A small number of genetic variants are consistently found at higher rates in people who live to 100.
FOXO3, SIRT1, IGF1R, TERT, TERC, and KLOTHO. Ten variants at the intersection of insulin signaling, cellular stress response, DNA repair, and telomere maintenance.
The Biology
Longevity genetics is a young but increasingly rigorous field. Most of the genome has no special association with exceptional lifespan. But a handful of loci. Particularly FOXO3, SIRT1, IGF1R, TERT, TERC, and KLOTHO. Show consistent enrichment in centenarian populations across multiple ethnicities and study designs. These genes sit at the intersection of insulin/IGF-1 signaling, cellular stress response, DNA repair, and telomere maintenance. The pathways most conserved across species as regulators of biological aging.
What Varia Analyzes
Three FOXO3 variants (rs2802292, rs4946936, rs2253310). The most replicated longevity locus in humans, confirmed in Japanese, German, and Italian centenarian cohorts; SIRT1 (rs3758391), a NAD+-dependent deacetylase central to caloric restriction response; IGF1R (rs2229765), a longevity-associated variant in the insulin-like growth factor signaling axis; TERT (rs2736100) and TERC (rs10936599), the catalytic and RNA template components of telomerase; and three KLOTHO variants (rs9536314, rs9527025, rs564481) defining the KL-VS haplotype. Which, when present in heterozygous form specifically, is associated with approximately 35% reduced risk of developing mild cognitive impairment or Alzheimer's disease in APOE4 carriers, based on a study of 22,748 participants (Belloy et al., JAMA Neurology, 2020).
Why It Matters
FOXO3 G allele homozygosity at rs2802292 is one of the few genetic findings independently replicated across multiple populations as genuinely associated with exceptional longevity. The KLOTHO KL-VS finding is particularly significant for APOE4 carriers. It is one of the most potent genetic modifiers of APOE4-associated Alzheimer's risk identified to date, and its protective effect is specific to the heterozygous state; homozygotes do not show the same magnitude of protection. The TERT and TERC findings provide a combined picture of telomere maintenance capacity that neither locus captures alone.
Key sources
- Willcox BJ, et al. FOXO3A genotype is strongly associated with human longevity. PNAS. 2008.
- Flachsbart F, et al. Association of FOXO3A variation with human longevity confirmed in German centenarians. PNAS. 2009.
- Kuningas M, et al. SIRT1 gene, age-related diseases, and mortality: the Leiden 85-plus study. J Gerontol A Biol Sci Med Sci. 2007.
- Codd V, et al. Identification of seven loci affecting mean telomere length and their association with disease. Nat Genet. 2013.
- Belloy ME, et al. Association of Klotho-VS heterozygosity with risk of Alzheimer disease in individuals who carry APOE4. JAMA Neurol. 2020.