03.2020 | THE SCIENTIST 39T
he little black mouse’s feet dan-
gled above the table as the ani-
mal clutched a horizontal wire
with its two front paws. After just a few
seconds, it lost its grip and fell onto a
pile of bedding below. For a mouse its
age—just six months old, typically its
physical prime—that was quite unusual.
As Mayo Clinic veterinary technicians
Christina Inman and Kurt Johnson
knew, young mice would usually man-
age to hoist their hind legs up to the
wire so that they’re hanging from all
four limbs, allowing them to last min-
utes, sometimes even hours, on the
endurance test.
It was late 2016, and the two vet
techs were in charge of testing the phys-
ical performance of dozens of young
mice as part of a study led by Mayo ger-
iatrician and aging researcher James
Kirkland. The experiment was blinded,
so Inman and Johnson knew nothing of
the animals’ treatments, but they would
later learn why that mouse, along with
five others, had scored so miserably on
the wire task: two weeks before, another
mouse’s fat progenitor cells, which had
been exposed to irradiation or other
stressors, were implanted into their
lower abdomens. The transplanted cells
had been transfixed into a zombie-like
state by the treatment; they couldn’t
proliferate, but they wouldn’t die. They
had reached cellular senescence.
For decades, scientists had ignored
senescent cells—which are trapped in
a long-term state of cell cycle arrest—
dismissing them as artifacts of cell
culture with no significance inside
living organisms. But in recent years,
Kirkland and other researchers have
established senescence as an important
physiological process that appears to
play seemingly opposing roles in vivo.
On the one hand, senescent cells are
thought to mediate tissue development
when they form in the embryo, and also
to promote tissue regeneration and
wound repair in later life. However,
as these zombie cells accumulate with
age, they can ooze inflammatory pro-
teins believed to cause tissue dysfunc-tion and to push neighboring cells into
senescence. Indeed, animal studies have
suggested that destroying senescent
cells can slow down age-related physi-
cal decline and boost overall health,
and many researchers who study aging
now regard senescence as a driver of
the physical decline characteristic of
old age and a contributor to a range of
age-related diseases.To Kirkland, senescent cells are not
unlike pathogens that infect multi-
ple tissues and drive various maladies.
Implanting around 1 million senescent
cells into each of the six young mice
crippled their fitness performance com-
pared with that of control mice that had
received implants of non-senescent fat
cells. Repeating the procedure with just
half a million cells in a slightly older
set of mice increased their risk of death
within a year—typically due to cancer,
lung and gut diseases, or neurodegener-
ation—compared with controls. “Trans-
planting senescent cells accelerated most
or all of the diseases that mice die of in
old age,” Kirkland tells The Scientist. But
he had a plan to impede the decline.
In another experiment, techni-
cians fed 20-month-old mice—roughly
the equivalent of 57- to 67- year-old
humans—a mixture of two drugs that
Kirkland had previously demonstrated
could selectively kill senescent cells:
dasatinib, a drug often used in con-
junction with chemotherapy, and quer-
cetin, a flavonoid found in onions andapples. Just two weeks after receiving
the combo treatment, the mice ran fur-
ther, performed better on other physi-
cal tests, and were 36 percent less likely
to die the following year compared with
animals that had received injections of
senescent cells but no drug cocktail,
Kirkland and his colleagues reported
in 2018.^1 Together with other research,
these findings fortified the idea that
killing off senescent cells can rescue old
animals from the physical deterioration
that comes with age, and extend the
duration of healthy, disease-free life.
Now, researchers, pharmaceutical
companies, and investors are working
on ways to destroy senescent cells in
hopes of one day alleviating the ravages
of old age in people. Several biotechs
have sprouted in recent years to identify
compounds that target senescent cells
and put such “senolytic” drugs to the
test in humans—efforts that are sup-
ported by considerable funding influxes
from both federal and private sources.
The National Institutes of Health (NIH)
has recently awarded several seven-
figure grants to support Phase 2 testing
of senolytics in cancer treatment, for
example, and the prospect of conquer-
ing age-related debility has reportedly
attracted investment from billionaires
such as PayPal cofounder Peter Thiel
and Amazon CEO Jeff Bezos.
Making use of the surge in inter-
est, Kirkland and others have cautiously
launched a wave of clinical studies to eval-
uate whether senolytic agents offer prom-
ise in treating serious age-related ail-
ments such as osteoarthritis, kidney and
lung fibrosis, and Alzheimer’s disease.
Although many questions remain about
senescence and its role in the aging pro-
cess, these researchers argue that unlike
other agents hyped as elixirs of youth that
have repeatedly failed to show benefits in
clinical studies, the concept of senolytics
will stand the test of time.
“That getting rid of senescent cells
is enough to effectively rejuvenate an
animal—that tells you they’re a really
important driver of aging,” says Lorna
Harries, a molecular geneticist at theThat getting rid of
senescent cells is
enough to eff ectively
rejuvenate an animal—
that tells you they’re a
really important driver
of aging.
—Lorna Harries, University of Exeter