Mice with less body fat are known to live longer than their plumper peers. Now, researchers have identified a molecular pathway that might explain this link. According to the new work, a protein called SIRT1 seems to spur fat breakdown in food-deprived animals by thwarting the actions of a protein that activates fat storage-promoting genes.
Slashing calories slows aging in numerous species, and scientists have uncovered some of the proteins that foster this phenomenon. For instance, yeast usually require Sir2p, SIRT1's cousin, to gain life extension from food scarcity. Frédéric Picard of the Massachusetts Institute of Technology and colleagues wondered whether SIRT1 does the same thing in rodents. Because calorie restriction induces fat breakdown in white fat cells, they probed possible links between lipid processing and SIRT1. The researchers boosted or suppressed SIRT1 production in cultured mouse fat cells. Cells that made extra SIRT1 accrued much less fat than normal, whereas cells with stunted SIRT1 production stockpiled extra. Moreover, mice engineered to generate smaller than normal quantities of SIRT1 carried relatively little fat in their blood, indicating that their cells hung onto it. These observations suggest that SIRT1 inhibits fat accumulation. How does it do that? Additional experiments revealed that SIRT1 stymies PPARγ, which is known to jack up the activity of several genes that boost fat production. So calorie restriction may prompt SIRT1 to block PPARγ, thus inhibiting fat accumulation in cells and prodding the movement of fat into the bloodstream, the researchers speculate. The work represents "a big step," says David Sinclair, a molecular biologist at Harvard Medical School in Boston. The new results suggest that SIRT1 might connect a lean diet with long life, just as the yeast enzyme does, he says. Sinclair and the authors caution that calorie restriction involves more than fat reduction, and Sinclair says that the mechanism proposed in this study likely represents "a small piece in the overall puzzle of how life extension works." Right now, however, it's a front-runner in the race to understand how diet regulates mammalian longevity.