Getting geroprotective drugs to market for specific disease applications is the first step in eventually making them available for healthier aging.
The silver tsunami is coming.
By 2050, the number of people in the world over the age 60 will double, making up a fifth of the world’s population. Two-thirds of them will live in low-income and middle-income countries but health systems and economies worldwide will feel the strain.
Older people tend to have a disproportionate amount of health problems. A study in 2014 found people over 60 account for almost a quarter of the global disease burden, even though they only made up 12 percent of the world’s population.
We will see a flood of new cancer tumors, cases of heart disease and stroke, frailty, metabolic syndromes and diabetes, and countless other age-related diseases. The number of people suffering dementia alone is expected to triple, all fueled by our greater longevity and shifting demographics, which the United Nations refers to as the “defining global trend of our time.”
Dealing with this coming storm will depend on addressing all manner of issues. To name just a few: health disparities, gaps in preventive care, the need to detect diseases sooner, social stigma attached to mental illness, our inability to treat dementia, financial toxicity, and health misinformation.
One daring solution could be to find ways of addressing aging itself, by developing drugs to broadly prevent age-related diseases. It’s a dream embraced by many longevity experts today, but can we actually achieve it?
Proto.life asked some of the world’s leading experts in the field what it will take to get an FDA-approved pill that makes it possible to live a longer or healthier life. Though there was no consensus as to what the first longevity or “geroprotective” drug will be, several of these experts expressed confidence that it’s only a matter of time.
Getting there won’t be easy, however.
The enemy of longevity is time
“What I think we have right now are a lot of things that are really promising in worms and a few things that are promising in mice,” says Kristen Fortney, CEO of BioAge, a biotech company in Richmond, California developing drugs to treat diseases related to aging.
James Peyer, the CEO of the New York-based biotech company Cambrian Bio—which seeks to develop therapeutics to lengthen healthspan (the period of life spent in good health)—agrees. He says the first geroprotective drug to gain FDA approval may even be something that is already known today—perhaps a drug already approved for another indication—and has only to be validated through clinical trials for longevity.
“We have actually 80 interventions, of which about 20 are drugs that extend healthy lifespan in mice,” he says, referring to all the known drugs on the market that could potentially be repurposed as well as all the experimental compounds in the pipeline not yet approved to treat any disease that look promising as future geroprotective drugs. Probably a handful of the 80 have sufficient evidence to support running a large clinical trial, Peyer says.
But therein lies the problem.
Doing clinical trials for longevity is hard. It’s expensive. Historically, many have even said it’s impossible. Peyer recalls when he was starting his career, he heard the same thing over and over again from friends and colleagues at pharma companies, investment firms, and universities: He should forget it. You can’t run a trial for aging, they would tell him.
In some ways they’re not wrong. It’s easy enough to give an experimental drug to worms or mice, whose lives are measured in weeks or months. But to do the gold-standard large-scale, double-blind, randomized clinical trial for longevity in people would take years. It would be hard, expensive, and at the end of the day would face the brutal possibility of failure, given the reality that a large proportion of drugs fail in late-stage clinical trials.
“If you took an experimental drug, and I took a placebo, how long would we have to wait to see a real outcome?” Peyer asks me. “Six years,” he says, not waiting for a response. “They take six years and they cost $150 million.” That’s how long you would have to wait and how much it would cost to demonstrate improvements in health outcomes—things like fewer age-related diseases, less hospitalization, and longer life.
The other issue is that any potential longevity drug is a really a preventive medicine, since it would stave off age-related diseases and improve health outcomes broadly. There are all kinds of preventive drugs on the market—blood thinners, beta blockers, antimalarials, asthma medicines, cholesterol lowering drugs, and vaccines, just to name a few categories. But with the exception of vaccines, taking a drug that has never been in humans before and going straight into a prevention trial is almost never done.
“If you’re going to take a drug that has never demonstrated human safety and efficacy before and try to go straight into that six year, $150 million shot on goal, and then maybe afterwards you’ll have revenues,” Peyer says, “it’s risky.” Six costly years, six risky years—and there’s no way around it. That’s why people always warned him it couldn’t be done.
“Everybody in this field has this problem,” Fortney says.
Instead a preventive medicine is typically tested first for its ability to treat a specific illness. Once it proves safe in humans and effective for that smaller indication, then it moves into the more costly, larger prevention trials. And that’s how many companies in the field are moving forward—using what Peyer calls the stepping-stone approach.
The idea of targeting treatments for specific age-related diseases is to create value. It avoids the six-year risk of a broader longevity trial and instead tests the drug in well-defined populations, perhaps even people who have a genetic disease and will be highly likely to benefit from the therapy. They may respond more quickly, show results sooner, and allow for shorter, less expensive clinical trials. If and when those clinical trials are successful, they will prove a drug’s safety, demonstrate its efficacy, and help to identify biomarkers. And once the drug is approved for that one indication, it can be tested more broadly as a geroprotective longevity drug.
