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A conserved ubiquitination pathway determines longevity in response to diet restriction

Nature volume 460, pages 396–399 (2009)Cite this article

Abstract

Dietary restriction extends longevity in diverse species, suggesting that there is a conserved mechanism for nutrient regulation and prosurvival responses1. Here we show a role for the HECT (homologous to E6AP carboxy terminus) E3 ubiquitin ligase WWP-1 as a positive regulator of lifespan in Caenorhabditis elegans in response to dietary restriction. We find that overexpression of wwp-1 in worms extends lifespan by up to 20% under conditions of ad libitum feeding. This extension is dependent on the FOXA transcription factor pha-4, and independent of the FOXO transcription factor daf-16. Reduction of wwp-1 completely suppresses the extended longevity of diet-restricted animals. However, the loss of wwp-1 does not affect the long lifespan of animals with compromised mitochondrial function or reduced insulin/IGF-1 signalling. Overexpression of a mutant form of WWP-1 lacking catalytic activity suppresses the increased lifespan of diet-restricted animals, indicating that WWP-1 ubiquitin ligase activity is essential for longevity. Furthermore, we find that the E2 ubiquitin conjugating enzyme, UBC-18, is essential and specific for diet-restriction-induced longevity. UBC-18 interacts with WWP-1 and is required for the ubiquitin ligase activity of WWP-1 and the extended longevity of worms overexpressing wwp-1. Taken together, our results indicate that WWP-1 and UBC-18 function to ubiquitinate substrates that regulate diet-restriction-induced longevity.

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Figure 1: wwp-1 is required and specific for the extension of lifespan by dietary restriction.
Figure 2: WWP-1 ubiquitin ligase activity is essential for diet-restriction-induced longevity.
Figure 3: WWP-1 exhibits ubiquitin ligase activity in a UBC-18 dependent manner in vitro.
Figure 4: WWP-1 and UBC-18 function together to regulate diet-restriction-induced longevity.

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Acknowledgements

We thank members of the Dillin laboratory for discussion, and P. Marks and H. Sun for their help. We thank A. Brunet for the solid-plate diet-restriction protocol. wwp-1(ok1102) was generated by the C. elegans Gene Knockout Consortium, and some strains were provided by the Caenorhabditis Genetics Center, which is funded by the National Institutes of Health (NIH) National Center for Research Resources (NCRR). This work was supported by grants from the National Cancer Institute (CA 14195, CA 54418 and CA 82683) to T.H., and grants from the National Institute of Diabetes and Digestive and Kidney Diseases (DK 070696) and the National Institute on Aging (AG 027463 and AG 032560), and the Ellison Medical and Glenn Medical Foundations to A.D. A.C.C. was supported by an American Cancer Society Postdoctoral Fellowship and The Rossi Endowment. T.H. is a Frank and Else Schilling American Cancer Society Professor.

Author Contributions A.C.C. designed the experiments and analysed the data. A.C.C. and Z.L. performed the experiments. A.D. and T.H. supervised the design and data interpretation. The manuscript was written by A.C.C. and edited by A.D. and T.H. All authors discussed the results and commented on the manuscript.

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Authors and Affiliations

  1. Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA,

    Andrea C. Carrano, Zheng Liu, Andrew Dillin & Tony Hunter

  2. The Howard Hughes Medical Institute, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA,

    Zheng Liu & Andrew Dillin

  3. The Glenn Center for Aging Research, 10010 North Torrey Pines Road, La Jolla, California 92037, USA,

    Zheng Liu & Andrew Dillin

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  1. Andrea C. Carrano
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Correspondence to Andrew Dillin.

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Carrano, A., Liu, Z., Dillin, A. et al. A conserved ubiquitination pathway determines longevity in response to diet restriction. Nature 460, 396–399 (2009). https://doi.org/10.1038/nature08130

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