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.

项目摘要 我们对健康衰老的了解存在一个根本的差距：虽然我们了解如何改变遗传改变 许多生物的平均寿命，我们不明白为什么每个人群中的某些人都领导 比这个平均水平更长和 /或健康的寿命（或更短 /更健康的寿命）。这是批判知识：不足 站立为什么某些人的寿命长或比预期的更短的基因型可能会导致诊断 确定那些有寿命短或健康状况不佳的风险的人，甚至采取干预措施以诱发这些长寿，健康的状态。 这项工作将使用一般相同的秀丽隐杆线虫来研究衰老的个体间变异性。尽管 这种可变性通常被忽略为“生物噪声”，我们的总体假设是个体间的假设 可以理解，预测和 改变。为了研究这一点，我们开发了一个创新的成像系统，其中许多孤立的秀丽隐杆线被饲养 在相同的环境中，可以终身测量报告基因表达和身体功能。 该提案的具体目的是确定两组有趣的观察的遗传基础我们 使用此系统制造。首先，我们发现MicroRNAS miR-71和LIN-4的转录调节原因 年轻人致力于特定的未来寿命。 AIM 1将一般会剖析此命运过程 病变。其次，我们发现，人口平均水平的传统测量结果混淆了 因为它可以通过两种不同的方式进行改进：（1）通过增加最大可能的健康状态，或（2） 增加达到这一最大值的人群中个人的比例。 AIM 2将确定GE- 可以改变健康范围这两个方面的每个方面的网络途径。 AIM 1的假设是，在成年后的早期，是转录调节的“寿命承诺网络” LATORS将miR-71和LIN-4驱动到不同个体的不同稳定的设定点。我们有两个有效的测定 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）。我们建议在遗传分析中使用经典技术来确定最后 剩下的未知：构成该网络的miR-71和LIN-4周围的上游调节器。 AIM 2将检验IIS突变体影响HealthSpan的两个方面的假设，我们的工具 现在允许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 通过相同的效应途径，其寿命的最大健康范围；但是（2）IIS影响 人口的一部分通过非寿命对病原体耐药性的影响达到最大。 这项工作都是创新的，无论是用于研究单个动物和评分健康的技术，都在 要测试的特定假设。通过确定允许的遗传相互作用，它将产生重大影响 人群中的特定个人享受延长的寿命和健康。这些互动将代表 未来干预措施的自然目标。