Role of FOXO transcription factors in organismal longevity

The insulin signaling pathway plays a crucial conserved role in the regulation of organismal longevity from nematode to mammals. A key downstream regulatory target of the insulin pathway is the FOXO family of Forkhead transcription factors. We have previously found that FOXO transcription factors (FOXO TF) are directly phosphorylated in response to insulin or growth factor signaling by the protein kinase Akt, which results in the sequestration of FOXO TF in the cytoplasm, away from their target genes. We found that FOXO TF also integrate stress stimuli, through the phosphorylation and acetylation of key residues and through binding with the SIRT1 deacetylase. Interestingly, stress stimulation triggers the relocalization of FOXO TF to the nucleus. When present in the nucleus, FOXO TF induce a wide set of important cellular responses, including cell cycle arrest, DNA repair or apoptosis, by upregulating a series of target genes. Since the ability to repair DNA damage, is highly correlated with increased organismal longevity, one way in which FOXO TFs may regulate lifespan is by increasing resistance to oxidative stress. Our current model is that the FOXO TFs represent central molecular sensors of the extracellular environment and modulate the gene expression profile by interacting with key protein partners, thereby eliciting a series of cellular responses that may contribute to general organismal longevity.