{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T09:24:15Z","timestamp":1783329855116,"version":"3.54.6"},"posted":{"date-parts":[[2026,6,25]]},"reference-count":44,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T00:00:00Z","timestamp":1782345600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"crossref","award":["U19AG023122"],"award-info":[{"award-number":["U19AG023122"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"crossref","award":["AG024824"],"award-info":[{"award-number":["AG024824"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"crossref","award":["Career Training in the Biology of Aging T32 - NIH\/NIA T32-AG000114"],"award-info":[{"award-number":["Career Training in the Biology of Aging T32 - NIH\/NIA T32-AG000114"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"crossref","award":["R35 GM137795"],"award-info":[{"award-number":["R35 GM137795"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>The pace of aging can be delayed by mutations, dietary manipulations, and drugs, yet the metabolic mechanisms underlying longevity interventions remain poorly understood. Here we present a multi-tissue metabolomic analysis of male UM-HET3 mice treated from 4 to 12 months of age with five validated longevity interventions: rapamycin, acarbose, 17\u03b1-estradiol, canagliflozin, or caloric restriction. Using a feature-stabilized XGBoost pipeline applied to seven tissues, we show that metabolomic profiles can identify treated mice as likely recipients of a lifespan-extending intervention well before survival differences emerge. A leave-one-intervention-out procedure confirmed that models trained on any four interventions successfully classified mice from a fifth, unseen intervention, implying shared metabolic alterations across mechanistically distinct treatments. The most influential metabolites \u2014 defined as the minimum set explaining 50% of cumulative model gain \u2014 differed substantially across tissues. Only ergothioneine, a dietary antioxidant, ranked highly in more than two tissues: it was elevated by all five interventions in plasma and brain, and by four of five in muscle. Enrichment analyses further identified coordinated remodeling of lipid classes in plasma, perigonadal fat, and kidney. These findings reveal tissue-specific metabolic reprogramming shared across mechanistically distinct longevity interventions and, pending validation against interventions that do not extend lifespan, suggest a path toward metabolomic screening of candidate anti-aging drugs.<\/jats:p>","DOI":"10.64898\/2026.06.24.734388","type":"posted-content","created":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T15:30:43Z","timestamp":1782401443000},"source":"Crossref","is-referenced-by-count":0,"title":["Multi-Tissue Metabolomic Signatures of Five Longevity Interventions Converge on Ergothioneine and Lipid Remodeling in Male UM-HET3 Mice"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8985-4325","authenticated-orcid":false,"given":"Bretton","family":"Badenoch","sequence":"first","affiliation":[{"name":"Department of Molecular and Cellular Pathology, University of Michigan, Ann Arbor, MI, 48103, 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