Robert Berger takes a small weekly dose of rapamycin in the hope of extending his “healthy life as much as possible.” Photo / Carolyn Fong, The New York Times
Rapamycin is typically prescribed as an immunosuppressive, but off-label users believe it can do much more.
In March, Robert Berger, 69, a self-proclaimed “better-living-through-chemistry type of person,” started taking a small dose of rapamycin once a week with the goal of increasing his “health span” – the amount of time he might live without serious disease.
Rapamycin is typically prescribed to organ transplant patients to suppress their immune systems. But many scientists and longevity seekers like Berger think the drug can do much more than that: they say it can delay ageing and age-related diseases.
Berger, who lives in Saratoga, California, learned about rapamycin through a friend who runs Rapamycin News, an online forum for people who experiment with the drug. He said he hasn’t experienced any “‘Oh my God, I’m a different person’ kind of change” since taking it, though his dentist remarked that his gums looked healthier than they had in a long time, and he feels like he has more energy these days. But he admits “it’s really hard to tell: how much is this placebo?”
On podcasts, social feeds and forums devoted to anti-ageing, rapamycin is hailed as the “gold standard” for life extension. Longevity influencers Peter Attia and Bryan Johnson are believers, both saying they’ve taken rapamycin for years, and touting research to their millions of followers that shows the drug can extend the life spans of mice by more than 20%.
There isn’t data on how many people use rapamycin for anti-ageing purposes, since the drug is taken off label or purchased from overseas providers. Like Berger, some of the other users interviewed for this article said they believed rapamycin has provided mild benefits, such as helping them lose weight, alleviating their aches and pains or even causing them to regrow dark hair years after going grey.
But while users are optimistic and the evidence that rapamycin can increase longevity in animals is promising, the research in humans is thin and long-term side effects are uncertain. In the few studies in which rapamycin has been compared with a placebo, tangible benefits are hard to come by.
Scientists first learned about the longevity-enhancing potential of rapamycin, also called sirolimus or Rapamune, in 2006, when a study showed that it could extend the life span of yeast. Enthusiasm mounted three years later, when another group of researchers found that mice given the drug lived roughly 12% longer.
Other medications had been tested for their possible anti-agring properties as part of a National Institute on Aging research programme, but “rapamycin was the first one that actually made a difference in longevity and health span in both male and female mice,” said Dr Dean Kellogg Jr., a professor of medicine and geriatrics at the University of Texas Health Science Center at San Antonio.
After that came studies in worms, flies and more mice – almost all showing that rapamycin extended life span.
“The demonstration that you could get the same effect across broad evolutionary distance – yeast, worms, fruit flies, mice – that really got people believing that this was something important and fundamental,” said Matthew Kaeberlein, who published the first study on rapamycin in yeast while he was a researcher at the University of Washington. (He is now the CEO at Optispan, a longevity startup.)
Preliminary data presented earlier this year at the American Aging Association annual meeting suggested that rapamycin also works in closer cousins to humans: marmosets given the drug showed roughly a 10% increase in life span. While the study isn’t done yet, the lead researcher, Adam Salmon, a professor of molecular medicine also at UT Health San Antonio, said of the six animals that are still alive, five received rapamycin and one a placebo.
Scientists think rapamycin increases life span in animals, and maybe people, too, by inhibiting the mTOR complex, a fundamental biological pathway that is involved in many aspects of cellular health. Suppressing mTOR sets off a domino chain of events, altering several key processes in ways that appear to be beneficial for long-term survival. For example, it seems to decrease inflammation and ramp up a cellular trash removal process known as autophagy.
“If you look at the hallmarks of ageing, you can find evidence in the literature that rapamycin affects all of them,” Kaeberlein said.
Some experts think that rapamycin may slow down the ageing process itself; others believe that it increases longevity by delaying or even preventing the onset of deadly age-related diseases. For example, inflammation is linked to diabetes and cardiovascular disease, not to mention general aches and pains, so reducing it is thought to be broadly beneficial. And it’s conceivable that increasing autophagy could help to clear out toxic proteins that start to accumulate with age – like amyloid and tau, which are widely thought to cause Alzheimer’s disease.
Anthony Holman, 54, had previously experimented with fasting to try to optimise his health, but “as it turns out,” he said, “I enjoy eating”. About two years ago, he came across research that suggested rapamycin has some of the same biological effects as fasting. Around that time, he also learned that he carries one copy of a gene that increases his risk for Alzheimer’s disease. Motivated to do everything he could to try to stave off the condition, he sought an off-label prescription for rapamycin at a concierge longevity medicine clinic.
