Reduced insulin/IGF signaling (IIS) increases lifespan and this effect is dependent upon the DAF-16 FoxO transcription factor. However, the processes regulated by IIS/FoxO that directly control aging remain poorly understood. Previous studies have shown that genes involved in metabolism, stress resistance, cell cycle arrest and apoptosis are directly regulated by FoxO. The longevity of
daf-2 insulin/IGF receptor mutants is also dependent upon AMP-activated protein kinase (AMPK)1,2. This enzyme acts as a fuel gauge of the cell3: When the AMP:ATP ratio increases, AMPK is activated and phosphorylates key metabolic enzymes, resulting in increased catabolism and reduced biosynthesis. AMPK is a heterotrimer with a catalytic a-subunit, and regulatory b- and g-subunits3. Binding of AMP to the g-subunit activates AMPK. There is evidence that DAF-16 acts downstream of AMPK, e.g. the longevity resulting from an AMPK activation mutation is suppressed by mutation of
daf-16, and AMPK phosphorylates DAF-16 (ref. 4). In an attempt to identify direct targets of DAF-16, DamID (DNA adenine methyltransferase identification) was used in combination with microarray analysis (see abstract by E. Schuster et al.). Results using this approach imply that two of the five predicted AMPK g subunits are up-regulated by DAF-16. Moreover, microarray data5,6 reveals up-regulation of an a-subunit gene,
aak-2 and a b-subunit gene,
aakb-1, in
daf-2 relative to
daf-16;
daf-2. Thus, DAF-16 is predicted to increase expression of the entire AMPK heterotrimer. This suggests action of AMPK downstream as well as upstream of DAF-16, and the presence of a positive feedback loop. We are now investigating further the relationship between IIS and AMPK in the control of aging in C. elegans. 1. Apfeld et al. Genes Dev. 18, 3004-9 (2004). 2. Curtis et al. Aging Cell 5, 119-26 (2006). 3. Hardie & Carling. Eur. J. Biochem. 246, 259-273 (1997). 4. Greer et al. Curr. Biol. 17, 1646-56 (2007). 5. McElwee et al. Genome Biol. 8, R132 (2007). 6. McElwee et al. J. Biol. Chem. 279, 44533-43 (2004)..