Sirtuin activators mimic caloric restriction and delay ageing in metazoans

  • A Corrigendum to this article was published on 02 September 2004

Abstract

Caloric restriction extends lifespan in numerous species. In the budding yeast Saccharomyces cerevisiae this effect requires Sir2 (ref. 1), a member of the sirtuin family of NAD+-dependent deacetylases2,3. Sirtuin activating compounds (STACs) can promote the survival of human cells and extend the replicative lifespan of yeast4. Here we show that resveratrol and other STACs activate sirtuins from Caenorhabditis elegans and Drosophila melanogaster, and extend the lifespan of these animals without reducing fecundity. Lifespan extension is dependent on functional Sir2, and is not observed when nutrients are restricted. Together these data indicate that STACs slow metazoan ageing by mechanisms that may be related to caloric restriction.

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Figure 1: Effect of polyphenolic STACs on sirtuins.
Figure 2: C. elegans survival on resveratrol.
Figure 3: Survival of wild-type female D. melanogaster adults fed resveratrol or fisetin.
Figure 4: Survival of D. melanogaster adults with mutant alleles of Sir2 fed resveratrol (100 µM).

References

  1. 1

    Lin, S. J., Defossez, P. A. & Guarente, L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 289, 2126–2128 (2000)

    ADS  CAS  Article  Google Scholar 

  2. 2

    Gasser, S. C. M. The molecular biology of the SIR proteins. Gene 279, 1–16 (2001)

    CAS  Article  Google Scholar 

  3. 3

    Hekimi, S. & Guarente, L. Genetics and the specificity of the aging process. Science 299, 1351–1354 (2003)

    CAS  Article  Google Scholar 

  4. 4

    Howitz, K. T. et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425, 191–196 (2003)

    ADS  CAS  Article  Google Scholar 

  5. 5

    Landry, J. et al. The silencing protein SIR2 and its homologs are NAD-dependent protein deacetylases. Proc. Natl Acad. Sci. USA 97, 5807–5811 (2000)

    ADS  CAS  Article  Google Scholar 

  6. 6

    Imai, S., Armstrong, C. M., Kaeberlein, M. & Guarente, L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403, 795–800 (2000)

    ADS  CAS  Article  Google Scholar 

  7. 7

    Smith, J. S. et al. A phylogenetically conserved NAD + -dependent protein deacetylase activity in the Sir2 protein family. Proc. Natl Acad. Sci. USA 97, 6658–6663 (2000)

    ADS  CAS  Article  Google Scholar 

  8. 8

    Tanner, K. G., Landry, J., Sternglanz, R. & Denu, J. M. Silent information regulator 2 family of NAD-dependent histone/protein deacetylases generates a unique product, 1-O-acetyl-ADP-ribose. Proc. Natl Acad. Sci. USA 97, 14178–14182 (2000)

    ADS  CAS  Article  Google Scholar 

  9. 9

    Tanny, J. C., Dowd, G. J., Huang, J., Hilz, H. & Moazed, D. An enzymatic activity in the yeast Sir2 protein that is essential for gene silencing. Cell 99, 735–745 (1999)

    CAS  Article  Google Scholar 

  10. 10

    Guarente, L. Sir2 links chromatin silencing, metabolism, and aging. Genes Dev. 14, 1021–1026 (2000)

    CAS  Google Scholar 

  11. 11

    Tissenbaum, H. A. & Guarente, L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410, 227–230 (2001)

    ADS  CAS  Article  Google Scholar 

  12. 12

    Rogina, B., Helfand, S. L. & Frankel, S. Longevity regulation by Drosophila Rpd3 deacetylase and caloric restriction. Science 298, 1745 (2002)

    CAS  Article  Google Scholar 

  13. 13

    Jiang, J. C., Jaruga, E., Repnevskaya, M. V. & Jazwinski, S. M. An intervention resembling caloric restriction prolongs life span and retards aging in yeast. FASEB J. 14, 2135–2137 (2000)

    CAS  Article  Google Scholar 

  14. 14

    Kenyon, C. A conserved regulatory mechanism for aging. Cell 105, 165–168 (2001)

