DISCOVER DETERMINANTS OF INDIVIDUAL LIFESPAN AND HEALTH

发现个人寿命和健康的决定因素

• 批准号: 10320013
• 负责人: Kerry Kornfeld
• 金额: $ 41.95万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320013
• 关键词: Address; Adult; Affect; Age; Age of Onset; Aging; Animals; Bacteria; Biological; Biological Assay; Caenorhabditis elegans; Data; Diagnostic; Environment; Environmental Risk Factor; Feedback; Food; Future; Genes; Genetic; Genetic Transcription; Genotype; Health; Heritability; Human; Individual; Individual Differences; Insulin; Insulin-Like Growth Factor I; Intervention; Knowledge; Lead; Length; Life; Longevity; Measurement; Measures; MicroRNAs; Molecular; Mutation; Noise; Organism; Pathogenesis; Pathway interactions; Phenotype; Physiological; Population; Process; Reporter; Resistance; Risk; Route; Signal Pathway; Signaling Protein; System; Techniques; Testing; Time; Transcriptional Regulation; Work; age effect; age related; base; experience; gene regulatory network; genetic analysis; healthspan; healthy aging; imaging system; improved; individual variation; innovation; inter-individual variation; mutant; pathogen; social culture; tool; young adult

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.

项目概要 我们对健康衰老的认识存在根本性差距：虽然我们了解如何从基因上改变 许多生物体的平均寿命，我们不明白为什么每个种群中的某些个体会导致 比这个平均值更长和/或更健康的生活（或更短/更不健康的生活）。这是关键知识： 弄清楚为什么有些人的寿命比其基因型预期的要长或短，可能会导致诊断 识别那些面临短命或健康不良风险的人，甚至采取干预措施来诱导这些长寿、健康的状态。 这项工作将使用基因相同的秀丽隐杆线虫来研究个体间衰老的变异性。尽管 这种变异性经常被忽视为“生物噪音”，我们的首要假设是个体之间的差异 寿命和健康寿命的差异是由可以理解、预测和理解的调节过程造成的 改变了。为了研究这一点，我们开发了一种创新的成像系统，其中饲养了许多分离的秀丽隐杆线虫 在相同的环境中，允许终身测量报告基因的表达和生理功能。 该提案的具体目标是确定我们所观察到的两组有趣观察结果的遗传基础。 使用该系统制作的。首先，我们发现 microRNA mir-71 和 lin-4 的转录调控导致 年轻人承诺特定的未来寿命。目标1将从基因角度剖析这个命运组合的过程 承诺。其次，我们发现传统的健康寿命衡量标准——人口平均数——是令人困惑的。 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（2）通过 增加人口中达到这一最大值的个人比例。目标 2 将确定 ge- 可以改变健康寿命的这两个方面的网络途径。 目标 1 的假设是，在成年早期，转录调节的“生命周期承诺网络” lator 将 mir-71 和 lin-4 驱动到不同个体的不同、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的 仍然未知：构成该网络的 mir-71 和 lin-4 周围的上游监管机构。 目标 2 将检验 IIS 突变体影响健康寿命两个方面的假设，我们的工具 现在让我们通过不同的机制直接测量。具体来说，我们建议：(1) IIS 影响 通过与延长寿命相同的效应器途径实现最大健康寿命；但是 (2) IIS 影响 通过对病原体抵抗力的与寿命无关的影响达到最大值的人口比例。 这项工作在用于研究个体动物和评估健康寿命的技术以及在 待检验的具体假设。通过识别允许的遗传相互作用，它将产生重大影响 人口中的特定个体享有延长的寿命和健康。这些相互作用将代表 未来干预的自然目标。