Genetic Basis of Lifespan and Healthspan Extension by ACE Inhibition in Drosophila

项目摘要 对广泛物种的研究已经建立了一套共同的进化保守特征 包括与年龄相关的活动能力下降和线粒体功能衰竭。这些证据表明， 药理学干预改善健康衰老和延长寿命的潜力。药理 通过抑制血管紧张素转换酶（ACE）阻断肾素血管紧张素系统（RAS）， 是一种有效的治疗方法，可以改善与年龄相关的身体功能障碍， 人类衰老血管紧张素转换酶抑制剂在减少年龄相关的组织损伤方面的有益作用，如 骨骼肌，可能部分归因于药物保护线粒体功能的能力。然而，在这方面， 在人体研究中，响应RAS阻断的身体表现的改善变化很大，可能 这是由于个体之间的遗传变异。由于缺乏了解，这一领域的研究进展缓慢。 生物学连接衰老，遗传学和对药物治疗的反应， 用于生物学和干预研究的适当动物模型。为了解决这个问题，我们建议利用 ACE在物种间的进化保守性，以确定抗衰老作用的遗传基础。 ACEi赖诺普利在无脊椎动物模型D.黑腹菌这项研究建立在一个强大的 基因组学资源，果蝇遗传参考小组（DGRP），其中包括遗传上不同的 来自自然种群的果蝇品系。我们的初步研究使用了三种遗传多样的DGRP 线显示，赖诺普利治疗延长寿命，并改善年龄特异性步行D. 黑腹，但它这样做在一个基因型特异性的方式。我们的数据还表明，基因型特异性 对赖诺普利的反应可能部分通过线粒体功能的变化程度起作用， 受药物治疗的影响。为了解决这一假设，我们建议使用全基因组关联 在400个新的DGRP系中进行定位，以首先鉴定对ACEi应答的变体、基因和遗传途径， 改善与年龄相关的运动活性下降并延长寿命（目的1）。功能遗传学研究 利用候选基因的RNA干扰（RNAi），然后提出验证ACEi对 并测试这些影响是否通过线粒体功能的变化介导 骨骼肌（目标2）。最后，我们建议评估ACEi对基因的全基因组效应， 在胸肌中RNAi延长寿命的基因的表达和代谢组，和/或 为了深入了解ACEi调节寿命和健康寿命的机制， (Aim 3）。完成拟议的研究将确定调控基因和代谢途径， ACEi介导的老年人体能改善。

PROJECT SUMMARY Studies across a broad range of species have established a common set of evolutionarily conserved hallmarks of aging, including age-related decline in mobility and mitochondrial failure. This evidence points to the potential for pharmacological intervention to improve healthy aging and extend longevity. Pharmacological blockade of the Renin Angiotensin System (RAS) by inhibition of the angiotensin-converting enzyme (ACE) is an effective therapy in improving age-related impairment of physical function and is a potential strategy to slow human aging. The beneficial effect of ACE ihibition in reducing age-associated damage of tissues, such as the skeletal muscle, may be attributed in part by the drug’s capacity to preserve mitochondrial function. However, improvement in physical performance in response to RAS blockade varies widely in human studies, potentially due to genetic variation among individuals. Research in this area has been slowed by lack of understanding of the biology that connects aging, genetics, and response to drug treatment and because of the shortage of appropriate animal models for biological and intervention studies. To tackle this issue, we propose to leverage the evolutionary conservation of ACE across species to determine the genetic basis for the anti-aging effect of the ACEi Lisinopril in the invertebrate model D. melanogaster. The proposed research builds on a powerful genomics resource, the Drosophila Genetic Reference Panel (DGRP), which consists of genetically distinct lines of flies derived from a natural population. Our preliminary studies using three genetically diverse DGRP lines revealed that treatment with Lisinopril extends lifespan and improves age-specific walking in D. melanogaster, but it does so in a genotype-specific manner. Our data also suggest that genotype-specific responses to Lisinopril may act, in part, through variation in the degree to which mitochondrial function is affected by the drug treatment. To address this hypothesis, we propose to use genome-wide association mapping in 400 new DGRP lines to first identify variants, genes and genetic pathways that respond to ACEi to ameliorate age-related decline in locomotor activity and extend lifespan (Aim 1). Functional genetic studies using RNA interference (RNAi) of candidate genes are then proposed to validate the effects of ACEi on lifespan and healthspan and to test whether these effects are mediated via changes in mitochondrial function in skeletal muscle (Aim 2). Finally, we propose to evaluate the genome wide effects of ACEi on gene expression and the metabolome for genes for which RNAi in thoracic muscle extends lifespan and/or healthspan in order to gain insight into the mechanism(s) by which ACEi modulates lifespan and healthspan (Aim 3). Completion of the proposed studies will identify genetic and metabolic pathways that regulate the ACEi-mediated improvement in physical performance in older individuals.