Depending on who you ask, we may be on the cusp of a great leap forward in longevity medicine. “In probably the next three to four years, you will have this pill basket” of anti-aging drugs, says Dr. Vijay Yadav, an assistant professor of genetics and development at Columbia University. Based on the patient’s health profile, he says a clinician could tap into the basket’s selections and prescribe something to improve health during their final decades: “Let us see whether we can add 10 more years of a healthy life to you.”
You’d have to be remarkably bullish to believe those drugs will prove to greatly boost the quality and length of late life in the imminent future. Even Dr. Yadav doubts that the potential of these therapies will be fully understood—and thus implemented most effectively—in his lifetime. After all, proper testing would take decades. Yet some experts in the burgeoning field of geroscience—the study of aging—are increasingly confident that a batch of different molecules undergoing analysis for anti-aging properties contains game-changers. “It is similar to running horses in a race,” says Dr. Yadav. Among the potential prize ponies are prescription drugs like rapamycin, metformin, and senolytics, alongside supplements like alpha-ketoglutarate and taurine. The aim is to perfect an array of molecules that not only extend the life expectancy of users, but also boost overall health during their final years.
But despite the potentially transformative nature of these molecules, some spectators have found progress to be needlessly slow. “The way our system is structured, there's just no incentive to do those trials,” says Dr. Matt Kaeberlein, a biologist and pathology professor at the University of Washington and a prominent figure in the world of gerontology. Because many of the promising candidates are already generic drugs, the rate of research has been gradual. Without serious money to make, even the prospect of a non-metaphorical Holy Grail can’t motivate the pharmaceutical industry.
The structure of FDA trials are also an awkward fit with geroscience: When testing the efficacy of an anti-aging therapy, what do you measure? There’s not a catch-all biomarker. “That’s still a significant hurdle,” says Dr. Ben Miller, chair of the Aging and Metabolism Research Program at the Oklahoma Medical Research Foundation. “If we go to the FDA with a blood pressure medication, we measure blood pressure to know if the drug is working or not. With aging, it's really hard to go with what marker you're going to use.”
Nonetheless, progress has continued. Closely watching the advance are so-called biohacker communities, online groups that digest any new data to guide their own regimens of potential longevity drugs—typically therapies for other illnesses taken off-label—hoping for a headstart on treatments whose effectiveness will later be fully proven. There’s no way to pin down exact numbers, but approximately 20,000 people visit rapamycin.news each month, home to a clique of people taking the drug for its purported anti-aging properties, according to its founder.
The search for life-lengtheners has long attracted bunk science and charlatans, and the addition of outsider research—legitimate or not—could give medical experts pause. “That's something that the aging community is really wrestling with right now,” says Dr. Miller. “Aging has really been pushed to the forefront, which is a good thing. But we're trying to get past the pseudoscience of the Fountain of Youth and that kind of thing.”
But even as that tension persists, amateur discourse around these drugs may have the effect of drawing the attention of physicians. A primary feature of digital communities devoted to gerontology is to share where certain therapies may be procured. It provides not just an access point for future users, but Dr. Kaeberlein says it could also serve to reassure prospective prescribers. “There's a small group of them at first,” he says. “But once they see some of their colleagues doing this—and maybe their colleagues have 100 or 500 patients on rapamycin—then they start to feel comfortable.” Thus, as the online community of people allegedly taking these drugs grows, its relationship with the medical community becomes more reciprocal, and a given drug’s credibility “percolates through the medical community that way.”
Some drugs have managed to spur excitement on both sides of the professional divide. For the last several years, metformin and rapamycin have both been popular choices for users, particularly in tandem. “They’re talked about in the same breath,” says Dr. Kaeberlein. Both are old, generic drugs; metformin is most commonly used to treat diabetes while rapamycin is an immunosuppressant and typical therapy to enable organ transplants. They were two of the drugs to first gain traction as potential therapies for longevity.
Rapamycin is a molecule native to the soil of Easter Island. By the 1970s, scientists discovered that it had immunosuppressive properties, making it a useful drug for facilitating organ transplants. In the early 2000s, research found that rapamycin targeted a molecule called mTOR (a very clever acronym for molecular target of rapamycin). Not long after, mTOR was tied to both age-related illnesses like cancer and aging itself. The thinking is that because rapamycin can target and contain mTOR, it may control aging and age-related diseases.
Along the same timeline, metformin emerged as a possible therapy for longevity, too. Long used to treat type 2 diabetes by regulating blood sugar levels, metformin was tested on cancerous mice in a 2005 study. The results appeared to show that the drug extended the lifespan of the mice, in some cases by 13 percent. The study also suggested that the way metformin mitigated cancer in mice—by reducing insulin levels—might also be “a hallmark of increased longevity.” Then, a 2014 study appeared to show that metformin actually increased the survivability of diabetics taking the drug to levels even greater than non-diabetics who weren’t taking it.
For a time, both appeared to be promising developments in the race to elongate life. More recent science has put an end to those similarities. “Some are still bullish about metformin,” says Dr. Kaeberlein, but that in general enthusiasm “has cooled dramatically.”
Some of the reasons can be found in a report conducted by researchers in Denmark last year. In a meta analysis of the original study, the researchers came to a much different conclusion from 2014: “We found the opposite: increased mortality in metformin diabetics,” says Matthew Thomas Keys, a PhD student in epidemiology at the University of Southern Denmark who helmed the study. Key and his colleagues also found a number of methodological flaws in the 2014 study that could falsely inflate the survivability of diabetics on metformin. Among them were immortal time bias, where a study assumes all subjects have been taking a drug for the same amount of time. (If a study lumps people who’ve been on a drug regimen for 10 years with others who started it yesterday, survivability could be inflated.) Similarly, the 2014 study relied on diabetics strictly using metformin; taking just one drug to treat diabetes suggests a less severe case. “It dramatically underestimated mortality in the treatment group receiving Metformin,” says Keys.
Some wind remains in metformin’s sails, but rapamycin appears to be pulling ahead. Since 2002, the National Institute of Aging has conducted tests on drugs with potential age-delaying properties through its Interventions Testing Program. “Metformin failed in all of its tests,” says Keys, while “the star winner of this so far has been rapamycin.”
The communities closely following anti-aging developments seem to have taken notice. It’s an imperfect barometer, but a survey on rapamycin.news showed that more than two-thirds of respondents had started on the therapy in just the last year. It's still extremely unclear whether that bet will pay off—but if it does, it won't be a fringe biohacker treatment for long.