A drug taken by thousands of Americans to improve longevity might have an unexpected side effect, a study has found. It may blunt some of the health benefits of exercise.
The drug, rapamycin, is approved by the Food and Drug Administration to prevent organ-transplant rejection in people. But recent studies in yeast, flies and mice showed that relatively low doses of the drug often increase the creatures’ lifespans, prompting many longevity enthusiasts to start using it off-label to extend their lifespans.
The new study, published this month in the Journal of Cachexia, Sarcopenia and Muscle, is among the first to look at interactions between rapamycin and exercise. The researchers anticipated rapamycin would enhance the effects of exercise, while also initiating health improvements of its own.
But the results surprised them, said Brad Stanfield, a physician and researcher in Auckland, New Zealand, who led the study. The sedentary, older people taking a low dose of rapamycin once a week during the study wound up gaining less strength and physical function from an exercise program than other volunteers of the same age who were taking a placebo. They also developed more aches, fatigue and, in one case, a serious infection.
These findings resonate because, exercise is the most effective way to improve health and longevity as we age. “It is important to understand how potential health span-extending drugs” such as rapamycin “interact with other health span-extending treatments like exercise,” said Benjamin Miller, who studies aging and metabolism at the Oklahoma Medical Research Foundation in Oklahoma City. He was not involved with the new study.
“Since exercise is the benchmark,” he continued, “we do not want to inhibit its potential benefits.”
How rapamycin works
In the 1960s, rapamycin famously was discovered when a scientific expedition to Easter Island, known locally as Rapa Nui, found an unknown type of bacteria in the soil. The bacteria were used to produce rapamycin, which proved to be a potent immunosuppressant at high doses.
Subsequent research showed the drug also inhibits the action of an important cellular enzyme called mTOR (short for mammalian target of rapamycin) that helps control cells’ growth and vitality. In general, mTOR, which increases after exercise, aids muscle building by jump-starting processes that increase protein uptake; without enough mTOR, muscles and other tissues can’t bulk up and, instead, may atrophy.
But if cells are exposed to too much mTOR, they neglect an important task, known as autophagy, that involves clearing out cellular detritus. The buildup of internal debris can weaken or kill cells and speed aging.
Maintaining the right balance of mTOR is a key to healthy longevity.
But in most animals, including us, mTOR levels rise with age, potentially contributing to physical decline. So, a few years ago, researchers began experimenting with rapamycin, hoping low doses would inhibit mTOR and promote autophagy without suppressing immunity or blocking muscle growth, helping to extend healthy lifespans.
Which it did, they found, at least in flies, worms, yeast and some strains of mice, many of which lived at least 10 percent longer if they received rapamycin late in life.
Could rapamycin make exercise even healthier?
But experiments in people are tricky. Our lifespans are far longer than those of flies, worms, yeast or mice. It would take decades and boundless funding to determine whether rapamycin directly extends our lives.
But it might be possible to see whether and how rapamycin works in conjunction with exercise, Stanfield reasoned. At the moment, aerobic fitness and grip strength are two of the most reliable indicators of longevity, studies show; the fitter and stronger people are, the longer they are likely to live.
Could the right dose of rapamycin help make exercise even better for us during aging, by moderating the undesirable effects of excessive mTOR without hindering the enzyme so much that strength and function gains from exercise wound up reduced?
Rapamycin versus placebo
For the study, Stanfield partnered with researchers familiar with rapamycin and recruited 40 inactive, older men and women in New Zealand, most of them in their 70s. (Stanfield funded the study himself by mortgaging his home, selling vitamins and soliciting donations through his large social media following.)
Researchers checked the volunteers’ fitness, strength and functional abilities and then randomly assigned them to receive capsules containing a low dose of rapamycin or placebo once a week. The volunteers also started the same, simple at-home exercise program involving 10 to 25 minutes of stationary cycling and 30 seconds of standing and sitting as many times as possible, to build functional strength.
People took their assigned pills once a week, 24 hours after exercising and at least a day before their next session. The researchers believed this schedule would prevent rapamycin from blunting exercise gains and would amplify them.
The study continued for 13 weeks. The volunteers then returned for more testing.
A signal ‘in the wrong direction’
“It was a surprise,” Stanfield said, when he and his colleagues analyzed the subsequent data.
Across the board, in every measure, the people taking the placebo performed better than those taking rapamycin. The effects were most pronounced in the 30-second sit-to-stand test, where the men and women receiving placebo completed more repetitions than the rapamycin group.
The people in the placebo group also generally had better grip strength and rated their mental and physical well-being higher than those on rapamycin. Side effects such as soreness were more common in the rapamycin group, and one person in that group developed pneumonia, a known risk from the drug. (It’s impossible to know whether the drug was responsible in this case.)
The results suggest rapamycin probably lingered in people’s bodies long enough to impede mTOR activity after exercise and prevent muscles from responding to workouts as robustly as they otherwise would, Stanfield said. The effects weren’t large, but “the signal was definitely in the wrong direction,” he said.
The study’s limits
This was a small, short-term study and relied on people exercising, unsupervised, at home. The exercise also was light, Miller said, so no one improved their health or fitness substantially, making it difficult to parse differences between the groups. And the volunteers on rapamycin received the same dose of the drug at the same time each week. Different dosing or timing might have produced different outcomes.
Perhaps most important, the researchers didn’t look inside people’s muscles, to see how rapamycin was affecting mTOR levels and muscle cell responses. The cost would have been prohibitive, Stanfield said.
“There is still a lot to learn,” Miller said. His lab is studying individualized responses to rapamycin, and he suspects the drug may yet turn out to be useful in keeping some older people’s muscles healthy. But those experiments aren’t yet complete.
For now, “I do not think people should be taking rapamycin off-label,” Stanfield said. “I just don’t think we know enough about the benefit-versus-costs ratio.” He doesn’t take or prescribe the drug, he said, preferring hikes with his family as a longevity protocol.
The post A cheap drug used by longevity enthusiasts may have a surprising impact on exercise appeared first on Washington Post.