    CAS  Article  Google Scholar 

  15. 15

    Masoro, E. J. Caloric restriction and aging: an update. Exp. Gerontol. 35, 299–305 (2000)

    CAS  Article  Google Scholar 

  16. 16

    Koubova, J. & Guarente, L. How does calorie restriction work? Genes Dev. 17, 313–321 (2003)

    CAS  Article  Google Scholar 

  17. 17

    Sinclair, D. A. Paradigms and pitfalls of yeast longevity research. Mech. Ageing Dev. 123, 857–867 (2002)

    CAS  Article  Google Scholar 

  18. 18

    Kaeberlein, M., McVey, M. & Guarente, L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev. 13, 2570–2580 (1999)

    CAS  Article  Google Scholar 

  19. 19

    Chippindale, A. K., Leroi, A. M., Kim, S. B. & Rose, M. R. Phenotypic plasticity and selection in Drosophila life-history evolution. J. Evol. Biol. 6, 171–193 (1993)

    Article  Google Scholar 

  20. 20

    Chapman, T. & Partridge, L. Female fitness in Drosophila melanogaster: an interaction between the effect of nutrition and of encounter rate with males. Proc. R. Soc. Lond. B 263, 755–759 (1996)

    ADS  CAS  Article  Google Scholar 

  21. 21

    Walker, D. W., McColl, G., Jenkins, N. L., Harris, J. & Lithgow, G. J. Evolution of lifespan in C. elegans. Nature 405, 296–297 (2000)

    ADS  CAS  Article  Google Scholar 

  22. 22

    Marden, J. H., Rogina, B., Montooth, K. L. & Helfand, S. L. Conditional tradeoffs between aging and organismal performance of Indy long-lived mutant flies. Proc. Natl Acad. Sci. USA 100, 3369–3373 (2003)

    ADS  CAS  Article  Google Scholar 

  23. 23

    Soleas, G. J., Diamandis, E. P. & Goldberg, D. M. Resveratrol: a molecule whose time has come? And gone? Clin. Biochem. 30, 91–113 (1997)

    CAS  Article  Google Scholar 

  24. 24

    Edgecomb, R. S., Harth, C. E. & Schneiderman, A. M. Regulation of feeding behavior in adult Drosophila melanogaster varies with feeding regime and nutritional state. J. Exp. Biol. 197, 215–235 (1994)

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank S. Parkhurst for the dSir2-pRSETc plasmid, and J. Whetstine, H. Yang and Y. Shi for advice and reagents. C. elegans strain VC199 (sir-2.1(ok434)) was generated by the C. elegans Reverse Genetics Core Facility at the University of British Columbia. This work was supported by the National Institute on Aging, the Harvard-Armenise Foundation, the Donaghue Foundation, and a generous gift from Harmon Rasnow. S.L.H. is an Ellison Medical Research Foundation Senior Investigator, and D.S. and M.T. are Ellison Medical Research Foundation Fellows. J.W. is supported by an NSF Graduate Research Fellowship.

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Correspondence to Marc Tatar or David Sinclair.

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D.S. and K.H. have filed a provisional patent based on this and other studies. D.S. expects that he will own more than $10,000 equity in a company after September 2004; however, this will not exceed 5% equity.

Supplementary information

Supplementary Figure S1

Mortality plots for C. elegans (on dead and live E. coli) and D. melanogaster (males and females) on resveratrol treatment. (PDF 30 kb)

Supplementary Table ST1

Summary of results from lifespan trials of C. elegans treated with resveratrol on both live and dead E. coli. Wild-type and sir-2.1 mutants are shown. (PDF 21 kb)

Supplementary Table ST2

Summary of results from lifespan trials of D. melanogaster males and females treated with resveratrol and fisetin. Various strain backgrounds, dSir2 alleles, and dietary conditions are shown. (PDF 31 kb)

Supplementary methods

Methods for sirtuin purification and sirtuin deacetylation assays. (DOC 22 kb)

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Wood, J., Rogina, B., Lavu, S. et al. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 430, 686–689 (2004). https://doi.org/10.1038/nature02789

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