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

Nature volume 410, pages 227–230 (2001)Cite this article

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.

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Figure 1: Genetic map of duplication strains.
Figure 2: Increased dosage of sir-2.1 extends lifespan.
Figure 3: sir-2.1 functions in the dauer signalling pathway.

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Acknowledgements

We thank P. Garrity, M. Hunter-Ensor, C. Ceol, O. Hobert, F. Slack, G. Ruvkun, M. Kaeberlein, M. McVey, M. Alkema and A. Dines for suggestions, encouragement and discussions throughout this work; E. Ford, M. Alkema, B. Hersh and M. Hunter-Ensor for critically reading the manuscript; C. Wolkow for the FUDR protocol; O. Hobert for the integration protocol; S. Moseley for help with statistical analysis; H. R. Horvitz for providing lab space where this work was done, and N. An and H. R. Horvitz for providing some of the strains used in this study; G. Ruvkun and P. Delerme for use and help with the microinjection scope; and G. Ruvkun and S. Kennedy for the primer sequence of SO77 and SO78. Many strains were sent by T. Stiernagle at the Caenorhabditis Genetics Center which is funded by the National Institutes of Health National Center for Research Resources. H.A.T. is funded by the Helen Hay Whitney Foundation. L.G. is funded by grants from the NIH, the Ellison Medical Foundation, and the Howard and Linda Stern Fund.

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  1. Department of Biology, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Heidi A. Tissenbaum & Leonard Guarente

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Correspondence to Leonard Guarente.

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Tissenbaum, H., Guarente, L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410, 227–230 (2001). https://doi.org/10.1038/35065638

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