Development of C. elegans Exercise Model for Evaluating Healthy Aging Mechanisms

描述(申请人提供)：考虑到照顾老年人口的深刻的社会和经济挑战，促进健康老龄化的战略是老龄研究的中心焦点。运动已经被证明可以预防糖尿病和癌症等衰老疾病；运动还可以促进延长活动量，并可以增强免疫系统功能。因此，从分子上理解运动的益处如何转化为健康的衰老是很有意义的，但这个问题还没有在基因水平上得到广泛的解决。我们研究了959细胞线虫健康衰老的基本过程。最近，我们有了一个令人着迷的发现--线虫可以通过锻炼来展示训练的好处。我们的初步研究表明，哺乳动物运动所需的AMPK对线虫的训练也是必要的，运动的线虫比不运动的线虫衰老得更优雅。由于了解运动如何产生组织特异性和生物体范围的健康益处是至关重要的，而穷尽遗传学尚未应用于这个问题，因此我们建议开发线虫运动模型。目标1是优化线虫的运动训练方案。我们将改变不同的游泳方案，以建立一个最佳的训练方案，根据最先进的运动分析程序的评估，在训练和未训练之间产生最稳健的差异。数据将定义一种方案，该方案可以应用于强大的线虫模型中运动益处的遗传、分子、药理学和细胞生物学分析。目标2是测试肌肉对训练的反应是否从线虫到人类都是保守的。我们将询问是否需要人类运动训练中所需的训练诱导线粒体生物发生、特定转录变化和特定基因活动才能使线虫获得训练益处。这项工作将为线虫运动训练伴随的分子和细胞生物学变化提供第一个文件，并将构成运动机制是否保守的第一个测试。目的3是为了证明，运动可以改善多器官系统的功能，否则衰老动物的多器官系统功能就会下降。我们还将开始研究特定的长寿途径是否被激活，以促进运动的益处。数据将提供第一个证据，证明运动对线虫衰老有积极影响，并可能突出受影响的特定衰老生物标志物。我们的研究还可能涉及胰岛素信号、EGF信号和/或饮食限制长寿途径对运动的好处。我们提议的线虫运动模型的开发将建立一个强大的新系统，用于解决基本的运动益处机制，这些机制可能会启发分子策略来维持健康的人类。

DESCRIPTION (provided by applicant): Given the profound social and economic challenges of caring for the elderly population, strategies for promoting healthy aging are a central focus fo aging research. Exercise has been documented to protect against diseases of aging such as diabetes and cancer; exercise also promotes extended mobility and can enhance immune system function. Molecular understanding of how exercise benefits translate into healthy aging is thus of clear interest, but this issue has not been addressed extensively at the genetic level. We study fundamental processes relevant to healthy aging in the 959-celled nematode C. elegans. Recently we made a fascinating discovery- C. elegans can exercise to exhibit training benefits. Our initial studies suggest that AMPK, needed for mammalian exercise benefit, is also needed for C. elegans training, and that nematodes that exercise age more gracefully than those that do not exercise. Because it is critical to understand how tissue-specific and organism-wide health benefits are induced by exercise, and exhaustive genetics have not been applied to this problem, we propose to develop a C. elegans exercise model. Aim 1 is to optimize an exercise training protocol for C. elegans. We will vary swim regimens to establish an optimal training protocol that generates the most robust difference between trained and untrained as evaluated by a state-of-the-art motion analysis program. Data will define a protocol that can be applied in genetic, molecular, pharmacological, and cell biological analyses of exercise benefits in the powerful C. elegans model. Aim 2 is to test whether muscle responses to training are conserved from nematodes to humans. We will ask whether training-induced mitochondrial biogenesis, specific transcriptional changes, and specific gene activities needed in human exercise training are required for C. elegans training benefits. This work will provide the first documentation of the molecular and cell biological changes that accompany exercise training in C. elegans and will constitute the first test of whether exercise mechanisms are conserved. Aim 3 is to show that exercise improves function of multiple organ systems that would otherwise decline in aging animals. We will also begin to address whether specific longevity pathways are activated to contribute to exercise benefits. Data will provide the first evidence of a positive impact of exercise on C. elegans aging, and might highlight specific aging biomarkers that are affected. Our studies may also implicate insulin signaling, EGF signaling, and/or dietary restriction longevity pathways in exercise benefits. Our proposed development of the C. elegans exercise model will establish a powerful new system for addressing fundamental exercise benefit mechanisms that might inspire molecular strategies for healthy human maintenance.