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
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Rose, M.R. Genetics of aging in Drosophila. Exp. Gerontol. 34, 577–585 (1999).
Guarente, L. & Kenyon, C. Genetic pathways that regulate ageing in model organisms. Nature 408, 255–262 (2000).
Finch, C.E. Longevity, Senescence, and the Genome (The University of Chicago, Chicago, 1990).
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).
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).
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).
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).
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).
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).
Lakowski, B. & Hekimi, S. The genetics of caloric restriction in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 95, 13091–13096 (1998).
Lakowski, B. & Hekimi, S. Determination of life-span in Caenorhabditis elegans by four clock genes. Science 272, 1010–1013 (1996).
Ewbank, J.J. et al. Structural and functional conservation of the Caenorhabditis elegans timing gene clk-1. Science 275, 980–983 (1997).
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).
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).
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).
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).
Fraser, A.G. et al. Functional genomic analysis of C. elegans chromosome I by systematic RNA interference. Nature 408, 325–330 (2000).
Kamath, R. et al. Systematic functional analysis of the C. elegans genome using RNAi. Nature (in press, 2002).
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).
Tsang, W.Y. & Lemire, B.D. Mitochondrial genome content is regulated during nematode development. Biochem. Biophys. Res. Commun. 291, 8–16 (2002).
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).
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).
Tzagoloff, A., Gatti, D. & Gampel, A. Mitochondrial aminoacyl-tRNA synthetases. Prog. Nucleic Acid Res. Mol. Biol. 39, 129–158 (1990).
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).
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).
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).
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).
Pearl, R. The Rate of Living (University of London Press, London, 1928).
Finkel, T. & Holbrook, N.J. Oxidants, oxidative stress and the biology of ageing. Nature 408, 239–247 (2000).
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).
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).
Larsen, P.L. Aging and resistance to oxidative damage in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 90, 8905–8909 (1993).
Kumar, A. et al. Subcellular localization of the yeast proteome. Genes Dev. 16, 707–719 (2002).
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).
Maechler, P. & Wollheim, C.B. Mitochondrial function in normal and diabetic β-cells. Nature 414, 807–812 (2001).
Wallace, D.C. Mitochondrial diseases in man and mouse. Science 283, 1482–1488 (1999).
Griparic, L. & van der Bliek, A.M. The many shapes of mitochondrial membranes. Traffic 2, 235–244 (2001).
Paumard, P. et al. The ATP synthase is involved in generating mitochondrial cristae morphology. EMBO J. 21, 221–230 (2002).
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).
Osiewacz, H.D. Genes, mitochondria and aging in filamentous fungi. Ageing Res. Rev. 1, 425–442 (2002).
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).
Jazwinski, S.M. New clues to old yeast. Mech. Ageing Dev. 122, 865–882 (2001).
Vanfleteren, J.R. & Braeckman, B.P. Mechanisms of life span determination in Caenorhabditis elegans. Neurobiol. Aging 20, 487–502 (1999).
Lin, S.J. et al. Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature 418, 344–348 (2002).
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).
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).
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
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Rights 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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng1056
This article is cited by
-
Simple model systems reveal conserved mechanisms of Alzheimer’s disease and related tauopathies
Molecular Neurodegeneration (2023)
-
The million-molecule challenge: a moonshot project to rapidly advance longevity intervention discovery
GeroScience (2023)
-
Deconvolution of the epigenetic age discloses distinct inter-personal variability in epigenetic aging patterns
Epigenetics & Chromatin (2022)
-
Optogenetic rejuvenation of mitochondrial membrane potential extends C. elegans lifespan
Nature Aging (2022)
-
The unfolded protein response reverses the effects of glucose on lifespan in chemically-sterilized C. elegans
Nature Communications (2022)