Genetic Dissection of Mechanisms by Which Exercise Promotes Systemic Health

经常锻炼对健康和衰老质量产生深远的积极影响。尽管如此，我们的理解 令人惊讶的是，介导全身运动益处的分子机制仍然不完整。在 特别是，肌肉工作如何转化为系统范围的维护，疾病威慑，甚至 年轻化，是太少了解利用治疗应用。我们建议解决 从一个新的角度，以创新技术，轻松的基因操作， 随时间推移的体内神经元整合测定。我们开发了一个C。elegans运动模型， 使我们能够解决三个目标，这些目标将共同促进对生物学基础的理解。 运动的好处在肌肉领域之外，重点是神经元老化。 目标1将：a）测试C。经典哺乳动物运动训练途径相关基因的同源物 对于在强度适应中的作用，B）解决对选定的应激/寿命途径基因的潜在需求 c）确定动物范围内转录变化， 陪伴着训练有素的国家。工作将建立一个深入的机制框架分析行使 的益处，并解决从线虫到人类的运动适应途径的保护程度。 我们将坚定地建立一个新的遗传模型，在这个模型中，可以解剖运动对整个动物的好处。 在目标2和3中，我们将重点转移到运动对神经元健康的影响上。 目标2将定义运动对神经元健康的影响，同时解决总体假设， 运动诱导神经元的功能，结构和分子适应，延缓其与年龄相关的 下降我们将对触觉感受器神经元进行详细的分析，描述运动如何改变 神经元功能、形态重建、对神经毒性疾病蛋白质毒性的易感性，以及 线粒体的状态。我们将应用选定的测定来评估其他神经元类型， 以前所未有的细胞细节记录运动如何影响体内神经系统老化。 Aim 3将利用C. elegans实验系统来解剖组织网络， 运动适应所需的基因促进肌肉和神经元的健康益处。我们将：a）解决 肌肉训练所需的选定关键基因是否自主/非自主地影响 B）测试编码分泌蛋白的运动诱导基因在促进神经元健康方面的作用 神经适应我们将获得初步的见解，组织相互作用的电路参与系统范围内的 运动的好处，我们可能会发现运动诱导的神经元健康的驱动程序。 有明确的证据表明，运动是最有效的抗衰老，抗疾病，促进健康的干预措施 医学上已知的，在自然环境下和随着时间的推移，运动的维持能力的遗传解剖 应该产生新的见解，指导改善人类健康和老龄化质量的战略。

Regular exercise exerts a profound positive impact on health and the quality of aging. Still, our understanding of the molecular mechanisms that mediate systemic exercise benefits remains surprisingly incomplete. In particular, details of how work in muscle translates to system-wide maintenance, disease deterrence, and even rejuvenation, are too poorly understood to be harnessed for therapeutic applications. We propose to address this knowledge gap from a new angle that features innovative technology, facile gene manipulation, and integrative in vivo neuronal assays over time. We have developed a C. elegans exercise model that uniquely positions us to address three aims that together will advance understanding of the fundamental biology of exercise benefits outside of the muscle domain, with a focus on neuronal aging. Aim 1 will: a) test C. elegans homologs of genes involved in classical mammalian exercise training pathways for roles in strength adaptation, b) address potential requirements for selected stress/longevity pathway genes in exercise-induced enhancement of muscle strength; c) define animal-wide transcription changes that accompany the trained state. Work will establish a deep mechanistic framework for analysis of exercise benefits and address the degree of conservation of exercise adaptation pathways from nematodes to humans. We will firmly ground a novel genetic model in which whole-animal benefits of exercise can be dissected. In Aims 2 and 3, we shift our emphasis to address impact of exercise on neuronal healthspan. Aim 2 will define the impact of exercise on neuronal healthspan while addressing the overall hypothesis that exercise induces functional, structural, and molecular adaptations in neurons, delaying their age-associated decline. We will conduct a detailed analysis of touch receptor neurons, characterizing how exercise changes neuronal function, morphological restructuring, susceptibility to neurotoxic disease protein toxicity, and mitochondrial status over adult life. We will apply selected assays to evaluate additional neuronal types to document in unprecedented cellular detail how exercise influences in vivo nervous system aging. Aim 3 will exploit unique features of the C. elegans experimental system to dissect the tissue network via which genes needed for exercise adaptation promote muscle and neuronal health benefits. We will: a) address whether selected key genes needed for muscle training act autonomously/nonautonomously to impact neuronal healthspan, and b) test exercise-inducible genes encoding secreted proteins for roles in promoting neuronal adaptations. We will gain initial insights into the tissue-interaction circuits involved in system-wide exercise benefits and we may uncover exercise-induced drivers of neuronal healthspan. Given unequivocal evidence that exercise is the most effective anti-aging, anti-disease, pro-health intervention known in medicine, genetic dissection of exercise's maintenance capacities in native context and over time should yield new insights that guide strategies for improving human health and the quality of aging.