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

果蝇 ACE 抑制延长寿命和健康寿命的遗传基础

• 批准号: 10437098
• 负责人: Robert R. H Anholt
• 金额: $ 49.82万
• 依托单位: CLEMSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10437098
• 关键词: Address; Affect; Age; Aging; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Animal Model; Area; Binding; Bioenergetics; Biological; Biological Models; Biology; Blood Vessels; Blood flow; Candidate Disease Gene; Cardiovascular system; Categories; Cell physiology; Chest; Data; Drosophila genus; Drosophila melanogaster; Enzyme Inhibition; Enzyme Inhibitor Drugs; Enzymes; Failure; Female; Gene Expression; Genes; Genetic; Genetic Variation; Genetic study; Genomics; Genotype; Goals; Health Status; Homologous Gene; Human; Hypertension; Impairment; Individual; Individual Differences; Intervention; Intervention Studies; Invertebrates; Lisinopril; Locomotion; Longevity; Mediating; Metabolic Pathway; Metabolism; Mitochondria; Modeling; Morphology; Motor Activity; Muscle; Muscle Mitochondria; Ontology; Organ; Pathway interactions; Peptidyl-Dipeptidase A; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phenotype; Physical Function; Physical Performance; Play; Population; Publishing; RNA Interference; Regulatory Pathway; Renin-Angiotensin System; Research; Resources; Role; Signal Pathway; Skeletal Muscle; System; Testing; Tissues; Variant; Vertebrates; Walking; Work; age effect; age related; anti aging; base; blood pressure medication; design; differential expression; effective therapy; fly; gene conservation; genome wide association study; genome-wide; genomic biomarker; genomic predictors; healthspan; healthy aging; hemodynamics; improved; in vivo; inhibitor therapy; insight; knock-down; male; metabolome; mouse model; novel; preservation; response; senescence; trait; transcriptome

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.

项目摘要 跨广泛物种的研究建立了一组共同​​的进化构成标志 衰老，包括与年龄相关的活动性和线粒体衰竭的下降。该证据指出 药理干预的潜力以改善健康的衰老并延长寿命。药理 通过抑制血管紧张素转换酶（ACE）为 一种有效的疗法来改善与年龄相关的身体机能损害，并且是降低的潜在策略 人类衰老。 ACE IBININIT在减少组织年龄相关的损害方面的有益作用，例如 骨骼肌可能部分归因于该药物保持线粒体功能的能力。然而， 在人类研究中，对RAS封锁的响应响应的身体性能的改善有可能 由于个体之间的遗传变异。由于缺乏了解 连接衰老，遗传学和对药物治疗的反应的生物学以及由于短缺 适当的动物模型用于生物学和干预研究。为了解决这个问题，我们建议利用 跨物种对ACE的进化保护，以确定抗衰老作用的遗传基础 无脊椎动物模型D. Melanogaster中的ACEI Lisinopril。拟议的研究以强大的 基因组学资源，果蝇遗传参考面板（DGRP），由遗传上的不同 自然人口衍生的苍蝇线。我们使用三个普遍不同DGRP的初步研究 线条表明，赖诺普利的治疗可以延长寿命，并改善了D的年龄特异性步行。 Melanogaster，但它以基因型特异性方式这样做。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程度变化来部分作用 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 映射400个新的DGRP线，首先识别对ACEI响应的变体，基因和遗传途径 改善运动活动与年龄相关的下降并延长寿命（AIM 1）。功能性遗传研究 然后提出使用候选基因的RNA干扰（RNAi）来验证ACEI对 寿命和健康范围，并测试这些效果是否是通过线粒体功能的变化介导的 在骨骼肌中（AIM 2）。最后，我们建议评估ACEI对基因的基因组广泛影响 表达和代谢组的基因代谢组，胸肌中的RNAi延长了寿命和/或 HealthSpan是为了深入了解ACEI调节寿命和HealthSpan的机制 （目标3）。拟议研究的完成将确定调节的遗传和代谢途径 ACEI介导的老年人的身体表现改善。