FOXO3a is one of the very few genes for which an association with longevity has been identified in multiple human studies – though one should bear in mind that even though it shows up fairly reliably, the effect size is small. Still, near all such associations between human genetic variants and longevity cannot be replicated. Given this, there is an interest in understanding exactly how FOXO3a acts to influence life span. Here, researchers provide evidence that is suggestive of an effect on the burden of mutations in nuclear DNA, particularly double strand breaks. This is interesting in the context of recent work that links DNA repair activity for double strand breaks with the progressive detrimental shift in gene expression that takes place with age.

Genomic instability is one of the hallmarks of aging, and both DNA damage and mutations have been found to accumulate with age in different species. Certain gene families, such as sirtuins and the FoxO family of transcription factors, have been shown to play a role in lifespan extension. However, the mechanism(s) underlying the increased longevity associated with these genes remains largely unknown and may involve the regulation of responses to cellular stressors, such as DNA damage.

Here, we report that FOXO3a reduces genomic instability in cultured mouse embryonic fibroblasts (MEFs) treated with agents that induce DNA double-strand breaks (DSBs), that is, clastogens. We show that DSB treatment of both primary human and mouse fibroblasts upregulates FOXO3a expression. FOXO3a ablation in MEFs harboring the mutational reporter gene lacZ resulted in an increase in genome rearrangements after bleomycin treatment; conversely, overexpression of human FOXO3a was found to suppress mutation accumulation in response to bleomycin. We also show that overexpression of FOXO3a in human primary fibroblasts decreases DSB-induced γH2AX foci. Knocking out FOXO3a in mES cells increased the frequency of homologous recombination and non-homologous end-joining events. These results provide the first direct evidence that FOXO3a plays a role in suppressing genome instability, possibly by suppressing genome rearrangements.