Can this ‘anti-aging’ drug live up to the hype? Here’s what we know.

The quest for the fountain of youth may go back centuries, but it's only in the past two decades that scientists may be close to finding it-at least as it pertains to yeast, flies, and mice.

The elixir of interest to both researchers and longevity seekers is the prescription drug rapamycin. Some anti-aging influencers like Peter Attia, a physician and popular podcaster who devoted a chapter to the drug in his recent bestseller, Outlive, are enamored by its possibilities. But whether it truly extends life and expands people's disease-free years remains an unanswered question.

Years of research in mice have shown that rapamycin "is the most robust and reproducible drug" when it comes to increasing lifespan and slowing the aging process, says Matt Kaeberlein, a longtime rapamycin researcher at the University of Washington in Seattle who recently cofounded a for-profit longevity technology company, Optispan. "If you take old mice where there's already been a decline in function and you start treating them with rapamycin, the function comes back up."

Some people have seized on these results to take low doses of the drug now, despite the many unknowns about its efficacy and safety. They're able to do so because the medicine was approved by the U.S. Food and Drug Administration in 1999 to help suppress the immune system in people receiving an organ transplant; once a drug is available, doctors can prescribe it for any condition.

But "waiting for the science is probably the safe move," says Dudley Lamming, head of the molecular physiology of aging lab at the University of Wisconsin-Madison, who coauthored a comprehensive review of research on rapamycin in Nature Aging last year.

WHAT DOES RAPAMYCIN DO IN THE BODY?

Rapamycin works by suppressing a signaling enzyme known as mTOR (short for mechanistic target of rapamycin), which is a fundamental decision maker for most cells in the body and brain. The protein's main purpose is to sense whether nutrition is available or in short supply. When food is abundant, mTOR broadcasts for cells to grow and divide.

When food is scarce, cells reduce their replication. The body instead shifts to pruning and tuning existing tissue. Anyone who spent time during the COVID-19 lockdowns mending all the previously neglected parts of their home can undoubtedly relate.

"The cells focus their energy into recycling damaged proteins, repairing damaged organelles like mitochondria, and upregulating other cellular defenses that might help, for instance, keep the genomic DNA intact and stable," Lamming says.

The result is cells, tissues, and organ systems that are healthier than before.

The nutrition-sensing action is so important that mTOR is present in nearly every organism, from single-celled amoeba to humans, which makes sense from an evolutionary perspective, Kaeberlein says. During periods of famine, the successful strategy "is to become stress resistant, survive long enough that you can still be reproductively active when the famine is over," he says.

Studies have long shown that mice that eat fewer calories live longer, and scientists now speculate that the resulting reduction in mTOR may at least partially drive this phenomenon. That makes mTOR inhibiting drugs like rapamycin appealing candidates for extending the human lifespan or health span, which are the years a person lives without debilitating ailments.

FROM RAPA NUI TO THE RESEARCH LAB

Rapamycin was discovered by chance in 1964 when Canadian scientists came to the South Pacific's Easter Island to study the health of its native inhabitants. They discovered a potent antifungal agent in the soil samples they brought back, and biochemist Suren Sehgal named the compound rapamycin (after Rapa Nui, the indigenous name for the island).

When the pharmaceutical company he worked for merged and shut his lab, Sehgal stashed a jar of the compound in his home freezer until 1987, when he was able to resume the work. The drug proved such a potent immune system modulator that Wyeth Pharmaceuticals received FDA approval to market a high-dosage, daily regimen to prevent organ rejection. (A chemically similar drug, everolimus, was approved to treat cancers in 2016.)

(Rapamycin - the Easter Island drug that extends lifespan of old mice)

In the early 2000s, several labs working with various organisms, from yeast to fruit flies and worms, discovered that mutations in the genes that code for mTOR affect lifespan and that inhibiting the protein with drugs like rapamycin does as well.

Interest in the compounds exploded after a study published in Nature in 2009 revealed that female mice who were fed rapamycin when they were two years old-elderly in rodent years-lived 14 percent longer, while male mice lived nine percent longer.

"This was the first time you had a drug you could start at the 60-year equivalent in mice," rather than by adolescence as other life-enhancing medicine studies require, Kaeberlein says.

