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.
The Genetics of Telomere Dynamics in Okinawans proposal will investigate how genes affect the ability of cells within the human body to continue dividing as they age and contribute to human healthspan. This study focuses on understanding human telomeres, which are located at the ends of the chromosomes of our bodies'cells and tell the cells when to stop dividing. When cells stop dividing they die and this can affect the health of al tissues of the body. This, in turn, may affect the rate of aging and the risk for development of age-related diseases, such as heart disease and dementia. Research on factors that lead to healthy aging help us to better understand how people age and remain relatively free of major chronic diseases. This will help us develop therapies that result in less age-related disease and disability and increase our quality of life at older ages.