A groundbreaking study from Karolinska Institutet has unveiled a promising new approach to slowing optic nerve damage in glaucoma through the use of specific vitamin supplements. Published in the esteemed journal Cell Reports Medicine, the research identifies an innovative metabolic therapy involving vitamins B6, B9, and B12, together with choline, that substantially protects retinal neurons independent of traditional intraocular pressure management. This breakthrough challenges longstanding assumptions about the biological drivers of glaucoma and shines a light on the intricate metabolic dysfunction underlying the disease’s progression.
Glaucoma remains one of the leading causes of irreversible blindness worldwide, characterized by the progressive degeneration of the optic nerve. Elevated intraocular pressure (IOP) has long been recognized as the primary risk factor and therapeutic target. Conventional treatments, including medicated eye drops, laser therapy, and surgical intervention, primarily focus on lowering this pressure to slow disease progression. However, the therapeutic response among patients varies widely, and many continue to experience vision loss despite optimized pressure control. This discrepancy highlights the urgent need to better understand other pathogenic mechanisms contributing to optic nerve degeneration.
For years, homocysteine—a sulfur-containing amino acid involved in one-carbon metabolism—has been suspected as a potential factor in glaucomatous neurodegeneration. Elevated homocysteine levels have been implicated in vascular and neurodegenerative diseases, raising questions about its role in glaucoma pathology. The team led by James Tribble, assistant professor at the Department of Clinical Neuroscience, undertook extensive investigations utilizing both rodent glaucoma models and clinical patient data to dissect whether homocysteine directly drives optic nerve damage or is merely a secondary biomarker of disease.
Through rigorous experiments, researchers administered elevated homocysteine to rats afflicted with glaucoma and unexpectedly observed no exacerbation of optic nerve injury. Complementary human studies further corroborated these animal findings: circulating homocysteine concentrations did not correlate with disease severity or rate of progression among glaucoma patients. Genetic analyses also failed to show increased disease prevalence in individuals with susceptibilities to hyperhomocysteinemia. Collectively, these data convinced the researchers that homocysteine is not causative but rather a byproduct of underlying metabolic dysfunction within the retina.
Delving deeper, the researchers explored one-carbon metabolic pathways integral to homocysteine processing in the retinal tissue of both rodents and humans. They uncovered a striking pattern of metabolic aberrations linked to the retina’s impaired utilization of crucial B vitamins and choline—nutrients essential for proper methylation reactions, nucleotide synthesis, and neurotransmitter production. This metabolic dysfunction slows retinal cellular metabolism at a local scale and appears to be intimately involved in glaucomatous neurodegeneration.
“Our work demonstrates that metabolic disruption, rather than homocysteine itself, is the key driver of retinal injury in glaucoma,” explains James Tribble. “The inability of retinal cells to effectively use vitamins B6, B9, B12, and choline fundamentally compromises cellular health and resilience, which opens a new therapeutic avenue that goes beyond lowering eye pressure.”
Building on these insights, the team conducted interventional studies in animal models of glaucoma, administering a vitamin cocktail containing B6, B9 (folate), B12, and choline. The results were compelling: in mice with slower-progressing glaucoma phenotypes, the treatment halted all further optic nerve degeneration. In rats exhibiting more aggressive disease courses, vitamin supplementation significantly reduced the rate of nerve damage. Crucially, these neuroprotective effects were achieved without any manipulation of intraocular pressure, indicating that addressing metabolic insufficiency acts via a novel pathway distinct from IOP modulation.
This discovery challenges the dogma that glaucoma management must focus exclusively on lowering eye pressure and opens possibilities for adjunctive treatments aimed directly at retinal metabolism. If these initial animal findings translate successfully to human patients, they could herald a paradigm shift in preserving vision for millions with glaucoma worldwide.
Encouraged by the promising preclinical outcomes, Karolinska Institutet has initiated a clinical trial recruiting patients at S:t Eriks Eye Hospital in Stockholm. The study includes individuals with both primary open-angle glaucoma, which typically exhibits slower progression, and pseudoexfoliation glaucoma, known for more aggressive optic nerve damage. The trial will rigorously evaluate whether vitamin supplementation can similarly slow or halt nerve loss in humans, potentially ushering in a safe, accessible, and cost-effective neuroprotective therapy.
Previous attempts to use vitamins for glaucoma treatment yielded inconclusive results, mainly due to limited understanding of disease metabolism. This study’s focused approach on one-carbon metabolism and targeted nutrient supplementation represents a conceptual leap forward. By restoring essential vitamin-dependent metabolic processes, the therapy addresses a root contributor of neuronal vulnerability rather than symptomatic pressure elevation alone.
The implications extend beyond glaucoma, as metabolic impairments in vitamin utilization may underlie other neurodegenerative conditions. Understanding and correcting these biochemical deficits could provide broader insight into protecting the nervous system from chronic injury and age-related decline.
This research is the culmination of support from several prestigious Swedish funding bodies, including the Swedish Research Council, the Swedish Eye Health Fund, the Jeansson Foundations, the Crown Princess Margareta Foundation for the Visually Impaired, the Åke Wiberg Foundation, and the Petrus & Augusta Hedlund Foundation. It exemplifies a collaborative research spirit aimed at translating cutting-edge basic science into tangible clinical benefits.
In summary, this pioneering study challenges traditional glaucoma paradigms by demonstrating that dysfunctional one-carbon metabolism compromises the retina’s ability to use vitamins critical for neuroprotection. Administering supplements of vitamins B6, B9, B12, and choline halts or slows optic nerve damage independent of intraocular pressure regulation. With a clinical trial underway, this metabolic therapeutic strategy may soon complement existing treatments, offering new hope for patients threatened by this sight-robbing disease.
Subject of Research: Animals
Article Title: Dysfunctional one-carbon metabolism identifies vitamins B6, B9, B12, and choline as neuroprotective in glaucoma
News Publication Date: 8-May-2025
Web References:
DOI link
References:
Tribble J, Wong V, Stuart K, Chidlow G, Nicol A, Rombaut A, Rabiolo A, Hoang A, Lee PY, Rutigliani C, Enz T, Canovai A, Lardner E, Stålhammar G, Nguyen C, Garway-Heath D, Casson R, Khawaja A, Bui B, Williams PA. Dysfunctional one-carbon metabolism identifies vitamins B6, B9, B12, and choline as neuroprotective in glaucoma. Cell Reports Medicine. 2025; online 8 May 2025. doi:10.1016/j.xcrm.2025.102127
Image Credits: Stefan Zimmerman
Keywords: Glaucoma, Vitamin B12, Vitamin B, Gene therapy, Eye diseases
