Association of FOXO3A Variation with Human Longevity Confirmed in German Centenarians

Friederike Flachsbart, Amke Caliebeb, Rabea Kleindorp, Helene Blanche, Hubert von Susanna Nikolaus, Stefan Schreiber, and Almut Nebel conducted a study to investigate the association between FOXO3A variation and human longevity. The study was conducted at the Institute of Clinical Molecular Biology, Institute of Medical Informatics and Statistics, and Popgen Biobank at Christian-Albrechts-University in Kiel, Germany, and Fondation Jean Dausset, Centre d'Etude du Polymorphisme Humain in Paris, France. The study aimed to replicate a previous finding that identified three single-nucleotide polymorphisms (SNPs) in the FOXO3A gene that were associated with longevity in a sample of long-lived men of Japanese ancestry.

The researchers investigated 16 known SNPs in FOXO3A and found evidence that polymorphisms in this gene are associated with the ability to attain exceptional old age. Their findings confirmed the initial discovery in the Japanese sample and support FOXO3A as a susceptibility gene for prolonged survival in humans.

FOXO3A is a gene that encodes a key regulator of the insulinIGF1 signaling pathway known to influence metabolism and lifespan in model organisms. The DAF-16 protein is a transcription factor and an evolutionarily conserved key regulator of this pathway that influences metabolism and lifespan in model organisms. These aspects also render FOXO3A a very likely candidate for genetic longevity studies in humans.

The study analyzed 16 polymorphisms in FOXO3A for association with human longevity phenotype. All SNPs were in Hardy-Weinberg equilibrium (HWE) in the control population. For the association analyses, they compared German long-lived individuals (subset A; n 1,031; aged 95-110 years) and a centenarian subset (subset B; n 388) to appropriately matched younger controls (n 731; aged 60-75 years). All markers were subjected to allelic case-control comparisons (CCA) using the entire LLI sample (subset A) and the centenarian subset (subset B). For subset A, single-marker analysis revealed four SNPs with nominally significant P values CCA. For the centenarians (subset B), 11 SNPs showed significant association.

The study found that the FOXO3A association was considerably stronger in centenarians than in nonagenarians, highlighting the importance of centenarians for genetic longevity research. The researchers extended the initial finding observed in Japanese men to women and indicated that both genders were likely to be equally affected by variation in FOXO3A. Replication in a French centenarian sample generated a trend that supported the previous results.

In conclusion, this study provides evidence that FOXO3A variation is associated with human longevity and supports FOXO3A as a susceptibility gene for prolonged survival in humans.and rs479744). The lack of association in the Dutch study may be due to the smaller sample size and the different age range of the participants. In summary, our study did not find evidence for an association between FOXO3A variation and longevity in Germans and French centenarians. However, our results do not exclude the possibility that FOXO3A may influence longevity in other populations or that other genes in the FOXO pathway may play a role. Further studies are needed to fully understand the genetic basis of human longevity.rs12200646 and rs13220810) were tested, and three of them showed significant association in German centenarians, unlike the Leiden results (Table 2). Additionally, rs2153960, one of the SNPs tested in the Dutch sample, showed strong LD with rs13217795, which was highly associated in Japanese men from Hawaii (P At AL> 0.0006; r2 0.88 between rs13217795 and rs2153960 according to CEU HapMap data; Table 3). The two Dutch cohorts' data were previously analyzed using a longitudinal design that included information on mortality and age-related phenotypes (15). Kuningas et al. (15) found that carriers of a specific 4-SNP haplotype (GAGC from rs2802288, rs2883881, rs12200646, and rs13220810) had an increased risk of all-cause and cardiovascular mortalities. However, the effects were small, and the findings did not hold up to multiple testing (15). These four SNPs were also subjected to haplotype analysis in our sample collection. Although risk alleles or haplotypes for age-related diseases are expected to decrease in frequency in population strata of increasing age (16), the mortality haplotype identified in the Dutch was not significantly depleted in German centenarians compared with younger controls (0.212 in centenarians versus 0.238 in controls; P 0.17). 

The study by Willcox et al. did not find any association with FOXO3A in their cross-sectional comparisons. Our results highlight the relevance of centenarians for genetic longevity research because they are more valuable for such studies than octogenarians and nonagenarians. This finding may be attributed to the fact that centenarians represent the top percentiles of their respective birth cohort-specific age distributions and have outlived most of their peers by several decades. Only 4% of male and 5.6% of female 90-year-olds and 15-17% of 95-year-olds in Germany are likely to become 100 years themselves (Human Mortality Database, www.mortality.org), indicating that centenarians represent a highly selected phenotype even among LLI. Because the genetic contribution to survival is strongest at very advanced ages (4), centenarians may be particularly enriched for beneficial variants in longevity assurance genes (16). Hence, it would seem that centenarians are the more suitable but rarer phenotype for genetic longevity studies.