in the
experimental group - about double. Even the participants reported memory
improvement, indicating that the changes were noticeable in day-to-day tasks.”
"What's unique in this study is that brain-processing activities seemed to help aspects of
memory that were not directly exercised by the program - a new finding in memory
research." Glenn Smith, lead researcher.
Dr. Smith cautions that these results are statistically significant but the extent of the
memory boost was only about 4 percent. The overall memory gain for the control group
was about 2 percent. He points out that there is little evidence that brain enhancing
techniques like mnemonics, workshops, crosswords or playing piano offer long-lasting
memory improvement. Nor does he believe that these results offer insights on preventing
Alzheimer’s and other dementias since his participants were in generally good mental
health.
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On the other hand, a 4% increase in memory retention might be all you need to find your
car keys or remember a family birthday. Even a small improvement in processing speed
and accuracy might delay mental deterioration and could be enough to make your life
more pleasant and rewarding.
Several websites offer similar interactive stimulation. I sit on the Scientific Advisory
Board of Lumosity.com that also sponsors research to determine if its programs have
beneficial effects on memory and cognition. At this time, Lumosity has over 2 million
subscribers who, like me, find the exercises enjoyable and potentially beneficial.
It doesn’t matter if you run marathons or walk the dog around the block, whether you try
to outwit online gamers or play along with Alex Trebec on Jeopardy, your body and mind
still get a work out that could save your aging brain.
~
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FUTURE TREATMENTS
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I intend to live forever or die trying. ~ Groucho Marx
You can decide whether or not to live a longer, healthier life. If you eat right, exercise
daily and challenge your mind you will be in a better position to handle stress and
improve your brain at any age. It’s never too late to start!
New drugs, gene therapies, vaccines, dermal patches, even laser treatments are already
available or in clinical trials to help save your aging brain. None of these treatments is a
miracle cure for old age or dementia but they can make a critical difference in the health
and wellbeing of some people some of the time.
PERSONALIZED MEDICINE
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As new technologies unravel the complexities of aging and disease they point the way
toward interventions that treat individuals rather than populations. The more we learn
about the complex interplay of molecular interactions, feedback loops and overlapping
molecular pathways, the better we appreciate how profoundly different we are from one
another.
Until now the established “standards of care” were based on statistical analysis of large
populations. A one size fits all approach to medicine may not meet your specific needs
because your gene expression patterns are unique. In the future, advances in molecular
profiling that can identify your personal biomarkers of cognition and aging will form the
basis of customized treatments tailored to your personal genomic, metabolic and
proteomic needs.
COMT Genotype
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Here’s an example. Dopamine regulates attention and working memory among other
things. What happens to your brain when you take a prescription drug that affects
dopamine? Will your memory suffer? Will you lose your mental edge? Jose Apud, a
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lead researcher at the Genes, Cognition and Psychosis Program of the National Institute
of Mental Health is already looking for answers.1
The amount of dopamine available to your brain is controlled by an enzyme called
COMT (catecholamine-O-methyltransferase), which degrades dopamine. Humans have
two genetic versions (alleles) of the COMT gene - COMTmet and COMTval - producing
slightly different COMT enzymes. Apud slowed down the enzyme using an inhibitor
called tolcapone to see if a little extra dopamine in the brain would change the cognitive
abilities of 47 volunteers.
Depending on the COMT variation, there were significant effects on executive function
and verbal episodic memory. Volunteers with val/val COMT genotype improved their
cognitive ability on tolcapone while those with met/met COMT worsened. During a
working memory test, 34 volunteers underwent functional magnetic resonance imaging
(fMRI) and these brain scans showed a significant tolcapone-induced change in the
efficiency of information processing in the prefrontal cortex of healthy volunteers.
Opposing effects like these demonstrate why different studies have contradictory results.
They also demonstrate how one drug can help one person but harm another. If we didn't
know about COMT genetic variants it would be very difficult to figure out why some
people have a positive response to tolcapone, some have a negative response and others
no response at all.
Are you val or met? Knowing your genetic details could help your doctor decide if you
will benefit from a certain treatment or not. This is the promise of personalized medicine
and one reason why it is such an active area of research.
