DISCOVER DETERMINANTS OF INDIVIDUAL LIFESPAN AND HEALTH

项目摘要 我们对健康老龄化的认识存在着一个根本性的空白：虽然我们知道如何从基因上改变衰老， 许多生物体的平均寿命，我们不明白为什么每个种群中的一些个体 更长和/或更健康的寿命（或更短/更不健康的寿命）。这是一个关键的知识：根据- 为什么有些人的寿命比他们的基因型预期的更长或更短，这可能会导致诊断， 确定那些有生命短暂或健康不佳风险的人，甚至采取干预措施，以诱导这些长寿的健康状态。 这项工作将使用基因相同的C。elegans来研究衰老过程中的个体间差异。虽然 这种变异性通常被忽视为“生物噪音”，我们的首要假设是， 寿命和健康寿命的差异是由可以理解、预测和 改变了为了研究这一点，我们开发了一种创新的成像系统，其中许多孤立的C。优雅的人 在相同的环境中，允许终身测量报告基因表达和生理功能。 这项建议的具体目标是确定两组有趣的观察结果的遗传基础， 使用这个系统。首先，我们发现微RNA mir-71和lin-4的转录调控导致了 年轻的成年人承诺一个特定的未来寿命。目标1将从遗传学角度剖析这一命运过程。 受戒。其次，我们发现，传统的健康寿命衡量标准，即人口平均水平， 因为它可以通过两种不同的方式来改善：（1）通过增加最大可能的健康寿命，或者（2）通过 增加了种群中达到这一最大值的个体的比例。目标2将确定通用电气- 这两个方面的健康寿命都可以改变的遗传途径。 目标1的假设是，在成年早期，转录调节的"寿命承诺网络"， 在不同的个体中，激光器将miR-71和LIN-4驱动到不同的、稳定的设定点。我们有两种有效的检测方法 对于网络的活动，我们知道不同的设定点通过胰岛素/ IGF-1样信号通路（IIS）。我们建议使用遗传分析中的经典技术来识别最后一个 尚不清楚的是：构成这一网络的mir-71和lin-4周围的上游调节因子。 目标2将测试IIS突变体影响healthspan的两个方面中的每一个的假设，我们的工具 现在我们可以通过不同的机制直接测量。具体而言，我们提出：（1）IIS影响 最大的健康寿命通过相同的效应途径，它增加寿命;但（2）IIS影响 通过对病原体抗性的寿命独立效应，达到最大值的人口比例。 这项工作是创新的，无论是在技术上用于研究个别动物和评分的健康跨度， 具体的假设要检验。它将通过识别基因相互作用产生重大影响， 人口中的特定个体享有延长的寿命和健康。这些互动将代表 未来干预的自然目标。

PROJECT SUMMARY There is a fundamental gap in our knowledge of healthy aging: while we understand how to genetically alter the average lifespan of many organisms, we do not understand why some individuals within every population lead longer and/or healthier lives (or shorter / less healthy lives) than this average. This is critical knowledge: under- standing why some humans live longer or shorter than expected for their genotype could lead to diagnostics to identify those at risk for short life or ill health, or even interventions to induce these long-lived, healthy states. This work will use genetically identical C. elegans to study inter-individual variability in aging. Though this variability is often disregarded as “biological noise”, our overarching hypothesis is that inter-individual differences in lifespan and healthspan result from regulated processes that can be understood, predicted, and altered. To study this, we developed an innovative imaging system in which many isolated C. elegans are reared in identical environments, permitting lifelong measurement of reporter expression and physiological function. The specific objective of this proposal is to identify the genetic basis of two sets of intriguing observations we made using this system. First, we found that transcriptional regulation of the microRNAs mir-71 and lin-4 causes young adults to commit to a particular future lifespan. Aim 1 will genetically dissect this process of fate com- mitment. Second, we found that the traditional measure of healthspan, the population average, is confounded because it can be improved in two distinct ways: (1) by increasing the maximum possible healthspan, or (2) by increasing the proportion of individuals within the population that attain this maximum. Aim 2 will identify the ge- netic pathways by which each of these two aspects of healthspan can be altered. The hypothesis of Aim 1 is that, early in adulthood, a “lifespan commitment network” of transcriptional regu- lators drives mir-71 and lin-4 to different, stable set-points in different individuals. We have two potent assays for the activity of the network, and we know that different set-points lead to different lifespans via the insulin/ IGF-1-like signaling pathway (IIS). We propose to use classic techniques in genetic analysis to identify the last remaining unknown: the upstream regulators surrounding mir-71 and lin-4 that constitute this network. Aim 2 will test the hypothesis that IIS mutants influence each of the two aspects of healthspan, which our tools now allow us to directly measure, through distinct mechanisms. Specifically, we propose: (1) that IIS influences maximal healthspan via the same effector pathways by which it increases lifespan; but (2) that IIS influences the fraction of the population reaching that maximum by lifespan-independent effects on pathogen resistance. This work is innovative, both in the techniques used to study individual animals and to score healthspan, and in the specific hypotheses to be tested. It will have significant impact by identifying genetic interactions that allow specific individuals within a population to enjoy extended lifespan and health. These interactions will represent natural targets for future interventions.