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A novel group of drugs that target a gene linked to longevity could provide a way to turn back the clock on the diseases of aging. The compounds are 1,000 times more potent than resveratrol, the molecule thought to underlie the health benefits of red wine, and have shown promise in treating rodent models of obesity and diabetes.

Human clinical trials to test the compounds in diabetes are slated to begin early next year, according to Sirtris Pharmaceuticals, based in Cambridge, MA, which developed the drugs. “As far as I’m aware, this is the first anti-aging molecule going into [testing in] man,” says David Sinclair, a biologist at Harvard Medical School, in Boston, and cofounder of Sirtris. (See “The Enthusiast.”) “From that standpoint, this is a major milestone in medicine.”

The new drugs target an enzyme called SIRT1, which belongs to a class of proteins known as sirtuins that have been shown to lengthen life span in lower organisms. Sinclair and others theorize that activating these enzymes, which play a role in cell metabolism, mimics the effects of caloric restriction–a low-calorie but nutritionally complete diet that dampens disease and boosts longevity in both invertebrates and mammals.

For several years, scientists have been on the hunt for a drug that could bring the benefits of caloric restriction without the strict diet. (See “The Fountain of Health.”) Last fall, Sinclair and his colleagues took a first step when they showed that mice given resveratrol, a molecule that activates SIRT1, stayed healthy when fed high-fat foods. (See “A Life-Extending Pill for Fat Mice.”) But there was a catch: mice were dosed with the human equivalent of more than 1,000 wine bottles’ worth of the compound, an amount not possible for humans to imbibe or take in pill form.

Now a team at Sirtris, led by CEO Christoph Westphal, has identified a group of compounds that activate SIRT1 1,000 times more potently than resveratrol does. According to findings published today in the journal Nature, the compounds bind to the enzyme and dramatically increase its activity. Because the new compounds are more powerful, much lower doses are likely needed to achieve the same beneficial effects. “We believe doses needed in humans for the novel compounds are probably on the order of hundreds of milligrams, similar to many marketed drugs,” says Westphal.

The Sirtris team focused initial animal tests on type 2 diabetes, a disease that results from the impaired ability to use insulin, and whose risk increases with aging. They found that the drugs improved insulin sensitivity and blood glucose levels in three rodent models: diet-induced obese mice, genetically obese mice, and a rat model of type 2 diabetes. “Theoretically, this is a perfect drug,” says Charles Burant, head of the Michigan Metabolomics and Obesity Center at the University of Michigan, in Ann Arbor. “Animals seem to have no change in weight, yet they have improved metabolic status.”

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Credit: Technology Review

Tagged: Biomedicine, drugs, aging

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