The future of Forkhead box O transcription factors

The Forkhead box O (FOXO) class of transcription factors is evolutionary conserved both structurally and at least in part also functionally. FOXO activation results in transcriptional programs that provide cellular resilience toward exogenous and endogenous challenges, especially challenges that provoke cellular oxidative stress. This FOXO-dependent mechanism of resilience explains by and large the observed longevity phenotype in model organisms where increased FOXO activity extends lifespan. This may even hold for human lifespan as genome-wide association studies show a strong linkage between FOXO3 and human lifespan. Despite decades of studies on FOXOs, there are still many unresolved questions. Here, we discuss some of these knowledge gaps, related to our general understanding of transcriptional control by FOXOs, the role of the intrinsically disordered regions that constitute over 50% of FOXOs sequence, the role of cellular context in determining isoform specificity, and finally, the importance of resilience in understanding FOXO function. The latter, we think, provides context to the evolutionary role of FOXOs. So, rather than providing an exhaustive summary of literature findings, we focus on some of the omissions in our knowledge of FOXO function. Resolving these outstanding questions, we think, will help to provide the necessary insight to know how and when to manipulate FOXO function in a manner that will contribute to healthy aging.