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

Nature volume 447, pages 545–549 (2007)Cite this article

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.

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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.

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References

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

    Article  CAS  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)

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  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)

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  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)

    Article  CAS  Google Scholar 

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

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  Google Scholar 

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

    Article  CAS  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)

    Article  ADS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  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)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  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)

    Article  CAS  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)

    Article  CAS  Google Scholar 

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

    Article  CAS  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)

    Article  ADS  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  ADS  CAS  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)

    Article  CAS  Google Scholar 

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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.

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

    Nicholas A. Bishop & Leonard Guarente

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  1. Nicholas A. Bishop
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Correspondence to Leonard Guarente.

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L.G. is a founder of Elixir Pharmaceuticals.

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

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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

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