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Fibrosis and inflammation occur soon after a pathological event and reflect perturbation of tissue repair that accompanies aging in general. Yet not old, but young animals are typically used for studying MI, emphasizing the unmet need for more relevant preclinical models. We previously determined that plasma dilution, also termed neutral blood exchange (NBE) (replacing ~50% of plasma with saline containing 5% albumin) broadly promotes tissue repair and maintenance, reduces fibrosis and inflammation in old mice, and improves the health of humoral and cellular compartments of blood in old people. Here, we developed a novel preclinical model via combining two complex surgeries in aged mice: jugular vein cannulation followed by plasma dilution with open heart cardiac ischemia\u2013reperfusion (I\/R). Using this approach, we found that a single dilution of old plasma that was performed 24\u2009h after I\/R significantly and broadly improved the recovery at molecular, cellular, tissue, and functional levels in aged mice. Candidate molecular pathways (JAK\/STAT and TGF\u2010\u03b2) and target proteins associated with these beneficial effects have been suggested by the bioinformatics on comparative proteomics between sham, I\/R, and I\/R plus NBE groups. While future studies are needed to establish the detailed processes and safety profiles of plasma dilution as a treatment of MI, this work provides important translational and mechanistic insights into recovery from cardiac injury in aged patients.<\/jats:p>","DOI":"10.1111\/acel.70525","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T11:27:37Z","timestamp":1777548457000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Plasma Dilution After Myocardial Ischemia\u2013Reperfusion Injury Promotes Cardiac Repair, Heart Performance, and Recovery of Motor Function and Endurance in Old Mice"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6896-4119","authenticated-orcid":false,"given":"Joana Marie C.","family":"Cruz","sequence":"first","affiliation":[{"name":"Department of Bioengineering and QB3 Institute University of California Berkeley  Berkeley California USA"},{"name":"College of Medicine, University of the Philippines Manila  Manila Philippines"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rana","family":"Alzalzalee","sequence":"additional","affiliation":[{"name":"Department of Bioengineering and QB3 Institute University of California Berkeley  Berkeley California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2372-7842","authenticated-orcid":false,"given":"Hayden","family":"Yeung","sequence":"additional","affiliation":[{"name":"Department of Bioengineering and QB3 Institute University of California Berkeley  Berkeley California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zainab","family":"Mahmood","sequence":"additional","affiliation":[{"name":"Department of Bioengineering and QB3 Institute University of California Berkeley  Berkeley California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0148-2499","authenticated-orcid":false,"given":"Qile","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Bioengineering and QB3 Institute University of California Berkeley  Berkeley California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4189-236X","authenticated-orcid":false,"given":"Negar","family":"Morshedian","sequence":"additional","affiliation":[{"name":"Department of Bioengineering and QB3 Institute University of California Berkeley  Berkeley California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6073-1900","authenticated-orcid":false,"given":"Zachery R.","family":"Robinson","sequence":"additional","affiliation":[{"name":"Department of Bioengineering and QB3 Institute University of California Berkeley  Berkeley California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1436-1606","authenticated-orcid":false,"given":"Karan R.","family":"Malhotra","sequence":"additional","affiliation":[{"name":"Department of Bioengineering and QB3 Institute University of California Berkeley  Berkeley California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6434-4772","authenticated-orcid":false,"given":"Michael J.","family":"Conboy","sequence":"additional","affiliation":[{"name":"Department of Bioengineering and QB3 Institute University of California Berkeley  Berkeley California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad Reza","family":"Mazahery","sequence":"additional","affiliation":[{"name":"Institute of Biology, College of Science University of the Philippines  Quezon City Philippines"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5730-7105","authenticated-orcid":false,"given":"Jose B.","family":"Nevado","sequence":"additional","affiliation":[{"name":"College of Medicine, University of the Philippines Manila  Manila Philippines"},{"name":"National Institutes of Health (NIH), University of the Philippines Manila  Manila Philippines"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4276-0644","authenticated-orcid":false,"given":"Irina M.","family":"Conboy","sequence":"additional","affiliation":[{"name":"Department of Bioengineering and QB3 Institute University of California Berkeley  Berkeley California USA"},{"name":"Generation Lab, Inc.  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