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Biomedicine

The Argument over Aging

Can a drug extend good health and postpone the effects of aging?

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.

Longevity lab: Harvard’s David Sinclair is testing compounds in mice that could be used to slow down the aging process in humans.

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.

Things Reviewed
  • The Youth Pill By David Stipp
    Current, 2010

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.

Even if Sirtris’s compounds don’t pan out as safe, effective drugs, the enzymes behind them have great medical potential, says Matt Kaeberlein, an assistant professor in the pathology department at the University of Washington, who is another former student of Guarente’s and a consistent critic of some of Sinclair’s work. These enzymes have been highly conserved through evolution, appearing in worms, flies, mice, and primates, and they play a central role in the biochemistry of the cell. Guarente says, “If the whole world gave up on sirtuins, I would still start another company for the next generation of sirtuin drugs based on what I know.”

But some scientists doubt that sirtuins hold the key to life extension; for one thing, sirtuin activation hasn’t been shown to extend life in healthy animals. A number of other molecular mechanisms are also under close scrutiny for their effects on aging. Kenyon, director of the Hillblom Center for the Biology of Aging at UCSF, points to a different drug, called rapamycin; as Stipp explains, one way it appears to lengthen life is by slowing the production of the proteins needed for cell division. As more proteins are produced, so are more defective proteins, which can accumulate in cells and contribute to the symptoms we see as aging.

Though rapamycin has not gotten nearly the attention or money that sirtuins have, some put far more faith in its age-slowing effects. “I’ve been in this area for about 35 years, and I honestly have never thought that in my lifetime there would be something like a pill that you could take that would have this impact on aging,” Arlan Richardson, director of the Barshop Institute for Longevity and Aging Studies at the University of Texas Health Science Center at San Antonio, says of the drug. Aging “may not be as intractable a problem as I thought,” he says. Rapamycin even worked on adult mice equivalent in age to 60-year-old people.

So why isn’t rapamycin more talked about? “The scientists involved with the rapamycin studies have been much less inclined to make bold claims,” Kaeberlein says. “That may be in part due to the fact that the mouse rapamycin studies were done as part of [a government] testing program, so there’s no commercial interest involved in selling a story.” But if sirtuins and rapamycin don’t work, researchers say, there are plenty of other possibilities to explore, from insulin signaling to mitochondrial function.

Stipp and others are confident that a “youth pill” is on the horizon–whether it comes from Sirtris or not. But some researchers are far less optimistic. Thomas Perls, for one, thinks it’s reckless to suggest that science is anywhere close to such a drug. “I think people just don’t get how incredibly complex aging is,” says Perls, an associate professor of medicine at Boston University’s School of Medicine, who for the last 16 years has run a study on centenarians. “Delivering the message that antiaging works, and that we’re now in prime time in producing substances that work, is incredibly irresponsible.”

Karen Weintraub is a freelance writer based in Cambridge, MA. She is the former Deputy Health/Science Editor at the Boston Globe.

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