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Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans

Abstract

Ageing is a fundamental, unsolved mystery in biology. DAF-16, a FOXO-family transcription factor, influences the rate of ageing of Caenorhabditis elegans in response to insulin/insulin-like growth factor 1 (IGF-I) signalling. Using DNA microarray analysis, we have found that DAF-16 affects expression of a set of genes during early adulthood, the time at which this pathway is known to control ageing. Here we find that many of these genes influence the ageing process. The insulin/IGF-I pathway functions cell non-autonomously to regulate lifespan, and our findings suggest that it signals other cells, at least in part, by feedback regulation of an insulin/IGF-I homologue. Furthermore, our findings suggest that the insulin/IGF-I pathway ultimately exerts its effect on lifespan by upregulating a wide variety of genes, including cellular stress-response, antimicrobial and metabolic genes, and by downregulating specific life-shortening genes.

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Figure 1: Effects of daf-2 and daf-16 RNAi on lifespan and the early ageing transcriptome.
Figure 2: Class 1 genes are upregulated (red) with daf-2 RNAi treatment and in daf-2 pathway mutants, and downregulated (green) with daf-16 RNAi treatment, whereas class 2 genes are upregulated with daf-16 RNAi treatment and downregulated with daf-2 RNAi treatment and in daf-2 pathway mutants.
Figure 3: INS-7 behaves as a DAF-2 agonist, and is part of a positive feedback loop predicted to amplify DAF-2 pathway activity.
Figure 4: Lifespans of daf-2 mutants fed dsRNA of class 1 genes.
Figure 5: Lifespans of animals subjected to RNAi of indicated class 2 genes.

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References

  1. Tatar, M., Bartke, A. & Antebi, A. The endocrine regulation of aging by insulin-like signals. Science 299, 1346–1351 (2003)

    Article  CAS  PubMed  Google Scholar 

  2. Holzenberger, M. et al. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421, 182–187 (2003)

    Article  ADS  CAS  PubMed  Google Scholar 

  3. Bluher, M., Kahn, B. B. & Kahn, C. R. Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 299, 572–574 (2003)

    Article  ADS  PubMed  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  PubMed  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  ADS  CAS  PubMed  Google Scholar 

  6. Larsen, P. L., Albert, P. S. & Riddle, D. L. Genes that regulate both development and longevity in Caenorhabditis elegans. Genetics 139, 1567–1583 (1995)

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Gems, D. et al. Two pleiotropic classes of daf-2 mutation affect larval arrest, adult behavior, reproduction and longevity in Caenorhabditis elegans. Genetics 150, 129–155 (1998)

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Riddle, D. L. & Albert, P. S. in C. elegans II (eds Riddle, D. L., Blumenthal, T., Meyer, B. J. & Priess, J. R.) 739–768 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1997)

    Google Scholar 

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

    Article  ADS  CAS  PubMed  Google Scholar 

  10. Gems, D. & Partridge, L. Insulin/IGF signalling and ageing: seeing the bigger picture. Curr. Opin. Genet. Dev. 11, 287–292 (2001)

    Article  CAS  PubMed  Google Scholar 

  11. Dillin, A., Crawford, D. K. & Kenyon, C. Timing requirements for insulin/IGF-1 signaling in C. elegans. Science 298, 830–834 (2002)

    Article  ADS  CAS  PubMed  Google Scholar 

  12. Wolkow, C. A., Kimura, K. D., Lee, M. S. & Ruvkun, G. Regulation of C. elegans life-span by insulinlike signaling in the nervous system. Science 290, 147–150 (2000)

    Article  ADS  CAS  PubMed  Google Scholar 

  13. Tissenbaum, H. A. & Ruvkun, G. An insulin-like signaling pathway affects both longevity and reproduction in Caenorhabditis elegans. Genetics 148, 703–717 (1998)

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 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  ADS  CAS  PubMed  Google Scholar 

  15. 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  ADS  CAS  PubMed  Google Scholar 

  16. Apfeld, J. & Kenyon, C. Cell nonautonomy of C. elegans daf-2 function in the regulation of diapause and life span. Cell 95, 199–210 (1998)

    Article  CAS  PubMed  Google Scholar 

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

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lithgow, G. J., White, T. M., Hinerfeld, D. A. & Johnson, T. E. Thermotolerance of a long-lived mutant of Caenorhabditis elegans. J. Gerontol. 49, B270–B276 (1994)

