Pathway
FOXO Transcription Factors
Last updated Sun May 17 2026 00:00:00 GMT+0000 (Coordinated Universal Time)
What they are
FOXO (Forkhead box O) transcription factors are the mammalian relatives of C. elegans DAF-16. They translocate to the nucleus when insulin/IGF-1 signalling is low and turn on genes for stress resistance, DNA repair, antioxidant defence, autophagy, and cell-cycle arrest.
Why they matter
- FOXO3 variants are among the most replicated human longevity loci, associated with extreme longevity across diverse populations (Ashkenazi, Okinawan, German, Italian).
- FOXO3 over-expression extends mouse lifespan in tissue-specific contexts.
- Loss of FOXO accelerates phenotypes of aging.
What activates FOXO
- Reduced insulin/IGF-1 signalling.
- Oxidative stress.
- Sirtuin-mediated deacetylation.
- AMPK activation.
- Exercise (acutely and chronically).
- Caloric restriction.
What FOXO turns on
- Manganese superoxide dismutase (MnSOD/SOD2).
- Catalase, GADD45.
- p27, p21 (cell cycle).
- Autophagy genes.
- DNA-damage response genes.
Related entries
References
- Martins, R., Lithgow, G. J. & Link, W. Long live FOXO: unraveling the role of FOXO proteins in aging and longevity. Aging Cell 15, 196–207 (2016).