For many
people, living longer brings health challenges: Osteoporosis, diabetes,
Alzheimer’s disease. And of course, zombie cells.
The technical
term is senescent cells. They’re damaged and unable to repair
themselves. They’re also more likely to linger in the body as we age —
like zombies — secreting inflammatory molecules that can hasten our
decline.
“They have this very robust secretory phenotype,” said Nathan K. LeBrasseur, PhD,
director of the Robert and Arlene Kogod Center on Aging at Mayo Clinic.
“They drive things such as impaired tissue regeneration, fibrosis,
degeneration, inflammation — a lot of the conditions that are clearly
central to age-related diseases. And that’s what’s exciting about these
cells as therapeutic targets.”
That
is, targets for senolytics, the still-experimental drugs and
supplements that eliminate senescent cells or tamp down their ill
effects. Cancer is a particularly promising research area for senolytics
(some existing chemo drugs have senolytic properties).
Proponents
like LeBrasseur aren’t preaching about extreme longevity, but the
health span/lifespan argument. They speak in practical terms about
making life easier for people as they get older.
“We’re
really not interested in making drugs to help us live until we’re 120
and feel like we’re 120,” he said. “If we have no effect on lifespan,
that’s perfectly fine, but let’s increase the number of active and
productive years that are not overly burdened by disease and
disability.”
It
sounds tantalizingly possible — and sort of gimmicky. The internet
teems with products claiming to be “antiaging” senolytics. But the
internet teems with a lot of things.
What’s real about senolytics as a future therapeutic option and how might they truly affect how people age?
The State of Senolytics
Since the first senolytics were discovered in 2015, much of the promising research has been in mice. Some early senolytics, like navitoclax (ABT-263) and ABT-737, have stalled out (they ended up killing platelets in people and speeding up ovarian aging in older female mice). So far, the most effective senolytics are existing chemotherapy drugs.
“We
don’t have this medicine cabinet full of options to take into humans,”
LeBrasseur said. “There’s a couple of repurposed drugs that are being
tried and trialed.”
Here’s where things stand now. Roughly 20 clinical trials are underway, and at least 10 more are planned or have
published some results. There are trials on senolytics for
osteoarthritis, COVID-19, Alzheimer’s, and Parkinson’s diseases,
according to Paul Robbins, PhD,
associate director of the Masonic Institute on the Biology of Aging and
Metabolism and a professor at the University of Minnesota. Another
trial is treating grafts from older donors with senolytics before
transplant. Amid these investigations, emerging evidence shows that
senolytics can reduce senescence in humans and provide other benefits.
Robbins points to the results of a “very positive trial” led by Unity Biotechnology, published last year. It showed that a senolytic called foselutoclax
benefited people with advanced diabetic macular edema. A single
injection in the back of the eye improved their sight, especially in the
dark, for at least 6 months. The drug works by inhibiting a protein
that regulates cell death, leading to a removal of senescent cells that
researchers believe spurs healing in the eye.
Another standout
senolytic is known as D+Q, a combination of dasatinib (a US Food and
Drug Administration [FDA]–-approved chemotherapy drug) and quercetin (a
flavonoid found naturally in many foods). Dasatinib targets certain
classes of receptors on the surface of some — but not all — senescent
cells, triggering “a natural death process,” LeBrasseur explained. “It’s
kind of flipping off a light switch in the cell, so it goes to sleep.”
Research published in 2017 and 2018 found that D+Q improved bone density, lifespan, and physical function in older mice. Co-author Ming Xu, PhD,
an associate professor at the University of Minnesota, said those
studies “laid the foundation for a number of ongoing clinical trials.”
A phase 1 clinical trial
showed that intermittent doses of D+Q improved physical function in 12
older people with idiopathic pulmonary fibrosis, a serious lung disease.
And a phase 2 trial
in 60 healthy postmenopausal women showed that D+Q boosted formation of
new bone tissue, but did not reduce bone resorption (the breakdown and
removal of old bone tissue).
Importantly, 10 women with the
highest baseline biomarkers for senescent cell burden benefited more —
with increases in bone formation, less bone resorption, and enhanced
wrist bone mineral density.
That
kind of finding can help move the needle, according to LeBrasseur. “One
challenge in our field is, how do we select individuals who best
respond to these interventions?” he said.
Major Roadblock: The Heterogeneity of Senescent Cells
Senescent cells are extremely heterogeneous, and researchers are still determining what that looks like in a broad sense. The SenNet Consortium,
funded by the National Institutes of Health Common Fund, is a vast
research network striving to spatially map senescent cells in human
tissues.
“It’s turned out to be a monster of a task,” said
Robbins. “A senescent cell in the kidney is different than the liver,
which is different than the brain.”
