Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration

Nature volume 418, pages 344–348 (2002)Cite this article

Abstract

Calorie restriction (CR) extends lifespan in a wide spectrum of organisms and is the only regimen known to lengthen the lifespan of mammals1,2,3,4. We established a model of CR in budding yeast Saccharomyces cerevisiae. In this system, lifespan can be extended by limiting glucose or by reducing the activity of the glucose-sensing cyclic-AMP-dependent kinase (PKA)5. Lifespan extension in a mutant with reduced PKA activity requires Sir2 and NAD (nicotinamide adenine dinucleotide)5. In this study we explore how CR activates Sir2 to extend lifespan. Here we show that the shunting of carbon metabolism toward the mitochondrial tricarboxylic acid cycle and the concomitant increase in respiration play a central part in this process. We discuss how this metabolic strategy may apply to CR in animals.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Calorie restriction (CR) and Hap4 overexpression extend lifespan and enhance rDNA silencing in a Sir2-dependent manner.
Figure 2: Respiration is required for calorie restriction (CR) and Hap4-overexpression-mediated lifespan extension.
Figure 3: Gene expression profile analysis of cells under calorie restriction (CR) and overexpressing Hap4.
Figure 4: Calorie restriction (CR) and Hap4 overexpression do not increase the oxidative stress response.

Similar content being viewed by others

References

  1. Weindruch, W. & Walford, R. L. The Retardation Of Aging And Diseases By Dietary Restriction (Thomas, Springfield, Illinois, 1998)

    Google Scholar 

  2. Roth, G. S., Ingram, D. K. & Lane, M. A. Calorie restriction in primates: will it work and how will we know? J. Am. Geriatr. Soc. 47, 896–903 (1999)

    Article  CAS  Google Scholar 

  3. Sohal, R. S. & Weindruch, R. Oxidative stress, caloric restriction, and aging. Science 273, 59–63 (1996)

    Article  ADS  CAS  Google Scholar 

  4. Yu, B. P. Modulation of Aging Processes by Dietary Restriction (CRC Press, Boca Raton, Florida, 1994)

    Google Scholar 

  5. 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)

    Article  ADS  CAS  Google Scholar 

  6. 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)

    Article  CAS  Google Scholar 

  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)

    Article  ADS  CAS  Google Scholar 

  8. 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)

    Article  ADS  CAS  Google Scholar 

  9. 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)

    Article  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  12. Smith, J. S. & Boeke, J. D. An unusual form of transcriptional silencing in yeast ribosomal DNA. Genes Dev. 11, 241–254 (1997)

    Article  CAS  Google Scholar 

  13. Pronk, J. T., Yde Steensma, H. & Van Dijken, J. P. Pyruvate metabolism in Saccharomyces cerevisiae. Yeast 12, 1607–1633 (1996)

    Article  CAS  Google Scholar 

  14. Stryer, L. Biochemistry (Freeman, New York, 1995)

    Google Scholar 

  15. Blom, J., De Mattos, M. J. & Grivell, L. A. Redirection of the respiro-fermentative flux distribution in Saccharomyces cerevisiae by overexpression of the transcription factor Hap4. Appl. Environ. Microbiol. 66, 1970–1973 (2000)

    Article  CAS  Google Scholar 

  16. de Winde, J. H. & Grivell, L. A. Global regulation of mitochondrial biogenesis in Saccharomyces cerevisiae. Prog. Nucleic Acid Res. Mol. Biol. 46, 51–91 (1993)

    Article  CAS  Google Scholar 

  17. Forsburg, S. L. & Guarente, L. Identification and characterization of HAP4: a third component of the CCAAT-bound HAP2/HAP3 heteromer. Genes Dev. 3, 1166–1178 (1989)

    Article  CAS  Google Scholar 

  18. Bakker, B. M. et al. Stoichiometry and compartmentation of NADH metabolism in Saccharomyces cerevisiae. FEMS Microbiol Rev. 25, 15–37 (2001)

    Article  CAS  Google Scholar 

  19. Longo, V. D., Gralla, E. B. & Valentine, J. S. Superoxide dismutase activity is essential for stationary phase survival in Saccharomyces cerevisiae. Mitochondrial production of toxic oxygen species in vivo. J. Biol. Chem. 271, 12275–12280 (1996)

