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ASSOCIATION OF THE PROTECTIVE FOXO3 LONGEVITY VARIANT WITH TELOMERE DYNAMICS DURING AGING

ABSTRACT: Abstract Telomere attrition in proliferative tissues is a hallmark feature of human aging. To date, identification of genetic influence on the rate of telomere attrition is poorly understood. The two genes with the most robust effect on human longevity are FOXO3 and APOE. Notably, we discovered a genetic variant of the FOXO3 gene that is strongly associated with human longevity. This observation has now been reproduced in independent studies of over a dozen different populations around the world. In the present study, we sought to assess the effect of the longevity associated variant of FOXO3 (rs2802292 - G allele) as well as variants of APOE on telomerase activity and the rate of telomere attrition during aging. The preliminary results from a cohort of Okinawan Japanese (N=120) ranging in age from 25 – 90 years, indicates no substantial effect of the variants for either FOXO3 or APOE on telomerase levels in peripheral blood leukocyte (PBL) samples. Analysis of the rate of telomere attrition during aging as a function of the different variants of APOE also revealed no significant effect. In contrast, carriers of 1 or 2 copies of the rare longevity-associated G allele of FOXO3 showed markedly reduced rates of telomere loss in PBL during aging, as compared to carriers of the more common variant of FOXO3 (TT). Interestingly, no loss of telomere length was observed as a function of age for G allele carriers. These results mark the first report on genetic influence on slowing the rate of telomere attrition in humans.

SUBMITTER: Davy P

PROVIDER: S-EPMC6242152 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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THE LONGEVITY ASSOCIATED ALLELE OF FOXO3 PROTECTS AGAINST TELOMERE ATTRITION DURING AGING

Project description:Abstract Telomere attrition in proliferative tissues is a hallmark feature of human aging. To date, the genetic influence on the rate of telomere attrition is poorly understood. Previously we discovered a variant of the FOXO3 gene that is strongly associated with human longevity, an observation that has been now reproduced in over a dozen independent studies. In the present study, we sought to assess the effect of the longevity associated variant of FOXO3 (rs2802292 - G allele) on the rate of telomere attrition during aging. The results from a cohort of Okinawan-Japanese (N=121), ranging in age from 25 – 94 years, demonstrates carriers of 1 or 2 copies of the longevity-associated G allele of FOXO3 showed markedly reduced rates of telomere loss in peripheral blood leucocytes as compared to carriers of the more common FOXO3 variant (TT – common genotype, m= -33bp/year, P=0.008). Interestingly, telomere shortening was not observed as a function of age for G allele carriers (m= -2bp/year, P>0.1). In an independent study of women (N=6,565) from the Nurses’ Health Study cohort, ranging in age from 40 to 70 years, a similar observation was found. Notably, carriers of the TT or GT FOXO3 genotype showed a significant decline in telomere length with age (m= -15.5 bp/year, P0.1). These results mark the first validated longevity gene variant showing an association with negligible loss of telomere length with age in humans.

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