[Researchers are investigating medicines that selectively kill
decrepit cells to promote healthy aging — but more work is needed
before declaring them a fountain of youth]
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COULD GETTING RID OF OLD CELLS TURN BACK THE CLOCK ON AGING?  
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Amber Dance
December 21, 2022
Knowable Magazine
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_ Researchers are investigating medicines that selectively kill
decrepit cells to promote healthy aging — but more work is needed
before declaring them a fountain of youth _

Cheek cells, by biologycorner (CC BY-NC 2.0)

 

James Kirkland started his career in 1982 as a geriatrician, treating
aging patients. But he found himself dissatisfied with what he could
offer them.

“I got tired of prescribing wheelchairs, walkers and incontinence
devices,” recalls Kirkland, now at the Mayo Clinic in Rochester,
Minnesota. He knew that aging is considered the biggest risk factor
for chronic illness, but he was frustrated by his inability to do
anything about it. So Kirkland went back to school to learn the skills
he’d need to tackle aging head-on, earning a PhD in biochemistry at
the University of Toronto. Today, he and his colleague Tamara
Tchkonia, a molecular biologist at the Mayo Clinic, are leaders in a
growing movement to halt chronic disease by protecting brains and
bodies from the biological fallout of aging.

If these researchers are successful, they’ll have no shortage of
customers: People are living longer, and the number of Americans age
65 and older is expected to double
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to 80 million, by 2040. While researchers like Kirkland don’t expect
to extend lifespan, they hope to lengthen “health span,” the time
that a person lives free of disease.

One of their targets is decrepit cells that build up in tissues as
people age. These “senescent” cells have reached a point — due
to damage, stress or just time — when they stop dividing, but
don’t die. While senescent cells typically make up only a small
fraction of the overall cell population, they accounted for up to 36
percent of cells
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in some organs in aging mice, one study showed. And they don’t just
sit there quietly. Senescent cells can release a slew of compounds
that create a toxic, inflamed environment that primes tissues for
chronic illness. Senescent cells have been linked to diabetes, stroke,
osteoporosis and several other conditions of aging.

These noxious cells, along with the idea that getting rid of them
could mitigate chronic illnesses and the discomforts of aging, are
getting serious attention. The US National Institutes of Health is
investing $125 million in a new research effort, called SenNet, that
aims to identify and map senescent cells
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in the human body as well as in mice over the natural lifespan. And
the National Institute on Aging has put up more than $3 million over
four years for the Translational Geroscience Network
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Kirkland that is running preliminary clinical trials of potential
antiaging treatments. Drugs that kill senescent cells — called
senolytics — are among the top candidates. Small-scale trials of
these are already underway in people with conditions including
Alzheimer’s, osteoarthritis and kidney disease.

“It’s an emerging and incredibly exciting, and maybe even
game-changing, area,” says John Varga, chief of rheumatology at the
University of Michigan Medical School in Ann Arbor, who isn’t part
of the TGN.

But he and others sound a note of caution as well, and some scientists
think the field’s potential has been overblown. “There’s a lot
of hype,” says Varga. “I do have, I would say, a very healthy
skepticism.” He warns his patients of the many unknowns and tells
them that trying senolytic supplementation on their own could be
dangerous.

Researchers are still untangling the biology of senescent cells, not
only in aging animals but in younger ones too — even in embryos,
where the aging out of certain cells is crucial for proper
development. So far, evidence that destroying senescent cells helps to
improve health span mostly comes from laboratory mice. Only a couple
of preliminary human trials have been completed, with hints of promise
but far from blockbuster results.

Even so, Kirkland and Tchkonia speculate that senolytics might
eventually help not only with aging but also with conditions suffered
by younger people due to injury or medical treatments such as
chemotherapy. “There may be applications all over the place,”
muses Kirkland.

