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 Science.
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According to Ie-Ming Shih, M.D., Ph.D., associate professor of pathology and oncology, who co-directs the laboratory with Wang, other gene typing methods can identify abnormalities within wide areas of the genome, but the tool used for this study, called digital karyotyping, is far more precise. "It's like narrowing down our search from the entire State of Maryland to a certain building in Baltimore City," he says.
In three of the seven cell lines, the scientists homed in on chromosome 11 after finding high levels of amplification in a region known for cancer-related genes. Further analysis of this region revealed that the Rsf-1 gene was overexpressed far more than 12 other genes in the same area.
Rsf-1 typically opens and closes the scaffolding structure of DNA, which acts as the gatekeeper to protein manufacturing. The Hopkins scientists say that when Rsf-1 is amplified, it may disturb this process and create more space for protein production of certain genes that may promote tumor growth.
"It's important for us to learn more about how Rsf-1 creates aggressive cancers in order to develop drugs that target it," says Wang. "But right now, we'll need to test larger samples to determine if Rsf-1 accurately predicts clinical outcome."
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