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Published: Friday, 8/19/2011

Study: Drug extends life of overweight mice

Medication protected rodents from obesity-related illness

NEW YORK TIMES

NEW YORK -- Sustaining the flickering hope that human aging might somehow be decelerated, researchers have found they can substantially extend the average life span of obese mice with a specially designed drug.

The drug, SRT-1720, protects the mice from the usual diseases of obesity by reducing the amount of fat in the liver and increasing sensitivity to insulin.

These and other positive health effects enable the obese mice to live 44 percent longer, on average, than obese mice that did not receive the drug, according to researchers led by Rafael de Cabo, a gerontologist at the National Institute on Aging.

Drugs closely related to the one used on the mice now are undergoing clinical trials.

The findings "demonstrate for the first time the feasibility of designing novel molecules that are safe and effective in promoting longevity and preventing multiple age-related diseases in mammals," Mr. de Cabo and colleagues wrote in Thursday's issue of the new journal Scientific Reports.

The drug is one of a set of chemicals designed by Sirtris, a small pharmaceutical company in Cambridge, Mass., to mimic resveratrol -- the trace ingredient of red wine thought to activate protective proteins called sirtuins.

The sirtuins help mediate the 30 percent extension of life span enjoyed by mice and rats that are kept on very low-calorie diets. Because few people can keep to such an unappetizing diet, researchers hoped that doses of resveratrol might secure a painless path to significantly greater health and longevity.

But large doses of resveratrol are required to show any effect, so chemical mimics like SRT-1720 were developed to activate sirtuin at much lower doses.

Sirtuins have proved to be highly interesting proteins, but the goal of extending the life span was set back when extensive trials of resveratrol showed it did not prolong mice's lives, although it seemed to do them no harm.

Another blow developed in 2009, when biologists at Pfizer reported that SRT-1720 and other resveratrol mimics did not activate sirtuins and did not have any beneficial effects in fat mice.

The new report, which did find benefits after studying large groups of mice for more than three years, may do much to rescue SRT-1720 from this shadow.

"This is good evidence that this compound has a positive effect on the physiology of the obese animal, and that is definitely promising for humans," said Jan Vijg, an expert on aging at the Albert Einstein College of Medicine in New York.

Mr. de Cabo and his team "make a reasonable case" that the compound works by activating sirtuins, although they have not proved it, Mr. Vijg said.

In one sense it does not much matter how the drug obtains its effects, as long as it works. But the credibility of SRT-1720 and its cousins also rests on their design as sirtuin activators.

Despite the positive new results with SRT-1720, Sirtris is not putting it into clinical trials because the company believes another of its resveratrol mimics, SRT-2104, is more promising.

That drug "is more suitable for human consumption," said David Sinclair of Harvard Medical School, an author of Mr. de Cabo's report and a co-chairman of Sirtris' scientific advisory board.

"Questions were raised about the molecules and if they are working the way we said they were," Mr. Sinclair said. "But with this paper, the weight of evidence is shifting back in favor of the premise that we can tweak the aging pathway with drugs."

Obese mice are a standard research tool, but experts differ as to how relevant they are to humans.

"They've poisoned the mice with this high-fat diet that makes them very sick indeed, and with SRT-1720 they can reverse some portion of that illness," said Dr. Richard Miller, an expert on aging mice at the University of Michigan.

Dr. Miller said the finding "looks like something people should pay a lot of attention to," but added that the study would have been even more interesting if it had shown an effect on normal mice.

Mr. de Cabo and his team included normal, untreated lean mice in their study as a control group for the treated and untreated fat mice.

The treated fat mice lived longer than the untreated ones but died long before the normal mice.

Mr. Sinclair said that this leg of the study had been started at the same time, but that the treated normal mice were taking longer to die and could not be reported with the others. Mr. de Cabo said the results were "encouraging" but could not be discussed until they are published early next year.

Some researchers feel that too much attention has been given to resveratrol and its sirtuin-activating mimics, and that other compounds like the antibiotic rapamycin may be even more promising.

But the sirtuins "are worth a lot of attention even though some of the early claims have proved hard to reproduce," Dr. Miller said.



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