Good cells gone bad

Biologists first noticed senescence when they began growing cells in
lab dishes more than 60 years ago. After about 50 cycles of cells
first growing, then dividing, the rate of cell division slows and
ultimately ceases. When cells reach this state of senescence, they
grow larger and start exhibiting a variety of genetic abnormalities.
They also accumulate extra lysosomes
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baglike organelles that destroy cellular waste. Scientists have found
a handy way to identify many senescent cells by using stains that turn
blue in the presence of a lysosome enzyme, called beta-galactosidase,
that’s often overactive in these cells.

Scientists have also discovered hundreds of genes that senescent cells
activate to shut down the cell’s replication cycle, change their
biology and block natural self-destruct mechanisms. Some of these
genes produce a suite of immune molecules, growth factors and other
compounds. The fact that specific genes consistently turn on in
senescent cells indicates there may be more to senescence than just
cells running out of steam. It suggests that senescence is a cellular
program that evolved for some purpose in healthy bodies. Hints at that
purpose have emerged from studies of creatures far earlier in their
lifespan — even before birth.

Cell biologist Bill Keyes was working on senescence in embryos back in
the early 2000s. When he stained healthy mouse and chick embryos to
look for beta-galactosidase, little blue spots lit up in certain
tissues. He soon met up with Manuel Serrano, a cell biologist at the
Institute for Research in Biomedicine in Barcelona, who’d noticed
the same thing. Cells with signs of senescence turned up in the
developing brain, ear and limbs, Keyes and Serrano reported in 2013.

Keyes, now at the Institute of Genetics and Molecular and Cellular
Biology in Strasbourg, France, focused on mouse and chick embryonic
limbs, where a thread of temporary tissue forms across the future
toe-tips. Unlike most embryonic cells, the cells in this thread of
tissue disappear before the animal is born. They release chemicals
that help the limb develop
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and once their work is done, they die. At a molecular level, they look
a lot like senescent cells
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Serrano, meanwhile, looked at cells in an organ that exists only in
embryos: a temporary kidney, called the mesonephros, that forms near
the heart. Once the final kidneys develop, the mesonephros disappears.
Here too, beta-galactosidase and other compounds linked to senescence
appeared
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in mouse embryos.

The cells in these temporary tissues probably disappear _because_ they
are senescent. Certain compounds made by senescent cells call out to
the immune system to come in and destroy the cells once their work is
done. Scientists think the short-term but crucial jobs these cells
perform could be the reason senescence evolved in the first place.

Other studies suggest that senescent cells may also promote health in
adult animals. Judith Campisi, a cell biologist at the Buck Institute
for Research on Aging in Novato, California, and others have found
senescent cells in adult mice, where they participate in wound
healing. Connective-tissue cells called fibroblasts fill in a wound,
but if they stick around, they form abnormal scar tissue. During
normal wound healing, they turn senescent, releasing compounds that
both promote repair of the tissue and call immune cells to come in and
destroy them.

In other words, the emergence of senescent cells in aging people
isn’t necessarily a problem in and of itself. The problem seems to
be that they hang around for too long. Serrano suspects this happens
because the immune system in aging individuals isn’t up to the task
of eliminating them all. And when senescent cells stay put, the
cocktail of molecules they produce, and the ongoing immune response,
can damage surrounding tissues.

Senescence can also contribute to cancer
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as Campisi has described in the _Annual Review of Physiology_, but the
relationship is multifaceted. Senescence itself is a great defense
against cancer — cells that don’t divide don’t form tumors. On
the other hand, the molecules senescent cells emit can create an
inflamed, cancer-promoting environment. So if a senescent cell arises
near a cell that’s on its way to becoming cancerous, it might alter
the locale enough to push that neighbor cell over the edge. In fact,
Campisi reported in 2001 that injecting mice with senescent cells made
tumors grow bigger faster
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Mighty mice

If senescent cells in an aging body are bad, removing them should be
good. To test this idea, Darren Baker, a molecular cell biologist at
the Mayo Clinic, devised a way to kill senescent cells in mice. Baker
genetically engineered mice so that when their cells turned senescent,
those cells became susceptible to a certain drug. The researchers
began injecting the drug twice a week once the mice turned one year
old — that’s about middle age for a lab mouse.

