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

基本信息

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
项目类别：
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

项目摘要

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性疾病的一部分是由于人口增长。饮食干预（例如卡路里限制（CR））可以改善甚至可以逆转这些并发症但CR饮食对于大多数人来说很难遵守。基于限制特定的大量营养素，例如蛋白质限制（PR）或特定必需氨基的限制酸在改善代谢健康并延长寿命的情况下显示出有望卡路里。 I和Lamming Lab表明，异亮氨酸限制（ILER）改善了葡萄糖稳态，伊勒诱导成纤维细胞生长因素21（FGF21），一种能量支出马，有些但不是所有记录的Iler的好处取决于FGF21。在F99阶段，我将首次确定是否需要FGF21 使用全身FGF21敲除的小鼠模型来扩展ILER的寿命。我还将测试脂肪和骨骼肌中MTORC1的必要性 - 异亮氨酸分解代谢的两个关键部位 - 在Iler上通过在骨骼肌或脂肪组织中专门删除猛禽来删除好处。这项研究将很好地桥接当我将重点从全身新陈代谢转移到我的毕业生和博士后工作之间差距衰老肌肉生物学的生理学。在K00阶段，我将利用经过验证的鼠标阻力运动训练模型来确定训练与MTORC1抑制剂雷帕霉素之间的相互作用，例如中间和旧小鼠的肌肉质量，纤维类型，强度和线粒体呼吸年龄以及包括脆弱在内的有机成果。我还将利用银行的组织检查肌肉来自依维莫司（Everolimus）的随机临床试验Konopka博士的老年人的结果已获得资金。最后，我将对骨骼肌健康，依维莫司（Everolimus）之间的相互作用进行探索性分析以及基于临床试验中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更接近成为一名全面的独立研究人员的目标对衰老中的营养和代谢进行有意义的研究。