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Compound That May Mimic Calorie Restriction Extends Life Span in Mice

The molecule is thought to activate proteins involved in metabolism and inflammation
lab mice


Scientists have known for decades how to make yeast, mice and other organisms live longer: give them less food.
Credit: Aaron Logan/Wikimedia Commons

A synthetic chemical that may mimic the effects of eating a low-calorie diet extends life span in mice, a new study has found. Previous research showed that mice on a high-fat diet lived longer when given this compound, known as SRT1720; the new work shows that mice on a standard diet also benefit from it. This study is just the latest in an extensive effort to find compounds that may help slow aging and aging-related diseases.

Scientists have known for decades how to make yeast, mice and other organisms live longer: give them less food. Although this might sound paradoxical, it is well established that severely restricting the caloric intake of many lab-raised animals, as long as their essential nutritional needs are met, significantly increases their life span.

But whereas calorie restriction may work for lab mice, it is unlikely to be widely embraced by more than a select few humans. And although there is clear evidence that calorie restriction does prolong the lives of some lab animals, when it comes to nonhuman primates, there are only two long-term studies on the subject. One study by a group at the University of Wisconsin found that calorie restriction increased life span and reduced the occurrence of various diseases in rhesus monkeys. In contrast, the other study, by the National Institute of Health’s National Institute on Aging, did not show improved survival of calorie-restricted rhesus monkeys, although they did have lower rates of cancer.

Despite these mixed results, scientists have been ramping up their efforts to find and test what they call calorie restriction mimetics: chemicals that can mimic the life-lengthening effects of calorie restriction by activating the same cellular pathways that low-cal diets activate—but without cutting calories. Although the exact mechanism linking calorie restriction and longevity is still a matter of debate among scientists, research efforts have narrowed the possibilities.

The pathway that has received the most attention involves the activation of proteins called sirtuins. These proteins are involved in a wide variety of processes, most notably metabolism and inflammation. Mice genetically modified to produce higher levels of these proteins were protected from diseases such as diabetes. And certain chemicals thought to activate sirtuins have been shown to have beneficial effects on the cardiovascular system and inflammation in mice.

A number of studies have looked at the sirtuin-activating capabilities of the naturally occurring compound resveratrol. The chemical, which is present in red wine, gained widespread attention when scientists showed that it boosts the life span of yeast, and a 2006 study found that obese mice also lived significantly longer when given resveratrol. Unfortunately, red wine likely does not contain sufficient levels of the chemical to have a measurable impact on human life spans, and studies of resveratrol supplements given to humans have shown varied results. Some scientists have also questioned whether resveratrol can actually directly activate sirtuins.

Recently, scientists have been testing synthetic chemicals that activate sirtuins much more efficiently than resveratrol, including SRT1720. The newest study, published in the February 27 Cell Reports, found that SR1720 extended the life span of mice on a standard diet by about 9 percent. They also confirmed their earlier work indicating that the compound extends the life span of mice fed a high-fat diet.

“I think the data in the paper is compelling,” says sirtuin researcher Leonard Guarente of the Massachusetts Institute of Technology, who is not a co-author of the study, although he is a consultant for a company involved in the research. He acknowledges it is impossible to say for sure that SRT1720 is activating sirtuins and nothing else. But “that qualification would hold for really any pharmacological intervention,” he observes.

It may be a long time before SRT1720 makes it into human medication, however, if it does at all. Even then, it would likely be targeted at specific ailments such as heart disease or diabetes, not longevity, says Rafael de Cabo, a researcher at the National Institute on Aging and the senior author of the paper. “There is no such a disease called ‘aging,’ defined by the F.D.A.,” he says. “You cannot process an application for a drug for curing aging.”

Guarente notes that testing this or other sirtuin-activating compounds on human longevity isn’t a possibility. “It would take a very, very, very long trial,” he says. Plus, “there are just so many things that affect longevity.” Rather, if the compounds do make it to market to treat specific diseases, a retrospective study would be the only way to find out if the chemicals also extended human life spans. “Certainly by 50 years, if there are a substantial number of people taking these compounds, I think you’d be able to make a call [as to] whether they’re affecting how long they live,” Guarente says.

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