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.

Two neurons mediate diet-restriction-induced longevity in C. elegans

Abstract

Dietary restriction extends lifespan and retards age-related disease in many species and profoundly alters endocrine function in mammals. However, no causal role of any hormonal signal in diet-restricted longevity has been demonstrated. Here we show that increased longevity of diet-restricted Caenorhabditis elegans requires the transcription factor gene skn-1 acting in the ASIs, a pair of neurons in the head. Dietary restriction activates skn-1 in these two neurons, which signals peripheral tissues to increase metabolic activity. These findings demonstrate that increased lifespan in a diet-restricted metazoan depends on cell non-autonomous signalling from central neuronal cells to non-neuronal body tissues, and suggest that the ASI neurons mediate diet-restriction-induced longevity by an endocrine mechanism.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Lifespan extension by dietary restriction.
Figure 2: skn-1 functions in the ASI neurons to mediate dietary restriction longevity.
Figure 3: The ASI neurons are necessary for dietary restriction longevity.
Figure 4: Dietary restriction activates skn-1 in the ASI neurons and increases whole-body respiration.
Figure 5: Model of skn-1 function during dietary restriction.

References

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

    CAS  Article  Google Scholar 

  2. Mobbs, C. V. et al. Neuroendocrine and pharmacological manipulations to assess how caloric restriction increases life span. J. Gerontol. A Biol. Sci. Med. Sci. 56 (Spec No 1). 34–44 (2001)

    Article  Google Scholar 

  3. de Cabo, R. et al. An in vitro model of caloric restriction. Exp. Gerontol. 38, 631–639 (2003)

    CAS  Article  Google Scholar 

  4. Bartke, A. et al. Extending the lifespan of long-lived mice. Nature 414, 412 (2001)

    ADS  CAS  Article  Google Scholar 

  5. Walker, G., Houthoofd, K., Vanfleteren, J. R. & Gems, D. Dietary restriction in C. elegans: from rate-of-living effects to nutrient sensing pathways. Mech. Ageing Dev. 126, 929–937 (2005)

    CAS  Article  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

  7. Houthoofd, K., Braeckman, B. P., Johnson, T. E. & Vanfleteren, J. R. Life extension via dietary restriction is independent of the Ins/IGF-1 signalling pathway in Caenorhabditis elegans. Exp. Gerontol. 38, 947–954 (2003)

    CAS  Article  Google Scholar 

  8. Kenyon, C. The plasticity of aging: insights from long-lived mutants. Cell 120, 449–460 (2005)

    CAS  Article  Google Scholar 

  9. Bowerman, B., Eaton, B. A. & Priess, J. R. skn-1, a maternally expressed gene required to specify the fate of ventral blastomeres in the early C. elegans embryo. Cell 68, 1061–1075 (1992)

    CAS  Article  Google Scholar 

  10. An, J. H. & Blackwell, T. K. SKN-1 links C. elegans mesendodermal specification to a conserved oxidative stress response. Genes Dev. 17, 1882–1893 (2003)

    CAS  Article  Google Scholar 

  11. Golden, T. R., Hinerfeld, D. A. & Melov, S. Oxidative stress and aging: beyond correlation. Aging Cell 1, 117–123 (2002)

    CAS  Article  Google Scholar 

  12. Zhenyu, Y., Jin, S., Yang, C., Levine, A. J. & Heintz, N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc. Natl Acad. Sci. USA 100, 15077–15082 (2003)

    ADS  Article  Google Scholar 

  13. Wilson, M. A. et al. Blueberry polyphenols increase lifespan and thermotolerance in Caenorhabditis elegans. Aging Cell 5, 59–68 (2006)

    CAS  Article  Google Scholar 

  14. Bargmann, C. I. & Horvitz, H. R. Control of larval development by chemosensory neurons in Caenorhabditis elegans. Science 251, 1243–1246 (1991)

    ADS  CAS  Article  Google Scholar 

  15. Jansen, G. et al. The complete family of genes encoding G proteins of Caenorhabditis elegans. Nature Genet. 21, 414–419 (1999)

    CAS  Article  Google Scholar 

  16. Libina, N., Berman, J. R. & Kenyon, C. Tissue-specific activities of C. elegans DAF-16 in the regulation of lifespan. Cell 115, 489–502 (2003)

    CAS  Article  Google Scholar 

  17. Alcedo, J. & Kenyon, C. Regulation of C. elegans longevity by specific gustatory and olfactory neurons. Neuron 41, 45–55 (2004)

    CAS  Article  Google Scholar 

  18. Lin, S. J. et al. Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature 418, 344–348 (2002)

    ADS  CAS  Article  Google Scholar 

  19. Houthoofd, K. et al. Axenic growth up-regulates mass-specific metabolic rate, stress resistance, and extends life span in Caenorhabditis elegans. Exp. Gerontol. 37, 1371–1378 (2002)