Proving your drug is safe and effective in a small group of patients is a much more compelling commercial story, Peyer says, and in recent years funding in the field has coalesced around this approach. Now at least a half dozen companies, including his own, are either ready to start or are already testing drugs in clinical trials for some specific cancer, muscle dysfunction, or metabolic disease in which some broad aging mechanism is at play.
“Doesn’t it de-risk your story if you can run a two-year trial?” Peyer says. “If your drug that you’re sitting on today is already worth $150 million a year in profits because it’s coming on the market for some rare disease, that is a completely digital, 0 to 1 difference in the investment case.”
Targeting the mechanisms of aging
The basic idea is simple, says Joe Betts-LaCroix, CEO of the San Francisco-based biotech company Retro Biosciences. Theoretically, geroprotective drugs would work by addressing one of the 12 fundamental hallmarks of aging, which we are beginning to understand more and more. Retro Bioscience’s main source of funding, a $180 million 2022 investment by OpenAI CEO Sam Altman, was revealed last month.
There are lots and lots of age-related diseases but far fewer overarching aging mechanisms that drive them.
“You can start with a disease that has the most acute manifestation in the shortest amount of time with response to some step change in an aging mechanism, produce that as a therapy that gets approved by a health authority, and then slowly expand from there,” Betts-LaCroix says.
According to Betts-LaCroix, this gets to the “deep hypothesis” of the aging biology world: There are lots and lots of age-related diseases but far fewer overarching aging mechanisms that drive them. Think of it like a leaky dam. If the dam breaks, the flood will cause massive property damage. People will be injured. Some might drown. Power will be knocked out. Mud will soil the streets. Mildew will take hold. Now you could address this problem by preparing sandbags for the flood, sweepers to clear the streets of mud, engineers to quickly restore power—or you could just fix the dam. That’s what the deep hypothesis suggests: fix the dam and avoid having to deal with the fallout from the flood.
“The idea is that if you can intervene really well in one aging pathway,” he says, “you can then treat and or prevent multiple downstream diseases at the same time with one therapy.”
Last summer, Betts-LaCroix dropped jaws when he predicted his company would have a drug on the market that would extend human lifespan by 10 years within a decade. “Making a public statement like that can help light a fire under the whole project,” he says. “Obviously, you can’t predict the future, so it’s not so much of a prediction as it is a commitment. It’s what feels like the right thing to do. It’s where the industry should go.”
We know that it’s possible to target overarching aging mechanisms because some people benefit from doing so already, by virtue of good genetic fortune, diet, exercise, or through some other means than drugs. “There already are a lot of people who make it to 100 or 110, so what’s different about their biology?” asks Fortney. “We know there are safe, effective ways to modulate biology to [keep you] healthier longer.”
Still, the ultimate goal of a geroprotective drug is not to address any one specific disease but the broad aging mechanism as a whole. “It’s to make the whole body more resilient to disease,” explains Nir Barzilai, a professor of medicine and genetics at Albert Einstein College in New York. “[If] you’re going through a tough disease, you have to have a good body for that. And gerotherapeutics are treating the whole body.”
The potential, says Alexandra Bause of Apollo Health Ventures, an early-stage venture capital firm based in Berlin, is to “really have a more holistic impact on health rather than just this old, outdated Whac-A-Mole approach where we have one disease or one symptom that we’re targeting.”
“That’s a strategic shift in how people have approached this longevity space that has unlocked the doors to the funding side of it,” she says. When her company was started in 2016 (co-founded by James Peyer), there was just one other longevity fund. But over the past few years many more funds and different types of funding models have emerged. “I think that’s great,” she says. “The more funding [going into] the space, the better.”
Bause described her company’s mission as extending healthy lifespans. They recently closed their second fund of €160 million and are in the process of doling it out to several different companies—some as investments and some are starting from scratch.
“The big question, however, is what comes next,” she says.
Still waiting for the TAME trial
The 800-pound gorilla in the room is the diabetes drug metformin. Safe and effective for treating diabetes, it was approved for treating type 2 diabetes in Europe as far back as the 1950s, and it received FDA approval in the United States in the mid-90s. In a number of clinical trials, metformin has appeared to also lengthen healthspan, helping people who have taken it improve their overall health, decrease their odds of being hospitalized, and help them live longer.
For that reason, metformin is often discussed as a potential geroprotective drug. This is why it’s now at the heart of an effort called the Targeting Aging with Metformin (TAME) trial, which many think could pave the way to clinically test drugs for broad aging mechanisms directly.
