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Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling

Nature Genetics volume 28, pages 139–145 (2001)Cite this article

Abstract

The lifespan of Caenorhabditis elegans is regulated by the insulin/insulin-like growth factor (IGF)-1 receptor homolog DAF-2, which signals through a conserved phosphatidylinositol 3-kinase (PI 3-kinase)/Akt pathway1,2,3,4,5,6,7. Mutants in this pathway remain youthful and active much longer than normal animals and can live more than twice as long. This lifespan extension requires DAF-16, a forkhead/winged-helix transcription factor8,9. DAF-16 is thought to be the main target of the DAF-2 pathway. Insulin/IGF-1 signaling is thought to lead to phosphorylation of DAF-16 by AKT activity, which in turn shortens lifespan. Here, we show that the DAF-2 pathway prevents DAF-16 accumulation in nuclei. Disrupting Akt-consensus phosphorylation sites in DAF-16 causes nuclear accumulation in wild-type animals, but, surprisingly, has little effect on lifespan. Thus the DAF-2 pathway must have additional outputs. Lifespan in C. elegans can be extended by perturbing sensory neurons or germ cells10,11. In both cases, lifespan extension requires DAF-16. We find that both sensory neurons and germline activity regulate DAF-16 accumulation in nuclei, but the nuclear localization patterns are different. Together these findings reveal unexpected complexity in the DAF-16-dependent pathways that regulate aging.

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Figure 1: DAF-16::GFP constructs.
Figure 2: Effect of mutant and wildtype DAF-16a:GFP proteins on lifespan.
Figure 3: Distribution of DAF-16a::GFP and DAF-16a::GFP/bKO proteins in L2 larvae and in dauers.
Figure 4: DAF-16aAM::GFP/bKO was localized in nuclei in both daf-16(mu86); daf-2(+) and daf-16(mu86); daf-2(e1370) backgrounds.
Figure 5: Localization of DAF-16a::GFP/bKO in cilium-structure sensory mutants and in germ-line ablated animals.
Figure 6: DAF-16a::GFP distribution in animals exposed to heat.

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Acknowledgements

H.H. and N.L. contributed equally to this work. We thank B. Harmon, T. Yu, M. Singer, Q. Ch'ng and L. Yang for help with microscopy; B. Albinder for technical assistance; and all members of the Kenyon lab for discussions and comments on the manuscript. Some nematode strains were provided by the Caenorhabditis Genetics Center, which is supported by the National Center for Research Resources. This work was supported by a grant from the National Institutes of Health to C.K., who is the Herbert Boyer Professor of Biochemistry and Biophysics.

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  1. Kui Lin

    Present address: Department of Cell Biology and Technology, Genentech, Inc., South San Francisco, California, USA

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  1. Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California, USA

    Kui Lin, Honor Hsin, Natasha Libina & Cynthia Kenyon

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Correspondence to Cynthia Kenyon.

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Lin, K., Hsin, H., Libina, N. et al. Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling. Nat Genet 28, 139–145 (2001). https://doi.org/10.1038/88850

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