“Forget Silicon Valley biotech wonder drugs. Leading gerontologists are making an historic bet on metformin”.
Featured Art: Scott Gelber
Old age is, we know, a gauntlet of chronic illness that almost no one gets through without some deep unpleasantness. Most people who reach the upper end of the average human lifespan begin, at some point, to accumulate diseases. For the most lethal maladies of the elderly — heart disease and cancer — the relationship between age and disease is logarithmic. As we grow older, our risk of contracting a chronic disease doesn’t just increase—it accelerates.
Michael Cantor would like to avoid this fate. He’s not a fanatic—not the type to haunt biohacking subreddits for self-quantification tips or take dozens of unproven anti-aging treatments in the off chance one will buy him some yardage. Cantor is a patent lawyer with a prominent practice in West Hartford, Connecticut, where his wife is the mayor. “I don’t even like to take aspirin,” he says. “I’m very nervous to do anything with respect to any other kinds of drugs.” But still, if there were a reasonable way to stave off death — he’d like to try it.
A decade ago, on a cycling trip in Bordeaux, Cantor met a man named Nir Barzilai, and the two became friends. A former Israeli army medic, now director of the Institute for Aging Research at the Albert Einstein College of Medicine in New York, Barzilai has become a globetrotting evangelist for what is known as the “geroscience hypothesis”: the idea that if you use drugs to target the underlying biological mechanisms that drive aging, you can also delay, or even altogether prevent, the cascade of disease that accompanies the end of the typical human life.
For the past several years, an effort has been underway in the field of gerontology to get a drug targeting aging approved by the FDA, with Barzilai leading the charge. The drug in question is no new wonder pill, but a diabetes medication called metformin: an ordinary, generic, typically chalky-white pill that costs a few pennies apiece.
Cantor was already familiar with metformin, but not as an anti-aging remedy; he had been prescribed it by a local weight-loss clinic. A few years ago, intrigued by his friend’s work on aging, he broached the subject of longevity.
Metformin, Barzilai and his team believe, will be the first drug ever to be officially approved to treat aging.
“Over dinner one night, I said to Nir, ‘You know, I’m leaving this weight-loss clinic, which means they’re going to stop prescribing metformin. But I think I’d like to stay on it,’” Cantor says. Barzilai wrote the prescription himself, and Cantor now takes metformin off-label in hopes that it will grant him a few extra years of life, or at least of health.
“I’ve bought into this idea — it’s not just an idea, it’s a fact — that you don’t really die of old age,” Cantor says. “Most people die of age-related disease.”
Although metformin’s age-extending powers are unproven, Cantor doesn’t mind being a guinea pig. He thinks the drug is subtly improving his health. “My experience is only positive,” he says. “It’s changed my metabolism.”
In the world of anti-aging research, there are any number of exciting potions in the pharmaceutical pipeline with the purported potential to extend the average human lifespan by several years or more. There are senolytics, which act like snipers, snuffing out old cells that have stopped dividing and have begun to secrete destructive inflammatory cytokines. Rapamycin, an immunosuppressant derived from an Easter Island bacterium that has lab mice living 25 percent longer than their unmedicated peers.
Metformin, by contrast, is decidedly unsexy. Currently the eighth most-prescribed drug in the United States, metformin has been plodding along in the medical world since the 1950s, when French doctors began using it to help diabetics keep their blood sugar under control. Scientists are now looking at it in a new light, ever since diabetes researchers observed that it appears to extend the lifespan of medicated patients slightly beyond that of ordinary nondiabetics—just enough to notice an effect, but nothing radical.
“Metformin is basically the first and the weakest drug that will delay aging.”
Soon, Barzilai and a team of gerontologists from 14 top aging research centers will begin a clinical trial to study the effects of metformin on aging. The trial will be an ambitious six-year, $77 million effort, involving 3,000 patients and many of the brightest lights in the field of gerontology. Metformin, Barzilai and his team believe, will be the first drug ever to be officially approved to treat aging in the 112-year history of the FDA. Along the way, they hope to achieve nothing short of radical transformation in the way we think of health care for the aging.
Metformin as an old-age remedy is a high-stakes bet, and its supporters are putting everything on the table. If the clinical trial proves to be a bust, the effort to develop age-treating drugs will be set back years, if not longer.
For all its importance to the emerging science on aging, metformin is a very boring drug. Even the name of the upcoming clinical trial has all the inherent hype of a wet blanket: TAME, an acronym that stands for “Targeting Aging with Metformin.” On its face, it seems unlikely that such a plain little pharmaceutical would be the focus of such a critical trial. Since the patent is expired, no drug company stands to make billions off it, and it’s certainly not going to make anyone live forever. Even Barzilai, who has essentially staked his career on the lifespan-extending prospects of metformin, has a hard time mustering a lot of enthusiasm about the drug itself. “Metformin is basically the first and the weakest drug that will delay aging,” he says.
