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.

Signalling through RHEB-1 mediates intermittent fasting-induced longevity in C. elegans

Nature volume 457, pages 726–730 (2009)Cite this article

Abstract

Dietary restriction is the most effective and reproducible intervention to extend lifespan in divergent species1. In mammals, two regimens of dietary restriction, intermittent fasting (IF) and chronic caloric restriction, have proven to extend lifespan and reduce the incidence of age-related disorders2. An important characteristic of IF is that it can increase lifespan even when there is little or no overall decrease in calorie intake2. The molecular mechanisms underlying IF-induced longevity, however, remain largely unknown. Here we establish an IF regimen that effectively extends the lifespan of Caenorhabditis elegans, and show that the low molecular weight GTPase RHEB-1 has a dual role in lifespan regulation; RHEB-1 is required for the IF-induced longevity, whereas inhibition of RHEB-1 mimics the caloric-restriction effects. RHEB-1 exerts its effects in part by the insulin/insulin growth factor (IGF)-like signalling effector DAF-16 in IF. Our analyses demonstrate that most fasting-induced upregulated genes require RHEB-1 function for their induction, and that RHEB-1 and TOR signalling are required for the fasting-induced downregulation of an insulin-like peptide, INS-7. These findings identify the essential role of signalling by RHEB-1 in IF-induced longevity and gene expression changes, and suggest a molecular link between the IF-induced longevity and the insulin/IGF-like signalling pathway.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

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

Figure 1: IF extends C. elegans lifespan.
Figure 2: RHEB-1 has a dual role in dietary restriction.
Figure 3: DAF-16 partially mediates IF-induced longevity.
Figure 4: Microarray analyses identify fasting-regulated genes involved in IF-induced longevity.

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

Microarray data have been deposited with Gene Expression Omnibus at NCBI under the accession number GSE9682.

References

  1. Bordone, L. & Guarente, L. Calorie restriction, SIRT1 and metabolism: understanding longevity. Nature Rev. Mol. Cell Biol. 6, 298–305 (2005)

    Article  CAS  Google Scholar 

  2. Anson, R. M., Jones, B. & de Cabod, R. The diet restriction paradigm: a brief review of the effects of every-other-day feeding. Age (Omaha) 27, 17–25 (2005)

    Article  CAS  Google Scholar 

  3. Lakowski, B. & Hekimi, S. The genetics of caloric restriction in Caenorhabditis elegans . Proc. Natl Acad. Sci. USA 95, 13091–13096 (1998)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bishop, N. A. & Guarente, L. Two neurons mediate diet-restriction-induced longevity in C. elegans . Nature 447, 545–549 (2007)

    Article  ADS  CAS  PubMed  Google Scholar 

  5. Panowski, S. H., Wolff, S., Aguilaniu, H., Durieux, J. & Dillin, A. PHA-4/Foxa mediates diet-restriction-induced longevity of C. elegans . Nature 447, 550–555 (2007)

    Article  ADS  CAS  PubMed  Google Scholar 

  6. Kaeberlein, M. et al. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310, 1193–1196 (2005)

    Article  ADS  CAS  PubMed  Google Scholar 

  7. Hansen, M. et al. Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans . Aging Cell 6, 95–110 (2007)

    Article  CAS  PubMed  Google Scholar 

  8. Kapahi, P. et al. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr. Biol. 14, 885–890 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Saucedo, L. J. et al. Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nature Cell Biol. 5, 566–571 (2003)

    Article  CAS  PubMed  Google Scholar 

  10. Long, X. et al. TOR deficiency in C. elegans causes developmental arrest and intestinal atrophy by inhibition of mRNA translation. Curr. Biol. 12, 1448–1461 (2002)

    Article  CAS  PubMed  Google Scholar 

  11. Smith, E. D. et al. Age- and calorie-independent life span extension from dietary restriction by bacterial deprivation in Caenorhabditis elegans . BMC Dev. Biol. 8, 49 (2008)

    Article  PubMed  PubMed Central  Google Scholar 

  12. Pan, K. Z. et al. Inhibition of mRNA translation extends lifespan in Caenorhabditis elegans . Aging Cell 6, 111–119 (2007)

    Article  CAS  PubMed  Google Scholar 

  13. Greer, E. L. et al. An AMPK-FOXO pathway mediates longevity induced by a novel method of dietary restriction in C. elegans . Curr. Biol. 17, 1646–1656 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Guarente, L. & Kenyon, C. Genetic pathways that regulate ageing in model organisms. Nature 408, 255–262 (2000)

    Article  ADS  CAS  PubMed  Google Scholar 

  15. Derry, W. B., Putzke, A. P. & Rothman, J. H. Caenorhabditis elegans p53: role in apoptosis, meiosis, and stress resistance. Science 294, 591–595 (2001)

    Article  ADS  CAS  PubMed  Google Scholar 

  16. Hinnebusch, A. G. Translational regulation of GCN4 and the general amino acid control of yeast. Annu. Rev. Microbiol. 59, 407–450 (2005)

