“This study and later ones gave a
‘biological reason’ for senescent cells to
exist, which was to protect from can-
cer,” says Bill Keyes, a cell biologist
who studies senescence at the Institute
of Genetics and Molecular and Cellular
Biology in France. This idea has since
been validated, while Keyes and oth-
ers have discovered that senescent cells
may affect biological processes from
embryogenesis to the induction of labor
to wound healing. (See “The Bright Side
of Senescence” below.)
Ye t it soon became clear that senes-
cence has a downside, too. Intrigued by
observations of accumulations of senes-
cent cells in aging tissues in humans, cell
and molecular biologist Judith Camp-
isi of the Buck Institute for Research
on Aging in California decided to take
a closer look at the genes and pro-
teins expressed by senescent cells. In
2008, she and her colleagues reported
that secretions from senescent cells
contained dozens of proteins such as
inflammatory and immune-modulating
cytokines that could damage neighbor-
ing cells.^4 These proteins would laterhelp explain many of the pathological
effects of senescent cells in aging tissues.Meanwhile, Mayo Clinic geneticist
Jan van Deursen was investigating the
high concentrations of senescent cells
he’d found in a mutant strain of mice
that displayed accelerated aging, or
progeria.^5 After some experiments sug-
gested the cells could be the cause of theanimals’ symptoms, van Deursen, Kirk-
land, and others designed a technique to
trigger apoptosis only in cells that pro-
duced the protein p16—an imperfect
marker of senescence. In 2011, the team
reported that using this approach to kill
senescent cells delayed the onset of the
animals’ cataracts and other age-related
pathologies in tissues across the body,
and maintained their muscle function
for longer.^6 Later, van Deursen’s team
demonstrated that the treatment had a
similar effect in naturally aging mice.^7
“There was the key demonstration
that actually if you clear [senescent
cells], it made a significant difference
in health,” Paul Robbins, a molecular
biologist at the University of Minne-
sota, says of van Deursen’s 2011 study.
Together with Campisi’s research, “that
changed everybody’s thinking” about
cellular senescence, Robbins adds.
Many researchers now view senes-
cence as a beneficial process that
evolved as a developmental and cancer
prevention mechanism, but one that
came with a tradeoff of the damage
senescent cells can cause as they accu-THE BRIGHT SIDE OF SENESCENCE
In the past few decades, researchers have not only uncovered the dark side of senescence, but also its apparent positive eff ects in living organ-
isms. In the 1990s, cell biologist Manuel Serrano’s work suggested that senescence may act as a mechanism to suppress the formation of
tumors. When cells are exposed to genetic or cellular damage that would normally trigger uncontrollable replication, the senescence program
would be activated as a means of arresting growth entirely, Serrano and other researchers argue. This would save the cell from passing on dam-
age to its progeny, and the organism from growing tumors. “Senescence protects us from cancer,” Serrano says.
Senescent cells may also be crucial in early development. Research led by Bill Keyes, a cell biologist at the Institute of Genetics and Molec-
ular and Cellular Biology in France, suggests that senescent cells could guide development in chick embryos. In the limb, a senescent cell could
“become secretory and start instructing and informing and telling the other cells... which cell type to become and how to pattern the limb,”
Keyes explains. Waves of senescence also occur in mouse and human embryos, where they may similarly guide cell diff erentiation and tissue
patterning of surrounding cells via the proteins they secrete. This proposed embryological mechanism may be the driver of senescence evolu-
tion, likely co-opted later as a cancer prevention feature in maturity, Serrano explains.
Other possible functions of senescence in development continue to emerge. Just last year, for instance, the University of Texas’s Ramku-
mar Menon, who studies fetomaternal communication, found that cells within the membranes surrounding human fetuses undergo senes-
cence when the fetus is fully developed and generate infl ammatory signals in the womb, which he proposes acts as a cue to the mother’s
body to initiate labor.
Senescence appears to maintain its importance throughout life: studies indicate that in addition to the proinfl ammatory factors that senes-
cent cells secrete, they also exude growth factors and enzymes that stimulate tissue repair. For this reason, “we need to be really intelligent
about how we manipulate it in the elderly to improve [health later in life],” notes cell and molecular biologist Judith Campisi of the Buck Insti-
tute for Research on Aging in California. A major challenge she sees in developing senolytic drugs will be to fi nd compounds that kill groups of
senescent cells that are harmful to their environment while sparing benefi cial ones. “I think that’s going to be the wave of the future,” she says,
“drilling down and understanding this complexity so that the drugs can be more tailored to eliminate subpopulations as opposed to all of them.”
Researchers argue that
while many agents
hyped as elixirs of
youth have repeatedly
failed to show benefi ts
in clinical studies, the
concept of senolytics
will stand the test
of time.