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

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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.