Effects of FOXO3 Polymorphisms on Survival to Extreme Longevity in Four Centenarian Studies.
Level 3 - non-randomized controlled study
Pooled cohort and genetic association study across four longevity cohorts
PubMed 28977569 · doi:10.1093/gerona/glx124
What was done
Analyzed 107 single-nucleotide polymorphisms (SNPs) across the FOXO3 gene using data from four longevity studies comprising 8,266 participants (case age range 96–119 years). The authors evaluated associations with survival to at least the top 1st percentile of lifespan for the 1900 birth cohort (≥96 years for white males, ≥100 years for white females), assessed brain tissue expression quantitative trait loci (eQTL), and performed survival analysis to evaluate whether any SNPs affected mortality risk after reaching the 1st percentile threshold.
What was found
The analysis replicated 17 previously published FOXO3 variants associated with survival to the 1st percentile of lifespan, with rs6911407 and rs2253310 showing the strongest eQTL effects on FOXO3 expression in brain tissue. In survival analysis beyond this extreme age threshold, none of the 17 replicated variants were significantly associated with mortality risk. A novel association with post-threshold mortality risk was observed for an uncommon homozygote genotype of rs9384680 (p = 2.68E-04), but this occurred in only 11 females.
Why it matters
These findings confirm that common FOXO3 genetic variants contribute to reaching extreme old age, but suggest they do not drive further survival differences once exceptional longevity has already been attained.
Limits
The study was restricted to white participants, limiting generalizability to other ancestries. The only variant linked to mortality risk beyond the 1st percentile of survival was based on an extremely small sample of 11 females. The abstract does not report effect sizes, hazard ratios, or confidence intervals.
Cited by
- supports The FOXO3 gene is well known to be associated with longevity and supercentenarians.