An AMPK-FOXO Pathway Mediates Longevity Induced by a Novel Method of Dietary Restriction in C. Elegans

Curr Biol. 2007 Oct 9;17(19):1646-56. doi: 10.1016/j.cub.2007.08.047. Epub 2007 Sep 27.

Abstract

Background: Dietary restriction (DR) is the most effective environmental intervention to extend lifespan in a wide range of species. However, the molecular mechanisms underlying the benefits of DR on longevity are still poorly characterized. AMP-activated protein kinase (AMPK) is activated by a decrease in energy levels, raising the possibility that AMPK might mediate lifespan extension by DR.

Results: By using a novel DR assay that we developed and validated in C. elegans, we find that AMPK is required for this DR method to extend lifespan and delay age-dependent decline. We find that AMPK exerts its effects in part via the FOXO transcription factor DAF-16. FOXO/DAF-16 is necessary for the beneficial effects of this DR method on lifespan. Expression of an active version of AMPK in worms increases stress resistance and extends longevity in a FOXO/DAF-16-dependent manner. Lastly, we find that AMPK activates FOXO/DAF-16-dependent transcription and phosphorylates FOXO/DAF-16 at previously unidentified sites, suggesting a possible direct mechanism of regulation of FOXO/DAF-16 by AMPK.

Conclusions: Our study shows that an energy-sensing AMPK-FOXO pathway mediates the lifespan extension induced by a novel method of dietary restriction in C. elegans.

Publication types

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

MeSH terms

  • AMP-Activated Protein Kinases
  • Animals
  • Animals, Genetically Modified
  • Caenorhabditis elegans / enzymology
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / physiology*
  • Caloric Restriction*
  • Forkhead Transcription Factors / physiology*
  • Longevity / physiology*
  • Multienzyme Complexes / physiology*
  • Protein-Serine-Threonine Kinases / physiology*
  • Signal Transduction / physiology*

Substances

  • Forkhead Transcription Factors
  • Multienzyme Complexes
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases