The genetic mechanisms that regulate human aging and longevity are poorly understood. Until recently, only variation within the APOE gene had been firmly associated with human lifespan and healthspan. We found that variation within the FOXO3 gene is also strongly associated with lifespan and healthspan in Okinawan-American and Japanese-American populations in Hawaii. Since that discovery, the FOXO3:human longevity relationship has become among the most highly replicated and robust findings in the genetics of human aging. However, the specific cellular and molecular mechanisms are presently unknown. Preliminary data suggest that telomere biology (e.g. telomerase expression, telomere shortening) is one potential mechanism through which these genes might act. The gradual shortening of telomeres with replicative age of cells is now well established as the primary molecular mechanism limiting the long term proliferative capacity of mammalian cells, including humans, so this is a plausible mechanism to test. Our preliminary work suggests that Okinawans may be enriched with protective genetic polymorphisms in both the FOXO3 and APOE genes. Therefore, we hypothesize that telomere biology may be, in part, under genetic influence of the FOXO3 and APOE genes. Since the Okinawan population has little population stratification and has also had a relatively homogeneous environment, they may be an informative population for testing our hypotheses regarding genetic influence over telomere biology. Thus, the SPECIFIC AIMS of the present study are as follows: 1. ESTABLISH a collection of biological samples from the Okinawan population that will be useful for telomere-related studies; 2. TEST (the hypothesis) that APOE and FOXO3 genotype are associated with telomerase activity; 3. TEST (the hypothesis) that APOE and FOXO3 genotype are associated with telomere length; 4. CONDUCT a validity study to relate saliva telomerase activity and telomere length with values from blood samples. Discovery of the mechanisms of healthy aging and the biologic pathways that affect vulnerability to disease and disability could have a dramatic impact on our ability to achieve healthy old age by identifying biological targets for new therapies.

R21AG042908

2013-09-01

2016-05-31