Publication Date:
2011-09-23
Description:
Overexpression of sirtuins (NAD(+)-dependent protein deacetylases) has been reported to increase lifespan in budding yeast (Saccharomyces cerevisiae), Caenorhabditis elegans and Drosophila melanogaster. Studies of the effects of genes on ageing are vulnerable to confounding effects of genetic background. 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 overexpression 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 overexpression 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 reported, 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 dependent. 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188402/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188402/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Burnett, Camilla -- Valentini, Sara -- Cabreiro, Filipe -- Goss, Martin -- Somogyvari, Milan -- Piper, Matthew D -- Hoddinott, Matthew -- Sutphin, George L -- Leko, Vid -- McElwee, Joshua J -- Vazquez-Manrique, Rafael P -- Orfila, Anne-Marie -- Ackerman, Daniel -- Au, Catherine -- Vinti, Giovanna -- Riesen, Michele -- Howard, Ken -- Neri, Christian -- Bedalov, Antonio -- Kaeberlein, Matt -- Soti, Csaba -- Partridge, Linda -- Gems, David -- 081394/Wellcome Trust/United Kingdom -- CA129132/CA/NCI NIH HHS/ -- R01 AG031108/AG/NIA NIH HHS/ -- R01 CA129132/CA/NCI NIH HHS/ -- R01AG031108/AG/NIA NIH HHS/ -- T32AG000057/AG/NIA NIH HHS/ -- Wellcome Trust/United Kingdom -- England -- Nature. 2011 Sep 21;477(7365):482-5. doi: 10.1038/nature10296.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Healthy Ageing and Department of Genetics, Evolution and Environment, University College London, Gower Street, London WC1E 6BT, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21938067" target="_blank"〉PubMed〈/a〉
Keywords:
Aging/genetics/physiology
;
Animals
;
Animals, Genetically Modified
;
Caenorhabditis elegans/genetics/metabolism/*physiology
;
Caenorhabditis elegans Proteins/*genetics/metabolism
;
Caloric Restriction
;
Crosses, Genetic
;
Drosophila Proteins/*genetics/metabolism
;
Drosophila melanogaster/genetics/metabolism/*physiology
;
Female
;
Gene Expression
;
Histone Deacetylases/*genetics/metabolism
;
Longevity/genetics/*physiology
;
Male
;
RNA, Messenger/analysis/genetics
;
Sirtuins/*genetics/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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