Study of Energy and Aging

描述（由申请人提供）：本提案响应了NIA的重大机遇呼吁，即“对老年人进行跨学科研究，以确定导致身体功能和能力受损的新生理因素和其他机制，应用创新的成像技术和其他非侵入性措施，以及高通量方法来表征和分析多种表型和潜在的贡献途径。“以步态速度减慢、劳力性疲劳和疲惫为特征的活动能力丧失是与年龄相关的功能衰退的标志。虽然运动能力下降与肌肉脂肪增加、肌肉质量下降和最大有氧能力下降有关，但目前使用常规磁共振成像（MRI）、计算机断层扫描（CT）、性能测试和循环生物标志物的研究尚未发现与年龄相关的减缓和运动能力丧失的明确生物生理学基础。迄今为止，对线粒体功能和三磷酸腺苷（ATP）能量产生的研究太少，无法理解能量代谢的各种成分在与年龄相关的运动障碍中的相对作用。 我们假设骨骼肌线粒体产生能量的能力下降在与年龄相关的运动能力下降中起着关键作用。为了验证这一假设，一个跨学科的团队将领导对“能量系统”的组成部分进行评估和分析，从肌肉供氧到步行的能量效率。这些评估包括用于体内肌肉ATP生成的磷光谱法、测量线粒体含量和功能的肌肉活检、运动时腿部的血流以及步行时的能量利用。我们将在300名年龄在70至89岁之间的男性和女性中进行这些测量，这些男性和女性具有良好的活动性，以及劳力性疲劳和疲惫。参与者将由匹兹堡大学、维克森林大学和阿肯色州大学的医学科学经验丰富的研究中心招募和检查，该研究将由旧金山弗朗西斯科协调中心协调。 能量与衰老研究（SEA）将对科学产生重大影响，通过重新关注对移动性残疾生理学的研究，提供数据库和样本库来测试新的范式，并建立新测量的价值，并将其开发用于本研究和未来的多中心和前瞻性研究中的高通量使用。SEA数据库和样本库可用于探索可能导致活动能力受损的其他因素以及能量学和其他衰老表型之间的关联。SEA将通过指导临床医生评估移动性残疾和疲劳的潜在可治疗原因来影响医疗保健。最终，这项工作可能会确定新的可修改的干预目标，以改善老年人的流动性和缓解疲劳。 公共卫生相关性：行动能力丧失和疲劳是衰老的常见后果，但其原因尚不清楚。为了确定ATP能量生成在这一过程中的作用，经验丰富的老年医学研究中心将收集肌肉标本中线粒体功能的测量结果和肌肉光谱中生成ATP的能力，评估全身生成ATP能量用于行走的能力，以及测量速度和行走400米的能力，包括评估劳力性疲劳和疲惫。由此产生的标本，图像和数据的资源将可用于未来的研究的决定因素受损的流动性和疲劳，可能会发现新的可修改的干预目标，以改善流动性和缓解老年人的疲劳。

DESCRIPTION (provided by applicant): This proposal responds to the NIA Grand Opportunity call for "Interdisciplinary studies on older persons to identify novel physiologic factors and other mechanisms contributing to impairments in physical function and capabilities, applying innovative imaging technologies and other noninvasive measures, and hi-throughput methods to characterize and analyze multiple phenotypes and potential contributory pathways." Loss of mobility characterized by slowing gait speed, exertional fatigue and exhaustion is a hallmark of age-related functional decline. While decreased mobility is associated with increased muscle fat, decreased muscle mass, and decreased maximal aerobic capacity, current studies using conventional magnetic resonance imaging (MRI), computed tomography (CT), performance tests, and circulating biomarkers have not found a clear biophysiologic basis for age-related slowing and loss of mobility. Studies of mitochondrial function and adenosine triphosphate (ATP) energy production have been, to date, too small to understand the relative roles of the various components of energy metabolism in age-related mobility disability. We hypothesize that decreased skeletal muscle mitochondrial capacity to generate energy plays a pivotal role in age-associated decline in mobility. To test this hypothesis, an interdisciplinary team will lead assessments and analyses of components of the 'energetics system' from muscle oxygen delivery to the energy efficiency of walking. These assessments include phosphorous spectroscopy for in-vivo muscle ATP generation, muscle biopsies with measurements of mitochondrial content and function, blood flow to the legs with exercise, and energy utilization during walking. We will make these measurements in 300 men and women aged 70 to 89 years old who are well characterized for mobility, and exertional fatigue and exhaustion. Participants will be recruited and examined by experienced research centers at the Universities of Pittsburgh, Wake Forest and Arkansas for Medical Sciences, and the study will be coordinated by the San Francisco Coordinating Center. The Study of Energy and Aging (SEA) will have a major impact on science by refocusing research on the physiology of mobility disability, providing a database and specimen bank to test the new paradigm, and establishing the value of novel measurements and developing them for hi-throughput use in this and future multicenter and prospective studies. The SEA database and specimen bank can be used to explore other factors that may contribute to impaired mobility as well as associations between energetics and other aging phenotypes. SEA will impact health care by guiding clinicians to the evaluation of potentially treatable causes of mobility disability and fatigue. Ultimately, this work may identify new modifiable targets for interventions to improve mobility and alleviate fatigue in older adults. PUBLIC HEALTH RELEVANCE: Loss of mobility and fatigue are common consequences of aging, but their causes are unknown. To determine the role of ATP energy generation in this process, experienced geriatric research centers will collect measurements of mitochondrial function from muscle specimens and capacity to generate ATP from muscle spectroscopy, assessments of whole-body capacity to generate ATP energy for walking, and measurements of speed and ability to walk 400 meters including assessment of exertional fatigue and exhaustion. The resulting resource of specimens, images, and data will be available for future studies of the determinants of impaired mobility and fatigue that may identify new modifiable targets for interventions to improve mobility and alleviate fatigue in older adults.