THE SEARCH FOR AN ANTI-AGING PILL
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Our understanding of the biological mechanisms that slow or reverse aging is not entirely
modern. For example, the idea that caloric restriction (CR) is a key to long life has
inspired ground breaking research for over half a century. With the help of new
technology that research continues today because the metabolic processes that involve
glucose and insulin also influence life span.
Insulin
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Insulin is the key that unlocks energy. Cells need access to sugar in order to make energy
and as glucose levels rise after a meal,
additional insulin is secreted into the
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bloodstream. When insulin is in short supply, cells have to adapt. If you were to begin a
program of caloric restriction today your glucose and insulin levels would soon drop. To
compensate, your cells will become increasingly sensitive to insulin. They will do more
with less.
How does this relate to aging? Nematode worms have genes similar to those that respond
to insulin in humans and by mutating those genes it is possible to extend a worms
lifespan up to four times longer than usual. The life span of yeast has also been extended
by tampering with genes that interfere with glucose processing. Similar genes have been
identified in fruit flies, such as the INDY gene, short for I'm Not Dead Yet.
2DG
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In 2002, inspired by studies from the 1940s and 1950s, researchers published new
findings concerning a glucose-like molecule called 2DG (2-deoxy-D-glucose) that lowers
insulin levels in the blood.2 Because it resembles glucose, 2DG enters cells very easily.
However, the enzyme required for glucose processing chokes on the byproduct produced
from 2DG and becomes less effective. As a result, the cells make less glucose byproducts and less ATP, just like caloric restriction.
To test if 2DG can mimic CR in healthy rats, Mark Mattson mixed low doses with rat
food for six months. Rats eating 2DG ate just as much food as the control rats but they
lowered their glucose and insulin levels and lost weight. Can 2DG also restore health in
ailing rats? Yes, it protected nerve cells just like CR and reduced some behavioral
deficits.
Unfortunately, 2DG proved safe only at certain low levels. For some animals, 2DG is
toxic at higher doses or over longer periods. This narrow zone separating safe from toxic
doses prevents humans from using 2DG. This is a problem common to many candidate
drugs in clinical trials. Low doses are ineffective for many people therefore the clinical
trial fails for lack of efficacy. High doses cause unacceptable side effects for some people
so the clinical trial fails for lack of safety. Drugs that could benefit some people are
abandoned because they are potentially dangerous to others.
Pharmacogenomics
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Back in the 1950’s doctors noticed that people did not always respond to anesthetics in
the same way.3 That led to an investigation into how a single gene might affect the action
of certain drugs but it led to the discovery that multiple genes are involved in drug
reactions. Genes are not simply turned off or on like a tap - they are expressed at different
rates over varying durations.
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The study of variable gene expression has led to the understanding that a common disease
can be caused by different groups of genes in different people. This also means that
different drugs are needed to treat different people with the same disease. If that sounds
complicated, it is. And yet pharmacogenomics is making strides in the diagnosis and
treatment of critical illnesses such as cancer, cardio vascular disorders, diabetes and HIV.
It also has the potential to rescue many drugs that were once abandoned, including drugs
linked to aging such as 2DG.
RESEARCH TO SLOW AGING
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Cynthia Kenyon at the University of California in San Francisco has studied the
interaction of genes in aging worms. The worm in question is C. elegans, a convenient
model for aging because the typical lifespan is about 20 days. In 1993, Kenyon's
laboratory identified two genes: daf-2, which shortens lifespan, and daf-16, with extends
it. Using RNA interference (RNAi) she found that blocking daf-2 more than doubles
lifespan and that blocking both daf-2 and daf-16 returns lifespan back to normal.
We now know that daf-16 not only extends lifespan but provides protection against
bacterial attack. In addition, it regulates genes that protect against oxidative stress (ROS)
and up-regulates genes for anti-oxidants (catalase, glutathione transferase and
mitochondrial superoxide dismutase).
