FOXO3 (Forkhead Box O3)
The longevity gene most reproducibly associated with centenarians
Definition
FOXO3 (Forkhead Box O3) is a transcription factor that activates expression of genes involved in oxidative stress resistance, DNA repair, programmed apoptosis, and autophagy. It is the gene most reproducibly associated with exceptional longevity (centenarians) in GWAS studies across multiple populations — Japanese, Italian, German, Danish, and American. Variants of the SNP rs2802292 in intron 2 of FOXO3 increase the probability of reaching 95-100 years by 1.5 to 2.7-fold.
Detailed explanation
FOXO3 is downregulated by the PI3K-AKT pathway activated by insulin and IGF-1, and upregulated by AMPK (low-energy sensor) and sirtuins (NAD+-dependent pathway). That's why interventions reducing insulin/IGF-1 signalling (caloric restriction, fasting, exercise) and those activating AMPK/sirtuins (metformin, NAD+, resveratrol) activate FOXO3 and bring the epigenetic pattern closer to that of centenarians.
Key target genes activated by FOXO3: SOD2 and CAT (antioxidant defence), GADD45A (DNA repair), BIM (selective apoptosis in irreparable damage), ATG12 and LC3 (autophagy), p27 (cell cycle control).
23andMe and most direct-to-consumer genetic tests include the SNP rs2802292 (protective G variant vs non-protective T variant). Approximately 25% of Europeans carry at least one G copy; GG homozygotes show the strongest association with exceptional longevity.
Practical implication: people with the 'non-protective' genotype can compensate partially with a lifestyle that activates FOXO3 — intermittent fasting, caloric restriction, intermittent intense exercise, supplementation with sirtuin and AMPK activators. Epigenetics always trumps DNA when used strategically.
Scientific sources
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