A conserved ubiquitination pathway determines longevity in response to diet restriction

Nature. 2009 Jul 16;460(7253):396-9. doi: 10.1038/nature08130. Epub 2009 Jun 24.


Dietary restriction extends longevity in diverse species, suggesting that there is a conserved mechanism for nutrient regulation and prosurvival responses. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / physiology*
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Caloric Restriction*
  • DNA-Binding Proteins / metabolism
  • Heat-Shock Response
  • Ligases / genetics
  • Ligases / metabolism*
  • Longevity / physiology*
  • Protein Binding
  • Receptors, Nicotinic / genetics
  • Receptors, Nicotinic / metabolism
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription Factors / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination / physiology*


  • Caenorhabditis elegans Proteins
  • DNA-Binding Proteins
  • Eat-2 protein, C elegans
  • Pha-4 protein, C elegans
  • Receptors, Nicotinic
  • Trans-Activators
  • Transcription Factors
  • skn-1 protein, C elegans
  • wwp-1 protein, C elegans
  • Ubiquitin-Protein Ligases
  • Ligases
  • Ubc-18 protein, C elegans