    Article  CAS  PubMed  Google Scholar 

  17. Henderson, S. T. & Johnson, T. E. daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans . Curr. Biol. 11, 1975–1980 (2001)

    Article  CAS  PubMed  Google Scholar 

  18. Murphy, C. T. et al. Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans . Nature 424, 277–283 (2003)

    Article  ADS  CAS  PubMed  Google Scholar 

  19. Hansen, M., Hsu, A. L., Dillin, A. & Kenyon, C. New genes tied to endocrine, metabolic, and dietary regulation of lifespan from a Caenorhabditis elegans genomic RNAi screen. PLoS Genet. 1, e17 (2005)

    Article  PubMed Central  Google Scholar 

  20. Hsu, A. L., Murphy, C. T. & Kenyon, C. Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science 300, 1142–1145 (2003)

    Article  ADS  CAS  PubMed  Google Scholar 

  21. Rajasekaran, N. S. et al. Human αB-crystallin mutation causes oxido-reductive stress and protein aggregation cardiomyopathy in mice. Cell 130, 427–439 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Murphy, C. T., Lee, S. J. & Kenyon, C. Tissue entrainment by feedback regulation of insulin gene expression in the endoderm of Caenorhabditis elegans . Proc. Natl Acad. Sci. USA 104, 19046–19050 (2007)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  23. Malone, E. A., Inoue, T. & Thomas, J. H. Genetic analysis of the roles of daf-28 and age-1 in regulating Caenorhabditis elegans dauer formation. Genetics 143, 1193–1205 (1996)

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Luong, N. et al. Activated FOXO-mediated insulin resistance is blocked by reduction of TOR activity. Cell Metab. 4, 133–142 (2006)

    Article  CAS  PubMed  Google Scholar 

  25. Lee, G. D. et al. Dietary deprivation extends lifespan in Caenorhabditis elegans . Aging Cell 5, 515–524 (2006)

    Article  CAS  PubMed  Google Scholar 

  26. Kaeberlein, T. L. et al. Lifespan extension in Caenorhabditis elegans by complete removal of food. Aging Cell 5, 487–494 (2006)

    Article  CAS  PubMed  Google Scholar 

  27. Weinkove, D., Halstead, J. R., Gems, D. & Divecha, N. Long-term starvation and ageing induce AGE-1/PI 3-kinase-dependent translocation of DAF-16/FOXO to the cytoplasm. BMC Biol. 4, 1 (2006)

    Article  PubMed  PubMed Central  Google Scholar 

  28. Hansen, M. et al. A role for autophagy in the extension of lifespan by dietary restriction in C. elegans . PLoS Genet. 4, e24 (2008)

    Article  PubMed  PubMed Central  Google Scholar 

  29. Steinkraus, K. A. et al. Dietary restriction suppresses proteotoxicity and enhances longevity by an hsf-1-dependent mechanism in Caenorhabditis elegans . Aging Cell 7, 394–404 (2008)

    Article  CAS  PubMed  Google Scholar 

  30. Fabrizio, P. et al. Sir2 blocks extreme life-span extension. Cell 123, 655–667 (2005)

    Article  CAS  PubMed  Google Scholar 

  31. Brenner, S. The genetics of Caenorhabditis elegans . Genetics 77, 71–94 (1974)

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Kamath, R. S., Martinez-Campos, M., Zipperlen, P., Fraser, A. G. & Ahringer, J. Effectiveness of specific RNA-mediated interference through ingested double-stranded RNA in Caenorhabditis elegans . Genome Biol. 2, research0002.1–research0002.10 (2001)

    Google Scholar 

  33. Maeda, I., Kohara, Y., Yamamoto, M. & Sugimoto, A. Large-scale analysis of gene function in Caenorhabditis elegans by high-throughput RNAi. Curr. Biol. 11, 171–176 (2001)

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank members of our laboratory for technical comments and helpful discussion. This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to E.N.). Some nematode strains used in this work were provided by the Caenorhabditis Genetics Center, which is funded by the NIH National Center for Research Resources (NCRR).

Author Contributions S.H. conceived the study, designed and performed the experiments, and wrote the manuscript with the help of E.N.; S.H. and T.Y. analysed the microarray data; M.U. conducted DAF-16::GFP localization experiments; E.N. supervised the project. All authors discussed the results and commented on the manuscript.

Author information

Authors and Affiliations

  1. Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto, 606-8502, Japan,

    Sakiko Honjoh, Takuya Yamamoto, Masaharu Uno & Eisuke Nishida

Authors
  1. Sakiko Honjoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takuya Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masaharu Uno
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eisuke Nishida
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eisuke Nishida.

Supplementary information

Supplementary Information

This file contains Supplementary Figures1-11 with Legends and Supplementary Tables 1-2. (PDF 2910 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Honjoh, S., Yamamoto, T., Uno, M. et al. Signalling through RHEB-1 mediates intermittent fasting-induced longevity in C. elegans. Nature 457, 726–730 (2009). https://doi.org/10.1038/nature07583

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature07583

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