Daf-2 and daf-16 genes are doubly interesting because they are transcription factors they regulate other genes. Their effects depend on how they mutually control the
expression of multiple genes, but they are not equal partners for daf-2 down-regulates
daf-16. This makes for a complex relationship but one worth investigating because both
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version of daf genes in worms are closely-related to two genes in mammals that encode
for insulin receptors and insulin-like growth factor (IGF-1) receptors.
The insulin/IGF-1 pathway has generated a lot of scientific interest. The daf genes
operate in the same signaling pathway that regulates the lifespan not only of fruit flies but
of mice, which has implications for other mammals like us. (Piper 2008) Already we can
extend the lifespan of a mouse by deleting either one copy of the IGF-1 receptor gene or
the insulin receptor substrate protein 1 (Irs1) from fat or the Irs2 gene, which mediates
the effects of insulin and IGF-1 in certain neurons.
Resveratrol
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You may have heard of resveratrol, a polyphenolic compound in red wine and grape juice
that extends the lifespan of yeast, worms and mammals. It works by activating sirtuins
(Sir), proteins linked to energy production and aging in the same insulin/IGF-1 pathway.
Together, sirtuins and resveratrol up-regulate genes that act on oxidative stress and
energy metabolism.
Resveratrol acts on Sir-2 to regulate aging in worms via daf-16. In mice, sirtuins regulate
IGF and growth hormones to control lifespan. The pathway is well conserved among
species and it probably evolved several times. Mutations in the insulin/IGF-1 signaling
pathway seriously affect lifespan, but thanks to these variations insects can live for a few
days or several years while mammals live for a few years or survive for over a century.
“The beauty of the insulin/IGF-1 system is that it provides a way to regulate all
of these genes coordinately. As a consequence, changes in regulatory genes
encoding insulin/IGF-1 pathway members or daf-16 homologues could, in
principle, allow changes in longevity to occur rapidly during evolution.” ~
Cynthia Kenyon 2003
Shared Pathways
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It’s clear that caloric restriction, mitochondrial processing and insulin signaling converge
to influence life expectancy. These aging pathways are intertwined and interdependent
and share conserved roles in regulating lifespan in worms, flies, rodents, monkeys and
almost certainly humans.4 They also have a shared weakness. Can you guess what it is?
Here’s a hint from the title of one of Cynthia Kenyon papers:
"Glucose shortens the life span of C. elegans by downregulating DAF-16/FOXO
activity and aquaporin gene expression."
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Blood sugar levels in middle age strongly predict survival.5 That was the finding of the
long-term Honolulu Heart Program Study concluded that over a decade ago. As we have
seen, energy production from sugar is a problem because neurons are susceptible to
damage from free radicals produced by their own mitochondria. Because an increase in
blood sugar triggers an increase in insulin secretion, it was thought that artificially
increasing insulin levels to cope with excessive sugar would be helpful. Not so.
A study by Lambert and Merry suggests that high insulin levels undo the benefits of
caloric restriction. They found that while CR decreases insulin and free-radicals in
mitochondria, artificially increasing insulin levels reduces the effects of CR in the
mitochondria of rats. The aging pathways are a confounding puzzle.
PREDICTING LONGEVITY IN HUMANS
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Are all these animal studies relevant to humans? Yes, because inhibiting insulin/IGF-1
signaling not only extends lifespan, it increases resistance to cancerous tumors in both
worms and mammals. Caloric restriction in animals results in much lower rates of cancer
than animals that eat more. We don’t know why. Finding the answer could be important
to many people.
When researchers analyzed all the possible genes targeted by DAF-16, they found that 29
of 734 genes influenced germline-tumor cell proliferation or p53-dependent apoptosis (cell
suicide). About half of them regulate normal aging. Many of those 29 genes evolved from
a common ancestor (orthologs) of known tumor suppressors (oncogenes) in humans.6
Biomarkers of Aging
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Let's look at three markers of health maintenance that are potential biomarkers of
longevity: body temperature, insulin and DHEAS (dehydroepiandrosterone sulfate), a
steroid hormone related to testosterone.
