Mechanisms of age-related motor activity decline in C. elegans

描述（由申请人提供）：衰老是一个基本过程，其特征是多种组织的生理功能逐渐下降（即功能性衰老），成年后死亡的可能性增加。运动活动下降代表了衰老动物和人类中最显著的生理下降之一。事实上，它与老年人的行动能力和身体机能受损有关，似乎是丧失独立性和死亡的一个风险因素。在人类中，与年龄相关的运动活动下降似乎是肌肉细胞和运动神经元的数量和功能下降的结果。然而，这些与年龄相关的变化的起源背后的细胞机制在很大程度上仍然未知。神经元对这种下降的贡献尤其未得到充分研究。线虫C.秀丽隐杆线虫由于其寿命短和易受遗传操作的影响，最近成为衰老研究的一个极好的模型系统。目前在模式生物中进行的衰老研究的大部分努力都是针对理解遗传和环境因素影响寿命的机制。然而，对C.优雅我们的研究目的就是要探索这些机制。C.秀丽线虫还表现出许多与高等生物相似的衰老表型，包括与年龄相关的运动活动下降。然而，同样的问题出现了，什么机制可能是在老化蠕虫中观察到的运动活动逐渐下降的基础。有趣的是，我们的研究表明，运动神经系统功能的进行性下降也可能有助于与年龄相关的运动活动下降，这是以前在C.优雅因此，在这项提案中，我们的目标是进一步剖析运动神经系统在与年龄相关的运动活动下降中的作用。更具体地说，使用一组电生理检测，我们想调查的细胞机制的年龄依赖性功能下降的神经肌肉接头（NMJ）在正常老化。我们研究的一个目标是最终开发新的治疗策略，可以预防或延迟老年人经常发生的与年龄相关的活动能力下降和疲劳增加。事实上，我们的初步研究结果表明，通过毒蕈碱乙酰胆碱受体（mAChR）激动剂对衰老神经系统的药理学刺激以及已知减缓衰老的基因的遗传操作可以改善老年蠕虫的运动功能。因此，在本提案的第二部分，我们将重点了解这些药理学或遗传干预措施改善老年动物运动活动的生理和细胞机制。

DESCRIPTION (provided by applicant): Aging is a fundamental process characterized by progressive declines in physiological functions of multiple tissues (i.e. functional aging) and an increased likelihood of death at later adult ages. Motor activity decline represents one of the most prominent physiological declines in aging animals and humans. In fact, it has been linked to impairments in mobility and physical functioning in the elderly and appears to act as a risk factor for loss of independence and mortality. In humans, the age-related decline in motor activity appears to be the result of decreases in the number and function of both muscle cells and motor neurons. However, the cellular mechanisms underlying the origin of these age-related alterations remain largely unknown. The neuronal contribution of such decline is particularly understudied. The nematode C. elegans has recently emerged as an excellent model system for aging studies because of its short lifespan and amenability to genetic manipulation. Much of the current efforts in aging research carried out in model organisms have been directed at understanding the mechanisms by which genetic and environmental cues influence longevity. However, very little is known about the mechanisms underlying functional aging in C. elegans. The goal of our research is to investigate these mechanisms. C. elegans also exhibits many aging phenotypes that resemble those found in higher organisms, including the age-related decline in motor activity. However, the same question arises as to what mechanisms may underlie the progressive decline in motor activity observed in aging worms. Interestingly, our studies suggested that the progressive decline in the function of motor nervous system might also contribute to the age-related decline in motor activity, which was previously not known in C. elegans. Therefore, in this proposal, we aim to further dissect the role of the motor nervous system in the age-related decline in motor activity. More specifically, using a set of electrophysiological assays, we would like to investigate the cellular mechanisms underlying age-dependent functional decline at the neuromuscular junctions (NMJs) during normal aging. One goal of our research is to ultimately develop new therapeutic strategies that could prevent or delay the age-related declines in mobility and increases in fatigability that often occur in the elderly population. In fact, our preliminary results indicate that pharmacological stimulation of the aging nervous system by a muscarinic acetylcholine receptor (mAChR) agonist as well as genetic manipulations of genes known to slow aging can improve motor function in aged worms. Thus, in the second part of this proposal, we will focus on understanding the physiological and cellular mechanisms by which these pharmacological or genetic interventions improve motor activity in aged animals.