DOZENS OF ANIMAL STUDIES, BUT FEW IN PEOPLE

Numerous mouse studies have since expanded on these effects, including Kaeberlein's 2016 research showing lifespan increased 60 percent when the medicine was given in middle age.

In addition, researchers have identified several areas where rapamycin or other mTOR inhibitors improve the age-related health issues in mice, including the immune system, heart function, female fertility, and gum disease.

More recent studies have expanded to primates. In June, scientists studying middle-aged marmoset monkeys presented interim results at the American Aging Association conference, revealing that rapamycin increased lifespan by some 15 percent. However, a different study by the same researchers posted online found it did not improve the animals' osteoarthritis. In fact, in some cases the disease worsened.

Kaeberlein is readying to test rapamycin's function in pet dogs as part of his Dog Aging Project. Because dogs share an environment and often emotions with humans, results about their health and lifespan will be especially translatable, he says.

Researchers are still figuring out how to accurately test rapamycin's effectiveness in people. What mTOR inhibition seems to do is "make a lot of aging organ systems function a little better and decline a little slower, but 'a little better' and 'a little slower' is tough to prove in a clinical trial," says Joan Mannick, chief executive officer of Tornado Therapeutics in Boston, a company that is developing rapamycin derivative drugs.

Focusing on the immune system, Mannick and her team have run a few small trials of mTOR inhibitors in recent years. Several dozen older people on a low dose of the related drug everolimus boosted immune response to a flu vaccine by 20 percent. And when 264 people took either a combination of low-dose mTOR inhibitors or a placebo for six weeks, the former got fewer respiratory infections.

(It's not your life span you need to worry about. It's your health span.)

But it's unclear how much of these results stem from the placebo effect. In all of Mannick's studies, "people who think they're getting an anti-aging drug start feeling better," reporting more energy, improved eyesight, increased strength, and other benefits, she says.

Other scientists have recently begun preliminary human tests of mTOR inhibitors for age-related diseases, including insulin resistance, early Alzheimer's, and periodontal issues.

"As a dentist, I'm always limited in how to help patients who are getting older-experiencing more gum disease, tooth loss, less saliva. It's exciting to have these other interventions that we can investigate and perhaps someday ultimately provide," says Jonathan An, an assistant professor at the University of Washington's School of Dentistry in Seattle. His ongoing study evaluates rapamycin's effects on gum disease treatment in 20 elderly people.

NOT YET READY FOR PRIME TIME

Without large clinical trials in humans, no one can as yet feel confident about rapamycin's safety or its effectiveness at extending life or health. Side effects range from mouth canker sores to increased blood cholesterol and glucose. When someone takes rapamycin long enough, the drug activates a second protein group that drives these upticks. This is a reason companies like Mannick's are exploring compounds that solely target the more beneficial proteins.

Scientists are also not yet clear about the most effective dose or schedule.

There's a fine line between tamping down mTOR somewhat versus significantly. The latter can, ironically, shorten lifespan instead of expanding it.

Some longevity advocates have begun recommending rapamycin, but Mannick, urges caution. "We don't know yet what is the dose, what is the duration where the benefit is clearly outweighing any risk," she says. Until that is known from additional research, she won't feel comfortable taking the drug herself.

While Kaeberlein agrees that rapamycin isn't ready for widespread use, he has taken it for several three-month phases. In one instance, he says age-related inflammation in his shoulder largely disappeared. Subsequent experiences were less dramatic.

Attia cautions that any physician prescribing rapamycin to a patient

"should be able to explain what is known and what is not known and explain the limitations of prescribing a medication that has no biomarker and no demonstrated benefits in the species of interest, which is humans."

Those who are interested in trying the drug might consider volunteering for a clinical trial, Dudley suggests. Worldwide, more than 100 studies on mTOR drugs are currently recruiting patients, according to ClinicalTrials.gov. "That's the way we're going to learn more," he says.

While they can't be sure until the data are in, experts are hopeful. "It's really, really hard if you believe in evolution and you understand aging biology to argue that rapamycin is not going to slow biological aging in humans," Kaeberlein says. "Everything that I know about aging biology makes me believe that it probably will."

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