A WRINKLE IN TIME

Leonard Guarente didn't come up with the trick of calorie restriction, or strictly limiting nutrients to achieve longer life. And the idea sounded crazy back in 1986, when Guarente first proposed to study the biology of aging via calorie restriction. Aging was seen as too complex a topic for molecular biologists, and the effect of calorie restriction on aging, though detailed in scientific literature since the 1930s, was even more poorly understood. Guarente's colleagues called him "bonkers," but he didn't care: "I wanted to work on something risky," he says. "Besides, I had just gotten tenure, and at that point they couldn't get rid of me."

They certainly wouldn't want to now. Guarente is not the least bit bonkers--and, unbeknown to his colleagues at the time, he wasn't even the only scientist thinking about the molecular biology of calorie restriction. In the last decade, researchers have made great strides in understanding why a sudden drop in calorie intake can kick up the activity of a gene called SIR2 and prolong life in simple organisms.

At the head of the class are Guarente and a Harvard researcher named David Sinclair, both of whom are focusing on sirtuins, the family of proteins produced by SIR2 or its mammalian analogue, SIRT1. Guarente's lab has unraveled many of the basic molecular processes behind SIR2. For instance, a natural chemical called NADH can inhibit sirtuins' effects; Guarente's lab has determined that yeast with lower NADH levels lives longer. Sinclair's work has a slightly different focus--resveratrol, the chemical he has connected to calorie restriction's effects. (It's better known as the major reason red wine is touted as healthful.) Sinclair's work at Harvard has shown that heavy doses of resveratrol can prolong life span in yeast by 70 percent. Still another scientist, Marc Tatar, has garnered similar results in fruit flies.

The fact that calorie restriction works isn't all that surprising from an evolutionary point of view. In fact, calorie restriction is an extremely effective strategy for survival during lean times, when it's an imperative, not a choice. "Let's imagine I had a gene that could allow me to suspend reproduction and slow down aging during a famine," says Guarente. "When the famine ends, I'll still be around to reproduce." As a result, he adds, "every animal we know can do this."

Including humans, of course. But since few people particularly want to limit their calories drastically (least of all Americans), Guarente is searching for a pill that will have the same effect. Elixir, the same company building on Kenyon's work, is also using Guarente's--which means, someday, humans may reap the benefits of calorie restriction without even having to say the word diet. Sinclair has a competing company called Sirtris. He expects to get his drugs into clinics in just five years. Until then, he'll be drinking one glass of red wine a day--and toasting to what he hopes will be a huge success.

Supplemented: TWO CHEMICALS MADE OLD RATS NEW