Geriatr Gerontol Int 2011; 11: 233–235
LETTER TO THE EDITOR
How to fight with
senescent cells?
Dimitry A Chistiakov
Department of Molecular Diagnostics, National Research Center GosNIIgenetika, Charitable Foundation
“Science for Life Extension”, Moscow, Russia
Dear Editor,
ggi_654
233..235
Aging is a complex biological process influenced by a
variety of factors. One component of aging is the
damage caused by senescent cells. Senescent cells are
those that have lost the capability to reproduce themselves. Senescent cells are far from inert and, because of
their impaired metabolic state, produce abnormally
large amounts of some unpleasant proteins that are
harmful to their neighbors, stimulating excessive
growth and degrading normal tissue architecture.
Senescent cells gradually accumulate in aging tissue.1,2
The accumulation of senescent cells with advancing
age is associated with multiple non-beneficial and frequently irreversible changes in surrounding tissue environments that promote the development of certain agerelated diseases, including late-onset cancer.3
For example, aging chondrocytes, compared to young
cells, have been shown to synthesize shortened and less
structured protein components (aggrecans) of the cartilage and connective tissue.4 Senescent chondrocytes
were less responsive to the stimulation by insulin-like
growth factor 1 and other cytokines that regulate the
chondrocyte function to produce extracellular matrix
proteins.5 In old chondrocytes, accumulation of the
cell cycle inhibitor p16INK4a, an established senescent
marker, was also observed. The increase in intracellular
p16INK4a levels correlated with the activation of expression of matrix-degrading metalloproteases (MMP).4
Taken together, these events led to reduction of the
regenerative potential of the cartilage and contribute to
the pathogenesis of osteoporosis.6
The presence of senescent cells with their aberrant
secretome may alter the environment of the stem cell
niche, thus impairing their ability to function properly.
The removal of senescent cells alone may therefore
partly prevent the age-related decline in stem cell function providing a stronger repair process.
Because senescent cells are potentially detrimental to
the tissues in which they reside, anti-aging research
should be focused on three main aims for dealing with
this problem:
© 2011 Japan Geriatrics Society
1 Prevention: prevent cells from becoming senescent.
2 Removal: remove senescent cells as they appear.
3 Replacement: replacement of cells which have naturally or artificially been removed.
Revolutionary advances in the development of cell
replacement strategies through the transplantation of
stem cells and bioengineered tissues have been substantially considered in several recent reviews.7–9 In the field
of prevention and delaying cell senescence, significant
efforts were performed to block telomere-dependent
and telomere-independent mechanisms of senescence.
For example, overexpression of transgenic telomerase
was shown to significantly extend lifespan of a variety of
mature cell types10–12 However, expression of exogenous
telomerase must be carefully controlled to prevent tumorigenic immortalizing effects of this enzyme.13
Telomere-independent mechanisms of cell senescence are mainly mediated by cell cycle regulators
p53- and p16INK4a. Therefore, inhibiting p16/INK4aand p53-dependent signaling should delay the terminal
arrest of cell proliferation. Recent findings showed a
barrier role of the CDKN2A locus, encoding p16INK4a,
whose contaminant expression during the reprogramming of somatic cells into induced pluripotent stem
cells (iPSC) reduces the efficiency of reprogramming.14
Preliminary suppression of CDKN2A in somatic cells,
using the RNA interference technique, before reprogramming yielded the marked increase in reprogramming efficiency and numbers of iPSC colonies.15
Similarly, an increase in reprogramming efficiency was
achieved after inhibiting p53-dependent signaling that
induces apoptosis and expression of a negative cell
cycle regulator p21/Waf1, a product of the CDKN1
locus.16,17
Unfortunately, compared to cell replacement and cell
revitalization strategies, development of techniques for
detection and removal of senescent cells is in its infancy.
Evolutionarily, an organism develops several mechanisms to sense and clear itself from the balk of senescent
cells with the involvement of the immune system and
apoptosis. Senescent cells produce cytokines to attract
immune cells to their location (for their removal),18
doi: 10.1111/j.1447-0594.2010.00654.x
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DA Chistiakov
secrete MMP to allow the immune cells easy access and
secrete growth factors to stimulate the proliferation of
surrounding cells for its replacement once the cell is
removed.19
To successfully combat cell senescence, it is necessary
to know senescent biomarkers as potential targets for
recognizing and specific elimination of old cells by antisenescent agents. The in-depth knowledge and understanding of biological mechanisms used by an organism
to remove senescent and malfunctioning cells is crucial
for the development of efficient anti-aging therapies.