Even
within the same tissues, there can be numerous distinct subpopulations
of senescent cells, according to Xu. And totally different cells might
share senescence features. Take p16 and p21, two proteins identified as
drivers of cell senescence. Even if some cells highly express p16,
whereas others highly express p21, they might have senescent features in
common, causing a drug to clear cells that shouldn’t be cleared.
“The
problem is, we can’t really differentiate between them. We don’t have
good markers that separate them,” Robbins said. “But it seems that
functionally, if you treat with senolytics in an old animal, that’s
beneficial. There’s conflicting data in young animals about whether
there’s good or bad effects of trying to clear these cells.”
Adding
to the mystery: Not all senescent cells are bad. In fact, “senescence
has sort of evolved as an anticancer mechanism,” Robbins said. Some
senescent cells are linked to tumor suppression, wound healing, and
tissue repair. Generally speaking, the immune system clears these cells
not long after detecting them but immune dysfunction and other factors
like old age may prevent that and the cells can become pro-inflammatory and not so friendly.
Senescent
cells are damaged and unable to repair themselves, but not so damaged
that they self-destruct — a process called apoptosis. For reasons
scientists don’t fully understand, senescent cells upregulate pathways
that keep them from dying. It could be that the body has an “immune
memory” against senescent cells.
“There must be an advantage to having the cells survive and then have the immune system kill them,” Robbins said.
To
that end, many researchers are developing immunotherapies to target and
clear senescent cells. A team at Memorial Sloan Kettering Cancer Center
and Cold Spring Harbor Laboratory showed
that engineered immune cells used for treating blood cancers had a
senolytic effect in aging mice. Their metabolic function improved when
CAR T cells eliminated urokinase plasminogen activator receptor, a
senescent-associated protein. The treatment also protected against
metabolic decline in younger mice.
A Senolytic ‘Cocktail’
Chemotherapy
drugs, senolytic cell inhibitors, and immunotherapy are just some of
the emerging senolytic options. Robbins and his colleagues are working
on a senolytic lipid, a senolytic RNA, and senolytic natural compounds.
They’re part of a phase 2 clinical trial investigating if the senolytic drug Fisetin (a flavonoid found in many fruits and vegetables) can thwart severe COVID-19.
All
these senolytics “seem to target different classes of senescent cells,”
Robbins said. And different senescent cells could contribute to a
single disease. That’s why a “cocktail” of senolytics could ultimately
emerge, he said. Your cocktail could depend on whether “you’re just
trying to maintain your health vs trying to treat Alzheimer’s vs trying
to treat other conditions.”
Felix Wong, PhD,
co-founder of biotechnology company Integrated Biosciences, agrees.
“There’s not going to be just one blockbuster senolytic, but perhaps
many multiple different senolytics,” Wong said.
Two years ago, Wong’s team used deep learning to
discover three potential senolytic compounds from a database of 800,000
molecules. They trained a graph neural network, a type of artificial
intelligence model, to make predictions of senolytic activity based on
chemical structure alone. When injected into aged mice, the compounds
decreased the accumulation of senescent cells. Promising — but still a
long way from your medicine cabinet. Wong said that Integrated
Biosciences is still examining which disease models the compounds might
be efficacious in.
“The FDA doesn’t recognize aging as a disease, so you’ll have to go after a specific indication,” Wong said.
That’s true, at least for now. Last December, Advanced Research Projects Agency for Health (ARPA H), an agency within the US Department of Health and Human Services, launched Proactive Solutions for Prolonging Resilience (PROSPR).
The initiative could lead to a measurement of “intrinsic capacity” — a
potential yardstick for testing drugs that target aging more broadly —
according to LeBrasseur. Even so, he suggests it might be another decade
before the field can say with confidence that a senolytic works.
What About Nature’s Senolytic?
In the meantime, of course, there’s exercise. LeBrasseur’s research
has shown that higher levels of “habitual physical activity” — daily
activities like walking and getting up out of your chair that make you
“a little less sedentary” — is associated with lower biomarkers of
senescence in adults in their 70s and 80s.
“Exercise can prevent
senescence from occurring,” LeBrasseur said. “And there’s a lot of
favorable data to show exercise can help optimize immune health and
function, creating healthier environments and tissues for immune cells
to recognize, target, and eliminate senescent cells.”
Wong is
still hoping for a shift in thinking about the ability to treat aging.
He pointed out that glucagon-like peptide 1 (GLP-1) agonists show
benefits well beyond obesity, treating neurodegenerative and kidney
diseases associated with aging, for instance.
“The battle call is
out there. We all know that GLP-1 agonists are broadly, quote-unquote,
antiaging, and I think that represents a paradigm shift,” Wong said.
“There’s a growing appreciation for the fact that we can, using
therapeutic interventions, actually move the needle across different
age-related diseases.”
