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

描述（由申请人提供）：鉴于照顾老年人口所面临的深刻的社会和经济挑战，促进健康老龄化的策略是老龄化研究的中心焦点。有证据表明，锻炼可以预防糖尿病和癌症等老年性疾病；运动还能促进活动，增强免疫系统功能。因此，对运动益处如何转化为健康衰老的分子理解是显而易见的，但这个问题尚未在遗传水平上得到广泛解决。我们研究了与959细胞线虫健康衰老相关的基本过程。最近我们有了一个有趣的发现——秀丽隐杆线虫可以通过运动来表现出训练的好处。我们最初的研究表明，哺乳动物运动所需要的AMPK，也需要秀丽隐杆线虫的训练，并且运动的线虫比不运动的线虫更优雅地衰老。因为了解运动如何诱导组织特异性和整个生物体的健康益处是至关重要的，而详尽的遗传学尚未应用于这个问题，我们建议建立一个秀丽隐杆线虫运动模型。目的1是优化秀丽隐杆线虫的运动训练方案。我们将改变游泳方案，以建立一个最佳的训练方案，通过最先进的运动分析程序评估，在训练和未训练之间产生最强大的差异。数据将定义一个方案，可应用于遗传学、分子、药理学和细胞生物学分析的运动益处在强大的秀丽隐杆线虫模型。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。我们将询问训练诱导的线粒体生物发生、特定的转录变化和人类运动训练所需的特定基因活动是否需要秀丽隐杆线虫的训练益处。这项工作将提供伴随秀丽隐杆线虫运动训练的分子和细胞生物学变化的第一个文件，并将构成运动机制是否保守的第一个测试。目的3是证明运动可以改善多器官系统的功能，否则这些功能会在衰老的动物中下降。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。数据将为运动对秀丽隐杆线虫衰老的积极影响提供第一个证据，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/或饮食限制在运动益处中的长寿途径。我们提出的秀丽隐杆线虫运动模型的发展将建立一个强大的新系统来解决基本的运动益处机制，这可能会激发人体健康维持的分子策略。

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.