Metabolic regulation of healthy aging by diet, mTOR signaling, and skeletal muscle

通过饮食、mTOR 信号传导和骨骼肌对健康衰老的代谢调节

• 批准号: 10730054
• 负责人: Michaela Trautman
• 金额: $ 4.92万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-10 至 2025-09-09
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10730054
• 关键词: Adherence; Adipose tissue; Age; Age Months; Aging; Amino Acids; Animals; Award; Biological; Biology of Aging; Biopsy Specimen; Body Composition; Body Weight; Body Weight decreased; Branched-Chain Amino Acids; CCI-779; Caloric Restriction; Calories; Catabolism; Cell physiology; Clinical Trials; Complex; Cyclic AMP-Dependent Protein Kinases; Development; Diabetes Mellitus; Diet; Dietary Component; Dietary Intervention; Disease; Elderly; Energy Metabolism; Essential Amino Acids; Exercise; FRAP1 gene; Female; Fiber; Funding; Genetic; Glucose; Goals; Health; Hepatic; Histology; Hormones; Human; Individual; Insulin Resistance; Intervention; Isoleucine; Knock-out; Knowledge; Learning; Leucine; Longevity; Macronutrients Nutrition; Mediating; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Molecular; Molecular Analysis; Monitor; Mus; Muscle; Muscle function; Obesity; Outcome; Participant; Pathway interactions; Persons; Pharmaceutical Preparations; Phase; Physiology; Population; Postdoctoral Fellow; Prevention; Proteins; Recommendation; Regimen; Regulation; Research; Research Personnel; Respiration; Role; SDZ RAD; Science; Signal Transduction; Sirolimus; Site; Skeletal Muscle; Supplementation; Techniques; Testing; Time; Tissue Banks; Tissues; Training; Valine; Work; age related; age-related muscle loss; aging population; blood glucose regulation; clinical translation; cohort; diet and exercise; dietary; dietary restriction; energy balance; exercise regimen; exercise training; experimental study; fibroblast growth factor 21; fitness; frailty; glucose tolerance; healthspan; healthy aging; human old age (65+); improved; inhibitor; male; metabolic phenotype; middle age; mimetics; model organism; mouse model; muscle aging; muscle form; muscle hypertrophy; muscle strength; nutrition; pharmacologic; preservation; prevent; promoter; protein intake; randomized, clinical trials; resistance exercise; response; sarcopenia; side effect; skills

PROJECT SUMMARY Obesity, glucose and insulin resistance, and other metabolic disorders are on the rise due in part to the growing aged population. Dietary interventions such as calorie restriction (CR) can improve and even reverse these complications but CR diets are difficult for most people to adhere to. Alternative regimens based on restriction of specific macronutrients, such as protein restriction (PR) or limitation of specific essential amino acids, have shown promise in improving metabolic health and extend lifespan without needing to limit of calories. I and the Lamming lab have shown that Isoleucine restriction (IleR) improves glucose homeostasis, improve body weight and adiposity, and even extends the lifespan of mice. IleR induces fibroblast growth factor 21 (FGF21), an energy expenditure hormone and some but not all of the documented benefits of IleR are dependent on FGF21. During the F99 phase, I will determine for the first time if FGF21 is required for lifespan extending effects of IleR by using a mouse model of whole body FGF21 knockout. I will also test the necessity of mTORC1 in the adipose and skeletal muscle – two key sites of isoleucine catabolism – on IleR benefits by deleting Raptor specifically in the skeletal muscle or adipose tissue. This study will nicely bridge the gap between my graduate and postdoctoral work as I shift my focus from whole body metabolism and physiology to biology of aging muscle. In the K00 phase, I will utilize a validated mouse model of resistance exercise training to determine the interaction between training and the mTORC1 inhibitor rapamycin on skeletal muscle outcomes, such as muscle mass, fiber type, strength and mitochondrial respiration in both male and female mice of middle and old age, as well as organismal outcomes including frailty. I will also utilize banked tissues to examine muscular outcomes in older humans from a randomized clinical trial of everolimus Dr. Konopka has received funding for. Finally, I will conduct an exploratory analysis of the interaction between skeletal muscle health, everolimus, and dietary components based on the diet recall collected for each participant in the clinical trial. Completing these aims will bring me one step closer to my goal of becoming a well-rounded independent researcher conducting meaningful research on nutrition and metabolism in aging.

项目摘要 肥胖、葡萄糖和胰岛素抵抗以及其他代谢紊乱正在增加，部分原因是 不断增长的老龄人口。饮食干预，如热量限制（CR）可以改善，甚至逆转 这些并发症，但CR饮食是很难为大多数人坚持。替代方案基于 限制特定的常量营养素，如蛋白质限制（PR）或限制特定的必需氨基酸 酸，已经显示出改善代谢健康和延长寿命的希望，而不需要限制 卡路里 我和Lamming实验室已经证明，异亮氨酸限制（IleR）改善葡萄糖稳态， 改善体重和肥胖，甚至延长小鼠的寿命。IleR诱导成纤维细胞生长 因子21（FGF 21），一种能量消耗激素和IleR的一些但不是全部的记录益处 依赖于FGF 21。在F99阶段，我将首次确定是否需要FGF 21， IleR的寿命延长作用，通过使用全身FGF 21敲除的小鼠模型。我还将测试 mTORC 1在脂肪和骨骼肌中的必要性-异亮氨酸催化剂的两个关键位点-IleR 通过删除骨骼肌或脂肪组织中的Raptor而受益。这项研究将很好地连接 我的研究生和博士后工作之间的差距，因为我把我的重点从全身代谢， 从生理学到生物学的肌肉老化。 在K 00阶段，我将利用经过验证的抗阻运动训练小鼠模型来确定 训练和mTORC 1抑制剂雷帕霉素对骨骼肌结果之间的相互作用， 结果表明，老年小鼠肌肉质量、肌纤维类型、肌纤维强度和线粒体呼吸强度均高于成年小鼠 年龄，以及包括虚弱在内的有机体结果。我也会利用库存组织检查肌肉 科诺普卡博士获得资助的依维莫司随机临床试验在老年人中的结果。 最后，我将对骨骼肌健康，依维莫司， 以及基于临床试验中为每个参与者收集的饮食回忆的饮食成分。完成 这些目标将使我离成为一名全面的独立研究人员的目标更近一步 对衰老过程中的营养和代谢进行有意义的研究。