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FOXO transcription factors belong to the forkhead family of transcriptional regulators that is characterized by a conserved DNA binding domain termed the ‘‘forkhead box’’. FOXO proteins are normally present in an active state in a cell’s nucleus. In response to the binding of growth factors or insulin to the appropriate cell surface receptors, the activation of phosphatidylinositol 3-kinase (PI3K) is triggered. PI3K in turn activates several serine/threonine kinases, including protein kinase B (PKB/Akt) and the related SGK family enzymes. Activated Akt phosphorylates FOXO proteins at three consensus Akt phosphorylation sites, triggering the inactivation of these molecules and their export from the nucleus into the cytoplasm.

FOXO proteins have both distinct and overlapping functions, and their many target molecules are involved in processes as diverse as cell-cycle, DNA repair, cellular differentiation, and cell death. In proliferating cells, protection from cell death is mediated by activity of the phosphatidylinositol-3-OH kinase (PI(3)K)–PKB signalling pathway, which is dependent on the presence of glucose. In the absence of PI(3)K–PKB signalling, the FOXO subfamily of Forkhead transcription factors is activated. In most cell types, this leads to cell-cycle arrest and quiescence but not apoptosis, despite the absence of PKB activity.

Stimulation of SIRT1 transcription by FOXO3A was mediated through two p53 binding sites present in the SIRT1 promoter, and a nutrient-sensitive physical interaction was observed between FOXO3A and p53. SIRT1 expression was not induced in starved p53-deficient mice. Thus, in mammalian cells, p53, FOXO3A, and SIRT1, 3 proteins separately implicated in aging, constitute a nutrient-sensing pathway. Long-lived men presented several additional phenotypes linked to healthy aging. Several of these aging phenotypes were associated with the FOXO3A genotype. Long-lived men also exhibited several biologic markers indicative of greater insulin sensitivity, and this was associated with homozygosity for the FOXO3A GG genotype.