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

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 ener...

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Bibliographic Details
Published in:Current biology 2007-10, Vol.17 (19), p.1646-1656
Main Authors: Greer, Eric L., Dowlatshahi, Dara, Banko, Max R., Villen, Judit, Hoang, Kimmi, Blanchard, Daniel, Gygi, Steven P., Brunet, Anne
Format: Article
Language:English
Subjects:
AMP-Activated Protein Kinases
Animals
Animals, Genetically Modified
Caenorhabditis elegans - enzymology
Caenorhabditis elegans - genetics
Caenorhabditis elegans - physiology
Caloric Restriction
DEVBIO
Forkhead Transcription Factors - physiology
Longevity - physiology
Multienzyme Complexes - physiology
Protein-Serine-Threonine Kinases - physiology
Signal Transduction - physiology
SIGNALING
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Summary: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. 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. 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.
ISSN:0960-9822
1879-0445
DOI:10.1016/j.cub.2007.08.047