FOXO

FOXO proteins are a subclass of the forkhead family of transcription factors, and mammals express FOXO1, FOXO3, FOXO4 and FOXO6. ^{[1] [2]} The mammalian FOXOs are orthologues of the Caenorhabditis elegans transcription factor DAF-16. ^[3] FOXO factors were originally identified as downstream regulators of the insulin pathway and bind the promoters of a broad range of target genes controlling cellular energy production, oxidative stress resistance, and cell viability and proliferation. ^{[4] [5]} FOXO transcription factors play a pivotal role in cellular adaptation to diverse stress conditions and act as context-dependent tumor suppressors. ^[2] Because FOXO1, FOXO3, FOXO4 and FOXO6 have a broad and partly redundant range of cellular functions, isoform-specific targeting has been proposed as a way to obtain greater benefit with fewer side effects. ^[6]

The phosphatidylinositol-3-kinase (PI3K)-AKT signaling pathway is a central negative regulator of FOXO activity. ^[7] Insulin signaling inhibits FOXOs through reversible AKT phosphorylation of highly conserved consensus sites, which enables docking of 14-3-3 proteins and FOXO inactivation. ^{[2] [7]} Environmental stimuli including insulin, growth factors, nutrients and oxidative stress control FoxO activity primarily by regulating subcellular localization, through post-translational modifications such as phosphorylation, acetylation and ubiquitination. ^[8] For FOXO3a, these modifications drive shuttling between cellular compartments, with cytoplasmic localization corresponding to inactivation and nuclear or mitochondrial localization to activation. ^[9] Depending on the stress stimulus, activated FOXO3a can induce cell cycle inhibitors, pro-apoptotic genes, reactive oxygen species scavengers, autophagy effectors and gluconeogenic enzymes.

In C. elegans, DAF-16 is required for the doubling of lifespan seen in the absence of daf-2, the worm insulin receptor homologue, and the lifespan-extending capacity of DAF-16/FOXO correlates closely with its ability to induce stress response pathways. ^[3] Genetic evidence implicates FOXOs in lifespan regulation in hydra, C. elegans, Drosophila and mice, where increased FOXO activity extends lifespan in model organisms. ^{[6] [1]} In mice, heterozygous Foxo3 knockout abolished the lifespan-extending effect of 30% dietary restriction while retaining its tumor-inhibiting effect, whereas in heterozygous Foxo1 mice dietary restriction extended lifespan normally but its tumor-inhibiting effect was attenuated. ^[11] In humans, FOXO3 has been established as a major longevity gene, and its protective alleles are the second most replicated genetic factors associated with extreme or long life. ^{[2] [6]}

Dietary restriction attenuates the inhibitory effects of insulin, IGF-1 and other growth factors on FoxO1 and FoxO3, while AMPK and sirtuins also promote FoxO activity. ^[11] Fasting, protein restriction and reduced intake of methionine and branched-chain amino acids selectively affect the activity of AKT, FOXO, mTOR, NAD+, AMPK and FGF21, key components of nutrient-sensing geroprotective pathways. ^[12] Beyond AKT, FOXO family members are regulated positively by kinases such as JNK and AMPK and negatively by ERK-MAPK and CDK2. ^[7] SIRT1/FoxO signaling contributes to protein homeostasis, mitochondrial function and autophagy