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

描述（由申请人提供）：慢性应激个体的心血管疾病和死亡风险增加，因此，必须发现行为和生物学机制，通过这些机制可以减轻这些影响。人类和小鼠研究支持端粒/端粒酶维持系统在心血管疾病和死亡率中发挥的关键作用。端粒是染色体末端的保护帽，端粒酶是延长端粒的酶。慢性应激与端粒酶水平降低和端粒缩短有关，因此端粒维持可能在介导慢性应激-心血管疾病联系中起关键作用。另一方面，一直与改善心血管健康有关的运动预测了更长的端粒和增加的端粒酶水平。运动和慢性压力之间的相互作用很少被研究，因此运动对慢性压力个体的心血管益处知之甚少。目前的K99/R 00独立之路奖旨在建立在以前的跨部门工作的基础上，这些工作证明了运动在缓冲慢性压力-端粒长度相关性方面的潜力，最终目标是加深对心血管健康的理解和促进。首先，该奖项将提供机会，加强我对运动生理学的理解，测量和干预的使用，并与心血管疾病，运动干预和细胞衰老方面的领先专家完成成功的学徒。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，国家卫生研究院，疾病预防控制中心和约翰霍普金斯提供的简短课程。其次，使用来自年轻人冠状动脉风险发展（CARDIA）研究的数据，我将研究运动与中年人心血管功能的前瞻性关系，以及端粒长度可能的中介作用。我还将测试在20年的时间内保持较高水平的体力活动和生活压力积累与CVD风险的纵向关联，以及端粒长度在这些关联中可能发挥的中介作用。最后，我将对照顾者进行为期三个月的随机对照有氧训练干预，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，减少心理困扰。拟议的训练计划和一系列研究将加深我们对运动赋予心血管益处的生物学机制的理解，主要关注端粒长度和端粒酶活性水平作为介质。这些发现可以提供对心血管健康途径的新理解，这可能会导致创新的方法来鼓励有压力的个体进行更多的活动，这是一个难以实现的公共卫生目标。 公共卫生相关性：慢性压力是心血管疾病和早期死亡的重要预测因子，而发生这种情况的可能生物学机制是加速免疫细胞老化。目前的一系列自然和干预研究试图澄清压力和免疫细胞衰老在人类心血管疾病中的作用，重要的是测试运动在这些关系中可能发挥的缓解作用。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Chronic stress is an important predictor of cardiovascular disease and early mortality, and a possible biological mechanism through which this occurs is accelerated immune cell aging. The current series of naturalistic and intervention studies seek to clarify the role that stress and immune cell aging plays in cardiovascular disease in humans, and importantly to test the mitigating role that exercise may have in these relationships.