Letter | Published:

The sirtuin SIRT6 regulates lifespan in male mice

Nature volume 483, pages 218221 (08 March 2012) | Download Citation


The significant increase in human lifespan during the past century confronts us with great medical challenges. To meet these challenges, the mechanisms that determine healthy ageing must be understood and controlled. Sirtuins are highly conserved deacetylases that have been shown to regulate lifespan in yeast, nematodes and fruitflies1. However, the role of sirtuins in regulating worm and fly lifespan has recently become controversial2. Moreover, the role of the seven mammalian sirtuins, SIRT1 to SIRT7 (homologues of the yeast sirtuin Sir2), in regulating lifespan is unclear3. Here we show that male, but not female, transgenic mice overexpressing Sirt6 (ref. 4) have a significantly longer lifespan than wild-type mice. Gene expression analysis revealed significant differences between male Sirt6-transgenic mice and male wild-type mice: transgenic males displayed lower serum levels of insulin-like growth factor 1 (IGF1), higher levels of IGF-binding protein 1 and altered phosphorylation levels of major components of IGF1 signalling, a key pathway in the regulation of lifespan5. This study shows the regulation of mammalian lifespan by a sirtuin family member and has important therapeutic implications for age-related diseases.

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  1. 1.

    & Sirtuins in mammals: insights into their biological function. Biochem. J. 404, 1–13 (2007)

  2. 2.

    et al. Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature 477, 482–485 (2011)

  3. 3.

    et al. Dietary restriction: standing up for sirtuins. Science 329, 1012–1014 (2010)

  4. 4.

    et al. SIRT6 protects against pathological damage caused by diet-induced obesity. Aging Cell 9, 162–173 (2010)

  5. 5.

    The genetics of ageing. Nature 464, 504–512 (2010)

  6. 6.

    & Regulation of Caenorhabditis elegans lifespan by sir-2.1 transgenes. Nature 477, E1–E2 (2011)

  7. 7.

    et al. The evolutionarily conserved longevity determinants HCF-1 and SIR-2.1/SIRT1 collaborate to regulate DAF-16/FOXO. PLoS Genet. 7, e1002235 (2011)

  8. 8.

    et al. Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer. Nature Commun. 1, 3 (2010)

  9. 9.

    et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 124, 315–329 (2006)

  10. 10.

    et al. SIRT6 links histone H3 lysine 9 deacetylation to NF-κB-dependent gene expression and organismal life span. Cell 136, 62–74 (2009)

  11. 11.

    et al. Regulation of SIRT6 protein levels by nutrient availability. FEBS Lett. 582, 2417–2423 (2008)

  12. 12.

    et al. Aging in inbred strains of mice: study design and interim report on median lifespans and circulating IGF1 levels. Aging Cell 8, 277–287 (2009)

  13. 13.

    , , , & Statistical methods for testing effects on ‘maximum lifespan’. Mech. Ageing Dev. 125, 629–632 (2004)

  14. 14.

    et al. Tissue-specific expression and regulation of sexually dimorphic genes in mice. Genome Res. 16, 995–1004 (2006)

  15. 15.

    , & Significance analysis of microarrays applied to the ionizing radiation response. Proc. Natl Acad. Sci. USA 98, 5116–5121 (2001)

  16. 16.

    , & Short-term calorie restriction in male mice feminizes gene expression and alters key regulators of conserved aging regulatory pathways. PLoS ONE 4, e5242 (2009)

  17. 17.

    Genes and gene expression modules associated with caloric restriction and aging in the laboratory mouse. BMC Genomics 10, 585 (2009)

  18. 18.

    et al. Coordinated multitissue transcriptional and plasma metabonomic profiles following acute caloric restriction in mice. Physiol. Genomics 27, 187–200 (2006)

  19. 19.

    et al. Starvation response in mouse liver shows strong correlation with life-span-prolonging processes. Physiol. Genomics 17, 230–244 (2004)

  20. 20.

    et al. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421, 182–187 (2003)

  21. 21.

    , , & Insulin-like growth factor binding protein-1: recent findings and new directions. Proc. Soc. Exp. Biol. Med. 216, 319–357 (1997)

  22. 22.

    et al. IGF1 and its binding proteins 3 and 1 are differentially associated with metabolic syndrome in older men. Eur. J. Endocrinol. 162, 249–257 (2010)

  23. 23.

    , & Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 299, 572–574 (2003)

  24. 24.

    et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009)

  25. 25.

    et al. Transgenic mice with a reduced core body temperature have an increased life span. Science 314, 825–828 (2006)

  26. 26.

    et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 326, 140–144 (2009)

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We thank R. S. Levy-Drummer, C. Wachtel, S. Schwarzbaum and members of the Cohen laboratory for their comments on the manuscript. This study was supported by National Institutes of Health grant 1RO1 GM085022 to Z.B.-J. and by grants from the Israeli Academy of Sciences, the United States - Israel Binational Science Foundation, the Israel Cancer Association, the Koret Foundation, the Israel Cancer Research Fund, the Israel Health Ministry, I-CORE program (41/1), the Israel Science Foundation and the European Research Council to H.Y.C.

Author information

Author notes

    • Shoshana Naiman
    •  & Gail Amir

    These authors contributed equally to this work.


  1. The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel

    • Yariv Kanfi
    • , Shoshana Naiman
    • , Victoria Peshti
    • , Liat Nahum
    •  & Haim Y. Cohen
  2. Department of Pathology, Hadassah Medical Center and Hebrew University, Kiryat Hadassah, Jerusalem 91120, Israel

    • Gail Amir
  3. Lane Center for Computational Biology, School of Computer Science, Carnegie Mellon University, Pittsburgh, Pennsylvania 15217, USA

    • Guy Zinman
    •  & Ziv Bar-Joseph


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H.Y.C. designed experiments, analysed data and contributed to writing the paper. Y.K. designed and performed experiments, analysed data and contributed to writing the paper. S.N. designed and performed experiments and contributed to writing the paper. G.A. performed the histopathological analysis. V.P. and L.N. performed experiments. G.Z. and Z.B.-J. developed analytical tools, analysed data and contributed to writing the paper. S.N and G.A. contributed equally to this work.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Haim Y. Cohen.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Figures 1-3 with legends, Supplementary Tables 1-4 and 7 (see Separate files for Supplementary Tables 5 and 6), Supplementary Methods and Materials with additional references and a Supplementary Comment.

Excel files

  1. 1.

    Supplementary Table 5

    This table shows that all genes significantly changed between female WT vs. male WT (sheet 1), male Transgene vs. male WT (sheet 2), and female Transgene vs. female WT (sheet 3).

  2. 2.

    Supplementary Table 6

    This table contains significantly over-represented Gene Ontology (GO) terms returned by FuncAssociate at an adjusted P-value cutoff of p<0.05. GO terms are listed in descending order of significance for differentially expressed (DE) genes between female WT vs. male WT (sheet 1) and male Transgene vs. male WT (sheet 2). GO analysis for the genes that are intersecting between DE genes in both fWT-mWT and mTG-mWT is listed in the last sheet.

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