    Article  CAS  PubMed  Google Scholar 

  19. Orr, W. C. & Sohal, R. S. Extension of life-span by overexpression of superoxide dismutase and catalase in Drosophila melanogaster. Science 263, 1128–1130 (1994)

    Article  ADS  CAS  PubMed  Google Scholar 

  20. Sun, J., Folk, D., Bradley, T. J. & Tower, J. Induced overexpression of mitochondrial Mn-superoxide dismutase extends the life span of adult Drosophila melanogaster. Genetics 161, 661–672 (2002)

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Longo, V. D., Liou, L. L., Valentine, J. S. & Gralla, E. B. Mitochondrial superoxide decreases yeast survival in stationary phase. Arch. Biochem. Biophys. 365, 131–142 (1999)

    Article  CAS  PubMed  Google Scholar 

  22. Taub, J. et al. retraction: A cytosolic catalase is needed to extend adult lifespan in C. elegans daf-C and clk-1 mutants. Nature 421, 764 (2003)

    Article  ADS  CAS  PubMed  Google Scholar 

  23. Eisen, M. B., Spellman, P. T., Brown, P. O. & Botstein, D. Cluster analysis and display of genome-wide expression patterns. Proc. Natl Acad. Sci. USA 95, 14863–14868 (1998)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  24. Tusher, V. G., Tibshirani, R. & Chu, G. Significance analysis of microarrays applied to the ionizing radiation response. Proc. Natl Acad. Sci. USA 98, 5116–5121 (2001)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  25. Garigan, D. et al. Genetic analysis of tissue aging in Caenorhabditis elegans. A role for heat-shock factor and bacterial proliferation. Genetics 161, 1101–1112 (2002)

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Herndon, L. A. & Driscoll, M. Contributions of cell death to aging in C. elegans. Results Probl. Cell Differ. 29, 113–129 (2000)

    Article  CAS  PubMed  Google Scholar 

  27. Barsyte, D., Lovejoy, D. A. & Lithgow, G. J. Longevity and heavy metal resistance in daf-2 and age-1 long-lived mutants of Caenorhabditis elegans. FASEB J. 15, 627–634 (2001)

    Article  CAS  PubMed  Google Scholar 

  28. 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  PubMed  Google Scholar 

  29. Gregoire, F. M., Chomiki, N., Kachinskas, D. & Warden, C. H. Cloning and developmental regulation of a novel member of the insulin-like gene family in Caenorhabditis elegans. Biochem. Biophys. Res. Commun. 249, 385–390 (1998)

    Article  CAS  PubMed  Google Scholar 

  30. 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  PubMed  PubMed Central  Google Scholar 

  31. Kawano, T. et al. Molecular cloning and characterization of a new insulin/IGF-like peptide of the nematode Caenorhabditis elegans. Biochem. Biophys. Res. Commun. 273, 431–436 (2000)

    Article  CAS  PubMed  Google Scholar 

  32. Li, W., Kennedy, S. G. & Ruvkun, G. daf-28 encodes a C. elegans insulin superfamily member that is regulated by environmental cues and acts in the DAF-2 signaling pathway. Genes Dev. 17, 844–858 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ookuma, S., Fukuda, M. & Nishida, E. Identification of a DAF-16 transcriptional target gene, scl-1, that regulates longevity and stress resistance in Caenorhabditis elegans. Curr. Biol. 13, 427–431 (2003)

    Article  CAS  PubMed  Google Scholar 

  34. Yu, S., Avery, L., Baude, E. & Garbers, D. L. Guanylyl cyclase expression in specific sensory neurons: a new family of chemosensory receptors. Proc. Natl Acad. Sci. USA 94, 3384–3387 (1997)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  35. Mallo, G. et al. Inducible antibacterial defense system in C. elegans. Curr. Biol. 12, 1209–1214 (2002)

    Article  CAS  PubMed  Google Scholar 

  36. Banyai, L. & Patthy, L. Amoebapore homologs of Caenorhabditis elegans. Biochim. Biophys. Acta 1429, 259–264 (1998)

    Article  CAS  PubMed  Google Scholar 

  37. Wang, J. & Kim, S. K. Global analysis of dauer gene expression in Caenorhabditis elegans. Development 130, 1621–1634 (2003)

