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. 2009 Jul:1170:688-92.
doi: 10.1111/j.1749-6632.2009.04019.x.

AMP-activated protein kinase and FoxO transcription factors in dietary restriction-induced longevity

Eric L Greer  1 , Max R Banko, Anne Brunet
Affiliations

AMP-activated protein kinase and FoxO transcription factors in dietary restriction-induced longevity

Eric L Greer et al. Ann N Y Acad Sci. 2009 Jul.

Abstract

Aging is regulated by modifications in single genes and by simple changes in the environment. The signaling pathway connecting insulin to FoxO transcription factors integrates environmental stimuli to regulate lifespan. FoxO transcription factors are directly phosphorylated in response to insulin/growth factor signaling by the protein kinase Akt, thereby causing their sequestration in the cytoplasm. In the absence of insulin/growth factors, FoxO factors translocate to the nucleus where they trigger a range of cellular responses, including resistance to oxidative stress--a phenotype highly coupled with lifespan extension. Our recent results indicate that FoxO transcription factors are also regulated in response to nutrient deprivation by the AMP-activated protein kinase (AMPK) pathway. The energy-sensing AMPK directly phosphorylates FoxO transcription factors at six regulatory sites. AMPK phosphorylation enhances FoxO transcriptional activity, leading to the expression of specific target genes involved in stress resistance and changes in energy metabolism. The AMPK-FoxO pathway plays a crucial role in the ability of a dietary restriction regimen to extend lifespan in Caenorhabditis elegans. Understanding the intricate signaling networks that translate environmental conditions like dietary restriction into changes in gene expression that extend lifespan will be of critical importance to identify ways to delay the onset of aging and age-dependent diseases.

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Conflict of interest statement

Conflicts of Interest

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Model for the mechanisms underlying longevity in response to sDR in C. elegans. sDR would activate AMPK by increasing the AMP:ATP ratio. Activated AMPK would in turn phosphorylate and activate FoxO/ daf-16 and possibly other substrates. FoxO would induce the expression of a program of genes involved in stress resistance and alternative energy metabolism, which would lead to beneficial effects on lifespan and healthspan. (In color in Annals online.)
See this image and copyright information in PMC

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