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Rewriting Life

Genetic Fountain of Youth

Researchers have identified a genetic tweak that can slow aging in mice.

By disabling a gene involved in an important biochemical signaling pathway, scientists have discovered a way to mimic the well-known anti-aging benefits of caloric restriction, allowing mice to live longer and healthier lives. This finding, published online today in Science, offers a promising drug target for combating the many health problems associated with aging.

Aging machines: Mice lacking a functional version of the protein S6 kinase 1, an important regulator of the body’s response to nutrient availability, live longer and healthier lives than their normal counterparts. The mouse on the left lacks the protein.

“This research points the way to potential pharmacological approaches to treating aging-related diseases in humans,” says senior author Dominic Withers, professor of diabetes and endocrinology at University College London.

“It really defines this as a pathway that’s affecting aging all the way from yeast to mammals, which I think is pretty striking,” says Matt Kaeberlein, professor of pathology at the University of Washington and coauthor of a commentary accompanying the new study.

Caloric restriction has long been known to extend lifespan and reduce the incidence of age-related diseases in a wide variety of organisms, from yeast and roundworms to rodents and primates. Exactly how a nutritionally complete but radically restricted diet achieves these benefits has remained unclear. But recently several studies have offered evidence that a particular signaling pathway, involving a protein called target of rapamycin (TOR), may play a pivotal role. This pathway acts as a sort of food sensor, helping to regulate the body’s metabolic response to nutrient availability.

Withers and colleagues noticed that young mice with a disabled version of the protein S6 kinase 1 (S6K1), which is directly activated by TOR, bore strong resemblance to calorie-restricted mice: they were leaner and had greater insulin sensitivity than normal mice. The researchers wondered whether these benefits would persist into middle and late age, and whether the mice would live longer.

To find out, they bred two large groups of “knockout” mice that lacked a functional version of the gene for S6K1. One group lived out their lives undisturbed, providing a measure of the group’s natural lifespan. The other group was put through extensive testing of cognitive and motor performance and metabolic health.

In female mice, the results were profound. Knockout females lived substantially longer than their normal counterparts. At 600 days–the mouse equivalent of human middle age–they excelled at motor performance tests, outdoing normal mice at tasks requiring balance, strength, and coordination. They were also more inquisitive and apt to explore new environments, suggesting improved cognitive function. Physiological measures also pointed to better health: the knockout mice had stronger bones, better insulin sensitivity, and more robust immune cells. While male knockout mice did not have extended lifespans, they did have the same array of health benefits as females.

“We added life to their years, as well as years to their life,” says Withers.

The effects of disabling S6K1 were similar to those of caloric restriction, though less pronounced. Female mice without S6K1 lived up to 20 percent longer than normal mice; the longevity increase with caloric restriction can reach 50 percent. “That probably means that deleting S6 kinase is not capturing all the effects of caloric restriction,” says Withers, “but the range of health benefits is similar.”

Withers’s findings follow on the heels of a study published in July that showed that the drug rapamycin–which interferes with the same pathway by inhibiting TOR–extends lifespan in mice. Although rapamycin had a pronounced effect on longevity and health, the drug’s potential in humans is limited by its potent immunosuppressant effects. (Rapamycin is already used to prevent organ rejection in transplant patients.) Targeting S6K1 directly–effectively bypassing TOR, which acts on a number of other proteins–may circumvent this dangerous side effect.

“We’ve triaged out one of the downstream rapamycin targets, S6K1, and we appear to have a lot of the benefits without major side effects,” says Withers.

The new study also implicated the protein AMPK, a component of the TOR pathway even further downstream than S6K1, as a key potential drug target. The role of AMPK is especially intriguing because it is activated by metformin, a widely prescribed drug for treating type 2 diabetes. Withers says this means it may be possible in the next few years to design clinical trials that would test metformin’s ability to prevent or treat age-related diseases.

In future studies, Withers and his colleagues hope to begin teasing out the details of the link between TOR signaling and aging. Based on the new paper and other recent studies, it is increasingly clear that throwing a wrench into the TOR pathway can have powerful effects on the aging process across a wide variety of species. And it seems likely that caloric restriction achieves its benefits in part by tapping into the TOR pathway. But it’s not yet obvious why that is.

The TOR pathway is known to act as a kind of fuel gauge, sensing nutrient availability and responding by altering how efficiently proteins are manufactured. For instance, when food is scarce, the TOR pathway responds by scaling back protein synthesis. One hypothesis, according to Kaeberlein, is that while protein manufacture is reduced overall, a small subset of proteins might actually be upregulated. “It’s pretty speculative,” he says, but identifying the functions of those select few proteins could lead to new insights into the way aging works.

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