The Search for Longer Life

By the time it reaches the age of 18 days, the average roundworm is old, flabby, sluggish and wrinkled. By 20 days, the creature will likely be dead—unless, that is, it's one of Cynthia Kenyon's worms. Kenyon, director of the Hillblom Center for the Biology of Aging at the University of California, San Francisco, has tinkered with two genes that turn simple worms into mini-Methuselahs, with life spans of up to 144 days. "You can beat them up in ways that would kill a normal worm—exposing them to high heat, radiation and infectious microbes—and still they don't die," she says. "Instead, they're moving and looking like young worms. It's like a miracle—except it's science."

Since the days of Ponce de León, if not before, people have been seeking the elusive Fountain of Youth. Until recently, such pursuits were the realm of quacks and charlatans. And there are still plenty of snake-oil salesmen out there on the Internet and in so-called anti-aging clinics, hawking everything from longevity-bestowing Ecuadoran waters (which are probably harmless) to growth hormones (which could be downright dangerous for adults). But serious scientists are now bringing respectability to the field, unraveling the secrets of aging on a cellular level and looking for ways to slow it down. And while the science is still young (so to speak), legitimate longevity-boosting treatments could be available in 10 to 15 years—although the gains would be more modest than in Kenyon's worms.

The pursuit is not as quixotic as it may seem. Some critics of the scientific quest for longevity say it's God's will that we should die when our time comes. But in the past century, a clean water supply, antibiotics, vaccines and improved medical care have boosted life expectancy at birth by roughly 50 percent in the United States—from 48 for men and 51 for women in 1900 to 75 for men and 80 for women today. No one seems to object to that. "I'm 54," says Felipe Sierra, director of the division of aging biology at the National Institute on Aging. "A hundred years ago, I would have been dead by this age." Others argue that keeping people alive longer will further strain the social safety net. Yet for most scientists, the goal is not to tack years of sickness onto the end of life. "The goal is to extend youth," says Harvard molecular biochemist David Sinclair, who is working with a potential anti-aging compound called resveratrol. "I want to keep people healthier for longer and lessen the burden on the economy."

Studies are already yielding important clues on what produces healthy aging. One obvious answer is a healthy lifestyle, with plenty of exercise and a diet that includes lots of fruits, vegetables and whole grains. Seventh-day Adventists eat a vegetarian diet, don't smoke and spend a lot of time with family and church groups, which helps reduce stress. "They routinely live to 88 or so, which suggests those are ages most of us could attain with a healthy lifestyle," says Dr. Thomas Perls, director of the New England Centenarian Study.

But to make it to 100, like the 1,500 participants in Perls's study—or 110, like his "supercententarians"—it takes more than virtuous behavior and avoiding a collision with a Mack truck. A person needs genes that slow aging and boost defenses against age-related diseases. About half a dozen such genes have been identified out of perhaps 100 or so that might exist. The exceptional people with these genes seem to spend very little time sick—even when they defy all the rules. "We had one man who smoked three packs of cigarettes a day," says Perls. "He gave up smoking at 90, but he still drank three martinis a day—and he was out repairing his roof the day before I visited him. He died at 103."

Some of these beneficial genes appear to be involved in metabolic pathways related to growth, as well as the processing of fat and cholesterol. Kenyon manipulates a gene in her worms that reduces the action of insulin and a related hormone called IGF-1. "Lowering these hormones activates a gene called Foxo," she says, "which stimulates a whole host of responses that protect cells—boosting the immune system, increasing antioxidants, keeping proteins folded correctly." A study of Ashkenazi Jewish centenarians this year also found variations in genes governing IGF-1. A second study found protective changes in the Foxo genes of healthy 95-year-old men.

If there were no way to achieve these ends without having rare genes, then there would probably be no hope for most of us. (Only one in 6,000 Americans alive today is a centenarian.) But there may be another route to the same end, even if it's a path most of us will not want to follow—a severe low-calorie diet. Mice who eat 30 percent less live about a third longer. Similar effects in primates are just becoming available through a decades-long study in rhesus monkeys.

Obviously, no one can put people in cages, control their diets and follow them for 80 years to see how it all works out. But Dr. Luigi Fontana at Washington University School of Medicine is tracking 45 members of the Calorie Restriction Society, who voluntarily put themselves on such a diet. They are people like Tadd Ottman, 53, a software engineer in California. Since adopting a calorie-restriction diet in 2002, he's eaten just 1,500 calories a day, while being careful to meet nutritional requirements (one factor that distinguishes the practice from anorexia). He's dropped from 180 pounds to 130—and learned to cope with the effects: hunger pangs, reduced libido and feeling cold. On the bright side, his cholesterol has fallen from 244 to 169, his blood pressure is just 96 over 66 and he requires 45 minutes less sleep a night. "I'm like a long-distance runner," he says, "except that I don't exercise." He doesn't take in enough calories for much of that.

