Genetic variation underlying the response to longevity interventions

描述(申请人提供)：几乎所有的多细胞生物都会随着年龄的增长而逐渐退化生理功能--也就是说，随着年龄的增长，它们会逐渐退化。在过去的二十年里，对潜在的应激抗性和其他与年龄相关的表型的保守遗传途径的分子调控的显着洞察力增加了这样一种前景，即可以确定特定的药物干预措施，从而在他们整个生命周期内增强人类的健康。然而，这里的一个主要问题是，任何特定个体对药物治疗的反应可能高度依赖于他们特定的遗传背景；这一点已经在许多研究中观察到。因此，希望找出即使面对种群内巨大的基因变异也能保持预期效果的药物干预措施。线虫属为解决这一问题提供了理想的背景，因为(1)关键靶标途径的许多基本生物学是使用这一组中的一个成员(线虫)进行的，(2)非常相似的实验方法可用于测试一组相关物种的药物干预反应，这些物种跨越广泛的潜在遗传背景，相当于老鼠和人之间的距离。线虫病干预测试计划(CITP)的目标是检查各种药理制剂在这些物种(以及物种内的自然分离株)中的一致效果。在这里，我们的目标是(1)测量药物干预对多种线虫物种寿命的影响，(2)评估药物干预对健康的生理和生化措施的影响，以及(3)分析特定的分子和生理功能，这些功能是干预导致寿命延长和健康措施的基础。这些实验将使用各种创新的分析方法进行，以实现对个体寿命、生理、行为和健康的高通量、高精度估计。项目目标将通过联合管理结构实现，该结构由项目参与者和选定的外部成员组成的指导委员会监督，候选药物由指定的准入小组挑选。所有实验结果都将提供给更广泛的科学界，并发表在科学文献中。确定可以提高健康和生理表现的药物治疗，特别是在阻止通常与衰老有关的经常性功能退化方面，有可能彻底改变人们变老的方式--将健康状态延长到生命的更晚--从而在日益老龄化的社会中降低医疗保健服务的成本。

DESCRIPTION (provided by applicant): Nearly all multicellular organisms undergo progressive degradation of physiological function as they get older-that is, they age. Over the last two decades remarkable insights into the molecular regulation of conserved genetic pathways underlying stress resistance and other age-related phenotypes raises the prospect that specific pharmacological interventions can be identified that will enhance human health throughout the entirety of their lifespan. A major concern here, however, is that the response of any particular individual to a drug treatment may be highly dependent on their specific genetic background; something that has been observed in a number of studies. The hope, therefore, is to identify drug interventions that maintain their desired effects even in the face of substantial genetic variation within a population. The nematode genus Caenorhabditis provides an ideal context for addressing this issue because (1) much of the fundamental biology of the critical target pathways has been conducted using a member of this group (C. elegans) and (2) very similar experimental approaches can be used to test drug-intervention responses of a set of related species that span a broad range of potential genetic backgrounds, equivalent to the distance between mice and humans. The goal of the Caenorhabditis Intervention Testing Program (CITP) is to examine a variety of pharmacological agents for consistent effects across these species (and natural isolates within species). Here, we aim to (1) measure the effect of pharmacological interventions on the lifespan of multiple nematode species, (2) evaluate the impact of pharmacological interventions on physiological and biochemical measures of health, and (3) analyze the specific molecular and physiological functions hypothesized to underlie intervention-induced increases in lifespan and health measures. These experiments will be carried out using a variety of innovative assays that allow high throughput, high precision estimates of individual longevity, physiology, behavior and health. Project goals will be achieved via a joint management structure that is overseen by a Steering Committee of program participants and selected outside members, with drug candidates selected by an appointed Access Panel. All experimental outcomes will be made available to the broader scientific community, as well as being published in the scientific literature. Identifying drug treatments tha enhance health and physiological performance, particularly in regard to holding back the regular degradation of function usually associated with aging, has the potential to revolutionize the manner which people age-prolonging healthy states much later into life-thereby decreasing costs of healthcare delivery in an increasingly aging society.