After taking a small weekly dose for approximately 15 months, Holman, who lives outside Raleigh, North Carolina, said he hasn’t experienced many changes, positive or negative, though he has noticed a subtle decrease in daily aches and pains. “It’s almost like taking vitamins,” he said. “You don’t take vitamins because you’re expecting some immediate benefit. You take it to hopefully see a benefit over time.”
Whether or not people will see a benefit over time remains murky: results from the handful of studies conducted in humans have been much less clear-cut than the research on other animals.
The strongest piece of evidence, according to rapamycin enthusiasts, is not a sweeping finding about longer, healthier living. It’s a 2014 study in which adults aged 65 and older who took another mTOR inhibitor, called everolimus, had a more robust antibody response to the flu vaccine than those who got a placebo. The promise of those findings is limited, but not without value: typically, the immune system declines with age. The greater response to the vaccine implies the drug countered that effect.
“It really did suggest that in humans, these drugs, mTOR inhibitors, can improve something that becomes impaired with older adults,” said Adam Konopka, an assistant professor of geriatrics and gerontology at the University of Wisconsin, who was not involved in the research.
Subsequent studies have produced mixed results, and many have involved small numbers of participants and time frames that experts said were too short to really determine much.
The most recent study, which has not yet been peer-reviewed, is one of the largest to date and was conducted by AgelessRx, an online pharmacy that sells a low dose of rapamycin for longevity purposes. In it, more than 100 people took either rapamycin or a placebo once a week for nearly a year. There were no clinically significant differences in terms of physical benefits or negative side effects between the groups, though people on rapamycin reported feeling that their health had generally improved over the course of the study.
When broken down into subgroups, the handful of people taking the highest dose did see some additional benefits: men showed increased bone density and women had increased lean muscle mass; the women also said they experienced less pain than they used to.
“We do see some people who benefit a lot,” said Stefanie Morgan, vice-president of research and applied sciences at AgelessRx. But others “don’t really benefit at all”.
A small study Kellogg published in 2018 among adults 70 and older who took a daily dose of rapamycin for eight weeks also saw no clear benefits from the drug. However, the treatment group did experience a slight increase in a marker of insulin resistance compared with adults who received a placebo – something that could be a cause for concern, especially among people who already struggle to keep their blood sugar in check. Anecdotally, some of the people who take rapamycin off label (including Berger) have reported a similar side effect; others have seen an increase in their cholesterol levels.
Experts said it’s not surprising that there are few, if any, immediate benefits from taking rapamycin – and added that it doesn’t necessarily mean the drug isn’t working. In older animals, rapamycin appears to “prevent and preserve things” rather than rejuvenate them, Salmon said. “So unless you’re doing a long-term human study looking at preservation of health,” you shouldn’t expect to see significant improvements.
It’s difficult and expensive to do a decades-long longevity study in humans. Instead, scientists are launching new clinical trials to look at how rapamycin affects age-related diseases, including Alzheimer’s, as well as biological markers of aging.
If scientists can use rapamycin to “improve the different indices that become impaired with aging, then that can help serve as a proxy of health span,” said Konopka, who is running a clinical trial testing everolimus, the other mTOR inhibitor.
While a few scientists interviewed for this article said they had tried taking rapamycin, most said they were waiting for more studies in humans to shed light not just on the benefits, but also the risks.
In the research conducted so far, nausea and mouth sores were the most common side effects, though there are also the reports of increased cholesterol and insulin insensitivity.
“The way people are using rapamycin off label today – which is mostly once a week, not super high doses – the risks are pretty low,” said Kaeberlein, who has taken rapamycin himself. But, he added, they’re not nothing.
The bigger concern, considering rapamycin is more typically used to prevent organ transplant rejection, is that the drug will dampen people’s immune functioning and therefore increase their risk for infection and disease.
Transplant patients prescribed the drug take a higher dose than those who take it for ageing, and there haven’t been serious indications of immune suppression in the human longevity studies conducted so far. But it’s conceivable that a low dose could still cause people to get more infections, or more severe infections, particularly among those with underlying health conditions, said Andrew Dillin, a professor of molecular and cell biology at the University of California, Berkeley, who specialises in ageing.
“Let’s see, taking something that’s risky, that’s going to have no benefits?” Dillin said. “I’ll pass.”
This article originally appeared in The New York Times.
Written by: Dana G. Smith
Photographs by: Carolyn Fong
©2024 THE NEW YORK TIMES
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