Fontana has been studying Ottman and 44 others for an average of 12 years. "Their heart function is 15 years younger than their chronological age," he says. "They have the blood pressure of teenagers." Their C-reactive protein—a measure of damaging, chronic inflammation—is a fraction of normal. The only way they fall short of calorie-restricted mice (other than extended life span, which has not yet been demonstrated) is that they do not have lower levels of the hormone IGF-1, which is believed to play a major role in aging and cancer. "IGF-1 doesn't fall, because 25 percent of their calories come from protein, versus the recommended 15 percent," he says. "We don't see this in vegetarians."

Extreme calorie restriction is not a practice that most people should try. Too many people are likely to simply yo-yo out of any initial weight loss. And pregnant women and children should never attempt it, lest they hinder development.

But Harvard's Sinclair is hoping to develop pills that will mimic the benefits of calorie restriction—without depriving us of chocolate or crumpling our sex drive. In 2006, he published a much-heralded study in Nature on a compound from red wine called resveratrol. Obese mice that received concentrated doses were just as healthy as skinny mice. They also lived longer and had superior endurance. "They were Lance Armstrong mice, except they were fat," he says. In a study this year, lean mice on resveratrol also had less heart disease, fewer cataracts, stronger bones and better motor function—though they did not live longer than normal.

To the extent that resveratrol mimics calorie restriction and exercise, it may be because all three activate a protein called SIRT1, a member of the sirtuin family of enzymes. SIRT1 increases the formation of new mitochondria, the power plants of cells, and it revs up existing ones. Last month Sinclair published a study showing that SIRT1 also repairs chromosome breaks, helping to keep youthful genes switched on and aging genes turned off. And Kenyon says that SIRT1 boosts the same metabolic pathway that she enhances in her worms.

None of this proves that SIRT1 extends human life. But both Kenyon and Sinclair have helped set up businesses to pursue clinical applications of their work. Any drugs that result will not be approved for longevity, since the FDA approves drugs only to treat illnesses. Instead, both Sinclair's Sirtris Pharmaceuticals and Kenyon's Elixir Pharmaceuticals are pursuing pills for diabetes, one of the leading diseases of aging. Sirtris's formulation of resveratrol has been shown in early trials to lower blood sugar and insulin in patients with type 2 diabetes, and the company is entering trials with synthetic sirtuin activators that are up to 1,000 times more potent than resveratrol. Though 60 to 90 percent of drugs at these stages of testing ultimately fizzle out, GlaxoSmithKline purchased Sirtris over the summer for $720 million. "Half a dozen major drug companies are working on sirtuins," says Dr. Christoph Westphal, CEO of Sirtris. "Because they affect many diseases of aging, the potential market is huge."

Other future blockbusters could be drugs that repair telomeres, the DNA caps on the ends of chromosomes. Every time a cell divides, the telomeres become shorter. When they shrink too much, cells stop replicating and start to function poorly. The result is wrinkling and general deterioration—well-known problems of aging. But scientists hope to forestall the effects by boosting telomerase, an enzyme that rebuilds telomeres. "There are rare families with very low telomerase," says molecular biologist Elizabeth Blackburn of UC San Francisco. "They never make it to old age. They die first of infections, cancers or lung fibrosis."

That doesn't prove that boosting telomerase extends years of health. But it's a reasonable hypothesis. Last month the first evidence in mammals surfaced in a study from Spain. Mice that were bred to have enhanced levels of telomerase lived 40 percent longer—and had better glucose sensitivity and motor function, stronger skin and less inflammation. The relevance to humans is open to debate. But UCLA immunologist Rita Effros also published a study last month on immune cells that were drawn from people with HIV. The cells were treated in the lab with a telomerase activator from Geron Corp. "Sure enough, they killed viruses better, divided longer and acted more youthful," Effros says. It's not just people with HIV who stand to benefit. "Many diseases of aging involve a weakened immune system," she says. But because too much telomerase could theoretically boost cancer risks, "it will be a long and difficult job to make sure a telomerase drug is safe," says Blackburn.

Some folks aren't waiting. Telomere biologist Bill Andrews of Sierra Sciences is taking a telomerase-boosting supplement called TA-65. "I believe it's safer than driving my car to work," he says. Since he started taking it a year and a half ago, Andrews says he has moved from the back of the pack to the front in 100-mile runs known as ultramarathons. But don't expect to find TA-65 at your local Vitamin Shoppe. It is available only from TA Sciences—for $25,000 a year. And customers have to undergo a battery of tests every six months to gauge the results, none of which have been published yet.

It might be smarter to save the $25,000 and modify your lifestyle. Last month Blackburn published a study showing that 30 men on Dr. Dean Ornish's program (an ultralow-fat diet, exercise and stress reduction) increased their telomerase levels by 30 percent. "According to the World Health Organization, 80 percent of heart disease and 40 percent of cancers could be prevented with a healthy diet and lifestyle," says Fontana. For those of us in the wrong end of the gene pool, healthy habits may be the best life preserver around.

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