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The aging global population underscores the need to understand skeletal muscle aging, which is bottlenecked by the lack of in vitro models that recapitulate biological and functional features of aged human muscle as well as discrepancies between humans and animal models. Here, we present a 3D biomimetic aged skeletal muscle model using human primary skeletal muscle cells (SkMCs) embedded in a skeletal muscle\u2010derived decellularized extracellular matrix (dECM) scaffold. Constructs fabricated from aged and young SkMCs were systematically evaluated across structural, molecular, mitochondrial, calcium\u2010handling, and contractile readouts. Compared with young constructs, aged constructs recapitulated several aging\u2010associated biological and functional phenotypes, including smaller myotubes, altered myogenic and inflammatory marker expression, mitochondrial alterations, delayed calcium responses, and weakened contractile forces. This human\u2010relevant platform enables simultaneous assessment of biological and functional aspects of muscle aging and may serve as a translational tool to study mechanisms and screen therapies for age\u2010associated muscle disorders. This aligns with the FDA Modernization Act 2.0\u2014which recognizes in vitro human systems as alternatives to animal testing\u2014underscoring the practical relevance of this model.<\/jats:p>","DOI":"10.1002\/smsc.70386","type":"journal-article","created":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T03:47:54Z","timestamp":1789184874000},"source":"Crossref","is-referenced-by-count":0,"title":["A Biomimetic 3D Human Skeletal Muscle Microtissue for Modeling Biological and Functional Hallmarks of Aging"],"prefix":"10.1002","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9847-5650","authenticated-orcid":false,"given":"Sohae","family":"Yang","sequence":"first","affiliation":[{"name":"Department of New Biology DGIST  Daegu Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeong Sik","family":"Kong","sequence":"additional","affiliation":[{"name":"Department of Mechanical Engineering Pohang University of Science and Technology (POSTECH)  Pohang Kyungbuk Republic of Korea"},{"name":"POSTECH\u2010Catholic Biomedical Engineering Institute  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun Young","family":"Shin","sequence":"additional","affiliation":[{"name":"CTCELLS Corp.  Daegu Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung Chun","family":"Cho","sequence":"additional","affiliation":[{"name":"Well Aging Research Center DGIST  Daegu Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9946-3707","authenticated-orcid":false,"given":"Aseer","family":"Intisar","sequence":"additional","affiliation":[{"name":"Department of New Biology DGIST  Daegu Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3539-3118","authenticated-orcid":false,"given":"Min Young","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of New Biology DGIST  Daegu Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeong\u2010Jin","family":"Choi","sequence":"additional","affiliation":[{"name":"Advanced Bio and Healthcare Materials Research Division Korea Institute of Materials Science (KIMS)  Changwon Republic of Korea"},{"name":"Advanced Materials Engineering University of Science and Technology (UST)  Daejeon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun\u2010Il","family":"Lee","sequence":"additional","affiliation":[{"name":"Well Aging Research Center DGIST  Daegu Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5869-4330","authenticated-orcid":false,"given":"Dong\u2010Woo","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Mechanical Engineering Pohang University of Science and Technology (POSTECH)  Pohang Kyungbuk Republic of Korea"},{"name":"POSTECH\u2010Catholic Biomedical Engineering Institute  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4268-6886","authenticated-orcid":false,"given":"Minseok S.","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of New Biology DGIST  Daegu Republic of Korea"},{"name":"CTCELLS Corp.  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