Men with naturally lower body temperatures, lower insulin levels but higher DHEAS
appear to live significantly longer, according to George Roth of the Baltimore
Longitudinal Study of Aging. In rodents and monkeys, lower temperature and blood
insulin levels are highly-reproducible biomarkers of caloric restriction, which also slows
the decline of DHEAS in aging monkeys and humans. A coincidence? Probably not.
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Primate Markers of Caloric Restriction
Markers of Longevity in Human Longitudinal Study
We know that certain genetic mutations are associated with increased lifespan. For
instance, a variation of the IGF-1 receptor gene has kept some Germans alive and kicking
well into their second century.7.8.9.10 The human version of daf-16 is called FOX03A and
it too is linked to longevity. Ann Brunet at Stanford discovered that neural stem cells in
mice are affected by the human FOX03A gene and so she is attempting to create a mouse
with artificially elevated FOX03 levels to produce neurons that resist aging.
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GENES, COGNITION AND AGING IN HUMANS
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Slight alterations in the DNA sequence of genes and changes to where and when they are
expressed have a major impact on lifespan and cognitive decline. At present, we only
know a fraction of the genes involved and have very limited knowledge about variations
in the sequence and expression of genes in humans, especially among older, but healthy
people. However, we do know of several genes that regulate both aging and cognitive
decline:
•
•
•
•
•
•
COMT (catecholamine-O-methyltransferase)
BDNF (brain-derived neurotrophic factor)
NR2B (glutamate receptor)
daf-2/ insulin and insulin-like growth factor receptor
daf-16/FOXO transcription factor
ApoE (apolipoprotein)
A major goal of current research is to identify similar genes to determine how they work
and how they are regulated. Two technological advances are accelerating our ability to
make these discoveries: DNA sequencing of complete genomes at low cost and gene
expression microarrays that show us when and where genes are turned on.
The first human genome was sequenced in 2001 at a cost of about $3 billion. Today, your
genome can be sequenced for under $10,000. The goal now is to reduce the cost to a
fraction of that - a $1000 genome - making it feasible to sequence large numbers of
humans, chimps and bonobos in order to find the genes that cause differences in brain
size, learning and lifespan.
The longest well-documented human lifespan is about 120 years. That's twice as long as
our nearest relatives, the chimpanzees and bonobos, who live up to 55 years and whose
genes differ from ours by only a few percent. With sequences from many individuals of
each species, we can see which genetic differences are minor variations within a species
and which differences are linked to longer life or better brains.
In the future, we will be able to compare the genomes of thousands of humans to
determine what genetic variations within our species are present in the oldest, healthiest,
individuals. In the quest for the $1000 genome, two companies in Silicon Valley lead the
way. Complete Genomics (completegenomics.com) is building the world’s largest human
genome sequencing center. Pacific Biosciences is developing Single Molecule Real Time
(SMRT™) DNA sequencing technology to sequence a complete human genome in under
an hour for less than $100. (pacificbiosciences.com/video_lg.html )
H
H
How can sequences be used? Researchers have already compared the sequence of
humans, chimpanzees and other primates to identify gene mutations that appeared to
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have been positively selected in humans. One gene, the beta-2 adrenergic receptor, has a
common genetic variant in people. A study of two human populations showed that these
variants were associated with differences in IQ.11
Microarrays
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After we identify a gene that is involved in aging or cognition, we still need to learn
where it is expressed, what it does and how it is regulated. That’s where gene expression
microarrays come in. When a gene is turned on, it produces messenger RNA (mRNA) to
direct the synthesis of a protein. Microarrays tell us how much mRNA each gene
produces.
Caloric restriction, for example, induces hundreds, possibly thousands, of biological
changes making it difficult to separate cause and effect. Arrays provide a means for
simultaneous analysis of gene expression patterns and transcriptional responses for tens
of thousand of samples.
By increasing or decreasing expression we learn the function of a gene and see what
other genes do in response. Gene expression can be blocked by RNA interference or by
genetic modification where one or both copies of a gene are knocked out. If we want, we
can do the opposite and increase gene expression by inserting an additional copy of the
gene.
