Never Say Die

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.