Senolytics that target age-related “zombie” cells could be game-changing for extending lifespans and enabling long-haul space travel.
With the launch of any new therapeutic class of drugs comes an inevitable mix of hopeless romanticism and cautious optimism buttressed by an onslaught of opposing theoretical arguments promising either a silver bullet or a Pandora’s box.
Any new class of drugs faces intense scrutiny, but it’s particularly confounding when some people push its potential to save the world while others howl only of danger. This confusion is multiplied when the proposed panaceas are already being sold like snake oil across the internet and adopted into the daily regimens of clinical thought leaders while they’re still being rigorously tested in clinical trials, where they could be proven—or axed.
For those tracking the latest developments in the aging field (geroscience), this is where we find ourselves in the ongoing tale of the therapeutic class of drugs known as senolytics: The jury is still out. These senolytic agents, whether naturally occurring compounds or lab-synthesized chemicals, eliminate cells that are senescent—a seemingly inevitable state of arrested growth and replicative abilities causally linked to aging and age-related diseases. Although they are an adaptive mechanism to limit the proliferation of damaged cells and to disable potential malignant cell transformation, senescent cells pile up as we get older and can perpetrate all sorts of aging diseases like osteoporosis, cardiovascular disease, and neurodegenerative disorders, among others.
But are senolytics safe and effective—let alone the right way to deal with the gargantuan medical, societal, and economic issues elicited by people living longer and spending more years susceptible to age-related diseases?
The argument for removing senescent cells
Senescent cells are like a poison-tipped, double-edged sword living inside our bodies. On the one hand, the inability of these cells to replicate means that they do not contribute to the constant need for cellular turnover from wear and tear in our bodies. We are not born with a finite number of cells—we don’t even go to sleep with many of the same cells we woke up with at the start of the day. Certain tissues, such as our gut, skin, and blood, are constantly undergoing cell turnover. So senescent cells don’t help our bodies rejuvenate to keep up with the daily cellular demand for everyday functions, let alone helping it heal when injured or damaged. On the other hand, these seemingly zombie-like senescent cells, which aren’t dead but don’t function like a living cell, defy nature’s inherent programs to shrivel up and die. And that’s what makes them potentially poisonous. Senescent cells secrete compounds that woo the cells around them, luring them into a similar ghoulish fate.
The harmful disposition of senescent cells isn’t just theoretical. There is compelling evidence that senescence burden drives lots of diseases in many organs, including the liver, kidney, and heart. These cellular wraiths can spur tissue degeneration, increase susceptibility to age-related diseases, and pave the road for the death march toward frailty and eventual death.
No one wants to abstain from eating when they can take a pill or receive an injection to live longer.
But in nature, some creatures have found a way to override senescence. There are species with negligible senescence that do not exhibit aging, and there are even potentially immortal organisms like the tiny freshwater hydra (Hydra vulgaris), known for its regenerative abilities similar to the eponymous nine-headed creature from Greek myths. These creatures have motivated researchers to find ways of removing senescent cells to combat age-related diseases.
For example, some of the first evidence for the positive effects of removing senescent cells began with a study showing that mice, worms, and other animals that were intermittently calorically restricted had lower numbers of these undead cells—along with extended healthspans and longer lives.
But if those basic studies demonstrate the therapeutic promise of fasting to live longer, the human market for health products dictates a more sober reality: No one wants to abstain from eating when they can take a pill or receive an injection to live longer and in good health instead.
Bailing water from a sinking ship
But not everyone agrees with this basic assumption. Michael Fossel isn’t convinced that attacking senescent cells is the right entry point to improve healthspan and increase longevity. A former professor of clinical medicine at Michigan State University for almost 30 years and the founder and president of Telocyte, an anti-aging company, he argues that people are looking at senescent cells all wrong.
According to Fossel, senescent cells are not at the center of aging at all, but rather a byproduct. He argues that eliminating them is ineffective for getting ahead of aging and could even be counterproductive. To paint the picture, he evokes the analogy of the body as a large manufacturing facility.