But it is, in fact, metformin’s stodginess that makes it such a good candidate for the first anti-aging clinical trial. Using drugs to treat age is a venture into uncharted waters for the FDA; in order to convince federal regulators to take that step, TAME’s backers had to choose a drug that held no surprises. A safe drug, a known drug, a cheap drug, a drug that doctors prescribe to millions of patients every year without a qualm — that kind of drug could be the tip of the spear for aging research, opening a new path at the FDA to the approval of more daring drugs and emboldening pharmaceutical companies to join the hunt for metformin’s successors.
If aging isn’t a disease, the FDA has no regulatory authority to approve treatment for it.
The TAME trial has been in the works for years. With about a third of its funding secured from the non-profit American Federation of Aging Research and a major grant in the works from the National Institutes of Health, the trial is nearly ready to begin. To its main sponsors, some of whom are approaching their golden years themselves, progress has felt agonizingly slow. Before pursuing the funding needed to pull this off, the TAME researchers had to sell federal regulators, and indeed the wider medical research field, not just on metformin, but on the very concept of testing a drug for the malady of age.
Scientists involved with TAME say the main obstacle in their path is that the regulatory world just hasn’t caught up to the emerging science. In recent years, they say, science has learned quite a lot about how aging works and how drugs might be used to target it. The reason we don’t have a drug for aging yet isn’t that we haven’t come up with any good candidates. It’s that aging isn’t technically a disease.
“The FDA, its mandate says very clearly, is to regulate medications and devices used in the diagnosis and treatment of diseases,” says scientist George Kuchel, director of the University of Connecticut Centre on Aging and deputy editor of the Journal of the American Geriatrics Society.
If aging isn’t a disease, the FDA has no regulatory authority to approve treatment for it. And if the FDA won’t approve treatments, pharmaceutical companies won’t make them.
Absent an act of Congress, the FDA’s mandate isn’t likely to change to accommodate the goals of gerontologists. The TAME project seeks to make an end run around the whole logical conundrum by seeking approval to target a “composite of age-related diseases,” Barzilai says.
The prospect of radically altering the human lifespan raises all sorts of bioethical questions.
In other words: If they can show that by targeting the underlying biological pathways that make an aging body more susceptible to disease, metformin can stave off a host of chronic ills, the TAME researchers can get the FDA’s blessing.
Once metformin has the official labelling language to back up scientists’ anti-aging claims for the drug, the theory goes, pharmaceutical companies will be inspired to invest in more daring ventures — and then the truly miraculous drugs, the ones that could have us living healthily to 115 and beyond, might begin to flow through the pipeline.
The prospect of radically altering the human lifespan raises all sorts of bioethical questions. Will longer-lived people consume too many resources? Will policy be able to catch up with our changing lifespans? Will the best medical technology be unevenly distributed, like pretty much everything else is?
Barzilai has heard the arguments for years. He doesn’t think much of them.
“You know, I get kind of frustrated when people are asking me if it’s ethical that people will be healthier,” he says.
For a scientist, Barzilai is a good talker. People who’ve spent time with him in person talk about his puckish sense of humour, his boyish ebullience; Barzilai “could be the older brother to Mike Myers’ Austin Powers character,” as author Bill Gifford puts it.
On the phone, Barzilai is charming and enthusiastic, ever ready with the elevator pitch. I warn him that I have a provocative question: What is aging?
“Yeah, it is provocative,” he says. “The true answer will take much longer than your deadline.”
Defining aging sounds simple, until you have to do it. Pare away numerical age and the diseases that are the result of the aging process, and what is left? What is it that a tremulous, bedridden 70-year-old has that a spry 90-year-old doesn’t? Is it a loss of some measurable function? A molecule you can scan for in the blood? Certain genes turning off or on over time?
“It’s like, ‘What is porn?’ Right? You know it when you see it,” Barzilai says. “We all see what is aging, okay, without understanding what it is.”
If you’re looking at a person’s age in years, age is literally just a number, Kuchel says.
“It’s basically the number of times that the earth has turned around the sun during your life. That’s easy to measure. What’s harder to measure is what we call physiological aging or biological aging,” he says.
The TAME trial will look at biomarkers, or measurable indicators that a process is happening in the body that are known to be associated with aging. But the focus of the study is more broad: TAME mainly seeks to answer the question of whether metformin will help lengthen life and stave off disease.
To dig deeper into what, exactly, metformin is doing in the body, researchers have been working on a series of smaller, faster studies designed to home in on how it interacts with pathways known to be associated with aging. The first of these, a study dubbed the “Metformin in Longevity Study,” or MILES, was completed and published in 2017.
