Zombie Cells, Longevity, and What’s Possible

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.”