Genetic Dissection of Mechanisms by Which Exercise Promotes Systemic Health

经常锻炼对健康和衰老质量有深远的积极影响。尽管如此，我们的理解是 在调节全身运动益处的分子机制中，仍有令人惊讶的不完整。在……里面 具体地说，肌肉的工作如何转化为系统范围的维护、疾病威慑，甚至 返老还童，人们对此知之甚少，无法用于治疗应用。我们建议解决以下问题 这一知识鸿沟来自一个新的角度，以创新的技术、灵活的基因操作和 随着时间的推移，体内神经元的综合分析。我们已经开发了一种线虫运动模型，它是唯一的 使我们定位于解决三个目标，这三个目标一起将促进对 运动有益于肌肉领域以外的领域，重点是神经元老化。 目的1)测试线虫与经典哺乳动物运动训练途径相关基因的同源性 对于力量适应中的作用，b)解决选定的应激/长寿途径基因的潜在需求 在运动诱导的肌肉力量增强中；c)定义动物范围内的转录变化， 伴随着训练有素的状态。这项工作将为运动分析建立一个深层次的机制框架 有益于并解决从线虫到人类的运动适应途径的保存程度。 我们将坚定不移地建立一种新的遗传模型，在该模型中，可以剖析运动对整个动物的好处。 在目标2和目标3中，我们将重点转向运动对神经元健康跨度的影响。 目标2将定义运动对神经元健康跨度的影响，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，延缓与年龄相关的适应 拒绝。我们将对触摸感受器神经元进行详细的分析，描述运动是如何改变的 神经元功能、形态重建、对神经毒性疾病的易感性、蛋白质毒性以及 线粒体在成年后的状态。我们将应用精选的分析方法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。 目标3将利用线虫实验系统的独特功能来剖析组织网络，通过组织网络 运动适应所需的基因促进肌肉和神经元的健康。我们将：a)解决 选定的肌肉训练所需的关键基因是否自主/非自主地发挥作用 神经元健康跨度，以及b)测试运动诱导基因编码分泌蛋白的促进作用 神经元适应性。我们将对系统范围内涉及的组织相互作用电路有初步的了解 运动有益，我们可能会发现运动诱导的神经元健康寿命的驱动因素。 鉴于明确的证据表明运动是最有效的抗衰老、抗疾病、有利于健康的干预措施 医学上已知的是，对运动维持能力的遗传解剖在当地背景下和随着时间的推移 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.