Effects of exercise and life stress on telomere maintenance and CVD risk

摘要 长期应激的个体患心血管疾病和死亡的风险增加，因此， 迫切需要发现行为和生物机制，通过这些机制可以减轻这些影响。 人类和小鼠的研究支持端粒/端粒酶维持系统在 心血管疾病和死亡率。端粒是染色体末端的保护帽， 端粒酶是一种延长端粒的酶。慢性应激与端粒酶水平降低有关 和较短的端粒，因此端粒的维持可能在调节慢性应激中发挥关键作用- 心血管疾病链接。另一方面，锻炼，这一直与改善 心血管健康，预测端粒更长，端粒酶水平升高。它们之间的相互作用 运动和慢性应激很少被研究，因此运动对慢性心血管的益处 人们对压力过大的人知之甚少。目前的K99/R00独立之路奖旨在 在之前的横断面研究的基础上，证明了锻炼可以缓冲慢性压力的潜力- 端粒长度关联，最终目的是加深对端粒长度的理解和促进 心血管健康。首先，这个奖项将提供一个机会来加强我对运动的理解 生理、测量和在干预中的使用，并在领导下完成成功的学徒生涯 心血管疾病、运动干预和细胞老化方面的专家。拟议的培训将包括 通过加州大学旧金山分校、加州大学伯克利分校、美国国立卫生研究院、疾控中心和约翰·霍普金斯大学提供的简短课程。第二，使用来自 青年冠状动脉风险发展(CARDIA)研究，我将检查前瞻性 运动与中年人心血管功能的关系及其可能的中介作用 端粒长度。我还将测试保持较高水平体力活动的纵向关联 和20年来有心血管疾病风险的生活压力的累积，以及端粒长度的中介作用 可能会在这些协会中发挥作用。最后，我将进行为期三个月的随机对照有氧训练 对照顾者的干预与年龄匹配的等待名单对照组进行比较，目的是增加 白细胞端粒酶活性，提高运动能力和血压，降低心理 苦恼。建议的培训计划和一系列研究将加深我们对生物 运动给心血管带来益处的机制，主要关注端粒长度 和端粒酶活性水平作为中介。这些发现可以提供对以下途径的新理解 心血管健康，这可能会导致创新的方法，鼓励有压力的个人进行更多的活动，a 一直难以实现的公共卫生目标。

ABSTRACT Chronically stressed individuals are at increasing risk for cardiovascular disease and mortality, and as such, it is imperative to discover behavioral and biological mechanisms through which these effects could be mitigated. Human and mouse studies support the critical role that the telomere/telomerase maintenance system plays in cardiovascular disease and mortality. Telomeres are the protective caps at the ends of chromosomes and telomerase is the enzyme that lengthens telomeres. Chronic stress is related to decreased telomerase levels and shorter telomeres, and thus telomere maintenance may play a critical role in mediating the chronic stress- cardiovascular disease link. On the other hand, exercise, which is consistently linked to improved cardiovascular health, predicts longer telomeres and increased telomerase levels. The interplay among exercise and chronic stress is rarely examined and thus the cardiovascular benefits of exercise to chronically stressed individuals are poorly understood. The current K99/R00 Pathway to Independence Award seeks to build on previous cross-sectional work that demonstrates the potential for exercise to buffer the chronic stress- telomere length association, with the ultimate goal of deepening the understanding and promotion of cardiovascular health. First, the award will provide the opportunity to strengthen my understanding of exercise physiology, measurement and use in interventions, and to complete successful apprenticeships with leading experts in cardiovascular disease, exercise interventions, and cell aging. The proposed training will include brief courses offered through UCSF, UC Berkeley, NIH, CDC, and Johns Hopkins. Second, using data from the Coronary Artery Risk Development in Young Adults (CARDIA) study, I will examine the prospective relationships of exercise with cardiovascular functioning in middle-aged adults, and the possible mediating role of telomere length. I will also test the longitudinal associations of maintaining higher levels of physical activity and accumulation of life stress over a 20-year period with CVD risk, and the mediating role telomere length may play in these associations. Finally, I will conduct a three-month randomized controlled aerobic training intervention in caregivers compared to an age-matched wait list control group with the aims of increasing leukocyte telomerase activity, improving exercise capacity and blood pressure, and decreasing psychological distress. The proposed training plan and series of studies will deepen our understanding of the biological mechanisms through which exercise confers cardiovascular benefits, with a primary focus on telomere length and telomerase activity levels as mediators. These findings can provide new understanding of pathways to cardiovascular health that may lead to innovative ways to encourage greater activity in stressed individuals, a public health goal that has been difficult to attain.