Gene
FOXO3
Last updated Sat May 30 2026 00:00:00 GMT+0000 (Coordinated Universal Time)
Why this gene is special
FOXO3 (FOXO3a) is the mammalian counterpart of the C. elegans DAF-16 longevity-master regulator. Reduced insulin/IGF-1 signalling liberates FOXO3 from cytoplasmic exclusion, allowing it to enter the nucleus and drive stress-response, DNA-repair, antioxidant, and autophagy gene programmes.
Population-genetic evidence
Multiple independent centenarian cohorts (Hawaiian Japanese, Ashkenazi Jewish, Italian, German, Chinese) show consistent enrichment of FOXO3 longevity-associated alleles. The effect size is large for a common variant.
What it does in the cell
Targets include:
- Mitochondrial SOD2, catalase (antioxidant).
- GADD45 (DNA damage response).
- p27 / p21 (cell cycle).
- Autophagy genes.
- Some inflammation modifiers.
Practical takeaway
Unlike APOE, FOXO3 genotyping is not routinely actionable — there are no specific clinical decisions that depend on it. Its main interest is as a window into the conserved biology of aging and as a target for future pharmacology.
Lifestyle interventions that increase FOXO3 activity (exercise, caloric restriction, intermittent fasting) work regardless of genotype.
Related entries
FOXO transcription factors, Insulin/IGF-1 signalling, Centenarians.
References
- Willcox, B. J. et al. FOXO3A genotype is strongly associated with human longevity. Proc. Natl. Acad. Sci. USA 105, 13987–13992 (2008).