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Yet, with few exceptions, these studies are conducted in a limited number of isogenic strains. The path from laboratory discoveries to treatment in human populations is complicated by the reality of genetic variation in nature. To model the effect of genetic variation on the action of the drug rapamycin, here we use the growth of <jats:italic>Drosophila melanogaster<\/jats:italic> larvae. We screened 140 lines from the <jats:italic>Drosophila<\/jats:italic> Genetic References Panel for the extent of developmental delay and found wide\u2010ranging variation in their response, from lines whose development time is nearly doubled by rapamycin, to those that appear to be completely resistant. Sensitivity did not associate with any single genetic marker, nor with any gene. However, variation at the level of genetic pathways was associated with rapamycin sensitivity and might provide insight into sensitivity. In contrast to the genetic analysis, metabolomic analysis showed a strong response of the metabolome to rapamycin, but only among the sensitive larvae. In particular, we found that rapamycin altered levels of amino acids in sensitive larvae, and in a direction strikingly similar to the metabolome response to nutrient deprivation. This work demonstrates the need to evaluate interventions across genetic backgrounds and highlights the potential of omic approaches to reveal biomarkers of drug efficacy and to shed light on mechanisms underlying sensitivity to interventions aimed at increasing lifespan.<\/jats:p>","DOI":"10.1111\/acel.14292","type":"journal-article","created":{"date-parts":[[2024,8,13]],"date-time":"2024-08-13T04:24:05Z","timestamp":1723523045000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Wide\u2010ranging genetic variation in sensitivity to rapamycin in <i>Drosophila melanogaster<\/i>"],"prefix":"10.1111","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4268-7686","authenticated-orcid":false,"given":"Benjamin R.","family":"Harrison","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine and Pathology University of Washington School of Medicine  Seattle Washington USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mitchell B.","family":"Lee","sequence":"additional","affiliation":[{"name":"Ora Biomedical, Inc.  Tukwila Washington USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shufan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology University of Washington School of Medicine  Seattle Washington USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bill","family":"Young","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology University of Washington School of Medicine  Seattle Washington USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenneth","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology University of Washington School of Medicine  Seattle Washington USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiranut","family":"Sukomol","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology University of Washington School of Medicine  Seattle Washington USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vanessa","family":"Paus","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology University of Washington School of Medicine  Seattle Washington USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarina","family":"Tran","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology University of Washington School of Medicine  Seattle Washington USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology University of Washington School of Medicine  Seattle Washington USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hannah","family":"Fitchett","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology University of Washington School of Medicine  Seattle Washington USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu\u2010Chen","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology University of Washington School of Medicine  Seattle Washington USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philmon","family":"Tesfaye","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology University of Washington School of Medicine  Seattle Washington USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9444-275X","authenticated-orcid":false,"given":"Alia W.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology University of Washington School of Medicine  Seattle Washington USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaqing","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology University of Washington School of Medicine  Seattle Washington USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Danijel","family":"Djukovic","sequence":"additional","affiliation":[{"name":"Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine University of Washington School of Medicine  Seattle Washington USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Raftery","sequence":"additional","affiliation":[{"name":"Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine University of Washington School of Medicine  Seattle Washington USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7088-4495","authenticated-orcid":false,"given":"Daniel E. 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