Arrays use messenger RNA (mRNA) extracted from biological samples labeled with
fluorescent dye. Each point on the array is called a probe and corresponds to one gene.
The fluorescent intensity at each point is proportional to the amount of mRNA.
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Two-color arrays measure the relative expression of genes within two samples, such as
young and old brain cells in mice, on a single array.
DNA microarrays make it possible to study 10,000 genes within a single experimental
set-up. They can be used to measure the biological age of tissues and evaluate
interventions at the molecular level.
Affymetrix Arrays hybridize mRNA to a GeneChip that displays 200,000 points of
genetic information at one time.
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Cynthia Kenyon used microarrays to identify genes regulated by daf-16. After identifying
the genes, she used RNA interference to alter the expression of those genes and then
observed the effects on longevity.
Eric Blalock and colleagues at the Department of Molecular and Biomedical
Pharmacology at the University of Kentucky used microarrays to study gene expression
in the hippocampus of rats. Groups of rats, young, middle-aged and elderly, were trained
on two memory tasks: the Morris Spatial Water Maze (SWM) and the Object Memory
Task.12
One region of each animal’s hippocampus was analyzed on an individual microarray. As
expected, older animals were slower to remember and learn and the expression levels of
certain genes correlated with their performance on the memory tests. It was also clear that
some of their genes changed expression with age.
Age-related Changes in Expression of Specific Genes Required for Memory
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Age Related Gene Expression in Pathways that Affect Memory
The above chart is based on data from microarrays showing how aging affects different
molecular pathways. The most obvious pattern to emerge is that good things like
signaling slow down while bad things like inflammation pick up. Thanks to microarrays,
we have some idea of the sequence of events that leads to age-related cognitive
impairment.
One suggested model of aging based on this data goes like this:
1
2
3
4
5
6
7
8
9
10
11
12
Altered Ca2 signaling leading to decreased neural activity
Decreased activity-dependent signaling
Decreased energy metabolism
Decreased biosynthesis
Downregulated synaptic plasticity and axonal regression
Demyelination
Remyelination programs: cholesterol synthesis
Antigen presentation
Inflammatory response
Altered glial metabolism
Astroglial hypertrophy
Altered extracellular matrix13
In other words, use it or lose it. A decline in neural activity leads to neural vulnerability.
Fortunately, each step in this aging process is a candidate for future drug development,
gene therapy or laser treatment. Some of these interventions may arrive soon, some not
for a long time, but with better understanding come more opportunities to slow aging and
reduce cognitive decline.
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GFAP
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The first item on that list of factors that contribute to aging is calcium or Ca2 signaling.
We have known for some time that astrocytes, star-shaped support cells, produce fairly
strong intercellular calcium signals. Several research teams are looking for ways to
stimulate neurons in the central nervous system and high on their list is the GFAP gene
(Glial Fibrillary Acidic Protein), which is intimately involved with astrocytes.
We suspect that GFAP is responsible for maintaining the structural integrity of astrocytes
and yet when aging astrocytes begin to fail, GFAP levels start to rise. GFAP is such a
reliable indicator of neurological damage that it is used as a marker in stroke and brain
injury patients. Is this cause or effect? GFAP remains poorly understood but recent
experiments have found that lowering GFAP levels with RNAi silencing reverses damage
to astrocytes and promotes neurite growth within 24 hours.14,15
Nerve Growth Factors
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Another promising area of study involves the use of viruses to invade brain cells. Several
groups are researching ways to render a virus harmless and use it to piggyback Nerve
Growth Factors (NGF) into neurons to promote neuron survival, neurogenesis and
synapse growth.16
Ceregene in San Diego has begun a clinical trial using NGF to treat Alzheimer's disease.
A small Phase 1 study of the company’s CERE-110 gene product indicates that a single
dose is well tolerated. To evaluate its safety and effects on cognitive function and quality
of life over a two year period, a more stringent double-blinded Phase 2 study of 50
patients with mild to moderate Alzheimer’s disease is planned.
