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Biomedicine

The Longevity Gene

A gene that releases stored fat may be the key to a longer life.

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.

Racing to Finish the Puzzle
Although the finding is exciting, it still leaves some questions unanswered. Researchers at the Joslin Diabetes Center in Boston found that its possible to genetically engineer a mouse that automatically burns fat without calling the SIRT1 gene into action. These mice will live longer than others but not as long as mice on calorie-restricted diets. Guarente therefore suspects that the gene has other effects beyond triggering fat release. Some dozen researchers in his lab are now trying to figure out what they might be. For example, Kayvan Zainabadi, a biology graduate student, is trying to determine if SIRT1 also signals cells in the liver to break down fat, essentially cranking up metabolism. Graduate student Ed van Veen is investigating whether fat may produce something like a hormone that could regulate aging. Calorie restriction also increases sensitivity to insulin, a good indicator that an animal wont become diabetic. Several researchers are trying to find a connection between the SIRT1 gene and sensitivity to insulin.

As the members of Guarentes lab pore over cell cultures to the sound of hungry mice rustling in their cages, another group of scientists a short walk away at Elixir Pharmaceuticals is doing much the same thing. This group is hoping to find a medicine that will switch on the human equivalent of SIR2 and prevent age-related diseases, such as type 2 diabetes, cancer, and Alzheimers. Were not necessarily in the business of trying to find a longevity pill, says Peter DiStefano, Elixirs chief scientific officer. Right now, Elixir is testing promising potential drugs in animals and looking for pharmaceutical companies interested in licensing them. DiStefano hopes that within the next year or two, the company will begin clinical trials in humans. But once that process is well under way, he says, Its not far fetched at all to state that there may be a longevity benefit to this. But you have to caution that proving longevity is a pretty long endeavor. And a lot of us arent going to be around to see the outcome of it.

Nevertheless, plenty of other research groups at universities and companies around the world are salivating at the thought of SIR2s potential. Indeed, one of Guarentes main competitors is David Sinclair, one of his former postdoctoral fellows. Sinclair, now an associate professor of pathology at Harvard Medical School, disagrees with Guarente about what activates SIR2 in yeast. He believes that a molecule called nicotinamide and a gene called PNC1 control the activity of SIR2. Guarente, on the other hand, believes that the relative concentration of two molecules, NAD and NADH, determines SIR2s activity in yeast cells. In recent years, Sinclair has published several papers that attempt to disprove some of Guarentes theories and support his own. Theres been a big uproar over this, Guarente says. My feeling on thisand I told [Sinclair]was, A, I think were right, and B, I dont think its that important. The dispute about yeast is almost a moot point, Guarente says, because the way in which the SIR2 equivalent is activated in mammals, which is more relevant to how it works in humans, is probably different. But nonetheless, I think were right about yeast, Guarente says firmly.

Apart from the public battles in scientific journals, Sinclair is also competing with Guarente on the pharmacological side, having recently formed a company, Sirtris Pharmaceuticals, to create the same kinds of drugs that Elixir is pursuing. Its a race now between the two, says Picard, who left MIT this summer for a position at Laval University in Qubec City. They both have very big labs working hard. They both have companies working hard, too.

Guarente is aware that many people believe a pill that extends human life is not necessarily a good thing, potentially leading to overpopulation and possibly helping only the few wealthy people who could afford it. Guarentes own college-age son has argued with him about the validity of his research. He says, Youre only going to help people who already have long and healthy lives. Why not work on malaria? Guarente says he was not interested in medical implications when he started his research. I thought it was an interesting biological problem, an intellectual problem, and it drove me.I wasnt thinking practically at all. It was curiosity.

Even with all the attention SIR2 is gettingin large part because of his own effortsGuarente still suspects that much of the scientific community resists the idea that a single gene could have the power to control longevity. I think its increasingly more accepted than it was, but I think there [are] still a lot of people [who] cannot get their arms around the idea that there would be one critical gene. Guarente, however, hopes to live long enough to prove these naysayers wrong.

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