Telomere Attrition and Cardiovascular Disease

端粒是染色体末端的特殊结构，参与了体外培养体细胞的复制衰老。端粒长度被认为是生物衰老的一个可能的生物标志物，并且与年龄相关的疾病有关，包括原发性高血压、糖尿病和动脉粥样硬化。这些疾病可能反映了氧化应激和炎症状态的升高，这是预计会增加白细胞端粒侵蚀的因素。初步数据表明，血管疾病与老年人端粒缩短有关。来自心血管健康研究（CHS）的数据将被评估：(1)白细胞端粒长度与心血管疾病（CVD）发病率之间的关系，包括心肌梗死、中风和周围血管疾病；CHS是一项65岁以上成年人的纵向队列研究，最初于1989/ 1990年招募，随访10次年度临床检查；(2)与端粒缩短相关的总死亡率和死因特异性死亡率风险；(3)端粒磨损率随时间的变化与血管疾病状态的关系。总共1500名CHS参与者将被随机选择用于这些分析，DMA可用性是唯一的排除标准。使用测定端粒限制性片段（TRFs）的Southern方法，将从1992/93年收集的血液样本中测量基线WBC TRF长度。端粒磨损率将使用TRF测定1200个随访样本收集5年或更长时间后存活的参与者。将进行生存分析，以调查端粒动力学（即端粒长度和磨损率）与血管疾病、心血管疾病的亚临床测量、死亡率和死亡原因之间的关系。线性混合模型将评估端粒侵蚀随时间的疾病状态。本研究结果将增强对端粒动力学与心血管疾病发病率和死亡率之间关系的理解，为人类衰老生物学提供新的见解。

Telomeres, specialized structures at chromosomal ends, are involved in replicative senescence of cultured somatic cells. Telomere length has been implicated as a possible biomarker of biological aging and is associated with age-related diseases, including essential hypertension, diabetes and atherosclerosis. These disorders may reflect heightened states of oxidative stress and inflammation, which are factors expected to increase telomere erosion in white blood cells (WBCs). Preliminary data have demonstrated measures of vascular disease to be associated with shortened telomeres in older adults. Data from the Cardiovascular Health Study (CHS), a longitudinal cohort of adults over age 65 initially recruited in 1989/90 and followed for up to ten annual clinic exams, will be evaluated for (1) associations between WBC telomere length and incidence of cardiovascular disease (CVD) including myocardial infarction, stroke and peripheral vascular disease; (2) risk of total and cause-specific mortality associated with shortened telomeres; and (3) rates of telomere attrition over time in relation to vascular disease status. A total of 1500 CHS participants will be randomly selected for these analyses with DMA availability as the only exclusion criterion. Using the Southern method for determination of telomere restriction fragments (TRFs), baseline WBC TRF length will be measured from blood samples collected in 1992/93. Rate of telomere attrition will be estimated using TRF determination of 1200 follow-up samples collected five or more years later in participants surviving this long. Survival analyses will be done to investigate associations between telomere dynamics (i.e. telomere length and attrition rate) and incident vascular disease, subclinical measures of CVD, mortality, and cause of death. Linear mixed models will evaluate telomere erosion over time by disease status. Results of this study will enhance the understanding of the relationships between telomere dynamics and cardiovascular morbidity and mortality providing new insights into the biology of human aging.