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.

  • Article
  • Published:

A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity

Abstract

We report a systematic RNA interference (RNAi) screen of 5,690 Caenorhabditis elegans genes for gene inactivations that increase lifespan. We found that genes important for mitochondrial function stand out as a principal group of genes affecting C. elegans lifespan. A classical genetic screen identified a mutation in the mitochondrial leucyl-tRNA synthetase gene (lrs-2) that impaired mitochondrial function and was associated with longer-lifespan. The long-lived worms with impaired mitochondria had lower ATP content and oxygen consumption, but differential responses to free-radical and other stresses. These data suggest that the longer lifespan of C. elegans with compromised mitochrondria cannot simply be assigned to lower free radical production and suggest a more complex coupling of metabolism and longevity.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: RNAi inactivation of genes specific for mitochondrial function markedly extended lifespan.
Figure 2: A mutation of leucyl-tRNA synthetase extended lifespan.
Figure 3: Nematodes with compromised electron transport had altered mitochondrial morphology.
Figure 4: ATP content and oxygen consumption rates in mitochondrially compromised long-lived C. elegans.
Figure 5: Stress response in long-lived C. elegans with compromised mitochondria.
Figure 6: RNAi inactivation of two metabolic genes extended lifespan.

Similar content being viewed by others

References

  1. Rose, M.R. Genetics of aging in Drosophila. Exp. Gerontol. 34, 577–585 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  3. Finch, C.E. Longevity, Senescence, and the Genome (The University of Chicago, Chicago, 1990).

    Google Scholar 

  4. Kimura, K.D., Tissenbaum, H.A., Liu, Y. & Ruvkun, G. daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277, 942–946 (1997).

    Article  CAS  Google Scholar 

  5. Kenyon, C., Chang, J., Gensch, E., Rudner, A. & Tabtiang, R.A C. elegans mutant that lives twice as long as wild type. Nature 366, 461–464 (1993).

    Article  CAS  Google Scholar 

  6. Morris, J.Z., Tissenbaum, H.A. & Ruvkun, G. A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans. Nature 382, 536–539 (1996).

    Article  CAS  Google Scholar 

  7. Pierce, S.B. et al. Regulation of DAF-2 receptor signaling by human insulin and ins-1, a member of the unusually large and diverse C. elegans insulin gene family. Genes Dev. 15, 672–686 (2001).

    Article  CAS  Google Scholar 

  8. Ogg, S. et al. The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 389, 994–999 (1997).

    Article  CAS  Google Scholar 

  9. Lin, K., Dorman, J.B., Rodan, A. & Kenyon, C. daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. Science 278, 1319–1322 (1997).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  11. Lakowski, B. & Hekimi, S. Determination of life-span in Caenorhabditis elegans by four clock genes. Science 272, 1010–1013 (1996).

    Article  CAS  Google Scholar 

  12. Ewbank, J.J. et al. Structural and functional conservation of the Caenorhabditis elegans timing gene clk-1. Science 275, 980–983 (1997).

    Article  CAS  Google Scholar 

  13. Jonassen, T., Larsen, P.L. & Clarke, C.F. A dietary source of coenzyme Q is essential for growth of long-lived Caenorhabditis elegans clk-1 mutants. Proc. Natl. Acad. Sci. USA 98, 421–426 (2001).

    Article  CAS  Google Scholar 

  14. Ahmed, S., Alpi, A., Hengartner, M.O. & Gartner, A. C. elegans RAD-5/CLK-2 defines a new DNA damage checkpoint protein. Curr. Biol. 11, 1934–1944 (2001).

    Article  CAS  Google Scholar 

  15. Lim, C.S., Mian, I.S., Dernburg, A.F. & Campisi, J. C. elegans clk-2, a gene that limits life span, encodes a telomere length regulator similar to yeast telomere binding protein Tel2p. Curr. Biol. 11, 1706–1710 (2001).

    Article  CAS  Google Scholar 

  16. Benard, C. et al. The C. elegans maternal-effect gene clk-2 is essential for embryonic development, encodes a protein homologous to yeast Tel2p and affects telomere length. Development 128, 4045–4055 (2001).

    CAS  PubMed  Google Scholar 

  17. Fraser, A.G. et al. Functional genomic analysis of C. elegans chromosome I by systematic RNA interference. Nature 408, 325–330 (2000).

    Article  CAS  Google Scholar 

  18. Kamath, R. et al. Systematic functional analysis of the C. elegans genome using RNAi. Nature (in press, 2002).

  19. Friedman, D.B. & Johnson, T.E. A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility. Genetics 118, 75–86 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Tsang, W.Y. & Lemire, B.D. Mitochondrial genome content is regulated during nematode development. Biochem. Biophys. Res. Commun. 291, 8–16 (2002).

    Article  CAS  Google Scholar 

  21. Lee, R.Y., Hench, J. & Ruvkun, G. Regulation of C. elegans DAF-16 and its human ortholog FKHRL1 by the daf-2 insulin-like signaling pathway. Curr. Biol. 11, 1950–1957 (2001).

    Article  CAS  Google Scholar 

  22. Kelly, W.G., Xu, S., Montgomery, M.K. & Fire, A. Distinct requirements for somatic and germline expression of a generally expressed Caenorhabditis elegans gene. Genetics 146, 227–238 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Tzagoloff, A., Gatti, D. & Gampel, A. Mitochondrial aminoacyl-tRNA synthetases. Prog. Nucleic Acid Res. Mol. Biol. 39, 129–158 (1990).

