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

项目总结 肥胖、葡萄糖和胰岛素抵抗以及其他代谢紊乱正在上升，部分原因是 不断增长的老年人口。饮食干预，如卡路里限制(CR)，可以改善甚至逆转 这些并发症但CR节食对大多数人来说很难坚持。基于以下因素的替代方案 限制特定的常量营养素，如限制蛋白质(PR)或限制特定的必需氨基酸 酸，在改善新陈代谢健康和延长寿命方面显示出希望，而不需要限制 卡路里。 我和拉明实验室已经证明，异亮氨酸限制(ILER)可以改善血糖稳态， 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(FGF21)，一种能量消耗荷尔蒙和ILER的部分但不是全部已记录的好处 依赖于FGF21。在F99阶段，我将第一次确定是否需要FGF21 通过使用全身FGF21基因敲除的小鼠模型延长ILER的寿命。我还会测试一下 脂肪和骨骼肌--异亮氨酸分解代谢的两个关键部位--mTORC1的必要性 通过删除特定于骨骼肌或脂肪组织的Raptor而受益。这项研究将很好地沟通 我的研究生和博士后工作之间的差距，因为我把注意力从全身代谢转移到 衰老肌肉的生理学到生物学。 在K00阶段，我将利用经过验证的阻力训练小鼠模型来确定 训练和mTORC1抑制剂雷帕霉素对骨骼肌结果的相互作用，如 中老年雄性和雌性小鼠肌肉质量、纤维类型、力量和线粒体呼吸 年龄，以及包括虚弱在内的身体后果。我还会用储存的纸巾来检查肌肉 科诺普卡博士已获得资助，对老年人进行了埃维洛莫斯的随机临床试验。 最后，我将对骨骼肌健康、埃博利莫斯、 以及基于为临床试验中的每个参与者收集的饮食回忆的饮食成分。正在完成 这些目标将使我离成为一名全面发展的独立研究员的目标更近一步 对衰老过程中的营养和代谢进行有意义的研究。

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.