Effects of Metformin on Mitochondrial Health and Oxidative Stress in Age-Related Macular Degeneration: A Systematic Review.

Abstract

Age-related macular degeneration (AMD) is a chronic, progressive condition and a leading cause of irreversible central vision loss in older patients. It is driven by oxidative stress, mitochondrial dysfunction, chronic inflammation, and degeneration of retinal pigment epithelium (RPE) cells. Current AMD treatments include lifestyle modifications, nutritional supplements, and/or anti-vascular endothelial growth factor therapies and primarily aim to slow disease progression. As a result, interest has grown in repurposing established medications with potential cytoprotective properties. Metformin, a widely-used anti-diabetic agent, has been proposed as a candidate due to its anti-inflammatory and mitochondrial-modulating effects. We conducted a systematic review to identify studies published between January 2015 and November 2025 that evaluate metformin therapy in (1) adults with AMD and (2) experimental retinal models designed to replicate AMD-related degeneration or pathogenesis. Comparators included individuals with AMD who were not taking metformin therapy, were untreated, and/or were given standard treatment therapy. Outcomes of interest included in the review focused on clinical endpoints of AMD incidence and severity and mechanistic endpoints of mitochondrial function, oxidative stress markers, and cellular senescence. This systematic review includes evidence from epidemiologic, clinical, and experimental studies to link molecular mechanisms with observed disease progression. A total of 10 studies published met the inclusion criteria and demonstrated that metformin is associated with cytoprotective effects in RPE cells by reducing oxidative stress (ROS) and upregulating antioxidant enzymes through activation of the Nrf2 pathway. The drug was also shown to preserve mitochondrial function via activation of AMP-activated protein kinase by enhancing mitophagy, supporting DNA repair, and promoting mitochondrial biogenesis. Observational studies suggested that metformin use was associated with a lower risk of AMD development, particularly dry AMD, with stronger associations observed with a longer duration and higher cumulative exposure. However, findings were context-dependent. Under certain stress conditions, such as sodium iodate exposure, metformin-mediated inhibition of mitochondrial complex I appeared to increase oxidative stress, highlighting a potential "double-edged" effect. Overall, current preclinical and observational studies suggest a possible association between metformin use and mitochondrial modulation in AMD. Prospective studies are needed to clarify dosing, safety, and therapeutic relevance before clinical recommendations can be made.