A New Path to Longevity
Researchers have uncovered an ancient mechanism that retards aging. Drugs that tweaked it could well postpone cancer, diabetes and other diseases of old age.
On a clear November morning in 1964 the Royal Canadian Navy’s Cape Scott embarked from Halifax,Nova Scotia, on a four-month expedition. Led by the late Stanley Skoryna, an enterprising McGill University professor, a team of 38 scientists on board headed for Easter Island, a volcanic speck that juts out from the Pacific 2,200 miles west of Chile. Plans were a foot to build an airport on the remote island, famous for its mysterious sculptures of enormous heads, and the group wanted to study the people, flora and fauna
while they remained largely untouched by modernity.
The islanders warmly welcomed Skoryna’s team,which brought back hundreds of specimens of plants and animals, as well as blood and saliva from all 949 of the residents. But a test tube of dirt turned out to be the biggest prize: it contained a bacterium that made a defensive chemical with an amazing property—the ability to prolong life in diverse species.
Several research teams have now demonstrated that the chemical, named rapamycin, boosts the maximum life span of laboratory mice beyond that of untreated animals. Dubious anti-aging claims are sometimes made based on data showing increased average life span, which can be achieved by antibiotics or other drugs that reduce premature death yet have nothing to do with aging. In contrast, increased maximum life span (often measured as the mean life span of the longest-lived 10 percent of a population) is a hallmark of slowed aging. No other drug has convincingly extended maximum life span in any of our mammalian kin—gerontology’s long-awaited version of breaking the sound barrier. The success in mice has therefore been a game changer for scientists who study aging and how to mitigate its effects. Gerontologists dearly want to find a simple intervention for slowing aging,not merely to increase longevity but because putting a
brake on aging would be a broad-brush way to delay or slow progression of so much of what goes wrong with us as we get old, from cataracts to cancer.
For years gerontologists’ hopes of discovering antiaging compounds had been on a roller coaster.
Optimism rose with the discovery of gene mutations that extend maximum life span in animals and with new insights into how calorie restriction produces the same effect in many species. Yet the advances, for all their promise, did not reveal any drugs that could
stretch the outer limits of longevity in a mammal.
Although calorie restriction, which involves nutritionally adequate near-starvation diets, can both do that and delay cancer, neurodegeneration, diabetes and other age-related disorders in mice, very stringent dieting is not a feasible option for slowing aging in
In 2006 resveratrol, the famous ingredient in red wine that replicates some of calorie restriction’s effects in mice, seemed likely to break through the barrier when
it was shown to block the life-shortening consequences of high-fat diets in the rodents. But this substance, which is thought to act on enzymes known as sirtuins, later failed to extend maximum life span in mice fed normal diets. The disappointing picture suddenly brightened again when the rapamycin results were announced in mid-2009. A trio of labs jointly reported that rapamycin, by then known to inhibit cell growth, extended maximum life span by some 12 percent in mice in three parallel experiments sponsored by the National Institute on Aging. What is more, to gerontologists’ amazement, the drug extended average survival by a third in old mice that were presumed to be too damaged by aging to respond.
Rapamycin’s shattering of the life span barrier in mammals has riveted attention on a billion-year-old mechanism that appears to regulate aging in mice and other animals and may well do the same in humans. Its mainspring is a protein called TOR (target of
rapamycin) and the gene that serves as the protein’s blueprint. TOR is now a subject of intense scrutiny in both gerontology and applied medicine because a growing number of animal and human studies suggest that suppressing the activity of the mammalian version
(mTOR) in cells can lower the risk of major agerelated diseases, including cancer, Alzheimer’s, Parkinson’s, heart muscle degeneration, type 2 diabetes, osteoporosis and macular degeneration. The remarkable diversity of potential benefits implies that if medicines able to target mTOR safely and reliably could be found, they might be used to slow the aging process in people, as rapamycin has in mice and other species—a possibility with profound implications for preventive medicine. (Rapamycin itself, unfortunately,
has side effects that probably preclude testing whether it slows human aging.)
Similar predictions have been made for drugs that act on other molecules, notably the sirtuins. So what is different with mTOR? The finding that a drug has convincingly extended maximum life span in a mammal by acting on the molecule means that mTOR
is central to mammalian aging and that researchers are now a lot closer than ever before to finding ways to brake the aging process. “It sure looks like mTOR is the biggest game in town today and probably for the next decade,” says Kevin Flurkey, a gerontologist at
the Jackson Laboratory in Bar Harbor, Me., and a coauthor of the rapamycin study in mice.
THE RESEARCH LEADING TO the discovery of TOR’s influence on aging took shape when the Skoryna expedition turned over its soil samples to what was then Ayerst Laboratories in Montreal.
Pharmaceutical researchers had been finding antibiotics in pinches of dirt since the 1940s, and so Ayerst’s researchers screened the samples for antimicrobials.
In 1972 they sifted out a fungal inhibitor and named it rapamycin because Easter Island is also known locally as Rapa Nui. Ayerst initially hoped to use it to treat yeast infections. But then, scientists exploring its properties in cell-culture studies and on animals’
immune systems found that it can hinder proliferation of immune cells, prompting its development instead to prevent immune rejection of transplanted organs. In 1999 rapamycin received U.S. Food and Drug Administration approval for patients who had received a kidney transplant. In the 1980s researchers also learned that the drug inhibits tumor growth, and since 2007 two derivatives of it—Pfizer’s temsirolimus and Novartis’s everolimus—have been approved to treat various kinds of cancer.
Biologists found rapamycin’s ability to depress proliferation of both yeast and human cells highly intriguing—it suggested that the compound suppresses the actions of a growth-regulating gene conserved across the billion years of evolution between yeast and
people. (Cells grow; expanding in size, when they are a preparing to divide and proliferate.) In 1991 Michad N. Hall and his colleagues at the University of Basel in Switzerland identified the ancient target by discovering that rapamycin inhibits the effects of two
growth-governing yeast genes, which they named TOR1 and TOR2. Three years later a number of investigators, including Stuart Schreiber of Harvard University and David Sabatini, now at the Whitehead
(to be continued)
By David Stipp
source Scientific American