Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila

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Abstract
Overexpression of sirtuins has been reported to increase lifespan in Caenorhabditis elegans and Drosophila melanogaster. The effects of dietary restriction on the lifespan of flies have also been reported to be Sir2-dependent. Here it is shown that these findings are attributable to the confounding effects of genetic background. This work suggests that the life-extending effect of sirtuin overexpression may be limited to yeast, and also supports studies in yeast and C. elegans that show that the effects of dietary restriction are not mediated by sirtuins. 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.