MtDNA variant modifiers of cardiopulmonary responsiveness to physical activity

随着美国老年人预期寿命的持续延长，心血管疾病的患病率将上升， 年龄>75岁的人是美国人口中增长最快的部分。差的物理 健身是主要由久坐不动的生活方式引起的心肺功能差的主要原因。 增加身体活动仍然是改善心血管健康的优先事项，特别是在老年人中， 最容易患上慢性病的人群虽然人们普遍认为体力活动 无论年龄、性别、种族/民族或健康状况如何， 差别很大。大约40%的人没有达到临床意义的好处，尽管优秀的 坚持。另一方面，30%的依从性差的人的反应比预期的要好。基于 我们先前的观察表明，常见和罕见的非同义线粒体DNA（mtDNA）变异体， 与体力活动能量消耗和心肺结果相关，我们假设这些 变体可能识别对慢性体力活动的心肺反应性。这些数据形成 我们的中心假设是mtDNA序列变异解释了一部分的异质性， 对慢性体力活动的心肺反应性。我们有一个独特的机会来测试我们的中央 通过对储存的样本中的全部16.5kb mtDNA进行测序， 生活方式干预和老年人独立性研究（LIFE研究）的参与者。LIFE研究 是一项明确的III期多中心单盲随机对照试验， 活动计划与成功的老龄化健康教育计划。研究的平均随访时间 约为2.7岁，参与者为1，592名70-89岁的社区居住久坐者 储存的遗传物质。已完成的LIFE试点研究-一个由396名参与者组成的队列， 同样的干预12个月-将被用来复制显着的关联。我们的假设 常见和罕见mtDNA变异体对以下心肺指标反应性的影响 作为试验的一部分收集的数据：1）步行速度，2）血压，3）肺活量。 我们将在模型中整合临床、行为和遗传数据，以预测 心肺对体力活动的反应通过识别遗传修饰剂，这项研究将提供 建立个性化医疗框架的起点，以更好地改善心血管健康， 体力活动。识别这些遗传因素也可能为分子途径提供新的见解 调节心血管对慢性体力活动的适应。这种方法可以有很大的 在推动该领域朝着NIH的目标，即为快速老龄化的人提供个性化的行为干预方面， 美国参考

The prevalence of cardiovascular disease will rise as life expectancy of older Americans continues to increase, with persons aged >75 years representing the fastest growing segment of the US population. Poor physical fitness is a major contributor to poor cardiopulmonary function that is primarily caused by a sedentary lifestyle. Increasing physical activity remains a priority for improving cardiovascular health, especially in older adults, who are at the greatest risk of chronic health conditions. While it is generally recognized that physical activity benefits adults regardless of age, sex, race/ethnicity, or health status, the cardiopulmonary responsiveness varies greatly. Approximately 40% of people do not achieve a clinically meaningful benefit despite excellent adherence. On the other hand, 30% of people with poor adherence respond better than expected. Based on our previous observation that both common and rare nonsynonymous mitochondrial DNA (mtDNA) variants are associated with physical activity energy expenditure and cardiopulmonary outcomes, we postulated that these variants are likely to identify cardiopulmonary responsiveness to chronic physical activity. These data formed our central hypothesis that mtDNA sequence variation explains a portion of the heterogeneity in cardiopulmonary responsiveness to chronic physical activity. We have a unique opportunity to test our central hypothesis efficiently and cost-effectively by sequencing the entire 16.5kb of mtDNA in stored samples of participants in the Lifestyle Interventions and Independence for Elders Study (The LIFE study). The LIFE study is a definitive Phase 3 multicenter single-masked Randomized Controlled Trial that evaluates a physical activity program vs. a successful aging health education program. The average follow-up duration of the study is approximately 2.7 yrs, and the participants are 1,592 community-dwelling sedentary persons aged 70-89 yrs with stored genetic material. The completed LIFE Pilot study-a cohort of 396 participants randomized to the same interventions for 12 months-will be used to replicate significant associations. Our hypotheses address the effect of common and rare mtDNA variants on responsiveness to the following cardiopulmonary measures that are being collected as part of the trial: 1) walking speed, 2) blood pressure, and 3) pulmonary capacity. We will integrate clinical, behavioral, and genetic data in models to predict the heterogeneity in cardiopulmonary responsiveness to physical activity. By identifying genetic modifiers, this research will provide a starting point to build a personalized medicine framework to better improve cardiovascular health with physical activity. Identifying these genetic factors may also provide novel insights into the molecular pathways that regulate the cardiovascular adaptation to chronic physical activity. This approach could have a large impact in moving the field toward the NIH's goals of personalizing behavioral interventions for a rapidly aging America.