Longevity 2

For background information and a discussion of genetic heterogeneity of longevity, see 152430.

Mapping

Willcox et al. (2008) studied a cohort of elderly men of Japanese ethnicity initially evaluated between 1991 and 1993, at which time their mean age was 77.9 years. They reviewed this cohort and compared the 213 patients who had survived to age 95 or more, whom they considered the longevity cases, with the 402 participants who had died before the age of 81, considered the average-lived controls. Willcox et al. (2008) investigated 5 genes in the insulin/IGF1 (147440) signaling pathway; only FOXO3A (602681) was associated with longevity. In terms of biologic characteristics, the long-lived cases were leaner, had lower triglycerides, lower glucose, lower insulin levels, and a higher prevalence of the FOXO3A3 allele at the baseline examination. Willcox et al. (2008) investigated 5 genes, but only FOXO3A was associated with longevity. Comparing genotype frequencies of FOXO3A3 (rs2802292) between cases and controls revealed a highly significant difference (P = 0.00009 for the Pearson exact chi-squared statistics). After Bonferroni correction, this P value was 0.00135. Due to the high linkage disequilibrium between the 3 SNPs in FOXO3A, Willcox et al. (2008) further investigated the FOXO3A3 SNP only. The odds ratio (OR) for the homozygous minor versus homozygous major alleles for FOXO3A3 between the cases and controls was 2.75 (95% confidence interval (CI), 1.51-5.02, P = 0.0007), and the OR for heterozygous versus homozygous major alleles between the cases and controls was 1.91 (95% CI, 1.34-2.72, P = 0.0003). Willcox et al. (2008) concluded that their results suggested an additive effect on longevity. Long-lived men presented several additional phenotypes linked to healthy aging, including lower prevalence of cancer and cardiovascular disease, better self-reported health, and high physical and cognitive function, despite significantly older ages than controls. Several of these aging phenotypes were associated with the FOXO3A genotype. Long-lived men also exhibited several biologic markers indicative of greater insulin sensitivity, and this was associated with homozygosity for the FOXO3A GG genotype.

Li et al. (2009) tested the genetic contribution of FOXO1A (136533) and FOXO3A to longevity in the Han Chinese population. Six tagging SNPs from FOXO1A and FOXO3A were genotyped in 1,817 centenarians and younger individuals. Two SNPs of FOXO1A (at 13q14) were associated with longevity in women (P = 0.01-0.005), whereas all 3 SNPs of FOXO3A were associated with longevity in both genders (P = 0.005-0.001). In haplotype association tests, the OR (95% CI) for haplotypes TTG and CCG of FOXO1A in association with female longevity were 0.72 and 1.38 (P = 0.0033 and 0.0063, respectively). The haplotypes of FOXO3A were associated with longevity in men [GTC: OR (95% CI) = 0.67 (P = 0.0014); CGT: OR (95% CI) = 1.48 (P = 0.0035)] and in women [GTC: OR (95% CI) = 0.75 (P = 0.0094); CGT: OR (95% CI) = 1.47 (P = 0.0009)]. The association of FOXO1A with female longevity was replicated in 350 centenarians and 350 younger individuals from a different geographic location. The authors concluded that, unlike FOXO3A, FOXO1A is more closely associated with human female longevity, suggesting that the genetic contribution to longevity trait may be affected by gender.