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Biomedicine

The Healthy Skinny Pill

A new drug proves effective in fighting obesity and related diseases while increasing stamina in mice.

A pill that delivers the health benefits of diet and exercise without any of the effort is one step closer to becoming a reality. European scientists have found that mice fed a high-fat, high-calorie diet and prevented from exercising regularly can be protected from weight gain and metabolic disorders when given a drug that targets a gene linked to longevity. The treatment even increases the animals’ running endurance.

Marathon mice: Last year, scientists tested the health effects of resveratrol, a compound found in red wine, that targets the same pathway as the synthetic compound SRT1720. In both instances, mice fed these compounds have increased running endurance. The mouse on the right (fed resveratrol) runs for longer than the untreated mouse on the left.

The drug was developed last year by Sirtris Pharmaceuticals, based in Cambridge, MA, and preliminary studies of the compound showed it to be effective in treating mice models of type 2 diabetes, a disease that results in an impaired ability to produce or process insulin, the risk of which increases with age. Now scientists led by professor Johan Auwerx at Ecole Polytechnique Federale de Lausanne (EPFL), in Switzerland, have shown that the compound involved, known as SRT1720, also blocks weight gain and obesity-related disorders and increases muscle stamina.

In the study, scientists fed the mice a high-fat, high-calorie diet mixed with doses of SRT1720 for approximately 10 weeks. The mice were given 100 or 500 milligrams of fat per kilogram of body weight each day (a high dose even for humans). The mice did not exercise regularly, although the scientists tested the animals’ exercise capacity, or endurance, by making them run on a treadmill. “The mice treated with the compound ran significantly longer,” says Auwerx. The drug also protected the animals from the negative effects of high-calorie diets: metabolic disorders, obesity-related diseases, and insulin resistance. It even improved the mice’s cholesterol.

It is significant that the drug mimics the effects of a calorie-restricted diet, since this has previously been tied to increased life expectancy, says William Evans, a professor of geriatric medicine, nutrition, and physiology at the University of Arkansas for Medical Sciences.

It’s as if the couch-potato mice underwent a strict diet and exercise regime, says David Sinclair, a biologist at Harvard Medical School, in Boston, who is one of the cofounders of Sirtris but was not involved in the current study. The new study “is a major step forward, showing that we can design and synthesize potent, druglike molecules that could slow down the aging process,” says Sinclair.

The effects of the compound are similar to those of resveratrol, a molecule found in red wine that has previously been shown to extend life span and have health benefits in mice. But SRT1720 is a thousand times more potent than resveratrol, meaning that it could be taken in smaller doses. A person would have to drink hundreds of glasses of wine to get the same health benefits from resveratrol, and, while supplements are available, it is unclear whether they are as effective. “Resveratrol will pretty soon look like ancient technology,” says Sinclair.

The findings in the new study, which is published in the November issue of the journal Cell Metabolism, also answer a big scientific question: whether scientists searching for ways to combat aging have been targeting the right gene.

SRT1720, like resveratrol, works by targeting a gene known as sirtuin 1, or SIRT1, which many scientists believe plays a fundamental role in regulating life span. SIRT1 encodes for a class of proteins known as sirtuins, and it is a central controller of mitochondrial activity (mitochondria are the powerhouse energy providers to the cells). “Firing up mitochondria is one of the best treatments against diabetes and obesity because you burn off extra energy instead of storing it,” notes Auwerx.

However, unlike the new compound, resveratrol is not specific to SIRT1, and thus many experts have questioned whether the effects of resveratrol in mice were mediated by SIRT1 activation or by some other pathway.

The fact that another chemical activates the same gene and produces similar effects strongly suggests that the metabolic benefits can be attributed to SIRT1, says Leonard Guarente, an MIT biologist whose lab first discovered the sirtuin 1 gene. He is on Sirtris’s advisory board but wasn’t involved in the study. “This is a very important finding, and [it] means that [SIRT1 activators] are good candidates for lead compounds [in] antidiabetic drugs in humans,” Guarente says. SIRT1 could also be a target for other diseases related to aging, he adds, “which would be a silver bullet.”

“The scientific community is focusing on mitochondria as the most important organelle in muscle that affects the risk of diabetes, hypertension, and the loss of physical function in elderly people,” says Evans. “The compound may be one additional help or aid that we could use to treat these conditions. It is an exciting, new development.”

Sinclair says that a cousin molecule of SRT1720, which is even more potent, is currently in human trials and will enter clinical studies for the treatment of diseases like type 2 diabetes in 2009. “We could know as early as next year if the same types of benefits we see in mice, we see in humans,” he says.

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