Sci. Aging Knowl. Environ., 12 May 2004
Vol. 2004, Issue 19, p. nf48
[DOI: 10.1126/sageke.2004.19.nf48]

NEWS FOCUS

Calorie Restriction Un-SIR-tainty

Yeast don't need SIR2 to starve their way to long life

R. John Davenport

http://sageke.sciencemag.org/cgi/content/full/2004/19/nf48

HERSONISSOS, CRETE, GREECE--Like connections between characters in a Greek tragedy, the relation between calorie restriction (CR) and a longevity gene might not be what it has seemed. New work presented here 1 May at the 2nd International Conference on Functional Genomics of Ageing suggests that curbing food intake doesn't require the SIR2 gene to extend yeast longevity. The result challenges the prevailing model for how CR works, although some researchers don't rule out a contribution from SIR2.

Chopping calorie intake extends the lives of numerous species, and SIR2 seems to help. Extra doses of the gene increase the number of times a yeast cell divides, a measure of its life span (see Kaeberlein Perspective). Cutting a yeast's sugar supply doesn't prolong life in SIR2-deficient cells, suggesting that CR needs the gene to work its magic.

But new results challenge that view. As a first step toward scanning Saccharomyces cerevisiae's genetic dowry for all genes that influence life span, molecular biologist Brian Kennedy of the University of Washington, Seattle, and colleagues tabulated the longevity of yeast with deletions in previously identified aging-associated genes. Consistent with other results, yeast that lack SIR2 reproduced unusually few times, and those without a gene called FOB1 generated extra offspring. FOB1's protein product helps produce small circular bits of DNA, a process that limits yeast life span; SIR2's thwarts the formation of these circles.

Kennedy next probed how SIR2 and FOB1 tie in to CR's life-extending effects. Consistent with previous findings, a genetic manipulation that mimics a low-glucose diet didn't give SIR2-lacking yeast extra time. Unexpectedly, this genetic tweak allowed cells without FOB1 to persist longer than they usually do. The simplest explanation for the observation that FOB1 and CR augmented each other's effects on longevity is that CR works through a route other than minimizing the creation of DNA circles. The result perplexed the scientists: Because SIR2 and FOB1 influence DNA circle formation, the observations didn't square with the idea that CR works by activating SIR2.

The team attempted to solve this riddle by engineering yeast that lack both SIR2 and FOB1; the resulting cells had typical life spans. When the researchers grew these cells in reduced glucose concentrations or added the mutation that apes CR, the yeast lived longer than did those fed normally. The results reveal that, at least when FOB1 is missing, CR can work independently of SIR2.

To reconcile the new finding with the fact that CR doesn't extend life in the absence of SIR2 alone, Kennedy proposes that SIR2 and FOB1 influence life span through the synthesis of DNA circles, whereas CR extends life span through another--undefined--pathway. When SIR2 is missing, he posits, the DNA-circle pathway places an upper limit on life span that CR can't overcome. But when SIR2 and FOB1 are gone, that limit rises and CR can extend life span.

The suggestion that CR can extend life span without SIR2 provides "an exciting glimpse at a new pathway," says molecular geneticist Leonard Guarente of the Massachusetts Institute of Technology, although the results don't rule out a role for the gene in CR's life-extending effects, he adds. Further studies might uncloak new players in the theater of aging and develop their dramas.


May 12, 2004

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Citation: R. J. Davenport, Calorie Restriction Un-SIR-tainty. Sci. Aging Knowl. Environ. 2004 (19), nf48 (2004).








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