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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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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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