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Here, we use publicly available proteomic datasets to profile plasma ECM protein abundances across the human lifespan and reveal a distinct U\u2010shaped trajectory with age. Our ECM\u2010based aging clock, constructed from 14 plasma proteins, accurately predicts chronological age and remains robust across independent validations and different biofluids. Notably, this ECM clock distinguishes between healthy and diseased states. Cross\u2010species comparisons show that while specific predictive ECM proteins differ between humans and rodents, species\u2010specific ECM clocks reliably track aging, and rejuvenation interventions can reverse ECM aging signatures. We prioritize ECM proteins implicated causally in disease and explored drugs targeting these proteins. These findings establish circulating ECM proteins as sensitive biomarkers of aging and disease and suggest that targeting ECM remodeling may offer new strategies for promoting healthy aging.<\/jats:p>","DOI":"10.1111\/acel.70474","type":"journal-article","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T04:00:27Z","timestamp":1776312027000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["An Extracellular Matrix Aging Clock Based on Circulating Matrisome Proteins Predicts Biological Aging and Disease"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5265-6656","authenticated-orcid":false,"given":"Loet","family":"Coenen","sequence":"first","affiliation":[{"name":"Department of Neurobiology &amp; Aging Biomedical Primate Research Centre  Rijswijk the Netherlands"},{"name":"Department of Molecular Cell Biology and Immunology Amsterdam Neuroscience, Amsterdam UMC Location Vrije Universiteit Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5435-8004","authenticated-orcid":false,"given":"Adrian","family":"Moli\u00e8re","sequence":"additional","affiliation":[{"name":"Laboratory of Extracellular Matrix Regeneration, Institute of Translational Medicine, Department of Health Sciences and Technology ETH Z\u00fcrich  Schwerzenbach Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benoit","family":"Lehallier","sequence":"additional","affiliation":[{"name":"Alkahest Inc  San Carlos California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9198-8020","authenticated-orcid":false,"given":"Jinte","family":"Middeldorp","sequence":"additional","affiliation":[{"name":"Department of Neurobiology &amp; Aging Biomedical Primate Research Centre  Rijswijk the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Collin Y.","family":"Ewald","sequence":"additional","affiliation":[{"name":"Laboratory of Extracellular Matrix Regeneration, Institute of Translational Medicine, Department of Health Sciences and Technology ETH Z\u00fcrich  Schwerzenbach Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,15]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2010024\u201003164\u20107"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43587\u2010021\u201000067\u2010x"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000599"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.248039"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10555\u2010008\u20109121\u20103"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593\u2010022\u201001238\u20108"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43587\u2010024\u201000683\u20103"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/ejn.14910"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2009.04.013"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3904"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad1040"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature22067"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.00605"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fragi.2023.1112109"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2017.05.028"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12065"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13195\u2010022\u201001113\u20105"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nicl.2020.102229"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.embor.7400422"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.10.045"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010023\u201006563\u2010x"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580\u2010018\u20100020\u20103"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1159\/000504295"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1159\/000215589"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.023820"},{"issue":"4","key":"e_1_2_11_27_1","first-page":"187","article-title":"A Role for WISP2 in Colorectal Cancer Cell Invasion and Motility","volume":"10","author":"Frewer K. 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