Metformin Attenuates Ciliary Muscle Aging by Downregulating <scp>GSK</scp> ‐3β to Modulate Cell‐Cycle Progression and Autophagy

Presbyopia is linked to age-related decline in ciliary muscle (CM) function, yet pharmacologic strategies that target CM senescence remain limited. We investigated whether metformin (MET) mitigates CM aging in guinea pigs and explored the underlying mechanism. A D-galactose-induced CM aging model was established in vivo in guinea pigs and in vitro using primary ciliary smooth muscle cells (CSMCs). The effects of MET on age-related changes in tissue architecture, senescence markers, cell-cycle progression, autophagic activity, and mitochondrial homeostasis were assessed. In parallel, the involvement of glycogen synthase kinase-3β (GSK-3β) signaling in the actions of MET was examined. MET significantly attenuated D-galactose-induced 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-phase cell-cycle arrest. At the molecular level, MET decreased GSK-3β expression, stabilized β-catenin in the cytoplasm, facilitated its nuclear translocation, and thereby supported more physiological cell-cycle progression. In addition, MET restored autophagic activity in aged CSMCs and helped maintain intracellular and mitochondrial homeostasis. MET modulates the GSK-3β pathway to coordinate cell-cycle 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-related abnormalities in ocular accommodation and warrant further translational investigation.