A Strength Analysis Tool for Studying Healthy Aging via Exercise in C. elegans

 描述（由申请人提供）：运动可以说是我们可以采取的最有效的方法，以延缓与衰老相关的身体衰退，并防止迟发性疾病，如糖尿病，癌症和阿尔茨海默病。因此，从分子水平上理解运动的益处如何转化为健康的衰老，具有决定性的医学意义。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。秀丽线虫可以通过运动（游泳）来展示训练益处，并且似乎通过人类中保守的分子途径获得益处。我们最初的模型开发开辟了一个新的研究领域，以了解运动如何诱导组织特异性和生物体范围内的健康益处，并为识别可能促进健康衰老的运动模拟药物创造了一个新的范例。为了真正收获这个模型的潜力，我们需要测量微小的C的强度。优雅我们合作开发了一种强度测试，其中经过训练的动物穿过可变形支柱的矩阵，支柱偏转的程度用于计算力。我们的“NemaFlex”力检测设备是定量基础，我们希望在了解运动对健康老龄化的影响方面开辟新天地。在这里，我们提出了所需的发展，以提高测定通量和追求的应用程序，不仅锚这一技术作为一个重要组成部分的C。elegans运动评估，而且在这个强大的模型中加速了运动生物学和健康衰老的研究。目的1是开发一种新的高通量的工具，用于直接评估C。优雅 这一目标将产生一个必要的工具，分析C。elegans力量在多个生命阶段，定义的运动养生法，将成为锚协议在该领域，并揭示了在这个模型中的训练特点。目标2是使用NemaFlex评估运动模拟药物，以促进重点试点基因筛选。这一目标将为使用NemaFlex的遗传和药物发现建立关键的原理验证。目标3是以NemaFlex力量训练益处测量为基础，开始解剖运动与健康老龄化之间的功能和分子关系。 开始，我们将测试优化的力量训练如何跟踪随着年龄增长而下降的广泛的健康指标，我们将调查停止训练对 老化的质量，我们会问，如果运动模拟药物延长健康寿命在没有训练。我们的目标是创造新的技术，首次允许在强大的C。elegans遗传模型我们的目标的实现将锚运动和健康老龄化的遗传学研究的一个新的子领域，可能会影响广泛促进健康和延缓衰老的干预措施的设计。

 DESCRIPTION (provided by applicant): Exercise is arguably the most potent approach we can take to defer physical decline associated with aging and to protect against late onset diseases such as diabetes, cancer, and Alzheimer's disease. Molecular understanding of how exercise benefits translate into healthy aging is thus of definitive medical interest. 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 (swim) to exhibit training benefits, and appear to gain benefits by molecular pathways conserved in humans. Our initial model development opens up a new research area for understanding how tissue-specific and organism-wide health benefits are induced by exercise, and creates a novel paradigm for identifying exercise mimetic drugs that might promote healthy aging. To really harvest the potential of this model, we need to measure the strength of the tiny C. elegans. We collaborated to develop a strength test in which trained animals thread through a matrix of deformable pillars, and the extent of pillar deflection is used to calculate force. Our "NemaFlex" force detection device is the quantitative foundation with which we expect to break new ground in understanding exercise impact on healthy aging. Here we propose required development to enhance assay throughput and pursue applications that will not only anchor this technology as an essential component of C. elegans exercise evaluation but also accelerate studies on exercise biology and healthy aging in this powerful model. Aim 1 is to develop a novel high throughput tool for direct strength evaluation in C. elegans. This aim will generate an essential tool for analysis of C. elegans strength at multiple life stages, define the exercise regimen that will become the anchor protocol in the field, and reveal features of training in this model. Aim 2 is to use NemaFlex to evaluate exercise mimetic drugs & to facilitate focused pilot genetic screens. This aim will establish critical proof-of-principle for genetic and drug discovery using the NemaFlex. Aim 3 is to initiate dissection of the functional and molecular relationship between exercise and healthy aging, grounded in NemaFlex force measures of training benefits. To begin, we will test how optimized strength training tracks with a broad spectrum of healthspan indicators that decline with age, we will investigate impact of cessation of training on aging quality, and we will ask if exercise mimetic drugs extend healthspan in the absence of training. Our goals will create novel technology that for the first time permits facile quantitativ analysis of exercise adaptations in the powerful C. elegans genetic model. Accomplishment of our tractable aims will anchor a new subfield of genetic investigation of exercise and healthy aging that may influence design of interventions that broadly promote health and defer aging.