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info aging guides

BIOLOGY OF AGING

CELLULAR
SENESCENCE
An introduction to aging science brought to you by the
American Federation for Aging Research
WHAT IS CELLULAR no longer divide become what is that activate oncogenes—normal
SENESCENCE? called “senescent.” Cells taken cellular genes that, when mutated,
from older humans generally have contribute to the development
Cellular senescence is a process shorter telomeres than cells from of cancer. These diverse ­triggers
associated with aging that occurs young humans, so cells from older support the idea that cellular
at the level of our cells. Cellular humans generally divide fewer senescence evolved primarily to
senescence is sometimes called times before becoming replica- protect organisms from cancer.
replicative senescence. Forty years tively senescent.
ago, Dr. Leonard Hayflick and his Scientists have also noted that
colleague, Dr. Paul Moorhead, Critically short telomeres, which senescent cells are different from
discovered that many human resemble broken chromosomes, their younger counterparts. Like
cells—particularly fibroblast cells, are not the only causes of ”senes- older people themselves, cells ap-
which secrete substances that cence,” and so scientists often proaching senescence incur many
provide structure to tissues—had use the more general term ”cellular biological losses or take on new
a limited capacity to reproduce senescence.” Cellular senescence functions. Where younger cells
themselves in culture by dividing. produce structural or functional
They found that these and many proteins that maintain tissues in
other normal human cells derived a healthy state, cells approaching
from fetal, embryonic, or newborn senescence release enzymes that
tissue can undergo between 40 break down these proteins.
and 60 cell divisions, but then can
divide no more. This number is Senescent cells are not only
often referred to as the Hayflick ­associated with certain age-related
Limit. Hayflick also pointed out diseases, but may also be a direct
in a second report that there are reflection of the aging and longevity
two classes of cells: normal cells, determination process in humans
which do not divide indefinitely and animals. Even cells from the
and therefore are sometimes oldest people may still have some
termed ”mortal,” and cancer cells, divisions left. Many scientists
which often can divide indefinitely therefore believe that the biological
and therefore are often termed losses that precede the inability
“immortal.” to replicate increase vulnerability
to disease and death well before
Some scientists today believe the cells are incapable of further
that what determines the ­Hayflick division.
Limit for dividing cells is the length
of cells’ telomeres. ­Telomeres WHY IS CELLULAR
can be pictured as caps on the SENESCENCE IMPORTANT?
ends of chromosomes. Each
time a cell divides, it must first Scientists today focus on
double its chromosomes, so that ­several key aspects of cellular
each daughter cell receives a full ­senescence. The first may explain
complement of genetic material. Most normal human cells can why such a phenomenon would
But each time a chromosome exist. Scientists note that ­limiting
undergo between 40 and 60
reproduces itself, it loses a small the number of divisions a cell can
portion of its telomeres. When a
cell divisions, but then can undergo may serve to suppress
cell’s telomeres have reached a divide no more. tumor formation and cancer. With
critically short length, after 40 to each normal cell division, the
60 population doublings in young ­possibility of genetic mutation
can also be triggered by any type ­exists. Some of those mutations
human cells, the cell can no longer of severe damage to the genome
replicate its chromosomes and can make cells cancerous. A finite
or epigenome (the packaging and life span for cells would reduce
thus will stop dividing. These cells organization of the genome). It can
with shortened telomeres that can the likelihood that potentially
also be triggered by mutations ­cancerous cells can survive.

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Telomeres can be pictured as caps on the ends of chromosomes. Each time a cell divides,
it loses a small portion of its telomeres.

A second important phenomenon secreted proteins to communicate ­ nsure that a proper balance is
e
associated with cellular ­senescence their damaged state to the tissue maintained between ­circulating
is the many changes in ­function and help prepare the tissue for white blood cells and other
that occur in all cells as they repair. However, as senescent cells ­components of the blood.
­approach senescence. Many accumulate with age, the chronic
senescent cells stop functioning presence of the proteins they HOW IS CELLULAR SENESCENCE
as they did when they still had the ­secrete can eventually compro- RELATED TO AGING AND AGE-
­capacity to divide. These hundreds mise tissue integrity and function. RELATED DISEASES?
of functional losses that precede
the loss of division capacity in Replicative senescence also plays As normal cells become
normal cells mimic many of the an important role in the functioning ­senescent—whether due to
functional losses that occur in of many human systems, ­ongoing cell division, direct DNA
humans as we age, thus making ­including, for example, the ­damage, activated oncogenes
the study of these cells important ­immune system. When our ­bodies or any other cause—they incur
in learning more about aging. are confronted with infection, hundreds of biological changes
they produce white blood cells that affect many of their ­activities.
A third key feature of senescent called T lymphocytes that fight the Some of these changes are ­similar,
cells is their secretion of a large ­infection. Those white blood cells if not identical, to the kinds of
number of proteins that can affect reproduce themselves time and changes that we see occurring
neighboring cells. Many of these again in order to win this battle. in aging humans themselves.
secreted proteins are associated Cellular or replicative senescence, Scientists speculate that the many
with tissue repair and regenera- however, limits those lymphocytes losses in function that occur in
tion. Senescent cells, particularly to a specific number of repro- cells as they ­approach senes-
those with short telomeres or ductions. This may serve as one cence increase their vulnerability
genomic damage, may use these mechanism the body uses to to the diseases or pathologies that

Infoaging Guide to Cellular Senescence | 3


Our goal in this research and other
­research in the field of aging should
first be to understand why old cells
are more vulnerable to disease than
are young cells.

are so common in old age. Thus, and is thought to interact with p53. establish that link, revealing that
the study of ­cellular senescence They created transgenic mice that p44-transgenic mice had higher
­continues to provide important overexpress p44 and discovered circulating IGF-1 levels. Thus,
clues to the aging process at the that these ­animals showed signs ­hyperactivity of p53, caused by the
most fundamental level—the cell of premature aging after just four overexpression of p44, increased
and the pathways within the cell. months. This suggested that p44 IGF-1 levels. The new findings
increased the activity of p53, trig- indicated that ­hyperactive p53
One of those clues came in 2004 gering senescence and aging. can drive aging, at least in some
when Bernhard Maier, Heide ­tissues, by increasing ­production
­Scrable, and their colleagues at To find out why hyperactive p53 of IGF-1.
the University of Virginia demon- promotes aging, the research team
strated a direct link between p53, then looked at IGF-1 signaling. Clearly, p53 orchestrates an
a tumor-suppression pathway In animals such as nematodes ­equilibrium between ­several
that triggers senescence, and (roundworms), fruit flies, and mice, competing pathways that
the ­insulin-like growth factor-1 reducing IGF-1 levels increases ­balance tissue renewal and tumor
(IGF-1), an ­important pathway longevity, so finding a link be- ­suppression. Understanding this
linked to ­aging in mammals. The tween p53 and IGF-1 would add balance is crucial if we hope to
researchers actually focused on further clarification to the complex optimize protection from cancer
p44, which is expressed at low ­cellular pathways associated with while minimizing aging.
levels in mouse and human cells ­aging. The researchers did indeed

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Other evidence exists to ­suggest HOW IS CELLULAR mechanism that stops cell ­division
a relationship between ­cellular ­SENESCENCE RELATED TO may also serve to stop cancer
senescence and aging because CANCER? before it starts.
some of the senescent cells’
­functional losses appear to Scientists have postulated that Dr. Judith Campisi published a
­contribute to the aging process. cellular senescence evolved ­review of cellular senescence
For example, certain skin cells as a mechanism to prevent the in the journal Current Opinion
produce collagen during their ­incidence of cancer, a disease that in ­Genetics & Development in
younger, reproductive years. increases in frequency with aging. 2011. She noted that telomere
When they reach senescence While clearly not a failsafe ­method, ­shortening induces replicative
and can no longer divide, they without cellular senescence, senescence, the cessation of cell
produce ­collagenase, an enzyme cancer could well be inevitable division. Cellular senescence, in
that breaks down collagen. Some for all of us as we age. With each which the cells enter a phase in
researchers suggest that this cell ­division, cells can potentially which they have different functions
­process may be responsible for ­acquire mutations in their genes than they have while reproducing,
the thinning and wrinkling of skin that can lead to cancer, so a can come about after a variety
as we age.

Additional evidence comes from


research on Werner ­syndrome,
an inherited disease of ­premature
aging, which ­suggests that ­cellular
senescence can ­contribute
to ­age-related diseases.
­Comparisons of cells in culture
from younger persons with Werner
syndrome and older persons show
that both groups of cells have a
­limited ­ability to reproduce further.
Both cell types also go on to form
abnormal extracellular matrixes,
the frameworks that hold cells
together as tissues. This observa-
tion suggests that a small ­number
of senescent cells can affect
neighboring cells and tissues and
perhaps contribute to age-related
declines in the function of those
cells and tissues.

Some scientists also speculate


that the growth arrest ­associated
with replicative or ­reproductive
senescence may retard the
­regeneration or repair of damaged
tissue, which could play a role in
the aging of the body.

Understanding cellular senescence could result


in an increase in human life expectancy and more
disease-free years at the end of life.

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of stimuli. One such stimulus is at senescent cells that seem to that is possible. And because the
oxidative damage, and turning promote cancer. The ­researchers determinants of our longevity are
to a senescent phase can help studied senescent human fibro- driven indirectly by most, if not all,
cells that are suffering ­oxidative blasts, which are a variety of skin of our genes, it is also very unlikely
­damage to avoid becoming cells. They have found that these that tampering with that process is
­cancerous. senescent fibroblasts have the either probable or even desirable.
­effect of stimulating other skin
Because the very pathways that cells that are precancerous or Instead, our goal in this research
protect us from cancer, such as already cancerous to ­proliferate. and other research in the field of
p53, also drive the aging process, They do not stimulate normal aging should first be to understand
it seems that it might be dif- cells to proliferate. These ­studies why old cells are more ­vulnerable
ficult, if not impossible, to im- ­suggested that while ­cellular to disease than are young cells.
prove ­cellular tumor-suppression senescence suppresses the Once accomplished, those
mechanisms without accelerating formation of tumors in early life, ­differences, if exploitable, could
aging or to delay aging without senescent cells might promote the result in an increase in human life
causing cancer. However, recent formation of cancers in aging cells. expectancy and more disease-free
­studies with transgenic mice years at the end of life.
have shown that this might not RESEARCH INTO CELLULAR
be an ­inevitable conclusion. For SENESCENCE AND AGING
example, mice were created that
carried extra copies of a normally The goal of research on the
regulated p53 gene. These mice ­phenomenon of cellular senes-
displayed ­significant resistance to cence is not unlike the goal of all
cancer without showing signs of research on the biology of aging.
­premature aging. It is not to make us all immortal;
that is not only impossible but
On the other hand, work done at also undesirable. Nor is it to stop
the Lawrence Berkeley National or slow down the processes of
Laboratory in California has looked aging, because we do not know if

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