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Sirtris Pharmaceuticals was, until recently, the golden child of antiaging research. Founded by Harvard biochemist David Sinclair and venture capitalist ­Christoph Westphal, it produced research suggesting something almost too good to be true: that a chemical in red wine could help you live a longer, healthier life. With its young, photogenic founders, the startup was a media darling, the subject of dozens of breathless magazine and newspaper articles. Pharmaceutical giant GlaxoSmithKline was so impressed that it spent $720 million to buy Sirtris in 2008.

David Stipp’s new book The Youth Pill traces this meteoric rise and other events in the history of antiaging research, detailing how the science and personalities came together at just the right moment to create the successful company. In the mid to late 1990s, Stipp explains, what had been considered a fringe field began evolving into a focused attempt to uncover the biochemistry of aging. Scientists including Cynthia Kenyon at the University of California, San Francisco, and Leonard Guarente at MIT began to find genes linked to longevity in lower organisms such as yeast and worms, prompting a conceptual shift in our understanding of aging. Rather than inevitable decay, their work suggested, aging was a genetically controlled process–and thus one that could be manipulated.

Sirtris was one of the companies to emerge as this view of aging gained currency. At the heart of its drug development program are a class of enzymes called sirtuins: the molecular signals that they send appear to silence aging-related genes during times of starvation. The sirtuins’ role in aging was first identified in 1993 by ­Guarente and his colleagues. (Sinclair would later join the lab as a postdoc.) As Stipp explains, the role of these enzymes in aging made sense to scientists who had known for years that caloric restriction, or nutritionally adequate diets about 30 percent lower in calories than average, could extend the lives of yeast, worms, and mice (the effect was also later demonstrated in rhesus monkeys). Realistically, however, few people can stick to this type of diet. So for more than a decade, the primary goal of antiaging researchers has been to mimic caloric restriction with a pill, a prospect that Stipp describes as “the great free lunch.” Such a drug, he writes, would theoretically postpone aging in people, extending their years of good health and limiting their years of decline.

In 2003, Sinclair made headlines around the world when he announced that the red-wine component resveratrol, which had previously been linked to a reduction in heart disease, extended life span in yeast. He argued that the compound activated one of the sirtuins and proposed that it mimicked the effects of caloric restriction. Sinclair and Westphal launched Sirtris in 2004 with the aim of developing molecules that could stimulate the enzyme much more potently. The company is developing treatments not for aging itself–which the U.S. Food and Drug Administration doesn’t consider an illness–but for diseases of aging, such as diabetes, Alzheimer’s, and cancer.

As Stipp recounts, hopes for antiaging drugs captured media attention and investors’ imaginations. But a different conversation has played out in the academic community. Some scientists doubted whether resveratrol truly targeted the sirtuins. Researchers at drug maker Pfizer also published a study in January questioning whether one of Sirtris’s newer compounds targets the enzyme. The study failed to confirm the health benefits seen in earlier trials. To make matters worse, safety concerns have arisen over one of ­Sirtris’s resveratrol compounds. In May, Glaxo announced that it would not expand a clinical trial for multiple-myeloma patients until it better understood why some participants developed a dangerous kidney ailment.

The field of antiaging research is littered with failures, and the controversy over ­Sirtris’s compounds highlights just how difficult it has been to transform exciting scientific discoveries about the aging process into useful drugs. As Stipp illustrates, many candidates with promising antiaging benefits later failed to work in mammals or showed conflicting results.

Elixir Pharmaceuticals, which was cofounded by Kenyon and Guarente in 1999 to translate their findings on the genetics of aging into a pill, was once “the leading commercial effort to turn research on aging into antiaging drugs,” says Stipp. But the company has been far less successful than ­Sirtris in generating funding and excitement; today it employs just a handful of people, who are still pursuing sirtuins but have also moved on to developing other types of drugs. (Both Kenyon and Guarente have since left Elixir. Guarente joined Sirtris’s scientific advisory board in 2007.) Peter S. DiStefano, chief scientific officer of Elixir, is no fan of the rival company, accusing it of weak science and overzealous claims. “While Sirtris was way more successful than Elixir from a business perspective, at least I have my scientific integrity and can look at myself and say I did the right thing the right way,” he says.

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Credit: Rick Friedman/WPN

Tagged: Biomedicine

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