A conserved ubiquitination pathway determines longevity in response to diet restriction

Abstract

The fact that dietary restriction increases longevity in a range of different animal species suggests that there is a conserved mechanism at work. Carrano et al. now show that the E3 ubiquitin ligase WWP-1 is essential for such lifespan extension in the worm. The lifespan enhancing abilities of WWP-1 are specific to dietary restriction and require the transcription factor pha-4, and not the transcription factor daf-16 — best known for its involvement in lifespan extension via reduced insulin/IGF-1 signalling. This finding implicates the widely conserved ubiquitination pathway in the longevity response to dietary restriction. The fact that dietary restriction increases longevity in diverse species suggests that there is a conserved mechanism for nutrient regulation and prosurvival responses. The E3 ubiquitin ligase WWP-1 and the E2 ubiquitin conjugating enzyme UBC-18 are now shown to be essential for such lifespan extension in the worm Caenorhabditis elegans. 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.