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

描述(由申请人提供)：长期应激个体患心血管疾病和死亡的风险增加，因此，迫切需要发现能够减轻这些影响的行为和生物机制。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变短有关，因此端粒维持可能在介导慢性应激与心血管疾病的联系中发挥关键作用。另一方面，运动一直被认为与改善心血管健康有关，但它预测端粒更长，端粒酶水平更高。运动和慢性压力之间的相互作用很少被研究，因此，人们对运动对慢性应激个体的心血管益处知之甚少。目前的K99/R00独立路径奖寻求建立在以前的横截面工作的基础上，这些工作证明了锻炼可以缓冲慢性应激-端粒长度关联的潜力，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，以加强我对运动生理学、测量和干预使用的理解，并成功地完成与心血管疾病、运动干预和细胞老化方面的领先专家的学徒生涯。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。其次，使用青年冠状动脉风险发展研究(CARDIA)的数据，我将研究运动与中年人心血管功能的预期关系，以及端粒长度可能起到的中介作用。我还将测试在20年期间保持较高水平的体力活动和积累的生活压力与心血管疾病风险的纵向关联，以及端粒长度在这些关联中可能发挥的中介作用。最后，我将在照顾者中进行为期三个月的随机控制有氧训练干预，并与年龄匹配的等待名单对照组进行比较，目的是提高白细胞端粒酶活性，改善运动能力和血压，减少心理困扰。拟议的培训计划和一系列研究将加深我们对运动带来心血管益处的生物学机制的理解，主要关注作为中介的端粒长度和端粒酶活性水平。这些发现可以为心血管健康的途径提供新的理解，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，这是一个很难实现的公共卫生目标。 公共卫生相关性：慢性应激是心血管疾病和早期死亡率的重要预测因子，其发生的一个可能的生物学机制是免疫细胞加速老化。目前的一系列自然主义和干预性研究试图澄清压力和免疫细胞老化在人类心血管疾病中所起的作用，重要的是测试运动在这些关系中可能起到的缓解作用。

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.