FOXO3A polymorphisms linked to human longevity – again!

In my first contribution to Ouroboros, I reviewed a paper in which the authors found an allele of FOXO3A associated with long lived Japanese men. So it seemed highly appropriate that I wrote the review for a follow-up paper: Flachsbart et al. analyzed 16 polymorphisms in the FOXO3A allele in 1,031 long-lived individuals (95-110 years old, 388 centenarians included) and 731 younger controls. They found that polymorphisms in the FOXO3A gene were significantly associated with German centenarians and human longevity.

Association of FOXO3A variation with human longevity confirmed in German centenarians
Here, we have investigated 16 known FOXO3A SNPs in an extensive collection of 1,762 German centenarians/nonagenarians and younger controls and provide evidence that polymorphisms in this gene were indeed associated with the ability to attain exceptional old age. The FOXO3A association was considerably stronger in centenarians than in nonagenarians, highlighting the importance of centenarians for genetic longevity research. Our study extended the initial finding observed in Japanese men to women and indicates 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. Our findings confirmed the initial discovery in the Japanese sample and indicate FOXO3A as a susceptibility gene for prolonged survival in humans.

The next exciting advances in our knowledge of the molecular function of the FOXO3A protein will address how these polymorphisms affect protein function to impart this long-lived phenotype. FOXO3A (a human homo of the worm gene daf-16, whose function is necessary for lifespan extension conferred by daf-2/IGF-I pathway mutations) has been shown to play a role in insulin sensitivity, coronary heart disease, and diabetes which implicates FOXO3A as a “master regulator” that can regulate a wide variety of downstream targets which can have large effects on extending lifespan.

(Editor’s note: Liz will be taking a hiatus from blogging while she finishes her thesis. Let’s all wish her luck!)

ResearchBlogging.orgFlachsbart, F., Caliebe, A., Kleindorp, R., Blanche, H., von Eller-Eberstein, H., Nikolaus, S., Schreiber, S., & Nebel, A. (2009). Association of FOXO3A variation with human longevity confirmed in German centenarians Proceedings of the National Academy of Sciences, 106 (8), 2700-2705 DOI: 10.1073/pnas.0809594106