Treated mice maintained healthier kidney, heart, muscle and fat tissue
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mice, and though they were still susceptible to cancer, tumors
appeared later in life, the researchers reported in studies in 2011
and 2016. The rodents also lived, on average, five or six months
longer [[link removed]].

These results generated plenty of interest, Baker recalls, and set
senescence biology on the path toward clinical research. “That was
the boom — a new era for cellular senescence,” says Viviana Perez,
former program officer for the SenNet consortium at the National
Institute on Aging.

Baker followed up with a study of mice that had been genetically
modified to develop characteristics of Alzheimer’s. Getting rid of
senescent cells staved off the buildup of toxic proteins in the brain,
he reported, and seemed to help the mice to retain mental acuity
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their ability to remember a new smell.

Of course, geriatricians can’t go about genetically engineering
retirees, so Kirkland, Tchkonia and colleagues went hunting for
senolytic drugs that would kill senescent cells while leaving their
healthy neighbors untouched. They reasoned that since senescent cells
appear to be resistant to a process called apoptosis, or programmed
cell death, medicines that unblock that process might have senolytic
properties.

Some cancer drugs do this, and the researchers included several of
these in a screen of 46 compounds they tested on senescent cells grown
in lab dishes. The study turned up two major winners
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the cancer drug dasatinib, an inhibitor of several natural enzymes
that appears to make it possible for the senescent cells to
self-destruct. The other was quercetin, a natural antioxidant that’s
responsible for the bitter flavor of apple peels and that also
inhibits several cellular enzymes. Each drug worked best on senescent
cells from different tissues, the scientists found, so they decided to
use them both, in a combo called D+Q, in studies with mice.

In one study, Tchkonia and Kirkland gave D+Q to 20-month-old mice and
found that the combination improved the rodents’ walking speed and
endurance in lab tests, as well as their grip strength. And treating
two-year-old mice — the equivalent of a 75- to 90-year-old human —
with D+Q every other week extended their remaining lifespan
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percent, compared with mice that didn’t receive senolytics, the
researchers reported in 2018. Tchkonia, Kirkland and Baker all hold
patents related to treating diseases by eliminating senescent cells.

To the clinic

Scientists have since discovered several other medications with
senolytic effects, though D+Q remains a favorite pairing. Further
studies from several research groups reported that senolytics appear
to protect mice against a variety of conditions of aging, including
the metabolic dysfunction associated with obesity, vascular problems
associated with atherosclerosis, and bone loss akin to osteoporosis.

“That’s a big deal, collectively,” says Laura Niedernhofer, a
biochemist at the University of Minnesota Medical School in
Minneapolis who is a collaborator on some of these studies and a
member of the TGN clinical trials collaboration. “It would be a
shame not to test them in humans.”

A few small human trials have been completed. The first, published in
2019, addressed idiopathic pulmonary fibrosis, a fatal condition in
which the lungs fill up with thick scar tissue that interferes with
breathing. It’s most common in people 60 or older, and there’s no
cure. In a small pilot study, Kirkland, Tchkonia and collaborators
administered D+Q to 14 people with the condition, three times a week
for three weeks. They reported notable improvement
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in the ability of participants to stand up from a chair and to walk
for six minutes. But the study had significant caveats: In addition to
its small size and short duration, there was no control group, and
every participant knew they’d received D+Q. Moreover, the
patients’ lung function didn’t improve, nor did their frailty or
overall health.

Niedernhofer, who wasn’t involved in the trial, calls the results a
“soft landing”: There seemed to be something there, but no major
benefits emerged. She says she would have been more impressed with the
results if the treatment had reduced the scarring in the lungs.

