Telomere Attrition and Cardiovascular Disease

端粒是染色体末端的特化结构，参与培养的体细胞的复制衰老。端粒长度已被认为是生物衰老的一个可能的生物标志物，并与年龄相关的疾病，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的升高状态，这是预期增加白色血细胞（WBC）中端粒侵蚀的因素。初步数据表明，血管疾病的测量与老年人端粒缩短有关。来自心血管健康研究（CHS）的数据将被评价（1）WBC端粒长度与心血管疾病（CVD）发生率之间的关联，包括心肌梗死、中风和外周血管疾病，CHS是一个最初于1989/90年招募的65岁以上成年人的纵向队列，并随访了多达10次年度临床检查;（2）与端粒缩短相关的总死亡率和原因特异性死亡率风险;（3）与血管疾病状态相关的端粒随时间推移的磨损率。将随机选择共计1500名CHS参与者进行这些分析，DMA可用性作为唯一的排除标准。使用Southern方法测定端粒限制性片段（TRF），从1992/93年采集的血样中测量基线WBC TRF长度。端粒磨损率将使用TRF测定5年或更长时间后收集的1200个随访样本来估计，这些样本是在存活这么长时间的参与者中收集的。将进行生存分析，以研究端粒动力学（即端粒长度和损耗率）与血管疾病事件、CVD亚临床指标、死亡率和死因之间的相关性。线性混合模型将根据疾病状态评估端粒随时间的侵蚀。这项研究的结果将加强对端粒动力学和心血管疾病发病率和死亡率之间关系的理解，为人类衰老的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.