Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans

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Abstract
In Caenorhabditis elegans, mutations that reduce the activity of an insulin-like receptor (daf-2)1 or a phosphatidylinositol-3-OH kinase (age-1)2 favour entry into the dauer state during larval development3 and extend lifespan in adults3,4,5,6. Downregulation of this pathway activates a forkhead transcription factor (daf-16)7,8, which may regulate targets that promote dauer formation in larvae and stress resistance and longevity in adults9. In yeast, the SIR2 gene determines the lifespan of mother cells, and adding an extra copy of SIR2 extends lifespan10. Sir2 mediates chromatin silencing through a histone deacetylase activity that depends on NAD (nicotinamide adenine dinucleotide) as a cofactor11,12,13. We have surveyed the lifespan of C. elegans strains containing duplications of chromosomal regions. Here we report that a duplication containing sir-2.1—the C. elegans gene most homologous to yeast SIR2—confers a lifespan that is extended by up to 50%. Genetic analysis indicates that the sir-2.1 transgene functions upstream of daf-16 in the insulin-like signalling pathway. Our findings suggest that Sir2 proteins may couple longevity to nutrient availability in many eukaryotic organisms.