Barzilai is confident the drug has a beneficial effect on the biological mechanisms underlying aging.
The MILES study looked at just 14 patients and ran for only six weeks, but it gathered a wealth of precious data thanks to the patients themselves, who had to undergo grueling muscle and fat biopsies. The invasive protocols of the MILES study have yielded valuable results. Using each participant as their own control — comparing biomarkers in the same patient before and after metformin treatment — allowed the MILES researchers to get more statistical power than they would otherwise with a cohort this small.
“We have some idea of what metformin might be doing at the physiological level, but at the molecular level, we don’t really know what to look at. And this might be some of the first evidence of what we can see,” says Ameya Kulkarni, a PhD student in Barzilai’s lab and the main author on the MILES study. His work on MILES, Kulkarni says, will help the TAME researchers identify biomarkers to focus on the broader clinical trial and tease out exactly how the drug is interacting with the aging process.
Based on what scientists have already observed with diabetic and prediabetic patients taking metformin, Barzilai is confident the drug has a beneficial effect, however modest, on the biological mechanisms underlying aging. But it’s still important to do the work. All this careful evidence building for metformin will serve as a road map for how to build the case for the next anti-aging drug, and the next, and every one that follows after.
“Once the pharmaceuticals are going to come in, we’re going to get many drugs, combinations of drugs. We can really move the needle substantially. It will be unbelievable,” he says.
At that, Barzilai pauses to curb his own enthusiasm. “I didn’t like what I just said—it sounded like the president.”
The future gerontologists want is tantalizingly close.
In 2015, when they first began cautiously feeling out FDA regulators about the prospect of getting a drug approved to treat aging, Barzilai and fellow believers in the geroscience hypothesis feared that the regulatory hurdles in their path might be too high. Now, with three years of negotiations under their belts, the TAME scientists finally have enough confidence in the agency to proceed.
“The bottom line is that the FDA has bought into the idea,” Kuchel says. “That is, these geroscience-guided therapies — they very much consider that to be within their mandate. That’s kind of changed the whole landscape.”
The FDA hasn’t been the only obstacle in TAME’s path. Paradoxically, the study’s sheer ambition has worked against it in the search for federal funding: TAME involves so many people working at the forefront of gerontology research that it has been difficult to find peers to properly peer-review the grant proposals. The first TAME proposal to the National Institutes of Health was soundly rejected; the group has submitted a second proposal and is hopeful that the federal agency will ultimately fund roughly two-thirds of the study.
Many of the top scientists in gerontology are involved in TAME, and their colleagues at their home institutions are excluded from reviewing the study, on grounds of conflict of interest. It’s been a problem for them in seeking grants, says Jamie Justice, an assistant professor of gerontology at Wake Forest School of Medicine.
Peer review is technically anonymous, but by process of elimination, Justice says, most of the people sitting in judgement on TAME’s funding prospects aren’t gerontologists; they’re experts in specific diseases. That’s the exact research approach TAME’s backers are hoping to upend.
“It’s hard to find peers that aren’t in conflict with the trial and get the concept,” Justice says, adding that for many reviewers, TAME is “challenging the way they’ve run their entire career.”
The silos that separate disease experts from one another permeate the entire health care system, from academic and pharmaceutical research all the way down to patient care. Gerontologists hope that studies like TAME, which focus on health outcomes for a person rather than the incidence of a specific disease, will begin to help break down those barriers.
“This is a huge issue that we confront in geriatric care,” Kuchel says. “How to provide health care that’s really based on the whole person, rather than the bits and parts of them.”
Scientists are often far more cautious about using hyped-up language than the reporters who write about them are. But the researchers involved with TAME talk about the study in grandiose terms; they use words like revolutionary and ground-breaking. Some talk of it as a “paradigm shift,” invoking the spectre of philosopher Thomas Kuhn.
“We’re using metformin as a tool to develop a whole new science of how to study aging in a way that is going to be transformational,” Kuchel says.
Kuchel is fond of that famous aphorism by 19th-century philosopher Arthur Schopenhauer: “All truth passes through three stages. First, it is ridiculed. Second, it is violently opposed. Third, it is accepted as self-evident.”
The idea that age can be treated with drugs, Kuchel says, is currently somewhere between stages two and three.
The world may finally be ready for an old-age pill, but the gears of drug development turn slowly. Too slowly for Barzilai, who’s anxious to get beyond TAME and get on with the process of real discovery.
“It’s happening. It’s happening, but it’s frustrating how long it takes,” he says. “This is possible, but we need to start it everywhere we can and not let another generation be affected by aging without health.”