“Say you run a big factory. You’ve got a hundred people working in your factory, and over time you have decided you’re going to save money. You’re going to pay them less and less. Every year, a certain number of those people get cranky and crankier, and then ten of them go on strike,” he says. The senolytics-informed approach would be to fire those ten people but not hire anybody to replace them.
“Now you have ninety remaining people that are not only working for less—they’re doing more because they have to make up for the people you fired.”
Others are cautiously optimistic. James Kirkland, the director of the Robert and Arlene Kogod Center on Aging at the Mayo Clinic, which is at the forefront of senolytic clinical research, has a more grounded view.
He has high hopes for senolytics but firmly believes that the only way to evaluate them is within the context of carefully controlled clinical trials for serious diseases related to biological aging and the deterioration of cells and tissues—regardless of how old you may be. Such studies, Kirkland believes, are best suited for severe and life-threatening diseases where there is a very high risk–benefit ratio, such as Alzheimer’s, chronic kidney diseases, and bad coronavirus infections. Kirkland is a principal investigator for the Translational Geroscience Network, which is funded by the National Institute on Aging (NIA), a component of the U.S. National Institutes of Health (NIH), and he says that there are around 15 trials with senolytics that are now underway. We don’t know the final results yet, and the only trials that have been published so far were very early-stage.
Kirkland says senolytics aren’t ready for primetime because they are clinically unproven and could have terrible downsides. “You shouldn’t be buying them from Amazon,” he cautions. “We don’t know if they’re safe.
“I lie awake every night, worrying that we’re going to kill someone,” he adds. For example, the senolytic navitoclax had serious side effects on platelets, the colorless blood cell fragments that help clot blood and stop bleeding from injuries. Those side effects limited its practical use. When too much navitoclax was used, people ran the risk of developing thrombocytopenia—a condition characterized by abnormally low levels of platelets (also known as thrombocytes) in the blood.
Senolytic clinical trial improves sight
But Anirvan Ghosh, the CEO of senolytics company Unity Biotechnology, preaches that we are on our way to developing and validating safe therapeutics that will slow, halt, or reverse diseases of aging. He believes this class of drug could have a truly transformative effect.
At the heart of his excitement are anecdotes of patients with vision loss who have seen significant improvements during a clinical trial for a lead senolytic candidate called UBX1325. The phase 2 trial began enrolling candidates in May this year and is expected to complete in June 2022.
“When we dosed the first patients, there was this woman who could not [even] see the eye chart. She could not read the top letter from the eye chart from three feet away. She later wrote to us because she went on to be able to read two or three lines on the eye chart, which corresponds to improved vision, and how meaningful it was because it has such an impact on her independence.”
Improving vision is only the beginning. Eventually Unity will test senolytics on neurodegenerative disorders as well as diseases involving other organs with high senescence burden like the liver, always making sure to establish safety and a superior benefit risk compared to the standard of care.
“We have not had any drug-related adverse events,” Ghosh says. “This has increased our confidence about the ability for it to be safe.”
Longevity and space travel
Even though we’re only beginning to examine senolytics in a clinical setting, the sky’s the limit. In fact, it may be even higher, reaching to the outer planets and perhaps even the stars since senolytic drugs, or something like them, may be needed to help astronauts travel deeper into space.
“NASA is worried about astronauts and solar flares,” says Kirkland, since solar flares emit protons and other tiny particles at an incredibly high speed. “We found that a small dose of radiation from a solar flare is enough to make many cells senescent. If there’s a solar flare when they’re going to Mars, the astronauts will all be dead.” So he says NASA and the science community is getting quite interested in whether there is a way we can mitigate damage, measure senescence real-time in astronauts, and deal with this should it occur.”
We already know that space pilots and flight crew are more likely to die several years earlier than their peers of age-related diseases such as osteoporosis, diabetes, and certain cancers. That’s why he’s teamed up with NASA to see how senolytics work in space.
“We’ve got cells going up on the Axial flight early next year, and we’re taking the astronauts’ blood before and after the mission. They’re only going up to the ISS for ten days, but we’re going to be measuring senescent cells. The question is, ‘Will this or some other kind of intervention be necessary to make a flight to Mars safe?’”