    Article  Google Scholar 

  20. Houthoofd, K. et al. No reduction of metabolic rate in food restricted Caenorhabditis elegans. Exp. Gerontol. 37, 1359–1369 (2002)

    Article  Google Scholar 

  21. Bargmann, C. I. & Horvitz, H. R. Chemosensory neurons with overlapping functions direct chemotaxis to multiple chemicals in C. elegans. Neuron 7, 729–742 (1991)

    CAS  Article  Google Scholar 

  22. Dowell, P., Hu, Z. & Lane, M. D. Monitoring energy balance: metabolites of fatty acid synthesis as hypothalamic sensors. Annu. Rev. Biochem. 74, 515–534 (2005)

    CAS  Article  Google Scholar 

  23. Li, C. The ever-expanding neuropeptide gene families in the nematode Caenorhabditis elegans. Parasitology 131 (Suppl.). S109–S127 (2005)

    CAS  Article  Google Scholar 

  24. Ren, P. et al. Control of C. elegans larval development by neuronal expression of a TGF-β homolog. Science 274, 1389–1391 (1996)

    ADS  CAS  Article  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Avery, L. & Horvitz, H. R. Pharyngeal pumping continues after laser killing of the pharyngeal nervous system of C. elegans. Neuron 3, 473–485 (1989)

    CAS  Article  Google Scholar 

  27. Peckol, E. L., Zallen, J. A., Yarrow, J. C. & Bargmann, C. I. Sensory activity affects sensory axon development in C. elegans. Development 126, 1891–1902 (1999)

    CAS  PubMed  Google Scholar 

  28. Braeckman, B. P., Houthoofd, K. & Vanfleteren, J. R. Assessing metabolic activity in aging Caenorhabditis elegans: concepts and controversies. Aging Cell 1, 82–88 (2002)

    CAS  Article  Google Scholar 

  29. Timmons, L., Court, D. L. & Fire, A. Ingestion of bacterially expressed dsRNAs can produce specific and potent genetic interference in Caenorhabditis elegans. Gene 263, 103–112 (2001)

    CAS  Article  Google Scholar 

  30. Wang, D. et al. Somatic misexpression of germline P granules and enhanced RNA interference in retinoblastoma pathway mutants. Nature 436, 593–597 (2005)

    ADS  CAS  Article  Google Scholar 

  31. Apfeld, J. & Kenyon, C. Regulation of lifespan by sensory perception in Caenorhabditis elegans. Nature 402, 804–809 (1999)

    ADS  CAS  Article  Google Scholar 

  32. Mello, C. C., Kramer, J. M., Stinchcomb, D. & Ambros, V. Efficient gene transfer in C. elegans: extrachromosomal maintenance and integration of transforming sequences. EMBO J. 10, 3959–3970 (1991)

    CAS  Article  Google Scholar 

  33. Kim, K., Colosimo, M. E., Yeung, H. & Sengupta, P. The UNC-3 Olf/EBF protein represses alternate neuronal programs to specify chemosensory neuron identity. Dev. Biol. 286, 136–148 (2005)

    CAS  Article  Google Scholar 

  34. Jin, Y. in C. elegans: A Practical Approach (ed. Hope, I. A.) 69–96 (Oxford University Press, New York, 1999)

    Google Scholar 

  35. Lawless, J. F. Statistical Models and Methods for Lifetime Data (Wiley, New York, 1982)

    MATH  Google Scholar 

  36. Kamath, R. S. et al. Systematic functional analysis of the Caenorhabditis elegans genome using RNAi. Nature 421, 231–237 (2003)

    ADS  CAS  Article  Google Scholar 

  37. McKay, R. M., McKay, J. P., Avery, L. & Graff, J. M. C elegans: a model for exploring the genetics of fat storage. Dev. Cell 4, 131–142 (2003)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank H. R. Horvitz for allowing use of essential equipment, and members of the Guarente and Horvitz laboratories for advice and discussions. We thank D. Kim and F. Ausubel for the gift of an unpublished strain. Many of the strains used in this work were provided by the Caenorhabditis Genetics Center. This work was supported by a grant from the National Institutes of Health.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Leonard Guarente.

Ethics declarations

Competing interests

L.G. is a founder of Elixir Pharmaceuticals.

Supplementary information

Supplementary Information

This file contains Supplementary Figures S1 – S7, Supplementary Tables S1 – S2 and additional references. (PDF 2104 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Bishop, N., Guarente, L. Two neurons mediate diet-restriction-induced longevity in C. elegans. Nature 447, 545–549 (2007). https://doi.org/10.1038/nature05904

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature05904

Further reading

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

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