title: Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila.
abstract: 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.
authors.affiliation: Institute of Healthy Ageing and Department of Genetics, Evolution and Environment, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Camilla
authors.initials: C
authors.lastname: Burnett
authors.forename: Sara
authors.initials: S
authors.lastname: Valentini
authors.forename: Filipe
authors.initials: F
authors.lastname: Cabreiro
authors.forename: Martin
authors.initials: M
authors.lastname: Goss
authors.forename: Milán
authors.initials: M
authors.lastname: Somogyvári
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Piper
authors.forename: Matthew
authors.initials: M
authors.lastname: Hoddinott
authors.forename: George L
authors.initials: GL
authors.lastname: Sutphin
authors.forename: Vid
authors.initials: V
authors.lastname: Leko
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: McElwee
authors.forename: Rafael P
authors.initials: RP
authors.lastname: Vazquez-Manrique
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Orfila
authors.forename: Daniel
authors.initials: D
authors.lastname: Ackerman
authors.forename: Catherine
authors.initials: C
authors.lastname: Au
authors.forename: Giovanna
authors.initials: G
authors.lastname: Vinti
authors.forename: Michèle
authors.initials: M
authors.lastname: Riesen
authors.forename: Ken
authors.initials: K
authors.lastname: Howard
authors.forename: Christian
authors.initials: C
authors.lastname: Neri
authors.forename: Antonio
authors.initials: A
authors.lastname: Bedalov
authors.forename: Matt
authors.initials: M
authors.lastname: Kaeberlein
authors.forename: Csaba
authors.initials: C
authors.lastname: Soti
authors.forename: Linda
authors.initials: L
authors.lastname: Partridge
authors.forename: David
authors.initials: D
authors.lastname: Gems
mesh_terms: D000375:Aging / Q000235:genetics / Q000502:physiology; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D031204:Caloric Restriction; D003433:Crosses, Genetic; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D008136:Longevity / Q000235:genetics / Q000502:physiology*; D008297:Male; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D037761:Sirtuins / Q000235:genetics* / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D029721:Drosophila Proteins; D012333:RNA, Messenger; C507014:SIR-2.1 protein, C elegans; C447899:Sirt2 protein, Drosophila; D037761:Sirtuins; D006655:Histone Deacetylases