Functional Senescence (Research Objective #18). The proposed research study will examine telomere length as a marker of cardiovascular aging in humans. Telomeres are non-coding functional repeat sequences at the ends of chromosomes [5' (TTAGGG)n -3'], a predictable amount of which is lost at each cell division. In this way, the length of telomeric DNA is a """"""""mitotic clock"""""""" tracking the history of cell replication in a tissue. When telomeres reach a critically short length, cells become senescent, and a cascade of changes in gene expression and function are initiated. Thus, the loss of telomeric DNA may also effect declines in tissue function. Recent work suggests blood telomere length is a strong predictor of cardiovascular mortality, but the extent to which telomere length actually tracks the functional antecedants of cardiovascular death is unknown. Because telomere length is highly heritable, it may also be a powerful genetic marker of cardiovascular aging for genetic epidemiologic studies. A more thorough understanding of telomere biology during normal growth and aging is required, however, before telomere length may be effectively used in the epidemiologic context. In response to the NIA's """"""""Pilot Research Grant Program"""""""" (R03 PAR-03-056), a feasibility study is proposed that will examine a new marker of biological aging, telomere length from blood DNA, as a proxy measure for cardiovascular senescence. Using an existing database of prospective cardiovascular disease (CVD) risk factor data from a well-defined longitudinal cohort, matched with stored DNA samples for each individual, we aim to determine how telomere length corresponds to changes in CVD risk factors.
The specific aims of the proposed study are: 1) To estimate telomere length in 350 Fels Longitudinal Study participants aged 8-82 years using quantitative PCR, 2) To examine the effects of sex, age, puberty and menopause on telomere length, 3) To test the hypothesis that individuals with shorter telomeres have more deleterious changes in blood pressure and pulse pressure, blood lipid and lipoprotein concentrations, inflammatory markers, and aerobic fitness, and 4) To explore the impact that major lifestyle factors (tobacco and alcohol consumption, physical activity, and exogenous hormone use) have on telomere length. At the conclusion of this two-year study, we will have the first estimates of the relationship between telomere length and serial changes in cardiovascular health in children and adults of both sexes. Telomeric DNA length may thus be found to be a valuable plasma biomarker for the prediction and monitoring of cardiovascular health and aging.
| Lee, Miryoung; Martin, Hilarie; Firpo, Matthew A et al. (2011) Inverse association between adiposity and telomere length: The Fels Longitudinal Study. Am J Hum Biol 23:100-6 |
