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

线虫与年龄相关的运动活动下降的机制

• 批准号: 8825998
• 负责人: Ao-Lin Allen Hsu
• 金额: $ 37.11万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8825998
• 关键词: Adopted; Adult; Age; Aging; Aging-Related Process; Animal Model; Animals; Arecoline; Biological; Biological Assay; Biological Models; Caenorhabditis elegans; Cells; Cessation of life; Cues; Elderly; Environmental Risk Factor; Exhibits; Frail Elderly; Frequencies; Genes; Genetic; Goals; Health; Human; Impairment; Injury; Insulin; Insulin-Like Growth Factor I; Intervention; Lead; Link; Longevity; Michigan; Modeling; Motor; Motor Activity; Motor Neurons; Muscarinic Acetylcholine Receptor; Muscle; Muscle Cells; Nematoda; Nervous system structure; Neuromuscular Junction; Neurons; Organism; Pathway interactions; Phenotype; Physical Function; Physiological; Physiological Processes; Population; Process; Reporting; Research; Risk Factors; Role; Signal Transduction; Skeletal Muscle; Synapses; Synaptic Transmission; System; Testing; Tissues; Universities; acetylcholine receptor agonist; age related; aged; cohort; dietary restriction; environmental intervention; falls; functional decline; gene therapy; genetic approach; genetic manipulation; improved; mortality; motor function improvement; muscle form; muscle strength; mutant; neurophysiology; normal aging; novel therapeutics; postsynaptic; prevent

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.

描述（由申请人提供）：衰老是一个基本过程，其特征是多个组织的生理功能（即功能性衰老）的生理功能逐渐下降，而后来成年年龄的死亡可能性增加。运动活动的下降代表着衰老的动物和人类最突出的生理下降之一。实际上，它与老年人的流动性和身体机能的障碍有关，似乎是失去独立性和死亡率的危险因素。在人类中，运动活性与年龄相关的下降似乎是肌肉细胞和运动神经元数量和功能下降的结果。然而，这些与年龄相关的改变起源的基础的细胞机制在很大程度上尚不清楚。这种下降的神经元贡献特别研究了。线虫秀丽隐杆线虫最近成为一个出色的模型系统，用于衰老研究，因为它的寿命短，并且对遗传操纵的适应性。目前在模型生物中进行的衰老研究的许多努力都是针对理解遗传和环境线索影响寿命的机制的。但是，关于秀丽隐杆线虫中功能衰老的机制知之甚少。我们研究的目的是研究这些机制。秀丽隐杆线虫还表现出许多与较高生物体相关的衰老表型，包括运动活动与年龄相关的下降。但是，出现了同样的问题，即哪种机制可能是衰老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逐渐下降也可能导致与年龄相关的运动活动下降，这在秀丽隐杆线虫中以前尚不清楚。因此，在此提案中，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，使用一组电生理测定法，我们想研究正常衰老期间神经肌肉连接（NMJ）处年龄依赖性功能下降的细胞机制。我们研究的目标之一是最终制定新的治疗策略，以防止或延迟与年龄相关的流动性下降以及老年人群经常发生的疲劳性的增加。实际上，我们的初步结果表明，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慢衰老的基因的遗传操纵可以改善老化蠕虫的运动功能。因此，在本提案的第二部分中，我们将重点放在理解这些药理或遗传干预措施改善老年动物运动活性的生理和细胞机制上。