    Article  CAS  Google Scholar 

  20. Fabrizio, P., Pozza, F., Pletcher, S. D., Gendron, C. M. & Longo, V. D. Regulation of longevity and stress resistance by Sch9 in yeast. Science 292, 288–290 (2001)

    Article  ADS  CAS  Google Scholar 

  21. Melov, S. et al. Extension of life-span with superoxide dismutase/catalase mimetics. Science 289, 1567–1569 (2000)

    Article  ADS  CAS  Google Scholar 

  22. Orr, W. C. et al. Extension of life-span by overexpression of superoxide dismutase and catalase in Drosophila melanogaster. Science 263, 1128–1130 (1994)

    Article  ADS  CAS  Google Scholar 

  23. Taub, J. et al. A cytosolic catalase is needed to extend adult lifespan in C. elegans daf-C and clk-1 mutants. Nature 399, 162–166 (1999)

    Article  ADS  CAS  Google Scholar 

  24. Feng, J., Bussiere, F. & Hekimi, S. Mitochondrial electron transport is a key determinant of lifespan in Caenorhabditis elegans. Dev. Cell 1, 633–644 (2001)

    Article  CAS  Google Scholar 

  25. Lee, C. K., Klopp, R. G., Weindruch, R. & Prolla, T. A. Gene expression profile of aging and its retardation by caloric restriction. Science 285, 1390–1393 (1999)

    Article  CAS  Google Scholar 

  26. Guldener, U., Heck, S., Fielder, T., Beinhauer, J. & Hegemann, J. H. A new efficient gene disruption cassette for repeated use in budding yeast. Nucleic Acids Res. 24, 2519–2524 (1996)

    Article  CAS  Google Scholar 

  27. Hegde, P. et al. A concise guide to cDNA microarray analysis. Biotechniques 29, 548–550, 552–554, 556 (2000).

  28. Eisen, M. B., Spellman, P. T., Brown, P. O. & Botstein, D. Cluster analysis and display of genome-wide expression patterns. Proc. Natl Acad. Sci. USA 95, 14863–14868 (1998)

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank D. McNabb and members of the Guarente laboratory for suggestions; J. Smith for providing strains; T. Galitski for his contributions in the development of microarrays and analytical software tools; and T. Ideker for suggestions with microarray analysis. This work was supported by grants to L.G. from the National Institute of Health (NIH), The Ellison Medical Foundation, The Seaver Institute, and the Howard and Linda Stern Fund. S.-J.L. is supported by a NRSA individual award. G.R.F. is supported by the NIH and is an American Cancer Society Professor of Genetics. A.A.A. is supported by the NIH Training Grant in Genomic Sciences, sponsored by the Biotechnology Process Engineering Center. V.C.C. and L.A.S. are supported by grants from the NIH.

Author information

Author notes

  1. Matt Kaeberlein

    Present address: Longenity Inc., Medford, Massachusetts, 02155, USA

  2. Pierre-Antoine Defossez

    Present address: CNRS UMR 5665, Ecole Normale Superieure de Lyon, France

Authors and Affiliations

  1. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, USA

    Su-Ju Lin, Matt Kaeberlein, Pierre-Antoine Defossez & Leonard Guarente

  2. Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02142, USA

    Alex A. Andalis & Gerald R. Fink

  3. Department of Environmental Health Sciences, Johns Hopkins University School of Public Health, Baltimore, Maryland, 21205, USA

    Lori A. Sturtz & Valeria C. Culotta

Authors
  1. Su-Ju Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Matt Kaeberlein
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alex A. Andalis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lori A. Sturtz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pierre-Antoine Defossez
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Valeria C. Culotta
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gerald R. Fink
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Leonard Guarente
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Leonard Guarente.

Ethics declarations

Competing interests

L.G. and S.-J.L. hold financial interests in Elixir Pharmaceuticals, Inc., M.K. holds financial interests in Longenity Inc., and G.R.F. holds financial interests in Microbia, Inc.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lin, SJ., Kaeberlein, M., Andalis, A. et al. Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature 418, 344–348 (2002). https://doi.org/10.1038/nature00829

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature00829

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing