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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.
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
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