Aging Mitochondrial Fragmentation and Metabolic Inflexibility

衰老线粒体碎片和代谢不灵活

• 批准号: 9762823
• 负责人: GEORGE Austin BROOKS
• 金额: $ 57.08万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9762823
• 关键词: Adipocytes; Adipose tissue; Affect; Age; Aging; Biopsy; Blood; Carbohydrates; Cell Line; Cells; Closure by clamp; Complement; Dietary Fats; Energy-Generating Resources; Exercise; Fat emulsion; Fatty acid glycerol esters; Female; Gene Expression; Generations; Glucose; Glycerol; Harvest; Heparin; Human; Inbred F344 Rats; Individual; Infusion procedures; Insulin Resistance; Intravenous infusion procedures; Isotopes; Knock-out; Knockout Mice; Lipid Mobilization; Lipids; Lipolysis; Metabolic; Mitochondria; Mus; Muscle Cells; Muscle Mitochondria; Muscular Atrophy; Nonesterified Fatty Acids; OGTT; Organelles; Output; Palmitates; Pharmaceutical Preparations; Physical Fitness; Physical activity; Physiological; Population; Preparation; Production; Proteome; Rattus; Regulation; Rest; Reticulum; Rodent; Sample Size; Skeletal Muscle; Small Interfering RNA; Sodium; Strenuous Exercise; Structure; Testing; Tissues; Tracer; Variant; Woman; acipimox; age effect; cohort; design; flexibility; glucose disposal; human tissue; male; men; model design; negative affect; oxidation; oxidized lipid; preservation; protein expression; respiratory; response; sedentary; stoichiometry; subcutaneous

Summary/Abstract Metabolic flexibility refers to the ability to switch between carbohydrate (CHO) and fat oxidation in response to changing physiological conditions. A mixed-model design is proposed to interrogate the hypothesis that the loss of metabolic flexibility in aging is of mitochondrial origin. The design calls for studies on intact humans, human skeletal muscle (SM) and white adipose tissue (WAT) as well as on rat and mouse SM and WAT. A segment of the effort on cells and organelles isolated from young and old lab rodents will be necessary to perform extensive respiratory control studies as well as studies of mitochondrial dynamics and composition, whereas because of sample size limitations, studies an human mitochondrial preparations will be involve selective analyses. To test the main hypothesis four cohorts of humans will be studied: sedentary (< 2 hr vigorous PA/wk) and physically active (>5 hr PA/wk) young healthy controls (21-35 yr), older sedentary and physically active individuals (60-80 yr) of age. Tissues will be harvested from analogous rat populations, 3-4 month (mo) and 21-23 mo old male and female F344 rats and young (2-3 mo) and old (15 mo) GPR81 null mice (Aim 4).

摘要/摘要 代谢灵活性指的是在碳水化合物(CHO)和脂肪氧化之间切换的能力 不断变化的生理条件。提出了一种混合模型设计来验证这一假设 衰老过程中的代谢灵活性源于线粒体。该设计要求对完整的人类、人类骨骼进行研究 肌肉(SM)和白色脂肪组织(WAT)，以及大鼠和小鼠SM和Wat。努力的一部分 从幼年和老年实验啮齿动物身上分离出的细胞和细胞器将是执行广泛的呼吸控制所必需的。 研究以及线粒体动力学和组成的研究，而由于样本量的限制， 对人类线粒体制剂的研究将涉及选择性分析。检验主要假设的四个队列 将研究：久坐(2小时精力充沛的PA/wk)和体力活动(&gt；5小时PA/wk)健康的年轻人 对照组(21-35岁)、久坐不动和经常运动的老年人(60-80岁)。组织将从 相似的大鼠群体，3-4月龄(Mo)和21-23mo龄的雄性和雌性F344大鼠以及幼鼠(2-3月龄)和老年(15只) Mo)GPR81缺失小鼠(AIM 4)。