{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T18:29:38Z","timestamp":1790706578780,"version":"4.1.0"},"reference-count":57,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,1,14]],"date-time":"2022-01-14T00:00:00Z","timestamp":1642118400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["T32-AG058527"],"award-info":[{"award-number":["T32-AG058527"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Despite impressive results in restoring physical performance in rodent models, treatment with renin\u2013angiotensin system (RAS) inhibitors, such as Lisinopril, have highly mixed results in humans, likely, in part, due to genetic variation in human populations. To date, the genetic determinants of responses to drugs, such as RAS inhibitors, remain unknown. Given the complexity of the relationship between physical traits and genetic background, genomic studies which predict genotype- and age-specific responses to drug treatments in humans or vertebrate animals are difficult. Here, using 126 genetically distinct lines of Drosophila melanogaster, we tested the effects of Lisinopril on age-specific climbing speed and endurance. Our data show that functional response and sensitivity to Lisinopril treatment ranges from significant protection against physical decline to increased weakness depending on genotype and age. Furthermore, genome-wide analyses led to identification of evolutionarily conserved genes in the WNT signaling pathway as being significantly associated with variations in physical performance traits and sensitivity to Lisinopril treatment. Genetic knockdown of genes in the WNT signaling pathway, Axin, frizzled, nemo, and wingless, diminished or abolished the effects of Lisinopril treatment on climbing speed traits. Our results implicate these genes as contributors to the genotype- and age-specific effects of Lisinopril treatment and because they have orthologs in humans, they are potential therapeutic targets for improvement of resiliency. Our approach should be widely applicable for identifying genomic variants that predict age- and sex-dependent responses to any type of pharmaceutical treatment.<\/jats:p>","DOI":"10.3390\/genes13010143","type":"journal-article","created":{"date-parts":[[2022,1,14]],"date-time":"2022-01-14T12:34:04Z","timestamp":1642163644000},"page":"143","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Genome-Wide Analysis in Drosophila Reveals the Genetic Basis of Variation in Age-Specific Physical Performance and Response to ACE Inhibition"],"prefix":"10.3390","volume":"13","author":[{"given":"Mariann M.","family":"Gabrawy","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA"},{"name":"Biology of Healthy Aging Program, Division of Geriatric Medicine and Gerontology, School of Medicine, Johns Hopkins University, Baltimore, MD 21224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nick","family":"Khosravian","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George S.","family":"Morcos","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8360-8032","authenticated-orcid":false,"given":"Tatiana V.","family":"Morozova","sequence":"additional","affiliation":[{"name":"Program in Genetics, Department of Biological Sciences, North Carolina State University, Raleigh, NC 27607, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meagan","family":"Jezek","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy D.","family":"Walston","sequence":"additional","affiliation":[{"name":"Biology of Healthy Aging Program, Division of Geriatric Medicine and Gerontology, School of Medicine, Johns Hopkins University, Baltimore, MD 21224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Animal Science, Michigan State University, East Lansing, MI 48824, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter M.","family":"Abadir","sequence":"additional","affiliation":[{"name":"Biology of Healthy Aging Program, Division of Geriatric Medicine and Gerontology, School of Medicine, Johns Hopkins University, Baltimore, MD 21224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeff","family":"Leips","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/30374","article-title":"Human gene for physical performance","volume":"393","author":"Montgomery","year":"1998","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.2165\/00007256-200838120-00008","article-title":"Keeping pace with ACE: Are ACE inhibitors and angiotensin II type 1 receptor antagonists potential doping agents?","volume":"38","author":"Wang","year":"2008","journal-title":"Sports Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e980","DOI":"10.7717\/peerj.980","article-title":"ACE and UCP2 gene polymorphisms and their association with baseline and exercise-related changes in the functional performance of older adults","volume":"3","author":"Keogh","year":"2015","journal-title":"PeerJ"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1249\/01.mss.0000495265.83724.db","article-title":"The angiotensin-converting enzyme I\/D polymorphism and exercise-induced changes in physical function among Caucasian older adults","volume":"46","author":"Buford","year":"2014","journal-title":"Med. 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