Genetic Modification
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Some herpes viruses target human brain cells and could be genetically modified to
smuggle molecules into our neurons to manipulate gene expression. One possible target
for this method of treatment is NR2B, a molecule that makes memories. NMDA (Nmethyl D-aspartate) receptors in your synapses trigger plasticity but gene expression for
at least one type of those receptors (NR2B) declines with age, affecting memory and
learning.
Looking for a method to reverse this situation, Joe Tsien and team recently tweaked a few
genes to create smarter mice that over-express NR2B. Celebrated as Genius Mice on the
David Letterman show, they produce twice as much NR2B in the cortex and
hippocampus as usual with no obvious side effects. They learn significantly faster than
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wild-type mice in novel object recognition and are more adept at solving a water maze.17
Nerve Implants
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Fruit flies, worms, mice, monkeys and humans all strengthen synapses in much the same
way, a fact that provides surprising opportunities to discover new genes involved in aging
and cognition. The CREB protein, for example, regulates the strengthening of synapses
during learning and is part of an ancient system that exists in invertebrates and
mammals.18
Even fruit flies can serve as a model of human neurological disease. They have a
surprising range of learning skills and can be bred for learning ability so that later
generations become better at certain tasks such as avoiding an odor associated with shock
or assessing the degree of disadvantage between bad experiences. The genes that affect
learning and memory in fruit flies have counterparts in humans that are implicated in
Alzheimer’s disease, Down’s syndrome where damaged proteins cause problems.19
Rats, too, are a useful model of human cognition because their brains age much like ours.
We even have the same weak spot - the hippocampus - which is especially vulnerable to
plaque, stress and the effects of aging.20
In the 1980’s, a research team under Fred H. Gage replaced defective neurons in aging
rats with healthy ones. Old rats with the new implants scored better in the Morris water
maze than before the procedure. Several months later they continued to outsmart control
rats in the same exercise.21,22
In a similar experiment, neurons from the locus coeruleus of young rats were injected
into the same site in old rats. This location, which gets its name from the Latin for the
blue spot (yes, it really is blue) is associated with stress and panic. The implants certainly
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hit the spot because those old rats proved to be the equal of younger rats in memory
tasks.23
The hope is that nerve implants will help the human brain repair damaged nerves,
something it cannot do. Not all creatures have this limitation. Did you know that frogs
can regrow their optic nerve if it is damaged? Goldfish have a brain that grows and
renews itself throughout life. Regulated by estrogen, the goldfish brain constantly rewires itself and as the body grows, so the brain grows too. So far there seems to be no
fixed lifespan or obvious upper limit.
Why is it that frogs and fish can do something that mammals like us cannot? Damage to
nerves in your peripheral nervous system (PNS) can be repaired, but only if they are
outside your brain and spinal cord. For example, if you cut the nerves in your finger tip, it
temporarily loses the sense of touch but the feeling eventually comes back. That doesn’t
happen when the damage is to cells in your central nervous system. Taking a spare nerve
from the back of a leg and grafting it to a damaged optic nerve could guide the growth of
new neurons and restore vision.
The difference between your peripheral nervous system and your central nervous system
is not in the nerves themselves but in the cells that surround and support them. Glial cells
can outnumber neurons by fifty to one in some areas of your brain and many of them are
busy manufacturing a protein that sabotages repairs.
Nogo Gene
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The Nogo gene codes for the Nogo protein, so named because it stops severed nerves
from reconnecting. Nogo is widespread in the central nervous system, especially in the
neocortex, hippocampus, amygdala and spine – areas critical to intellectual and emotional
health.24
At times Nogo is essential but sometimes it can be inconvenient. Nogo turns off and on at
different stages in your life. Early on it is responsible for hardwiring the newly formed
nervous system of a human fetus. In young adults, it produces the myelin sheath that
insulates nerve fibers. For some reason, as we approach middle age, it begins to
contribute to dementia and Alzheimer’s disease. So how do we turn it off?
After suffering a spinal cord injury in 1995, Christopher Reeve of Superman fame set up
the Christopher and Dana Reeve Foundation and helped finance studies of the Nogo gene
at Yale University. The goal was to find a substance to block the Nogo protein or else to
develop a successful means of introducing stem cells to an injury site. Reeve firmly
believed that such discoveries were just around the corner. He was right.