The TGN is now running several small trials for conditions related to
aging, and other diseases too. Kirkland thinks that senescence may
even be behind conditions that affect young people, such as
osteoarthritis due to knee injuries
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childhood cancer survivors
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Tchkonia and Kirkland are also investigating how space radiation
affects indications of senescence in the blood and urine of
astronauts, in conjunction with two companies, SpaceX and Axiom Space.
They hypothesize that participants in future long-term missions to
Mars might have to monitor their bodies for senescence or pack
senolytics to stave off accelerated cellular aging caused by extended
exposure to radiation.

Kirkland is also collaborating with researchers who are investigating
the use of senolytics to expand the pool of available transplant
organs. Despite desperate need, about 24,000 organs from older donors
are left out of the system every year because the rate of rejection is
higher for these than for younger organs, says Stefan Tullius, chief
of transplant surgery at Brigham and Women’s Hospital in Boston. In
heart transplant experiments with mice, he reported that pretreating
older donor mice with D+Q before transplant into younger recipients
resulted in the donor organs working “as well or slightly better”
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young donors.

“That was huge,” says Tullius. He hopes to be doing clinical
trials in people within three years.

Healthy skepticism

Numerous medical companies have jumped on the anti-senescence
bandwagon
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notes Paul Robbins, a molecular biologist at the University of
Minnesota Medical School. But results have been mixed. One
front-runner, Unity Biotechnology of South San Francisco, California,
dropped a top program in 2020 after its senolytic medication failed to
reduce pain in patients with knee osteoarthritis
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“I think we just don’t know enough about the right drug, the right
delivery, the right patient, the right biomarker,” says the
University of Michigan’s Varga, who is not involved with Unity. More
recently, however, the company reported progress
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in slowing diabetic macular edema, a form of swelling in the back of
the eye due to high blood sugar.

Despite the excitement, senolytic research remains in preliminary
stages. Even if the data from TGN’s initial, small trials look good,
they won’t be conclusive, says network member Robbins — who
nonetheless thinks positive results would be a “big deal.” Success
in a small study would suggest it’s worth investing in larger
studies, and in the development of drugs that are more potent or
specific for senescent cells.

“I’m urging extreme caution,” says Campisi — who is herself a
cofounder of Unity and holds several patents related to
anti-senescence treatments. She’s optimistic about the potential for
research on aging to improve health, but worries that moving
senolytics quickly into human trials, as some groups are doing, could
set the whole field back. That’s what happened with gene therapy in
the late 1990s when an experimental treatment killed a study volunteer
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“I hope they don’t kill anyone, seriously,” she says.

Side effects are an ongoing concern. For example, dasatinib (the D in
D+Q) has a host of side effects
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ranging from nosebleeds to fainting to paralysis.

But Kirkland thinks that may not be an insurmountable problem. He
notes that these side effects show up only in cancer patients taking
the drug regularly for months at a time, whereas anti-senescence
treatments might not need to be taken so often — once every two or
three months might be enough to keep the population of senescent cells
under control.

Another way to reduce the risks would be to make drugs that target
senescent cells in specific tissues
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Niedernhofer and Robbins note in the _Annual Review of Pharmacology
and Toxicology_. For example, if a person has senescent cells in their
heart, they could take a medicine that targets only those cells,
leaving any other senescent cells in the body — which still might be
doing some good — alone.

For that strategy to work, though, doctors would need better ways to
map senescent cells in living people. While identifying such
biomarkers is a major goal for SenNet, Campisi suspects it will be
hard to find good ones. “It’s not a simple problem,” she says.

A lot of basic and clinical research must happen first, but if
everything goes right, senolytics might someday be part of a
personalized medicine plan: The right drugs, at the right time, could
help keep aging bodies healthy and nimble. It may be a long shot, but
to many researchers, the possibility of nixing walkers and wheelchairs
for many patients makes it one worth taking.

10.1146/knowable-122122-1

AMBER DANCE, a contributing writer at _Knowable Magazine_, looks
forward to a long, healthy retirement punctuated by regular
anti-senescence treatments.

This article originally appeared in _Knowable Magazine_
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endeavor from Annual Reviews. Sign up for the newsletter
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[Knowable Magazine | Annual Reviews]

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