A small number of genetic variants are consistently found at higher rates in people who live to 100.
FOXO3, TERT, TERC, and KLOTHO. 8 variants spanning insulin signaling, telomere maintenance, and the KL-VS haplotype.
The Biology
Longevity genetics is a young field. Most of the genome shows no special association with exceptional lifespan, but a few loci, FOXO3 above all, turn up more often in centenarians across several populations. TERT and TERC encode the two core parts of telomerase, the enzyme that maintains telomeres, and were identified in studies of telomere length. KLOTHO encodes a protein linked to aging biology, and one of its haplotypes, KL-VS, has been studied in relation to Alzheimer's disease.
What Varia Analyzes
8 variants. FOXO3 (rs2802292, rs4946936, rs2253310), the longevity-associated gene replicated across several centenarian populations; TERT (rs2736100) and TERC (rs10936599), the catalytic and RNA template components of telomerase, each associated with telomere length; and KL, the klotho gene (rs9536314, rs9527025, rs564481), from which the KL-VS haplotype is read.
Why It Matters
At FOXO3 rs2802292, the G allele is the one found more often in centenarians, and two copies carry the strongest association at this locus. For KLOTHO, the association depends on carrying exactly one copy of KL-VS. In a study of people aged 60 and older who carry APOE4 (Belloy et al., JAMA Neurology, 2020), KL-VS heterozygotes had lower odds of Alzheimer's disease (odds ratio 0.75 across 20,928 people in the case-control analyses), and those cognitively normal at the start were less likely to progress to mild cognitive impairment or Alzheimer's (hazard ratio 0.64). People with two copies did not show the same association. The TERT and TERC variants describe population associations with telomere length, not a measurement of your own telomeres.
Not in Varia's Catalog
Longevity variants often discussed alongside these are not in the catalog: SIRT1 (rs3758391) and IGF1R (rs2229765). Varia does not read these from your file, so a scan reports nothing about them either way.
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.
- 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.