Telomere Length as a Marker of Cardiovascular Aging

端粒长度作为心血管衰老的标志

• 批准号: 6942239
• 负责人: ELLEN W. DEMERATH
• 金额: $ 7.18万
• 依托单位: WRIGHT STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6942239
• 关键词: adolescence (12-20); adult human (21+); age difference; alcoholic beverage consumption; biomarker; blood pressure; body composition; cardiovascular disorder diagnosis; cardiovascular disorder risk; cell adhesion molecules; cholesterol; clinical research; diagnosis design /evaluation; gender difference; hormone therapy; human puberty; human subject; longitudinal human study; menopause; physical fitness; polymerase chain reaction; smoking; telomere

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.

描述（由申请人提供）：功能性衰老（研究目标#18）。 拟议的研究将检查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']，每次细胞分裂时都会丢失可预测的数量。这样，端粒 DNA 的长度就是追踪组织中细胞复制历史的“有丝分裂时钟”。当端粒达到极短的长度时，细胞就会衰老，并引发基因表达和功能的一系列变化。因此，端粒 DNA 的丢失也可能导致组织功能下降。最近的研究表明，血液端粒长度是心血管死亡率的有力预测因子，但端粒长度实际上在多大程度上跟踪心血管死亡的功能性前因尚不清楚。由于端粒长度具有高度遗传性，因此它也可能是遗传流行病学研究中心血管衰老的强大遗传标记。然而，在端粒长度可以有效地用于流行病学背景之前，需要对正常生长和衰老过程中的端粒生物学有更彻底的了解。为了响应 NIA 的“试点研究资助计划”（R03 PAR-03-056），提出了一项可行性研究，该研究将检查一种新的生物衰老标志物——血液 DNA 中的端粒长度，作为心血管衰老的替代指标。利用来自明确纵向队列的现有前瞻性心血管疾病 (CVD) 危险因素数据数据库，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 危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) 检验性别、年龄、青春期和更年期对端粒长度的影响，3) 检验端粒较短的个体危害更大的假设血压和脉压、血脂和脂蛋白浓度、炎症标志物和有氧健身的变化，以及 4) 探讨主要生活方式因素的影响（吸烟和饮酒、体力活动和外源激素的使用）对端粒长度有影响。在这项为期两年的研究结束时，我们将对端粒长度与儿童和成人心血管健康连续变化之间的关系进行首次估计。因此，端粒 DNA 长度可能是预测和监测心血管健康和衰老的有价值的血浆生物标志物。