Overexpression of sirtuins (NAD+-dependent protein deacetylases) has been reported to increase lifespan in budding yeast (Saccharomyces cerevisiae), Caenorhabditis elegans and Drosophila melanogaster1,2,3. Studies of the effects of genes on ageing are vulnerable to confounding effects of genetic background4. Here we re-examined the reported effects of sirtuin overexpression on ageing and found that standardization of genetic background and the use of appropriate controls abolished the apparent effects in both C. elegans and Drosophila. In C. elegans, outcrossing of a line with high-level sir-2.1 overexpression1 abrogated the longevity increase, but did not abrogate sir-2.1 overexpression. Instead, longevity co-segregated with a second-site mutation affecting sensory neurons. Outcrossing of a line with low-copy-number sir-2.1 overexpression2 also abrogated longevity. A Drosophila strain with ubiquitous overexpression of dSir2 using the UAS-GAL4 system was long-lived relative to wild-type controls, as previously reported3, but was not long-lived relative to the appropriate transgenic controls, and nor was a new line with stronger overexpression of dSir2. These findings underscore the importance of controlling for genetic background and for the mutagenic effects of transgene insertions in studies of genetic effects on lifespan. The life-extending effect of dietary restriction on ageing in Drosophila has also been reported to be dSir2 dependent3. We found that dietary restriction increased fly lifespan independently of dSir2. Our findings do not rule out a role for sirtuins in determination of metazoan lifespan, but they do cast doubt on the robustness of the previously reported effects of sirtuins on lifespan in C. elegans and Drosophila.
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We thank A. Gartner for providing an antibody against C. elegans SIR-2.1; D. Chen, P. Kapahi, S. Pletcher and D. Skorupa for providing data; S. S. Lee for permission to cite unpublished results; S. Helfand and J. Rine for providing fly strains; W. Mair for performing preliminary trials and R. Baumeister for useful discussion. Some nematode strains were provided by the Caenorhabditis Genetics Center, which is funded by the National Institutes of Health National Center for Research Resources. We acknowledge funding from the European Union (FP6-036894 to C.B., D.G., L.P. and S.V. and FP6-518230 to D.G. and C.S.), the Hungarian Science Foundation and Norway Grants (NNF-78794 to C.S.), INSERM and ANR, Paris (R.V., A.-M.O. and C.N.), the National Institutes of Health (CA129132 to A.B., R01AG031108 to M.K. and T32AG000057 to G.L.S.) and the Wellcome Trust (Strategic Award to C.A., F.C., D.G., L.P. and M.R.). C.S. is a Bolyai Research Scholar of the Hungarian Academy of Sciences and M.K. is an Ellison Medical Foundation New Scholar in Aging.
The file contains Supplementary Figures 1-12 with legends, Supplementary Tables 1-7 and Supplementary References.
About this article
Genome Medicine (2017)