Forkhead box(O) in control of reactive oxygen species and genomic stability to ensure healthy lifespan.

Significance: Transcription factors of the Forkhead box O class (FOXOs) are associated with lifespan and play a role in age-related diseases. FOXOs, therefore, serve as a paradigm for developing an understanding as to how age-related diseases, such as cancer and diabetes interconnect with lifespan. Understanding the regulatory inputs on FOXO may reveal how changes in these regulatory signaling pathways affect disease and lifespan.

Recent Advances: Numerous regulators of FOXO have now been described and a clear and evolutionary conserved role has emerged for phosphoinositide-3 kinase/protein kinase B (also known as c-Akt or AKT) signaling and c-jun N-terminal kinase signaling. Analysis of FOXO function in the context of these signaling pathways has shown the importance of FOXO-mediated transcriptional regulation on cell cycle progression and other cell fates, such as cell metabolism, stress resistance, and apoptosis in mediating disease and lifespan.

Critical Issues: Persistent DNA damage is also tightly linked to disease and aging; yet, data on a possible link between DNA damage and FOXO have been limited. Here, we discuss possible connections between FOXO and the DNA damage response in the context of the broader role of connecting lifespan and disease.

Future Directions: Understanding the role of lifespan in diseases onset may provide unique and generic possibilities to intervene in disease processes to ensure a healthy lifespan.