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We investigated whether metformin (MET) mitigates CM aging in guinea pigs and explored the underlying mechanism. A D\u2010galactose\u2013induced CM aging model was established in\u00a0vivo in guinea pigs and in\u00a0vitro using primary ciliary smooth muscle cells (CSMCs). The effects of MET on age\u2010related changes in tissue architecture, senescence markers, cell\u2010cycle progression, autophagic activity, and mitochondrial homeostasis were assessed. In parallel, the involvement of glycogen synthase kinase\u20103\u03b2 (GSK\u20103\u03b2) signaling in the actions of MET was examined. MET significantly attenuated D\u2010galactose\u2013induced senescence in CM tissue and primary CSMCs, as reflected by improved fibrillar organization, reduced expression of the senescence markers p21, p16 and p53, and relief of G1\/S\u2010phase cell\u2010cycle arrest. At the molecular level, MET decreased GSK\u20103\u03b2 expression, stabilized \u03b2\u2010catenin in the cytoplasm, facilitated its nuclear translocation, and thereby supported more physiological cell\u2010cycle progression. In addition, MET restored autophagic activity in aged CSMCs and helped maintain intracellular and mitochondrial homeostasis. MET modulates the GSK\u20103\u03b2 pathway to coordinate cell\u2010cycle progression with autophagic activity, thereby delaying CM aging and preserving key cellular features that underpin accommodative function. These findings suggest that MET may represent a potential noninvasive pharmacologic approach to mitigate age\u2010related abnormalities in ocular accommodation and warrant further translational investigation.<\/jats:p>","DOI":"10.1096\/fj.202600364r","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T14:00:57Z","timestamp":1778594457000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metformin Attenuates Ciliary Muscle Aging by Downregulating\n                    <scp>GSK<\/scp>\n                    \u20103\u03b2 to Modulate Cell\u2010Cycle Progression and Autophagy"],"prefix":"10.1096","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-8318-6319","authenticated-orcid":false,"given":"Jiaxue","family":"Wu","sequence":"first","affiliation":[{"name":"Chongqing Key Laboratory of Prevention and Treatment on Major Blinding Diseases, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases The First Affiliated Hospital of Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wen","sequence":"additional","affiliation":[{"name":"Chongqing Key Laboratory of Prevention and Treatment on Major Blinding Diseases, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases The First Affiliated Hospital of Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"HuiJie","family":"Cao","sequence":"additional","affiliation":[{"name":"Chongqing Key Laboratory of Prevention and Treatment on Major Blinding Diseases, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases The First Affiliated Hospital of Chongqing Medical University  Chongqing 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