    Article  CAS  PubMed  Google Scholar 

  38. Davis, W. L., Goodman, D. B., Crawford, L. A., Cooper, O. J. & Matthews, J. L. Hibernation activates glyoxylate cycle and gluconeogenesis in black bear brown adipose tissue. Biochim. Biophys. Acta 1051, 276–278 (1990)

    Article  CAS  PubMed  Google Scholar 

  39. Ried, K., Rao, E., Schiebel, K. & Rappold, G. A. Gene duplications as a recurrent theme in the evolution of the human pseudoautosomal region 1: isolation of the gene ASMTL. Hum. Mol. Genet. 7, 1771–1778 (1998)

    Article  CAS  PubMed  Google Scholar 

  40. Bussemaker, H. J., Li, H. & Siggia, E. D. Building a dictionary for genomes: identification of presumptive regulatory sites by statistical analysis. Proc. Natl Acad. Sci. USA 97, 10096–10100 (2000)

    Article  ADS  MathSciNet  CAS  PubMed  PubMed Central  Google Scholar 

  41. van Helden, J., Andre, B. & Collado-Vides, J. Extracting regulatory sites from the upstream region of yeast genes by computational analysis of oligonucleotide frequencies. J. Mol. Biol. 281, 827–842 (1998)

    Article  CAS  PubMed  Google Scholar 

  42. Furuyama, T., Nakazawa, T., Nakano, I. & Mori, N. Identification of the differential distribution patterns of mRNAs and consensus binding sequences for mouse DAF-16 homologues. Biochem. J. 349, 629–634 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Sijen, T. et al. On the role of RNA amplification in dsRNA-triggered gene silencing. Cell 107, 465–476 (2001)

    Article  CAS  PubMed  Google Scholar 

  44. Kirkwood, T. B. & Austad, S. N. Why do we age? Nature 408, 233–238 (2000)

    Article  ADS  CAS  PubMed  Google Scholar 

  45. Clancy, D. J. et al. Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein. Science 292, 104–106 (2001)

    Article  ADS  CAS  PubMed  Google Scholar 

  46. DeRisi, J. L., Iyer, V. R. & Brown, P. O. Exploring the metabolic and genetic control of gene expression on a genomic scale. Science 278, 680–686 (1997)

    Article  ADS  CAS  PubMed  Google Scholar 

  47. Lin, K., Hsin, H., Libina, N. & Kenyon, C. Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling. Nature Genet. 28, 139–145 (2001)

    Article  CAS  PubMed  Google Scholar 

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

    Article  ADS  CAS  PubMed  Google Scholar 

  49. DeRisi, J. et al. Genome microarray analysis of transcriptional activation in multidrug resistance yeast mutants. FEBS Lett. 470, 156–160 (2000)

    Article  CAS  PubMed  Google Scholar 

  50. van Helden, J., Andre, B. & Collado-Vides, J. A web site for the computational analysis of yeast regulatory sequences. Yeast 16, 177–187 (2000)

    Article  CAS  PubMed  Google Scholar 

  51. Lee, S. S., Kennedy, S., Tolonen, A. C. & Ruvkun, G. DAF-16 target genes that control C. elegans life-span and metabolism. Science 300, 644–647 (2003)

    Article  ADS  CAS  PubMed  Google Scholar 

  52. McElwee, J., Bubb, K. & Thomas, J. H. Transcriptional outputs of the Caenorhabditis elegans forkhead protein DAF-16. Aging Cell 1, 111–121 (2003)

    Article  Google Scholar 

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Acknowledgements

We thank all the members of the Kenyon laboratory, as well as Z. Gitai, for critical review and discussion of this work, and A. Dillin, J. Lehrer-Graiwer, D. Cristina, B. Albinder, and V. Tenberg for assistance. We also thank J. DeRisi and the DeRisi laboratory for assistance and advice on the design and use of microarrays, as well as T. Kirkwood for discussions about evolution. S.A.M., from the laboratory of C.I.B., participated in the statistical analysis and the whole-transcriptome analysis; A.F., R.S.K. and J.A. contributed the RNAi clones; and H.L. participated in the promoter analysis. C.T.M. is a Bristol-Myers Squibb Fellow of the Life Sciences Research Foundation. This work was supported by grants from the NIA and the Ellison Foundation to C.K.

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Correspondence to Cynthia Kenyon.

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Murphy, C., McCarroll, S., Bargmann, C. et al. Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature 424, 277–283 (2003). https://doi.org/10.1038/nature01789

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