An AMPK-FOXO pathway mediates longevity induced by a novel method of dietary restriction in C. elegans.
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.
Greer
Eric L
EL
Department of Genetics, Cancer Biology Program, Stanford University, Stanford, California 94305, USA.
Dowlatshahi
Dara
D
Banko
Max R
MR
Villen
Judit
J
Hoang
Kimmi
K
Blanchard
Daniel
D
Gygi
Steven P
SP
Brunet
Anne
A
D055372:AMP-Activated Protein Kinases; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000201:enzymology / Q000235:genetics / Q000502:physiology*; D031204:Caloric Restriction; D051858:Forkhead Transcription Factors / Q000502:physiology*; D008136:Longevity / Q000502:physiology*; D009097:Multienzyme Complexes / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D051858:Forkhead Transcription Factors; D009097:Multienzyme Complexes; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases