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Metformin Attenuates Ciliary Muscle Aging by Downregulating GSK-3β to Modulate Cell-Cycle Progression and Autophagy
Jiaxue Wu1, Yan Wen1, HuiJie Cao1
1Chongqing 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.
Summary
Metformin (MET) delays ciliary muscle (CM) aging by improving cell structure and function. This drug targets senescence and supports cellular health, offering a potential treatment for age-related vision changes.
Area of Science:
- Ophthalmology
- Gerontology
- Pharmacology
Background:
- Presbyopia, or age-related farsightedness, stems from declining ciliary muscle function.
- Current pharmacologic treatments for ciliary muscle senescence are limited.
Purpose of the Study:
- To investigate metformin's (MET) efficacy in mitigating age-related ciliary muscle (CM) aging.
- To explore the underlying molecular mechanisms of MET's action on CM aging.
Main Methods:
- Established a D-galactose-induced CM aging model in guinea pigs (in vivo) and primary ciliary smooth muscle cells (CSMCs) (in vitro).
- Assessed MET's effects on tissue architecture, senescence markers (p21, p16, p53), cell-cycle arrest, autophagy, and mitochondrial homeostasis.
- Examined the role of glycogen synthase kinase-3β (GSK-3β) signaling in MET's mechanism of action.
Main Results:
- MET significantly reduced D-galactose-induced senescence in CM tissue and CSMCs.
- MET improved fibrillar organization, decreased senescence markers, and relieved cell-cycle arrest.
- MET modulated the GSK-3β pathway, stabilizing β-catenin and promoting cell-cycle progression.
- MET restored autophagic activity and maintained cellular and mitochondrial homeostasis in aged CSMCs.
Conclusions:
- Metformin delays ciliary muscle aging by modulating the GSK-3β pathway, coordinating cell-cycle progression with autophagic activity.
- MET preserves cellular features essential for ocular accommodation, suggesting its potential as a noninvasive treatment for age-related vision impairment.
- Further translational research is warranted to investigate MET's therapeutic potential for presbyopia.
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