Forkhead Box O transcription factors: Key players in redox signaling

The Forkhead Box O (FOXO) transcription factors are famous for their role in longevity: both Caenorhabditis elegans and Drosophila melanogaster can extend their median and maximum lifespan in a FOXO-dependent manner, and certain single nucleotide polymorphisms in human FOXO genes are associated with reaching an age above 100 years. Ablation of FOXO1, 3a, and 4 in adult mice predisposes them to tumorigenesis and stem cell depletion, and the latter could at least partly be reversed by treatment with antioxidants. Indeed, FOXO has been known to regulate the defense against reactive oxygen species through transactivation of antioxidant genes like manganese superoxide dismutase and catalase. At the same time, reactive oxygen species regulate FOXO activity in many ways through an elaborate combination of activating as well as repressing post-translational modifications, including phosphorylation, acetylation, ubiquitinylation, and methylation. Hence, FOXO is at the centre of redox signaling, but it is unclear whether and how exactly redox signaling to and from FOXO contributes to its effects on longevity. In this forum issue we give an overview of the many facets of FOXO in worms, flies, mice, and humans.