The concept behind the TAME trial is to push beyond nine previous clinical studies around the world, all but one of which were observational—meaning that people in the trials took metformin with the full knowledge of their doctors. Those trials showed metformin can prevent mortality and give better health outcomes in people with diabetes, cardiovascular disease, cognitive decline, and cancer, Barzilai says. TAME is designed to test its protective effect against age-related diseases more broadly—and specifically as a double-blind, placebo-controlled clinical trial, the gold standard for establishing medical evidence.
Once launched it will enroll 3,000 people aged 65–79 who will be followed at 14 leading research institutions across the country. The volunteers will either take a placebo or an extended-release form of metformin once a day for six years. The study will follow the effect of the drug for preventing age-related diseases over time and give people better health outcomes like fewer hospitalizations.
A separate, shorter trial called TAME-BIO will enroll about 250 people at four medical centers and focus on finding general biomarkers of aging. “We want to show what biomarkers are changing if we prevent aging, basically,” Barzilai says.
The value of finding such biomarkers is that they could then become surrogate endpoints in clinical trials for other potential longevity drugs or other interventions. The FDA or another regulator could potentially be satisfied with a shorter trial of a geroprotective drug if it achieves its effect on those surrogate endpoints.
“That would allow us to do what Lipitor did,” Peyer says, which was to “jump straight from the rare disease to a surrogate endpoint trial.” Lipitor is a statin, and the statins were developed and approved initially to treat hypercholesterolemia, an indication with a relatively small number of patients. But they were then approved by the FDA to knock down cholesterol and prevent heart disease, opening up a massive market. While it was under patent, in fact, Lipitor became the best-selling drug in history.
Incentives like that don’t exist for metformin, however. Long off patent, there is no more market exclusivity to incentivize a private company to develop it as a geroprotective drug. “It’s actually one of the cheapest drugs in the world,” Peyer says. “About 10 cents a pill.”
“The NIH concluded that we are ‘out of our minds,’ thinking that aging can be targeted and that one drug can do it.”
No one’s ever going to become a billionaire selling a drug that’s already off patent, and that has made funding the $55–$75 million cost of the TAME trial difficult. The trial suffered a huge setback in the early days of COVID-19, when it was first scheduled to start. Just prior to the pandemic, the trial had secured its funding, more than half of which ($40 million) was pledged by an undisclosed donor. But the launch of the trial was delayed due to the pandemic, as so many clinical trials were, and then it lost funding. “I was really shocked and upset to learn that the whole TAME was off the table,” Barzilai says.
He and his team are still looking for funding. In January, Barzilai posted on social media how they failed to secure funds for the trial from the National Institutes of Health. “The NIH reviewed our U19 grant and concluded that we are ‘out of our minds,’ thinking that aging can be targeted and that one drug can do it. Of course, the supporting data that it’s doing it is strong and presented, but beliefs don’t allow facts to take over,” he wrote on Twitter.
Barzilai says funding for the smaller TAME-BIO trial is in place and that it will likely start this year. As for the larger TAME trial, there is a rumor about a substantial new funding commitment, but that could not be independently verified. “The minute we have the money we’ll start,” Barzilai says.
Strawberries and zombies
The mechanism of aging metformin addresses are changes at the level of cell-to-cell communication—one of the classic hallmarks of aging. But it is not unique.
There is another set of clinical trials currently underway to test drugs designed to modulate the age-related increase of senescent cells, another fundamental mechanism of aging.
Senolytics are a class of drugs designed to modulate in senescent cells, also known as zombie cells, since they cease functioning properly in later life but resist actually dying. They play crucial roles in embryogenesis during the earliest stages of our development and in wound repair throughout life, but they accumulate in our tissues as we age, causing undue inflammation and driving metabolic disease.
Calling them zombie cells is a bit misleading because they don’t eat other cells, but they do spread senescence like some zombie plague, causing widespread damage in the body. They are fierce, frightening, and foul.
“What we think is that these cells are actually trying to signal to the immune system,” says Robin Mansukhani, CEO and co-founder of San Francisco-based biotech company Deciduous Therapeutics. The issue is that the immune system does not or cannot respond, he says. Mansukhani’s company is built around the notion of using treatments to boost the body’s natural immune cells that get rid of unwanted senescent cells but become “anergic” or unable to mount a normal immune response as we age. His company is developing a therapy to activate an immune cell known as a natural killer T cell (NKT) to better police tissues, kill senescent cells, and improve glucose tolerance.
“It’s like if the car [the immune system] used to run at 65 miles an hour, now it’s running at 35, but it needs to run at 65 in order to be effective,” and keep senescent cells from accumulating and subsequently destroying various tissue systems, Mansukhani says.
