Development of a C. elegans Exercise Model for Evaluating Healthy Aging Mechanism

描述（由申请人提供）：鉴于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化研究的中心焦点。运动已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能力，并可以增强免疫系统功能。因此，对运动益处如何转化为健康老龄化的分子理解显然很有趣，但这个问题尚未在遗传水平上得到广泛解决。我们研究了959细胞线虫C.优雅最近我们有了一个有趣的发现-- C。优雅的人可以通过锻炼来展示训练的好处。我们的初步研究表明，AMPK，需要哺乳动物运动的好处，也需要C。线虫的运动，而运动的线虫比那些不运动的线虫衰老得更优雅。因为了解运动如何诱导组织特异性和生物体范围的健康益处是至关重要的，并且详尽的遗传学尚未应用于这个问题，我们建议开发一个C。优雅的锻炼模式。目的一是优化C.优雅我们将改变游泳方案，以建立一个最佳的训练协议，产生最强大的差异之间的训练和未经训练的评估由国家的最先进的运动分析程序。数据将定义一个协议，可以应用于遗传学，分子，药理学和细胞生物学分析的运动效益在强大的C。elegans模型目的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。我们将探讨训练诱导的线粒体生物合成、特定的转录变化和人类运动训练所需的特定基因活性是否是C。优雅的训练好处。这项工作将提供第一个文件的分子和细胞生物学的变化，伴随运动训练在C。并将构成运动机制是否保守的第一个测试。目的3是证明运动可以改善衰老动物多器官系统的功能，否则这些功能就会下降。我们还将开始研究特定的长寿途径是否被激活以促进锻炼的益处。数据将提供运动对C. elegans衰老，并可能突出受影响的特定衰老生物标志物。我们的研究也可能涉及胰岛素信号，EGF信号和/或饮食限制长寿途径在运动的好处。我们提出的C. elegans运动模型将建立一个强大的新系统，用于解决基本的运动益处机制，这可能会激发维持人类健康的分子策略。 公共卫生相关性：运动对老年人的健康有着深远的积极影响，据报道，运动可以预防与年龄相关的疾病，包括癌症，糖尿病和心血管疾病，并保持肌肉，免疫系统和神经系统功能。尽管如此，运动如何促进健康衰老在遗传水平上仍然知之甚少。我们建议在简单的动物C中开发第一个运动模型。elegans，表明训练的好处是由线虫和人类之间保守的机制介导的，并开始解决运动如何促进健康衰老。因为这种模型是唯一适合于体内研究和遗传操作，在C。elegans可能提供意想不到的见解，促进新的抗衰老干预措施的发展。

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. PUBLIC HEALTH RELEVANCE: Exercise has a profound positive impact on health of the aging population, having been reported to protect against age-associated diseases including cancer, diabetes, and cardiovascular disease, and to maintain muscle, immune system, and nervous system function. Still, how exercise promotes healthy aging remains poorly understood at the genetic level. We propose to develop the first exercise model in the simple animal C. elegans, show that training benefits are mediated by mechanisms conserved between nematodes and humans, and begin to address how exercise promotes healthy aging. Because this model is uniquely suited for in vivo studies and genetic manipulation, pioneering work in C. elegans may provide unexpected insights that promote development of novel anti-aging interventions.