Drastically reducing calorie intake, or caloric restriction, is known to extend the lifespan of species including yeast, worms and rodents. Previous research linked a gene called Sir2 with lifespan extension due to caloric restriction, but worms and yeast that lack Sir2 also live longer when put on a tough diet, showing that some other genes must be at work.
Researchers led by David Sinclair at Harvard Medical School and Su-Ju Lin at UC Davis' Center for Genetics and Development and Section of Microbiology screened for other life-extending genes in yeast. They found a gene called Hst2 that accounts for most of the difference.
Deleting Hst2 and Sir2 blocked most of the beneficial effect of caloric restriction. When Hst2 was overexpressed, so that the gene was more active than normal, the yeast lived longer than normal. A third gene, Hst1, appears to act when both Sir2 and Hst2 are missing.
Sir2 and the newly identified Hst genes account for all of the life-prolonging effects of caloric restriction in yeast, Lin said.
In yeast, the effects of aging seem to be due to a build-up of toxic circular DNA molecules that accidentally get copied out of ribosomal DNA, an unstable area of the yeast genome that contains hundreds of repeated sequences.
The researchers showed that caloric restriction drastically reduces recombination of ribosomal DNA, and that deleting Hst2 and Sir2 blocks this effect.
Very similar genes are found in widely different animals including worms, flies and rodents. But the targets of these genes are likely to be different, as the toxic DNA circles have not been identified in more advanced organisms, Lin said.
The work was published in the Sept. 16 issue of Science.