For years, the search for an anti-aging elixir focused on an ingredient found in red wine, resveratrol. But as studies have cast doubt on its ability to extend lifespans, evidence has mounted that an antibiotic produced by bacteria in soil on Easter Island has profound effects on longevity.
Boston-area researchers are working to untangle how that drug, called rapamycin, works and determine whether it could be harnessed to improve health.
Rapamycin has come a long way since its antifungal properties were described in the 1970s. Today, rapamycin and related derivatives are used to suppress the immune system and prevent rejection after an organ transplant, and to treat some cancers. But the renewed interest in the drug is for a much broader potential application: to slow or delay aging and to treat diseases that come with old age.
Rapamycin has been shown to increase lifespans in mice, whereas the better-known red-wine ingredient, resveratrol, has been shown to improve health but not consistently help the mice live longer.
Rapamycin is “the first drug that clearly extends longevity in a mouse model,” said Brian Kennedy, chief executive of the Buck Institute for Research on Aging. “It takes the aging field to a new level.”
Researchers do not recommend taking the drug, which can suppress the immune system and increase the risk for diabetes. However, a growing number of scientists are studying rapamycin to learn more about the biology of aging in the hope that it or a similar drug could one day prevent or treat diseases associated with aging, such as neurodegenerative and cardiovascular diseases.
David Sabatini, a member of the Whitehead Institute for Biomedical Research and a biology professor at the Massachusetts Institute of Technology, began studying rapamycin and the protein it targets when he was a graduate student. At the time, it was not clear whether they would be of broad biomedical interest, and other researchers encouraged him to abandon the work, he said.
“I really at the time considered it strongly — maybe I was off on this obscure corner of biology,” Sabatini said, recalling his doubts about the protein complex he was studying, called mTOR, for mammalian target of rapamycin. “Fortunately for me, it’s turned out to be really interesting.”
The pivotal result that helped stoke widespread interest in rapamycin’s effect on longevity was a surprising 2009 Nature study led by David Harrison, a scientist at Jackson Laboratory in Bar Harbor, Maine. The study found that giving rapamycin to older mice could significantly lengthen their lives. It was the equivalent, Harrison said, of giving the drug to 60-year-old humans and seeing their lives lengthened by about a decade.
“I think it would be highly significant in terms of public health,” Harrison said. “But in terms of basic mechanisms of aging, this isn’t reversing the aging process — it’s postponing many of the deleterious effects.”
Now, Harrison and others are working to understand more about what that means.
Starting rapamycin earlier in a mouse’s life has the same lengthening effect as starting it later, giving a clue that the drug is not delaying mutations that build up to cause cancer or something similar, Harrison said. If that were how it worked, starting rapamycin sooner would probably have a bigger effect.
Sabatini’s efforts to determine how rapamycin works are focused on discovering what it does in the body, which raised the prospect of harnessing its life-lengthening properties without detrimental side effects.
In a paper published earlier this year in the journal Science, Sabatini and colleagues reported a possible explanation for rapamycin’s tendency to increase the risk for diabetes.
He studied two complexes of proteins targeted by rapamycin and found that disrupting just one of the protein complexes extended the lifespans of mice, without having the negative effects on blood sugar regulation that could increase the risk of diabetes.
To Sabatini, that suggests that if researchers could develop a drug that could target one complex while leaving the other one alone, it might be possible to get the life-extending effects of rapamycin without the undesirable side effect.
“I think that starts to be some sort of evidence — the nuts and bolts of how it might have pro-longevity effects,” Sabatini said.
Kennedy, at the Buck Institute, published a paper this year showing that rapamycin improved the health and extended the lives of mice with a rare genetic cardiovascular condition.
Other researchers are interested in the drug’s potential against a variety of diseases associated with aging, from osteoporosis to Parkinson’s and Alzheimer’s diseases.
At the same time, longevity research has grown increasingly muddled, with sometimes conflicting results volleyed back and forth between laboratories like ping-pong balls. Last month, a 23-year study found that a diet with drastic restrictions on calories did not prolong the lives of rhesus monkeys, counter to what a similar study had reported three years earlier.
Even resveratrol, which was thought to mimic the effects of a calorie-restricted diet, has become mired in conflicting studies, generating scientific controversy. Results on rapamycin have, scientists said, been more consistent, and the hope is that it will reveal how aging occurs and provide insight into other junctions in the biological process where a drug or intervention might work.
“At the very least,” said Dr. T. Keith Blackwell, a senior investigator at Joslin Diabetes Center, “we’ll gather a lot of important information for acute interventions.”Carolyn Y. Johnson
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