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On his laptop computer, biology professor Leonard Guarente plays a video clip of 29-month-old mice hobbling around a cedar-chip-filled cage. Theyre scruffy, fat, slow moving, and over the hill by rodent standards. Then he plays a clip of another group of 29-month-old mice. Theyre svelte, frisky, and scrambling around like adolescents. Whats their secret? These mice have eaten about two-thirds as many calories as their portly peers. Not only does the meager diet seem to keep them light in the limbs, but they tend to live 30 percent longer than their well-fed friends and are less likely to contract age-related diseases, such as diabetes and cancer.

Scientists have known for nearly 70 years that calorie restriction extends the life spans of mammals by as much as 50 percent, but just how it works has remained a mystery. Guarente believes he has found the answer, and that it could potentially lead to extended life spans for people, too. For more than a decade, Guarente has been gradually solving the puzzle with the ambitious goal of discovering how to slow the aging process in humans without imposing a thousand-calorie-a-day diet. In 1999, he came to the surprising conclusion that manipulating just one gene, SIR2, could affect longevity. Guarente became so convinced that his findings could lead to antiaging pills that in 1999 he cofounded Cambridge-based Elixir Pharmaceuticals to commercialize them. In June, Guarente and his colleagues published a paper in the scientific journal Nature that detailed how a version of the SIR2 gene in mice releases fat from storage tissue, which seems to have a direct effect on how fast the animals age. Although Guarentes lab has yet to determine exactly why a reduction in fat allows animals to live longer, hes confident that medicines that cause the mechanism to spring into action arent too far around the corner. I think theres going to be an ever growing clamor to take advantage of this, Guarente says. And he believes life-span-lengthening medicines will be available within a decade.


Just One Gene
When Guarente first decided to study the causes of aging in the early 1990s, it was a topic tackled by few researchers. No one knew how to approach it. The early ideas, which were really quite persistent, were that if you eat less, everything just slows down, says Guarente. But he and two postdoctoral students decided to see if they could find a genetic cause for the phenomenon. In 1996, they found mutant yeast cells that lived 50 percent longer than normal cells and analyzed them, gene by gene. I said, We have a year to work on this, because Im not sure if theres anything to study, Guarente recalls. We got really interested, and it took a lot more than a year before I was sure we had something. We were seduced.

Over the next few years, the researchers tied the unusual longevity in the mutant yeast to one gene: SIR2. In other experiments, they discovered that when they inserted extra copies of SIR2 into normal yeast, it lived longer; when they deleted the gene, the yeast died prematurely. In 2000, the researchers found that a similar gene in worms worked the same way. It was exciting, Guarente says, because yeast and worms are such different creatures that in order to share a similar gene, they must have had a common ancestor. That means that any descendant of that ancestor, including us, has the same mechanism, he says.

At the very least, mice have it. In their Nature article, Guarente and his colleagues reported that when food is scarce, a mouses genetic equivalent of SIR2, SIRT1, produces a protein that turns off other genes that help store fat. The fat moves into the bloodstream, travels to other tissues, and gets burned. This keeps the mice lean and, for some as yet unknown reason, young looking and healthy into old age. Frdric Picard, a research scientist who worked with Guarente on the paper, remembers the day that he got clear results from the experiment. I was very happy, dancing all over. It was great, Picard says.

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