Sci. Aging Knowl. Environ., 9 June 2004
By squelching a fat-storage pathway, protein might connect diet with extended life
Like a cutthroat politician, a potential longevity protein acts by derailing another molecule with opposing aims. According to new work, SIRT1 seems to spur fat breakdown in food-deprived animals by thwarting the actions of PPAR, a protein that activates fat-storage genes. Fat loss prolongs life in mice, so the findings suggest a possible molecular pathway that links diet to mammalian longevity.
Slashing calories slows aging in numerous species (see Masoro Review), 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 (see Kaeberlein Perspective). Picard and colleagues wondered whether SIRT1 also mediates the effects of calorie restriction in rodents. Because calorie restriction induces fat breakdown in white fat cells, they probed possible links between lipid processing and SIRT1 as a first step toward investigating this issue.
The researchers induced cultured connective tissue from mice to become fat cells, which produce and store fat, and then either boosted or suppressed SIRT1 production. Cells that made extra SIRT1 accrued much less fat than normal, whereas cells with stunted SIRT1 production stockpiled unusually large amounts of it. These findings seem to hold true in animals as well: 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. To gain insight into the mechanism, the researchers measured the activity of genes that boost fat production in the genetically modified cells. Output increased in cells with diminished SIRT1 and decreased in cells with surplus SIRT1.
Because PPAR jacks up the activity of several of these genes, the researchers wondered whether SIRT1 works by stifling PPAR's operations. To test this idea, they performed two sets of experiments. First, they infused human embryonic kidney cells with a DNA snippet that encodes a fluorescent protein; PPAR controls production of this protein. Cells that made excess SIRT1 glowed less brightly than did cells with normal SIRT1 quantities, indicating that SIRT1 stymies PPAR function. Second, they found that SIRT1 can occupy some of the same DNA sequences that PPAR binds in cultured fat cells and in white fat tissue from fasted, but not fed, mice. Perhaps calorie restriction prompts SIRT1 to block PPAR from activating genes, thus 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 yeast enzyme prolongs life through its food-sensing capabilities, and the new results suggest that the mammalian version might similarly connect nutrient processing with long life, he says. Richard Miller, a biogerontologist at the University of Michigan, Ann Arbor, finds the study "very provocative" and predicts it will "inspire a good deal of further exploration of these issues." 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.
June 9, 2004
Science of Aging Knowledge Environment. ISSN 1539-6150