Ocular Vascular Health and Disease

One-carbon (1C) metabolism integrates the folate and methionine cycles to channel single-carbon units into nucleotide synthesis, redox balance, and S-adenosylmethionine-dependent methylation reactions that are essential for retinal development, maintenance, and repair. The eye's exceptionally high metabolic demand makes it particularly vulnerable to perturbations in these pathways, which are tightly dependent on the availability of B vitamins and related cofactors. Emerging clinical and experimental data indicate that disturbed 1C metabolism is a shared feature of the three leading causes of irreversible blindness worldwide, age-related macular degeneration (AMD), glaucoma, and diabetic retinopathy, through mechanisms that include hyperhomocysteinemia, oxidative stress, mitochondrial dysfunction, and microvascular injury. Conversely, recent studies show that replenishing the vitamins that support 1C metabolism, particularly folate, vitamins B6 and B12, and choline, improves ocular and systemic outcomes, with evidence for slowed glaucoma progression, reduced risk or severity of diabetic retinopathy, and protection against retinal vascular damage. This review synthesizes current knowledge on the biochemical architecture of folate-mediated 1C metabolism in the eye, including the compartmentalized roles of cytoplasmic, mitochondrial, and nuclear pathways in supporting DNA repair, mitochondrial RNA formylation, and homocysteine remethylation. We summarize evidence linking defects in these pathways to AMD, glaucoma, and diabetic retinopathy, highlighting convergent mechanisms such as impaired nucleotide synthesis, compromised photoreceptor repair, and endothelial dysfunction. We examine preclinical and clinical data on B vitamin and related nutrient supplementation as a strategy to restore 1C flux, normalize homocysteine, and mitigate neurovascular damage, including an ongoing trial testing B vitamin repletion in glaucoma. We discuss how 1C metabolism may serve as an integrative biomarker and therapeutic target across ocular diseases of aging, and outline opportunities for therapy, along with priorities for future randomized trials and mechanistic studies.