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

项目总结 对广泛物种的研究已经建立了一套共同的进化保守的特征 衰老，包括与年龄相关的活动能力下降和线粒体功能衰竭。这一证据表明 药物干预改善健康衰老和延长寿命的潜力。药理作用 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) 一种改善年龄相关性身体功能损害的有效疗法，也是减缓衰老的潜在策略 人类的衰老。血管紧张素转换酶抑制在减少与年龄相关的组织损伤方面的有益作用，如 骨骼肌，可能部分归因于该药物保护线粒体功能的能力。然而， 在人体研究中，对RAS封锁的体能改善有很大不同，可能 由于个体间的遗传差异。这一领域的研究由于缺乏对 将衰老、遗传学和对药物治疗的反应联系起来的生物学，因为缺乏 适用于生物学和干预研究的动物模型。为了解决这个问题，我们建议利用 血管紧张素转换酶在物种间的进化保守以确定其抗衰老作用的遗传基础 无脊椎动物模型中的ACEI赖诺普利。这项拟议的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)，由不同的基因组成 来自自然种群的苍蝇品系。我们利用三种不同基因的DGRP进行的初步研究 Lines透露，赖诺普利的治疗延长了D患者的寿命，并改善了年龄特定的步行能力。 但它是以一种特定于基因型的方式做到这一点的。我们的数据还表明，特定于基因型的 对赖诺普利的反应可能部分通过改变线粒体功能的程度来起作用。 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，以首次识别对ACEI反应的变异、基因和遗传途径 改善与年龄有关的活动能力下降，延长寿命(目标1)。功能遗传学研究 然后提出利用候选基因的RNA干扰(RNAi)来验证ACEI对 寿命和健康寿命，并测试这些影响是否通过线粒体功能的变化而介导 在骨骼肌中(目标2)。最后，我们建议评估ACEI对基因的全基因组效应。 胸肌RNAi延寿和/或延寿基因的表达及其代谢组 为了深入了解血管紧张素转换酶调节寿命和健康寿命的机制(S) (目标3)。拟议研究的完成将确定调节 血管紧张素转换酶抑制剂介导的老年人体能的改善。

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.