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Published online on November 1, 2004, 10.1073/pnas.0404184101

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Genetics
Sir2 mediates longevity in the fly through a pathway related to calorie restriction

( aging | life span | Rpd3 | histone deacetylase | Drosophila melanogaster )

Blanka Rogina and Stephen L. Helfand *

Department of Genetics and Developmental Biology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030

Edited by Bruce N. Ames, University of California, Berkeley, CA, and approved September 28, 2004 (received for review June 11, 2004)

Calorie restriction can extend life span in a variety of species including mammals, flies, nematodes, and yeast. Despite the importance of this nearly universal effect, little is understood about the molecular mechanisms that mediate the life-span-extending effect of calorie restriction in metazoans. Sir2 is known to be involved in life span determination and calorie restriction in yeast mother cells. In nematodes increased Sir2 can extend life span, but a direct link to calorie restriction has not been demonstrated. We now report that Sir2 is directly involved in the calorie-restriction life-span-extending pathway in Drosophila. We demonstrate that an increase in Drosophila Sir2 (dSir2) extends life span, whereas a decrease in dSir2 blocks the life-span-extending effect of calorie reduction or rpd3 mutations. These data lead us to propose a genetic pathway by which calorie restriction extends life span and provides a framework for genetic and pharmacological studies of life span extension in metazoans.

*To whom correspondence should be addressed.

Stephen L. Helfand, E-mail: shelfand{at}neuron.uchc.edu

www.pnas.org/cgi/doi/10.1073/pnas.0404184101
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