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

描述(申请人提供)：衰老是一个基本的过程，其特征是多个组织的生理功能进行性下降(即功能衰老)，成年后死亡的可能性增加。在衰老的动物和人类中，运动活动下降是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功能障碍有关，似乎是丧失独立性和死亡率的风险因素。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减少的结果。然而，这些与年龄相关的改变起源的细胞机制在很大程度上仍不清楚。这种衰退对神经元的贡献尤其未被充分研究。线虫因其短的寿命和对遗传操作的适应性，最近成为研究衰老的一个很好的模型系统。目前在模型生物中进行的衰老研究的大部分努力都是为了了解遗传和环境因素影响寿命的机制。然而，人们对线虫功能衰老的机制知之甚少。我们研究的目的就是探讨这些机制。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，同样的问题也出现了，即在老化的蠕虫中观察到的运动活动进行性下降的背后可能存在什么机制。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可能也是与年龄相关的运动活动下降的原因之一，这在线虫中以前是未知的。因此，在这项建议中，我们旨在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，我们希望通过一系列电生理测试，研究正常衰老过程中神经肌肉接头(NMJ)功能衰退与年龄相关的细胞机制。我们研究的目标之一是最终开发新的治疗策略，以防止或延缓老年人经常出现的与年龄相关的活动能力下降和疲劳性增加。事实上，我们的初步结果表明，毒鼠碱型乙酰胆碱受体(MAChR)激动剂对衰老神经系统的药理刺激以及已知减缓衰老的基因的遗传操作可以改善老龄蠕虫的运动功能。因此，在本提案的第二部分，我们将重点了解这些药物或遗传干预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.