Authors: Greer, Eric L; Dowlatshahi, Dara; Banko, Max R; Villen, Judit; Hoang, Kimmi; Blanchard, Daniel; Gygi, Steven P; Brunet, Anne
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.Keywords: AMP-Activated Protein Kinases; Animals; Animals, Genetically Modified; Caenorhabditis elegans/enzymology/genetics/*physiology; *Caloric Restriction; Forkhead Transcription Factors/*physiology; Longevity/*physiology; Multienzyme Complexes/*physiology; Protein-Serine-Threonine Kinases/*physiology; Signal Transduction/*physiology
Journal: Curr Biol
Date: Sept. 29, 2007
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Greer, Eric L, Dowlatshahi, Dara, Banko, Max R, Villen, Judit, Hoang, Kimmi, Blanchard, Daniel, Gygi, Steven P, Brunet, Anne (2007) An AMPK-FOXO pathway mediates longevity induced by a novel method of dietary restriction in C. elegans. Curr Biol 17: 1646-56.