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“I think the day I got most scared in my life was when he showed me his brother’s new compound bow,” recalls Sumich, who now owns a market-research company in Australia. “We went up to the park, and he would shoot it straight up in the air, and having lost sight of it, we would scatter for cover. That, to this day, is still the most stupid thing I have ever done.”

Sinclair attended the University of New South Wales and was studying gene regulation in yeast when he learned about longevity research during a conversation with Leonard ­Guarente, an MIT molecular biologist who was in Australia giving lectures. Back then–1993–most people assumed that aging was a complex and inevitable process that could not be regulated by just a few genes. But that year, Cynthia ­Kenyon, a biologist at the University of California, San Francisco, published a study showing how manipulating a single gene, daf2, could double the life span of a tiny roundworm. Guarente himself was beginning experiments on yeast that would lead to the discovery of the antiaging gene sir2 in 1995.

The field was so new and unproven, though, that ­Guarente talked about it only informally–as, for instance, when a young Australian scientist sat down next to him during a group lunch. “This was incredibly serendipitous,” says Sinclair. Inspired, he sold his Mazda Miata to buy a ticket to Boston to interview for a postdoc position in ­Guarente’s lab. During his interview, he gave a spirited whiteboard presentation arguing that scientists studying aging should look for genes that prolong life rather than genes and mecha­nisms that end it. He got the job.

While Sinclair was in Guarente’s lab in the late 1990s, he discovered that sir2 prevents aging in yeast by slowing down the accumulation of ERCs, circular strands of DNA that build up in organisms as they age, eventually killing them. Around the same time, others in Guarente’s lab made another crucial discovery: that a link may exist between sir2 and a molecule critical for metabolizing food, called NAD. The connection suggested that the longevity gene might be related to diet–specifically, Guarente postulated, to caloric restriction. A nutritionally complete diet containing 30 to 40 percent fewer calories than normal had long been known to extend life span in some animals, ramping up cell defenses and slowing down aging. Guarente and others theorize that in times of scarcity, such as famine or drought, this mechanism allows an organism to survive–and postpone reproduction–until the crisis is over. The link between sir2 and NAD, therefore, suggested to Guarente that caloric restriction might be affecting longevity by activating the antiaging gene.

Colleagues who were students in Guarente’s lab during this period remember Sinclair as highly ambitious. Shin‑ichiro Imai, then a postdoc, now a molecular biologist at Washington University in St. Louis, and still a friend, describes him as “obsessed,” with a penchant for aggressively pursuing his ideas. “He is an introvert who becomes an extrovert for what he’s working on,” Imai says.

Sinclair’s ambition has also complicated his relationship with his mentor, who helped him secure an appointment in Harvard Medical School’s department of pathology in 1999. Guarente, a lanky man with a shaved head and intense eyes, says he is proud of his protégé. In 2004, however, an article in Science described a rivalry between the two men that began during a meeting at Cold Spring Harbor in New York, where Sinclair stunned Guarente by disagreeing with him about how a key gene associated with caloric restriction increases life span in yeast. The two began publishing competing papers, vying head to head to figure out how sir2 and, later, other antiaging genes are regulated. “Most young scientists would not compete directly with their mentors, but David did,” says Imai.

Sinclair also said no to signing on with Elixir Pharmaceuticals, the company cofounded by Guarente and ­Cynthia Kenyon in 1999, which for a time he had hoped to join. By the time Elixir called, he had discovered the effects of ­resveratrol; in 2004 he surprised his former teacher by cofounding Sirtris, a company whose name incorporated that of the SIR genes that Guarente had helped to discover.

Both men say that Science overstated the extent of the rift between them. There was some tension for a couple of years, they say, but that has died down. They now collabo­rate on some experiments and articles, and they talk frequently. In a curious turnaround, Guarente left Elixir last year and has considered working with Sirtris, although he can’t join the company until the fall of 2007 because of a one-year noncompete clause in his contract with Elixir.

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Credit: Steve Brodner

Tagged: Biomedicine

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