The Role of Telomeres in Human Longevity and Aging
Telomeres play a critical role in cell senescence but their role in human longevity and aging is uncertain. Autosomal dominant Dyskeratosis congenita (DKC) is genetically linked to the chromosomal region harboring the gene for the RNA component of telomerase (the hTER gene), and affection status in these families segregates with mutations in the coding region of hTER that alter the sequence of that RNA. DKC patients have shortened telomeres and a variety of disorders including bone marrow failure, pulmonary fibrosis, malignancies, premature graying and loss of hair, poor wound healing, predisposition to infections, and osteoporosis. We have recently shown that the hTER mutations found in autosomal dominant DKC impair telomerase activity. Recently, the Genomics Core discovered that there are additional single nucleotide polymorphisms (SNPs) in the coding region of hTER gene in the general population whose possible health consequences have yet to be investigated. We have also recently shown that, in apparently normal elderly people, those with shorter telomeres have an increased risk of overall mortality and death from coronary heart disease (CHD) and infectious causes.
In a collaboration that arose from the Longevity Consortium, we propose to test the roles of telomere length and variants in the hTER gene in data and DNA from the Health, Aging and Body Composition (HABC) study, a community-based longitudinal study of 3,075 elderly men and women. We will test the hypothesis that elders with shorter telomere length have higher mortality rates. In this well-characterized cohort, we will also describe phenotypes of health and aging associated with shortened telomeres. We will also test the hypothesis that the presence of SNPs in the coding region of hTER are associated with shorter telomeres and an increased overall mortality. We can use the Consortium's Scientific Opportunity Funds to be rapidly confirm our findings using specimens and data from other cohorts participating in the Longevity Consortium. Testing these hypotheses in the banks of DNA and data from the prospective HABC study is a very efficient way to assess the role of telomeres and telomerase in human longevity and aging.