Martin Schwab at the University of Zurich has since found an antibody that blocks the
Nogo protein, allowing test tube samples
of rodent nerves to make repairs and grow
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hundreds of new connections. In a later experiment, rats with severed spines were able to
feed themselves and climb rope two weeks after receiving the same treatment. Research
continues, although much of it is still experimental.25
Neural Stem Cells
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Stem cell research is another matter. We used to think that adult mammals, humans in
particular, had no neural stem cells. It turns out that we do. Human stem cells can renew
themselves and then change into any one of a range of specialized cells. They grow in the
hippocampus and paraventricular nucleus (PVN) precisely where nerve cells originate in
the embryo and fetus. As progenitor cells, they can differentiate into three major types –
neurons, astrocytes and oligodendrocytes.
Neurons are nerve cells that transmit signals. Astrocytes primarily support and care for
neurons, stabilizing the chemical composition of surrounding fluid by removing and
recycling ions and neurotransmitters released during synaptic transmission.
Oligodendrocytes produce the myelin sheath that insulates axons in the central nervous
system (CNS) allowing electrical signals to travel faster.
For several years, I've worked with Geron Corporation on the development of stem cells
for use in treating spinal cord injuries. A major issue in transplanting stem cells is
ensuring that they grow into the type of tissue needed and do not turn into tumors. It is
critical that implanted stem cells follow the regulatory instructions from neighboring cells
in order to prevent tumor development.
In one of my early collaborations, we studied factors that control stem cell differentiation
in the test tube and more recently in animals. By 2009, Geron had designed a Phase I
multi-center trial to establish the safety of an embryonic stem cell product called
GRNOPC1. On July 30, 2010, after some initial delay, Geron Corporation received FDA
approval to begin the world's first clinical trial of human embryonic stem cell therapy for
people.
Neural Stem Cells and Alzheimer's Disease
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Another development occurred in August 2009, when researchers Mathew Blurton-Jones
and Frank LaFerla at the Institute for Memory Impairments and Neurological Disorders
at the University of California, Irvine, showed for the first time that neuronal stem cells
can repair memory loss in Alzheimer mice.26 This work is worth looking at in some
detail, both because of the exciting clinical potential and because it illustrates how
discoveries can be made.
They wanted to see where particular proteins were being produced in the brain so they
99
used a laboratory tool called Green Fluorescent Protein (GFP). This protein comes from
the jellyfish Aequorea Victoria and emits a bright green color when exposed to blue light.
By grafting GFP to a gene, they turn it into an easily-detected “reporter gene” whose
activity leaves a visual trace.
LaFerla and his colleagues had already created a transgenic mouse (named 3xTg-AD)
with three genes taken from humans that are linked to Alzheimer’s and promote plaque presenilin, amyloid-beta and tau – that all .
In humans, mutations in the presenilin gene increases the risk of early onset Alzheimer's
disease and sure enough, LaFerla's transgenic mice had plaques and tangles in the
hippocampus and cortex plus amyloid-beta deposits between cells prior to tangle
formation, both contributing to a loss of synaptic plasticity.
LaFerla wanted to find out if a Neural Stem Cell transplant (NSC) could save his mice.
First he labeled the stem cells with GFP for easy identification and then he injected them
into the left and right hippocampus of 18-month-old mice using stereotactic surgery, a
minimally invasive technique using 3-dimensional coordinates for pinpoint accuracy.
Within 24 hours, NSC mice were out-performing the Alzheimer control mice in the
Morris water maze and remembering where to find the former location of the hidden
platform almost twice as often. Astonishingly, they were performing at almost the same
level as healthy control mice. In the novel object recognition task, NSC transplant mice
with advancing Alzheimer’s actually improved their memory and learning.
100
Upon examining the hippocampus LaFerla found an increase in the number of new
synapses and determined that the transplanted neural stem cells had differentiated into
6% neurons, 40% astrocytes and 26% oligodendrocytes.
