Telomere Length as a Marker of Cardiovascular Aging

描述(申请人提供)：功能性衰老(研究目标18)。 这项拟议的研究将检验端粒长度作为人类心血管衰老的标志。端粒是位于染色体末端的非编码功能重复序列[5‘(TTAGGG)n-3’]，在每次细胞分裂时都会丢失可预测的数量。这样一来，端粒DNA的长度就是一个追踪组织中细胞复制历史的“有丝分裂时钟”。当端粒达到非常短的长度时，细胞就会衰老，基因表达和功能的级联变化就会启动。因此，端粒DNA的丢失也可能影响组织功能的下降。最近的研究表明，血液端粒长度是心血管死亡的有力预测因素，但端粒长度实际上在多大程度上跟踪心血管死亡的功能先兆尚不清楚。由于端粒长度是高度可遗传的，它也可能是遗传流行病学研究中心血管老化的一个强大的遗传标记。然而，在将端粒长度有效地用于流行病学之前，需要对端粒在正常生长和衰老过程中的生物学有更深入的了解。为了响应NIA的“先导研究资助计划”(R03 PAR-03-056)，一项可行性研究被提出，该研究将检验一种新的生物衰老标记物--血液DNA的端粒长度，作为心血管衰老的替代指标。利用现有的来自定义明确的纵向队列的预期心血管疾病(CVD)风险因素数据的数据库，并与每个人存储的DNA样本相匹配，我们的目标是确定端粒长度如何与CVD风险因素的变化相对应。拟议研究的具体目标是：1) 使用定量PCR估计350名8-82岁FELS纵向研究参与者的端粒长度，2)检查性别、年龄、青春期和更年期对端粒长度的影响，3)检验端粒较短的人在血压和脉压、血脂和脂蛋白浓度、炎症标志物和有氧健身方面有更多有害变化的假设，以及4)探索主要生活方式因素(烟酒消费、体育活动和外源性激素使用)对端粒长度的影响。在这项为期两年的研究结束时，我们将首次估计端粒长度与儿童和成人心血管健康的系列变化之间的关系，无论男女。因此，端粒DNA长度可能被发现是一个有价值的血浆生物标志物，用于预测和监测心血管健康和衰老。

DESCRIPTION (provided by applicant): 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.