Study of Energy and Aging

描述(由申请人提供)：这项建议响应了NIA的重大机遇号召，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的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致病途径。”以步速减慢、疲劳性疲劳和精疲力竭为特征的灵活性丧失是与年龄相关的功能下降的标志。虽然活动度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)、运动测试和循环生物标志物的研究尚未发现与年龄相关的活动减慢和丧失的明确生物生理学基础。到目前为止，对线粒体功能和三磷酸腺苷(ATP)能量产生的研究还太少，无法了解能量代谢的各个组成部分在年龄相关性行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降低在与年龄相关的活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从肌肉氧气输送到步行能量效率的“能量系统”组成部分的评估和分析。这些评估包括体内肌肉ATP生成的磷光谱，通过测量线粒体内容和功能进行肌肉活组织检查，运动时流向腿部的血液，以及步行时的能量利用。我们将对300名年龄在70岁至89岁之间的男性和女性进行这些测量，他们的特点是行动不便，体力疲惫和精疲力竭。参与者将由匹兹堡大学、维克森林大学和阿肯色州医学大学的经验丰富的研究中心招募和检查，这项研究将由旧金山协调中心协调。能量和衰老研究(SEA)将对科学产生重大影响，它将重新聚焦于行动障碍的生理学研究，提供一个数据库和样本库来测试新的范式，并建立新的测量方法的价值，并开发它们以在本研究和未来的多中心和前瞻性研究中高通量使用。SEA数据库和样本库可以用来探索其他可能导致行动能力受损的因素，以及能量和其他衰老表型之间的关联。SEA将通过指导临床医生评估行动不便、残疾和疲劳的潜在可治疗原因来影响卫生保健。最终，这项工作可能会为干预措施确定新的可修改的目标，以改善老年人的行动能力和缓解疲劳。 公共卫生相关性：行动不便和疲劳是衰老的常见后果，但其原因尚不清楚。为了确定ATP能量产生在这一过程中的作用，经验丰富的老年研究中心将收集肌肉标本中线粒体功能的测量结果和从肌肉光谱中产生ATP的能力，评估全身为行走产生ATP能量的能力，以及测量步行400米的速度和能力，包括体力性疲劳和疲惫的评估。由此产生的标本、图像和数据资源将可用于未来对行动能力受损和疲劳的决定因素的研究，这可能会为改善老年人行动能力和缓解疲劳的干预确定新的可修改的目标。

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.