AMP‐activated Protein Kinase and FoxO Transcription Factors in Dietary Restriction–induced Longevity

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.

The AMPK-FoxO3A axis as a target for cancer treatment

“…In fact, molecular pathways analyzed, activation of the AMPK-FoxO axis was shown to be sufficient and required for the dietary restriction effects to occur on both healthspan and lifespan. 53 In particular, Greer and colleagues have shown that dietary restriction-dependent lifespan extension was suppressed in AMPK defective nematodes and significantly reduced in FoxO mutant strains. On the contrary, the long lifespan of insulin receptor mutant nematodes was further enhanced by dietary restriction.…”

Forkhead box O transcription factors as possible mediators in the development of major depression

“…p38 phosphorylates FoxO3a at Ser7 and promotes the nuclear translocation and activation of FoxO3a (Ho et al, 2012); JNK may repress the PI3K/Akt signal pathway, thereby activating FoxO3a indirectly, meanwhile, it may phosphorylayte FoxO proteins in a direct way (Sunters et al, 2006). FoxOs may also play a critical role in the regulation of energy homeostasis when phosphorylated by the AMP-activated protein kinase (AMPK) at six sites (Greer et al, 2009). In contrast to the effect of the above kinases on FoxOs, MST binds to FoxO3a and phosphorylates it at Ser207; however, the phosphorylation of this site promotes its nuclear accumulation and subsequently the expression of proapoptotic genes (Sanphui and Biswas, 2013).…”

Genetics and Epigenetics of Aging and Longevity

“…NAD + -за-висимые деацетилазы SIRT1, HDAC1, 3, 4 активируют-ся при энергетическом голодании клетки; повышение их экспрессии продляет жизнь (Virtue, Vidal-Puig, 2008). AMPK, сенсор количества в клетке АМФ, способству-ет долголетию (Greer et al, 2009). Напротив, киназа TOR активируется при наличии аминокислот и ускоря-ет старение, ее ингибирование увеличивает продолжи-тельность жизни мышей (Harrison et al, 2009).…”