Neural mechanisms of age-related weakness

摘要 超过40%的老年人（OAs）报告说，他们在执行维持生活所必需的任务时受到限制。 独立虚弱是造成身体损伤的重要因素;事实上，虚弱 OAs的物理限制增加了四倍。因为力量是健康和长寿的重要因素， 需要更全面地了解虚弱的原因，以制定有针对性的干预措施， 增强OA的实力和功能。虽然与年龄相关的肌肉质量和质量的损失是部分原因， 对于虚弱，越来越多的证据表明，神经激活的缺陷与年龄相关的 弱点特别是，我们和其他人已经证明，与衰老和其他 条件（例如，废用、损伤、败血症）部分是由于神经兴奋性减退。在本申请中，我们寻求 从根本上推进我们对与年龄相关的疾病的机制和治疗策略的理解， 通过转化人类（目标1）和临床前啮齿动物（目标2）的虚弱和活动受限 这些实验将共同提供强有力的数据，表明神经元之间的因果关系。 低兴奋性和与年龄相关的虚弱。第一个目的是检验神经元的指数 hypoexcitability与更大的未来（纵向）损失的力量在OAs。在这里，我们将利用 从先前的R 01数据进行人体纵向研究，我们量化神经兴奋性指标， 老年人约8年后的瘦体重、力量和活动性。这些数据将用于确定相对 神经兴奋性和大腿瘦体重指数对老年人未来肌肉力量下降的贡献 成人，具有考虑替代机制的稳健设计。通过在人体中使用纵向设计， 这一目标将为神经兴奋性作为年龄相关性的关键预测因素提供最强有力的证据。 力量损失，这是从当前主要考虑肌肉因素（例如， 肌肉质量）。第二个目标将包括四个实验。实验1-3将使用5-HT 2c激动剂 （氯卡色林）具有众所周知的作用机制，可增加持续性内向电流和运动神经元 兴奋性SA2.1将检验5-HT 2c激动剂与受体之间存在倒U型关系的假设。 剂量和老年小鼠的运动功能反应。SA2.2将检验5-HT 2c激动剂将增强 通过增加神经兴奋来增强老年小鼠的运动功能，以证明MN兴奋性的降低 是老年小鼠运动功能障碍的重要原因。SA 2.3将检测氯卡色林治疗的慢性效应 对老年小鼠运动单位数量和功能的影响。SA2.4将测试他莫昔芬诱导基因缺失的影响 用Cre-Lox系统测定MN的5-HT_（2c）受体。从长远来看，这个概念验证，机制验证 这项工作可以作为神经治疗剂增强老年人运动功能的证据。

ABSTRACT More than 40% of older adults (OAs) report limitations to performing tasks that are essential to maintain independence. Weakness is an important contributor to physical impairments; indeed, weakness predisposes OAs to a four-fold increase in physical limitations. Because strength is a vital factor for health and longevity, more comprehensive understanding of the causes of weakness is needed to develop targeted interventions to enhance strength and function in OAs. While age-related loss of muscle mass and quality are partly responsible for weakness, there is increasing evidence that deficits in neural activation are critically linked to age-related weakness. In particular, we and others have demonstrated that weakness associated with aging and other conditions (e.g., disuse, injury, sepsis) is due, in part, to neural hypoexcitability. In this application, we seek to fundamentally advance our understanding of the mechanisms of and treatment strategies for age-related weakness and mobility limitations through translational human (Aim 1) and pre-clinical rodent (Aim 2) experiments that, collectively, will provide strong data indicating a causal association between neural hypoexcitability and age-related weakness. The first aim will test the hypothesis that indices of neural hypoexcitability are associated with greater future (longitudinal) losses of strength in OAs. Here, we will leverage data from a prior R01 to conduct a longitudinal study in humans where we quantify indices of neural excitability, lean mass, strength, and mobility after ~ 8-years in older adults. These data will be used to determine the relative contribution of indices of neural excitability and thigh lean mass on future decline in muscle strength in older adults, with a robust design accounting for alternative mechanisms. By using a longitudinal design in humans, this aim will provide the strongest level of evidence for neural excitability being a key predictor of age-related strength loss, which is a paradigm shift away from the current consideration of primarily muscular factors (e.g., muscle mass). The second aim will consist of four experiments. Experiments 1-3 will use a 5-HT2c agonist (lorcaserin) with a well-known mechanism of action that increases persistent inward currents and motoneuron excitability. SA2.1 will test the hypothesis that there is an inverted U-shape relationship between 5-HT2c agonist dose and motor function response in old mice. SA2.2 will test the hypothesis that a 5-HT2c agonist will enhance motor function in aged mice by increasing neural excitation to demonstrate that the reduction in MN excitability is a significant contributor to motor dysfunction in old mice. SA2.3 will test chronic effects of lorcaserin treatment on motor unit number and function in aged mice. SA2.4 will test the impact of tamoxifen-inducible genetic deletion of 5-HT2c receptors in MNs using Cre-Lox system. In the long-term, this proof-of-concept, proof-of-mechanism work could serve as evidence for a neurotherapeutic agent to enhance motor function in older adults.