{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T04:50:32Z","timestamp":1791348632305,"version":"4.3.1"},"posted":{"date-parts":[[2026,10,2]]},"group-title":"Systems Biology","reference-count":38,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:00Z","timestamp":1790899200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Fundamental Fund (FF) from the Science, Research and Innovation Promotion Fund (TSRI), Chiang Mai University","id":[{"id":"https:\/\/ror.org\/05m2fqn25","id-type":"ROR","asserted-by":"crossref"}]},{"name":"the Faculty of Medicine, Chiang Mai University","award":["FAC-MED-2569-0344"],"award-info":[{"award-number":["FAC-MED-2569-0344"]}],"id":[{"id":"https:\/\/ror.org\/05m2fqn25","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Fundamental Fund (FF) from the Science, Research and Innovation Promotion Fund (TSRI), Chiang Mai University","award":["FF, FY2568 Contract No. 207573"],"award-info":[{"award-number":["FF, FY2568 Contract No. 207573"]}],"id":[{"id":"https:\/\/ror.org\/05m2fqn25","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Health Systems Research Institute","award":["66-124"],"award-info":[{"award-number":["66-124"]}],"id":[{"id":"https:\/\/ror.org\/04yz0nm53","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Health Systems Research Institute","award":["68-060"],"award-info":[{"award-number":["68-060"]}],"id":[{"id":"https:\/\/ror.org\/04yz0nm53","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Mid-Career Research Grant of the National Research Council of Thailand.","award":["N42A670768"],"award-info":[{"award-number":["N42A670768"]}],"id":[{"id":"https:\/\/ror.org\/018wfhg78","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Maintenance of neuronal function during aging requires metabolic adaptation, yet how metabolite-sensitive chromatin regulators contribute to this process remains unclear. YEATS-domain proteins, including ENL and AF9, recognize histone acylation marks and are positioned at the interface between cellular metabolism and transcriptional regulation. We previously showed that pan-neuronal suppression of\n                  <jats:italic>dENL\/AF9<\/jats:italic>\n                  , the single\n                  <jats:italic>Drosophila<\/jats:italic>\n                  orthologue of mammalian ENL and AF9, extends lifespan, preserves healthspan, and enhances oxidative-stress resistance. Here, we used multi-omics and biochemical analyses to define the molecular state associated with neuronal\n                  <jats:italic>dENL\/AF9<\/jats:italic>\n                  suppression. Transcriptomic profiling revealed a markedly stronger response in aged than young male fly heads, with prominent enrichment of fatty-acid degradation and several intermediary metabolic pathways in the aged dataset. Guided by this age-related transcriptional response, we focused subsequent profiling on aged heads, where independent molecular layers converged on a distinct metabolic and energetic signature. Lipidomics identified reduced abundance of multiple triglyceride-related and fatty acid derivatives, while metabolomics revealed changes in central-carbon\/TCA-, nicotinamide-, and purine-associated features. Proteomics implicated mitochondrial and ATP-associated processes, accompanied by increased ATP abundance and a higher NAD\/NADH ratio. Matched lipidome-metabolome integration further identified citrate as a cross-omics feature inversely associated with altered triglyceride and ceramide species, linking central-carbon and lipid-associated components of the molecular signature. Together, these findings identify a stronger transcriptional response to neuronal\n                  <jats:italic>dENL\/AF9<\/jats:italic>\n                  suppression in aged flies and a distinct metabolic and energetic molecular signature in aged fly heads, providing candidate molecular correlates of the previously established longevity phenotype and a framework for studies of neuronal aging biology.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Graphical abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"755827v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.30.755827","type":"posted-content","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T09:25:12Z","timestamp":1790933112000},"source":"Crossref","is-referenced-by-count":0,"title":["Multi-omics profiling identifies a metabolic and energetic signature associated with neuronal\n                  <i>dENL\/AF9<\/i>\n                  suppression in aged flies"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3915-0260","authenticated-orcid":false,"given":"Ranchana","family":"Yeewa","sequence":"first","affiliation":[{"name":"Center of Multidisciplinary Technology for Advanced Medicine (CMUTEAM), Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pitiporn","family":"Noisagul","sequence":"additional","affiliation":[{"name":"Center of Multidisciplinary Technology for Advanced Medicine (CMUTEAM), Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sivamoke","family":"Dissook","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chansunee","family":"Panto","sequence":"additional","affiliation":[{"name":"Drosophila Centre for Human Diseases and Drug Discovery (DHD), Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Puttachat","family":"Poound","sequence":"additional","affiliation":[{"name":"Drosophila Centre for Human Diseases and Drug Discovery (DHD), Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salinee","family":"Jantrapirom","sequence":"additional","affiliation":[{"name":"Drosophila Centre for Human Diseases and Drug Discovery (DHD), Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand"},{"name":"Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0558-356X","authenticated-orcid":false,"given":"Luca","family":"Lo Piccolo","sequence":"additional","affiliation":[{"name":"Center of Multidisciplinary Technology for Advanced Medicine (CMUTEAM), Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026100621000987000_2026.09.30.755827v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/J.CMET.2018.05.011"},{"issue":"4","key":"2026100621000987000_2026.09.30.755827v1.2","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1016\/j.cmet.2019.09.001","article-title":"NAD+ in brain aging and neurodegenerative disorders","volume":"30","year":"2019","journal-title":"Cell 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