These transcription factors share the ability to be inhibited and translocated out of the nucleus on phosphorylation by proteins such as Akt/PKB in the PI3K signaling pathway (aside from FOXO6, which may be constitutively nuclear).

The use of FOXO3a knockout mice has revealed a diverse range of functions in both health and disease, namely infertility, lymphoproliferation, adenoma, organ inflammation, metabolism etc.

; yet despite the purported importance of FOXO transcription factors in aging, FOXO3A knockout mice do not show an obvious shortening of lifespan or accelerated aging [7] Yu & Fellows et al. (2018) demonstrated that FOXO3a activation in vascular smooth muscle cells induces prominent apoptosis and extracellular matrix breakdown in vitro and exacerbates atherosclerosis and vascular remodelling in vivo.

[8] FOXO3a also functions as a trigger for apoptosis through upregulation of genes necessary for cell death, such as Bim and PUMA,[9] or downregulation of anti-apoptotic proteins such as FLIP.

Ron DePinho's group generated Foxo3 knockout mice, and showed that female exhibit a dramatic age-dependent infertility, due to premature ovarian failure.