MtDNA variant modifiers of cardiopulmonary responsiveness to physical activity

体力活动心肺反应性的线粒体 DNA 变异修饰剂

• 批准号: 8614159
• 负责人: Carlos A. Vaz Fragoso
• 金额: $ 54.14万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-15 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8614159
• 关键词: Address; Adherence; Adult; Aerobic; Aerobic Exercise; Age; Aging; American; Americas; Ancillary Study; Attention; Behavior; Behavior Therapy; Behavioral Genetics; Blood Pressure; Body Weight; Cardiopulmonary; Cardiovascular Diseases; Cardiovascular system; Chronic; Clinical; Code; Communities; Complex; Control Groups; DNA Fingerprinting; DNA Sequence; Data; Databases; Dementia; Development; Diastolic blood pressure; Elderly; Electron Transport; Energy Metabolism; Enzymes; Ethnic Origin; Event; Exercise; Family Study; Fatigue; Foundations; Genes; Genetic; Genetic Materials; Genetic Variation; Genomics; Goals; Health; Health Status; Health education; Heterogeneity; Individual; Inherited; International; Intervention; Knowledge; Lead; Life Expectancy; Life Style; Lipids; Lung; Lung Capacity; Masks; Measures; Medicine; Mental Depression; Mitochondrial DNA; Modeling; Molecular; Movement; Nuclear; Observational Study; Outcome; Participant; Pathway interactions; Pattern; Persons; Pharmacotherapy; Phase; Physical Fitness; Physical activity; Pilot Projects; Play; Population; Prevalence; Procedures; Public Health; Publications; Quality of life; Race; Randomized; Randomized Controlled Trials; Recommendation; Research; Respiratory physiology; Risk; Role; Sampling; Sleep; Speed; Spirometry; Systolic Pressure; Testing; Time; Variant; Walking; Work; age related; aged; authority; base; blood glucose regulation; cohort; comparative efficacy; cost; design; disability; fitness; follow-up; gene discovery; genetic variant; high risk; improved; improved mobility; innovation; insight; lifestyle intervention; meter; muscle strength; new therapeutic target; novel; programs; public health relevance; response; sedentary; sex; trial comparing

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.

随着老年人的预期寿命不断增加，心血管疾病的患病率将上升， 年龄> 75岁的人代表了美国人口中增长最快的人群。身体不好 健身是主要是由久坐的生活方式引起的较差心肺功能的主要因素。 增加体育锻炼仍然是改善心血管健康的优先事项，尤其是在老年人中， 他们处于慢性健康状况的最大风险。虽然通常认识到体育锻炼 不论年龄，性别，种族/种族或健康状况如何，成年人的福利，心肺反应能力 变化很大。尽管出色，大约有40％的人没有获得临床意义 坚持。另一方面，依从性差的人中有30％的反应比预期的要好。基于 我们以前的观察结果，即常见和罕见的非同义线粒体DNA（mtDNA）变体是 与体育活动的能量消耗和心肺结局相关，我们假设这些 变体可能会鉴定出对慢性体育活动的心肺反应能力。这些数据形成 我们关于mtDNA序列变化的中心假设解释了一部分异质性 对慢性体育活动的心肺反应能力。我们有一个独特的机会来测试我们的中央 通过在存储的样品中对整个16.5kb的mtDNA进行测序，有效地有效地假设 生活方式干预措施的参与者和长老研究的独立性（生活研究）。生活研究 是一个确定的阶段3多中心单罩的随机对照试验，可以评估物理 活动计划与成功衰老的健康教育计划。研究的平均随访时间 大约2.7岁，参与者是1,592个久坐的久坐的人，年龄在70 - 89年 与存储的遗传物质。完整的生活试验研究 - A的396名参与者的队列随机分配给 相同的12个月干预措施将被用来复制重要的关联。我们的假设解决了 常见和稀有mtDNA变体对以下心肺措施的反应性的影响 作为试验的一部分收集的：1）步行速度，2）血压和3）肺部能力。 我们将在模型中整合临床，行为和遗传数据，以预测异质性 心肺对体育活动的反应。通过识别遗传修饰符，这项研究将提供 建立个性化医学框架以更好地改善心血管健康的起点 体育锻炼。识别这些遗传因素也可能为分子途径提供新的见解 调节心血管适应慢性体育锻炼。这种方法可能很大 将领域朝着NIH的行为干预措施迅速老化的个性化目标的影响 美国。