Genetic variation underlying the response to longevity interventions

描述（由申请人提供）：几乎所有的多细胞生物体随着年龄的增长，生理功能都会逐渐退化。在过去的二十年中，对作为抗应激和其他年龄相关表型基础的保守遗传途径的分子调控的显著见解提出了可以确定特定药理学干预的前景，这些干预将在整个生命周期中增强人类健康。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其特定的遗传背景;一些研究已经观察到这一点。因此，希望是确定药物干预措施，即使在人口中存在大量遗传变异的情况下，也能保持预期的效果。小杆线虫属为解决这一问题提供了一个理想的背景，因为（1）关键靶途径的许多基础生物学已经使用该组的一个成员进行（C。（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，相当于小鼠和人类之间的距离。小杆线虫干预试验计划（CITP）的目标是检查各种药理学试剂在这些物种（和物种内的天然分离株）中的一致作用。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指标的影响，（3）分析特定的分子和生理功能，这些功能被假设为干预诱导的寿命和健康指标增加的基础。这些实验将使用各种创新的检测方法进行，这些方法可以高通量、高精度地估计个体的寿命、生理、行为和健康。项目目标将通过一个联合管理结构来实现，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，候选药物由指定的访问小组选择。所有实验结果都将提供给更广泛的科学界，并在科学文献中发表。确定药物治疗，以提高健康和生理性能，特别是在阻止定期退化的功能通常与衰老有关，有可能彻底改变人们的方式，延长健康状态到生命后期，从而降低成本的医疗保健服务，在日益老龄化的社会。

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.