That might have been the end of the experiment, except that something was not quite
right. Typically, neural stem cells migrate toward injured cells and areas of plaques and
tangles (gliosis). In this case, the transplanted stem cells did not go there. Instead, there
were higher levels of BDNF, the protein that promotes cell differentiation and neural
growth.
LaFerla was surprised and curious to know if BDNF alone would benefit his aging mice.
He soon discovered that BDNF by itself did not significantly affect learning. It did,
however, improve memory as mice with a memory boost from BDNF crossed the
previous location of the hidden platform in the Morris water maze almost twice as often
as control mice.
Inspired by these and other recent discoveries, citizens in the state of California voted to
create a three billion dollar fund to create the California Institute for Regenerative
Medicine (CIRM) with a specific mandate to sponsor stem cell research. LaFerla himself
recently obtained a grant from CIRM to begin research that could eventually lead to
human studies.
Researchers are making progress. They are gaining a better understanding of cognition
and aging and working toward new treatments for dementia and Alzheimer’s disease.
Some treatments look promising, some are in development and others are already in
clinical trials.
101
Vaccine
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A vaccine is in the works that prevents plaques from forming in the brain. When
amyloid-beta builds up, the molecules link together and become toxic to brain cells.
Researchers in the UK recently discovered that when these molecules stick together in
pairs (dimers) that’s when they become toxic, but alone or in groups of three they are
harmless.
In theory, it should be possible to create an immunizing vaccine made of antibodies that
recognize the amyloid-beta protein and lock onto it to prevent the molecules from
sticking together. Without a fresh supply of sticky dimers, toxic amyloid-beta should
slowly degrade and disappear.
In one study, that is exactly what happened as amyloid-beta dispersed as expected.
However, neurons continued to wither and die. It is generally understood that amyloidbeta kills brain cells but in this case, the absence of the usual suspect was a challenge to
the long-held association of Alzheimer’s with plaques and tangles. As Dr. Jack Diamond,
director of the Alzheimer’s Association of Canada put it:
“Have we been wrong all these years, and it's not the Abeta (amyloid-beta)
that's causing nerve cells to die?”27
Dermal Patch
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A dermal patch is already on the market to treat mild to moderate dementia. It’s not a
cure but it does seem to delay memory loss and occasionally improve thinking. The
active ingredient is rivastigmine (ri va stig' meen) which helps to maintain acetylcholine
(ACh) levels in the brain. Dwindling acetylcholine levels is a characteristic of
Alzheimer’s and the hope is that rivastigmine will delay onset of the disease.28
Laser
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A laser treatment developed by Photothera uses near-infrared light to repair neurons
damaged by stroke. The procedure, which lasts under an hour, is non intrusive yet
reaches more than 2 cm into the brain to rescue dying neurons.
In a healthy brain, mitochondria create energy using oxygen to synthesize ATP,
something that cells damaged by stroke cannot do. However, even damaged mitochondria
absorb infra-red light via certain receptors (cytochrome C oxidase photo-receptors). In
test tube experiments and in animals this was sufficient to generate the proton gradient
required for ATP synthesis. Two human
clinical trials are complete and a third is
102
under way. This treatment could be available to the public in the very near future.
Laser treatment looks promising for a range of medical applications. Restoring energy
levels in muscles damaged by heart disease could restore oxygen flow to the brain. A
laser might promote the repair of cells in fast-twitch muscles, the first cells to die off with
age and the cause of many falls and broken bones in the elderly. Laser light may also be
used to treat vascular dementia and possibly to repair brain cells succumbing to
Alzheimer’s disease.
We learn something new everyday. What we think we know about the brain is constantly
challenged. Still, certain fundamentals continue to be true. You can’t avoid death or
taxes, but you can moderate mental and physical aging by making good food choices,
avoiding unnecessary calories, adding antioxidants to your diet, managing your stress and
exercising regularly. Sooner or later, many of us will need medical help to cope with the
effects of old age and it’s encouraging to know that revolutionary new treatments are in
the works to save your aging brain.
~
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Chapter 1: What’s Happening To My Brain
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127B
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