Along with general markers of cell senescence such
as telomere shortening and accumulation of p16INK4a,
there are specific senescent markers that are unique for
a certain cell type or lineage. For example, senescent
status of neutrophils is characterized by a high content
of the chemokine receptor CXCR4 but low density of
CXCR2 receptor molecules on their surface that
induces apoptosis-mediated destruction and subsequent phagocytosis of senescent neutrophils by macrophages in the bone marrow.20–22 In clearance of
senescent erythrocytes, a decreased expression of the
surface antigen CD47 plays a critical role. This antigen
binds to the macrophage surface receptor (signal regulatory protein-a) and inhibits the phagocytic activity of
macrophages.23
Therefore, knowledge about specific senescent
markers should be taken into account for the development of strategies that target and eliminate specific types
of senescent cells. Such a strategy has recently applied
for removal of senescent cytotoxic CD8+ T cells, carrying the inhibitory killer cell lectin-like receptor G1
(KLRG1), a marker of cells unable to undergo further
clonal expansion.24 Using monoclonal anti-KLRG1
antibody anchored to magnetic nanoparticles, Rebo
et al.25 successfully cleaned a whole-body blood of aged
C57BL/6 mice from senescent T cells, reducing their
count by a factor of 7.3 and reaching a level typically
seen only in very young animals. This approach has
great clinical promise, because it allows cleaning blood
from dysfunctional T lymphocytes, carrying receptors
for persistent herpes viruses (cytomegalovirus, Epstein–
Barr virus), whose age-dependent accumulation contributes to increased incidence of infectious disease in
elderly.24
To date, a variety of anticancer strategies, capable of
distinguishing between normal and cancer cells in order
to specifically deliver a cytotoxic agent and kill tumor
cells only, have been developed. The major targets of
the action of modern antitumor drugs are the inactivation of growth factors of cancer cells and their receptors,
inhibition of signal transduction mediated by oncogenic
tyrosine kinases, and suppression of molecules controlling specific properties of cancer cells.26 Lessons from
anticancer therapy should be translated into the antiaging research and its future clinical applications.
234 兩
Along with the development of anti-senescence strategies focused on the artificial “cleaning” of an organism
by specific removal or killing senescent cells, another
possibility is to restore or activate the natural, immunemediated ability of a body to remove senescent cells.
Because the immune system itself is governed by aging
mechanisms, its ability to remove senescent cells gradually decreases.27 Poor immune competence with aging
is closely linked to age-dependent thymic atrophy.
Immune aging is also accompanied by clonal expansions of anergic CD8+ T cells that have lost their ability
to properly function as normal cytotoxic T lymphocytes
and therefore unable to mediate the removal of senescent cells.28
A solution to restore the production of new cytotoxic
T cells with normal function is to create the bioengineered thymus capable to mimic the ability of the
natural thymus to “educate” the precursors of cytotoxic
T cells and other T lymphocytes. The artificial thymus
for the out-of-body use as a bioreactor for producing T
cells has been developed by Cytomatrix (Woburn, MA,
USA) in 2000.29 The generation of the bioengineered
thymus for transplantation is still a challenge.30,31 An
alternative strategy to restore the production of new
killer T cells is purging the defective cytotoxic T cells
from the system. This could be done with help of the
approach proposed by Rebo et al.25
Although a genuine anti-senescence drug is not available at the moment, current trends in the evolution of
cell therapy-based techniques suggest the possibility of
developing efficient anti-aging therapeutics in the near
future. The discovery of a universal surface biomarker(s)
that target(s) all or the majority of senescent cell types
should greatly help with the creation of a genuine antisenescence drug. Experiments with different types of
apoptotic, necrotic and damaged cells showed that
those cells carry on their surface a so-called membrane
attack complex that appears possibly as a result of CD46
and CD59 shedding into soluble forms.32 Both CD46
and CD59 are the complement regulator receptors that
reside on the surface of normal non-apoptotic cells.
Loss of these receptors induces formation of the membrane attack complex followed by the complementmediated lysis and phagocytosis of pre-apoptotic
senescent cells.33 Therefore, presence of the membrane
attack complex on the surface of senescent cells might
be considered in the design of a prototype “suicide”
anti-senescence drug that utilizes the complementmediated targeting and delivery of a cytotoxic agent
directly to the senescent cell.
Acknowledgments
This work was supported by grant no. 2009/13 from the
Charitable Foundation “Science for Life Extension”
(Moscow, Russia).
© 2011 Japan Geriatrics Society
Letter to the Editor
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