    Article  CAS  Google Scholar 

  24. Okimoto, R., Macfarlane, J.L., Clary, D.O. & Wolstenholme, D.R. The mitochondrial genomes of two nematodes, Caenorhabditis elegans and Ascaris suum. Genetics 130, 471–498 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Labrousse, A.M., Zappaterra, M.D., Rube, D.A. & van der Bliek, A.M. C. elegans dynamin-related protein DRP-1 controls severing of the mitochondrial outer membrane. Mol. Cell 4, 815–826 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  27. Hekimi, S., Lakowski, B., Barnes, T.M. & Ewbank, J.J. Molecular genetics of life span in C. elegans: how much does it teach us? Trends Genet. 14, 14–20 (1998).

    Article  CAS  Google Scholar 

  28. Pearl, R. The Rate of Living (University of London Press, London, 1928).

    Google Scholar 

  29. Finkel, T. & Holbrook, N.J. Oxidants, oxidative stress and the biology of ageing. Nature 408, 239–247 (2000).

    Article  CAS  Google Scholar 

  30. Lithgow, G.J., White, T.M., Melov, S. & Johnson, T.E. Thermotolerance and extended life-span conferred by single-gene mutations and induced by thermal stress. Proc. Natl. Acad. Sci. USA 92, 7540–7544 (1995).

    Article  CAS  Google Scholar 

  31. Honda, Y. & Honda, S. The daf-2 gene network for longevity regulates oxidative stress resistance and Mn-superoxide dismutase gene expression in Caenorhabditis elegans. FASEB J. 13, 1385–1393 (1999).

    Article  CAS  Google Scholar 

  32. Larsen, P.L. Aging and resistance to oxidative damage in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 90, 8905–8909 (1993).

    Article  CAS  Google Scholar 

  33. Kumar, A. et al. Subcellular localization of the yeast proteome. Genes Dev. 16, 707–719 (2002).

    Article  CAS  Google Scholar 

  34. Tsang, W.Y., Sayles, L.C., Grad, L.I., Pilgrim, D.B. & Lemire, B.D. Mitochondrial respiratory chain deficiency in Caenorhabditis elegans results in developmental arrest and increased life span. J. Biol. Chem. 276, 32240–32246 (2001).

    Article  CAS  Google Scholar 

  35. Maechler, P. & Wollheim, C.B. Mitochondrial function in normal and diabetic β-cells. Nature 414, 807–812 (2001).

    Article  CAS  Google Scholar 

  36. Wallace, D.C. Mitochondrial diseases in man and mouse. Science 283, 1482–1488 (1999).

    Article  CAS  Google Scholar 

  37. Griparic, L. & van der Bliek, A.M. The many shapes of mitochondrial membranes. Traffic 2, 235–244 (2001).

    Article  CAS  Google Scholar 

  38. Paumard, P. et al. The ATP synthase is involved in generating mitochondrial cristae morphology. EMBO J. 21, 221–230 (2002).

    Article  CAS  Google Scholar 

  39. Senoo-Matsuda, N. et al. A defect in the cytochrome b large subunit in complex II causes both superoxide anion overproduction and abnormal energy metabolism in Caenorhabditis elegans. J. Biol. Chem. 276, 41553–41558 (2001).

    Article  CAS  Google Scholar 

  40. Osiewacz, H.D. Genes, mitochondria and aging in filamentous fungi. Ageing Res. Rev. 1, 425–442 (2002).

    Article  CAS  Google Scholar 

  41. Kirchman, P.A., Kim, S., Lai, C.Y. & Jazwinski, S.M. Interorganelle signaling is a determinant of longevity in Saccharomyces cerevisiae. Genetics 152, 179–190 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Jazwinski, S.M. New clues to old yeast. Mech. Ageing Dev. 122, 865–882 (2001).

    Article  CAS  Google Scholar 

  43. Vanfleteren, J.R. & Braeckman, B.P. Mechanisms of life span determination in Caenorhabditis elegans. Neurobiol. Aging 20, 487–502 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  45. Rogina, B., Reenan, R.A., Nilsen, S.P. & Helfand, S.L. Extended life-span conferred by cotransporter gene mutations in Drosophila. Science 290, 2137–2140 (2000).

    Article  CAS  Google Scholar 

  46. Braeckman, B.P., Houthoofd, K., De Vreese, A. & Vanfleteren, J.R. Assaying metabolic activity in ageing Caenorhabditis elegans. Mech. Ageing Dev. 123, 105–119 (2002).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to E. Bachman and S. Krauss for assistance in oxygen consumption measurements and expert advice; A. Van der Bliek for Pmyo-3:mito:GFP plasmid and valuable insights; A. Fire for GFP plasmids; X. Li and J. Xu for technical support; M. Burbea for assistance in statistical analysis; B. Lowell, A. Frand, D. Kim and B. Weiss for critical reading of the manuscript; members of G.R.'s laboratory for helpful discussions; and C.G.C. for providing strains. This work was supported in part by a Damon Runyon postdoctoral fellowship to S.S.L., a US Army Breast Cancer Research Fellowship to A.G.F., a Howard Hughes Medical Institute Predoctoral Fellowship to R.S.K., a Wellcome Trust Senior Research Fellowship to J.A. and grants from the Ellison Research Foundation and US National Institutes of Health to G.R.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Gary Ruvkun.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lee, S., Lee, R., Fraser, A. et al. A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity. Nat Genet 33, 40–48 (2003). https://doi.org/10.1038/ng1056

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1056

This article is cited by

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