Several other efforts are already underway to bring senolytic cells to heel in specific age-related diseases like macular degeneration, diabetes, obesity, and Alzheimer’s. Proto.life spoke with Mayo Clinic professor James Kirkland, who heads the Translational Geroscience Network, an NIH-funded multicenter grant overseeing multiple clinical trials that involve Mayo, Harvard, Johns Hopkins, University of Michigan, and several other top-tier medical centers. The program is testing not just senolytics but drugs like metformin and rapamycin, NAD+ precursors, CD38 inhibitors, anti-inflammatories, and a bunch of other things that could prolong a person’s healthy lifespan.
One interesting trial, funded by the National Cancer Institute, involves comparing the combination of the cancer drug dasatinib plus the flavonol quercetin to the flavonol fisetin alone. Quercetin is a naturally occurring flavonol. It’s what makes apple peels taste bitter. Fisetin is another natural flavonol that’s found in strawberries and cucumbers—but in very low doses. “You’d have to eat 15 pounds of strawberries within 5 minutes to get the dose we’re giving,” Kirkland says.
The trial focuses on a cohort of 800 childhood cancer survivors who are followed by St. Jude’s hospital in Memphis. Giving kids chemo and radiation therapy before the age of ten, Kirkland explains, either kills cancer cells outright or it causes them to become senescent. Sometimes the cells escape senescence and come back as worse tumors. Other times, the cells stay senescent. That later causes the children to develop an accelerated aging-like state as adults.
“They’re dying at age 35 or 40 of Alzheimer’s, osteoporosis, diabetes, or unrelated cancers,” Kirkland says. “And they look like they’re 70.”
Besides that, there are other clinical trials currently underway testing these same senolytic compounds for many different conditions, Kirkland says—ranging from coronavirus infections to frailty to osteoporosis to looking at their efficacy in treating brain fog for people with chronic HIV/AIDS.
“We’ll see how they go,” he says. “I mean, in mice and monkeys and things, it looks good. But we don’t know yet.”
One word of caution
How soon will it be before we have an approved geroprotective “longevity” drug? Peyer imagines a day ten or so years from now when doctors will prescribe such drugs as they do medicines for cholesterol or hypertension—to lower your aging biomarkers the same way we take statins to lower cholesterol or antihypertensive drugs to lower blood pressure. He thinks in that imagined future they won’t be taken by everyone but specifically prescribed based on your risk markers.
“No drugs are perfect. It’s not going to be like some superfood that you can eat as much as you want and never have any negative consequences.”
Peyer would not predict exactly how it would play out. “I’m not enough of a Nostradamus to know,” he says. “No drugs are perfect. It’s not going to be like some superfood that you can eat as much as you want and never have any negative consequences.”
But the beauty of the coming longevity drugs, he predicts, is that most, if not all of the first ones to hit the market will be cheap-to-manufacture small molecules—similar, again, to the cholesterol-lowering statins. That could keep prices low, he says, and broaden their use. Some experts even predict that inexpensive geroprotective drugs could actually have their highest impact in terms of years of healthy life gained in low- and middle-income countries.
Why is that? Chronic, noncommunicable diseases like heart disease, cancer, and diabetes account for about 75 percent of all deaths worldwide, according to the World Health Organization, including some 17 million annual “premature” deaths claiming the lives of people under 70. Eighty-six percent of those people who are dying prematurely—exactly who geroprotective drugs could impact the most—live in low- and middle-income countries.
Some experts caution that we need to measure twice and cut once now to avoid missteps along the way. Bause of the Apollo Fund expressed concern over misses. “We need to make sure that we’re really careful at allocating these funds to the right products,” she says, because if too much funding goes into projects that flop, there may be reluctance to keep pouring in more funding.
“We need to make sure that the early projects are really successful, and we can validate the hypothesis behind the longevity investments,” she says.
Kirkland agrees that there is a risk that a high-profile failure could kill a field, but he says people should never expect every single trial is going to be positive. “I would be happy if one or two out of 20 trials showed something,” he says. “If we fail on some of the trials, it doesn’t mean we should stop.”
At the same time, Kirkland warns against people jumping the gun and starting to take experimental geroprotective drugs preemptively, without proof that they will work or knowledge of the risks.
“I don’t think people should be taking these things over the counter, and physicians should not be prescribing them,” says Kirkland. “We don’t know yet what the downsides might be.”
All the trials in which he is involved are testing these compounds on fatal conditions for which there are no good treatment options. These are “very, very serious conditions for which people have very little hope,” he says. The clinical trials are carefully designed and closely watched by drug safety monitoring boards staffed by experts who know who is getting the drug and who is getting the placebo. They are in place to stop a trial if need be, should adverse events occur.
“They haven’t stopped any of [the trials] so far, but it doesn’t mean an adverse event won’t occur—or that one might not occur two years from now or something,” Kirkland says. “We don’t know that.”