March 2006

The Fountain of Health

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Old Yeast
The identification of the life-extending effects of sir2 in yeasts was no accident: Lenny Guarente had been searching for the causes of yeast aging for almost a decade when he and his MIT graduate students methodically zeroed in on the gene in 1999. It was an important finding, but its real significance became more apparent over the next year and a half.

First, Guarente and his students found the sir2 gene in round worms. Since yeast and worms diverged evolutionarily billions of years ago, the presence of the same gene in both organisms suggested that it might be shared by other animals, including humans. Then came the bombshell. The expression of the sir2 gene required the presence of another molecule, called NAD; as any biologist knew, NAD is involved in numerous metabolic reactions in many organisms. "This finding that sir2 was NAD dependent meant to us that sir2 could connect aging to metabolism and therefore to diet," says Guarente. "Once you see this activity, a child could point out, Maybe this would connect to caloric restriction."

Perhaps not most children, but other molecular biologists certainly saw the connection, and labs around the world soon began to puzzle out the effects of sir2. Scientists knew that calorie restriction could have an impact on disease. And now there was evidence of a strong link between sir2 and calorie restriction. "If you put those together," says Guarente, "you can formulate a hypothesis that sir2 genes will impact diseases of aging."

Amidst this flurry of research, however, it was a 2003 paper in the journal Nature by Sinclair and his collaborators that really caught the attention of those hoping to turn the science of sirtuins into drugs. Sinclair identified a class of common chemicals, called polyphenols, that activate sirtuins. The findings suggested it might be possible to develop small-molecule drugs that could interact with sirtuins and turn on their apparent beneficial effects.

Six months after the Nature paper, Sinclair cofounded Sirtris with Christoph Westphal, then a partner at Polaris Venture Partners, a Waltham, MA-based venture capital firm. [Disclosure: Polaris general partner Robert Metcalfe is on Technology Review's board of directors.] Less than two years later, the startup has $45 million in venture financing and a series of drug candidates that activate SIRT1 and other sirtuins in mammals. Within a few years, says Westphal, now Sirtris's CEO, the company hopes to begin testing the safety of the sirtuin activators in humans. "We're aiming to mimic calorie restriction with small molecules," says Westphal. "The great break for us was to find those small molecules."

Meanwhile, members of Sinclair's Harvard lab are busy conducting experiments on thousands of mice to prove the benefits of sirtuins in treating disease and aging. The mice are stacked in endless rows of small, clean cages packed into a series of locked rooms. Some of the mice, partly bald and stiff jointed, have been genetically engineered to age prematurely. Other cages hold animals genetically destined to get colon or prostate cancers, while yet other mice will develop neurological impairments of a kind associated with Alzheimer's disease. The researchers crossbreed these mice with animals genetically engineered to overexpress one of the sirtuin genes, then monitor how the offspring fare -- whether the sirtuins fight off the diseases or prevent premature aging. Taken together, it is a massive effort to understand the role of sirtuins in mammals, with thousands of mice providing different pieces of the puzzle.

Given that the mice experiments are just a year old, and mice typically live for around three years, results are still preliminary. There is not yet any conclusive evidence, for one thing, that activating or overexpressing sirtuins increases the life span of the mice. But Sinclair says that the studies completed so far all show "that the diseases in the mice have been ameliorated."

The Fountain of Health

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