Breakthrough
In 2003, one unsolved mystery among the still-small cadre of longevity researchers was how to modulate genes, such as SIRT1, that regulate life span. Was there a compound that could be taken as a pill? Elixir and other companies and labs were beginning to screen thousands of chemicals to see if one would work as a gene activator, but none fit the bill.

In February 2003, in what was then his small, shoestring lab at Harvard, Sinclair was doing his own screening when he learned that scientists at Biomol Research Laboratories, a biotech company in Plymouth Meeting, PA, had observed that SIRT1 was activated by certain polyphenols, including resveratrol. Sinclair and Konrad Howitz, Biomol’s director of molecular biology, collaborated to isolate resveratrol and test it in yeast and fruit flies. “Never in my wildest dreams did I think we would find an activator of sir2,” says Sinclair.

In a 2004 Science interview, Sinclair added to his reputation as a zealot, calling resveratrol “as close to a miraculous molecule as you can find.” “One hundred years from now,” he said, “people will maybe be taking these molecules on a daily basis to prevent heart disease, stroke, and cancer.”

That same year, two scientists who were students in ­Guarente’s lab when Sinclair was there published a paper casting doubt on the underpinning of Guarente’s hypothe­­sis that caloric restriction activates sir2–a hypothesis that is critical to Sinclair’s own theories. (“I have independent-minded students, I guess,” Guarente told me with a wry smile.) The former students, Brian Kennedy and Matt ­Kaeberlein, both biologists at the University of Washington, claimed that, at least in yeast, caloric restriction could exert antiaging effects in the absence of sirtuins–the enzymes produced by sir2 and its mammalian homologues (such as SIRT1). Studies published soon after posed a more direct challenge to Sinclair’s contention that resveratrol mimics caloric restriction by activating sirtuins. Peter DiStefano, a coauthor of one of these studies and the chief scientific officer of Elixir, told me in 2005 that resveratrol does wondrous things, but it is unlikely to be an activator of the SIRT1 enzyme.

That skepticism, however, didn’t deter Sinclair. In 2004 he set out to prove that resveratrol indeed mimicked some effects of caloric restriction, joining with Rafael de Cabo of the National Institute on Aging to test the chemical on mice.

Mice live about two to three years; when I first visited Sinclair’s lab, in 2005, his test mice were about a year old. Sinclair was already ecstatic, because the resveratrol-fed mice seemed healthier than the controls; their cells were also aging remarkably slowly, even though the mice were being fed a fatty, unhealthy diet. When the paper on these experiments came out the following year in Nature, the results supported the claims Sinclair had been making about resveratrol in mammals. They showed that mice on a high-fat diet fed large doses of resveratrol were as healthy as mice on a regular diet. Resveratrol also improved the mice’s insulin sensitivity and increased their energy production.

The mice were given very high doses of resveratrol–22 milligrams per kilogram of weight. In comparison, a liter of red wine delivers 1.5 to 3 milligrams. To consume ­resveratrol at the same rate as the mice, a 150-pound human would need to drink roughly 1,500 bottles of wine (or take scores of pills) each day.

Sinclair’s paper came out within days of a study in Cell from the lab of Johan Auwerx of the Institute of Genetics and Molecular and Cellular Biology in Illkirch, France. ­Auwerx’s team, which was partially funded by Sirtris ­(Auwerx is on the company’s scientific advisory board), had given mice even higher doses of resveratrol–400 milligrams per kilogram. These mice stayed slender and strong on a high-fat diet, with the energy-charged muscles and reduced heart rate of athletes. The number of mitochondria in their cells increased, which improved the cells’ energy output.