Can Metabolic Supplements Slow Retinal Aging? Review Weighs the Evidence

Retinal neurodegeneration is a leading cause of irreversible vision loss worldwide, and a new review argues that age-related macular degeneration (AMD), diabetic retinopathy (DR), and glaucoma should be understood not only as distinct diseases but as manifestations of accelerated ocular aging.

To map the research landscape, the authors performed a structured search of PubMed/MEDLINE for studies published within the past ten years and queried ClinicalTrials.gov for registered interventional studies. The literature search yielded 89 included articles, and the registry search identified 46 records, of which 39 met eligibility criteria; adding 12 eligible trials found through the literature search brought the total to 51 registered clinical trials. Two reviewers independently screened the records, and the selection process was summarized in PRISMA-style flow diagrams. The authors note that this corpus is heterogeneous, characterized by modest sample sizes, diverse formulations, frequent reliance on intermediate biomarkers, and disease-specific variability in observed benefit.

Against this backdrop, one intervention stands apart in evidentiary maturity. The original Age-Related Eye Disease Study (AREDS) demonstrated that a formulation containing antioxidant vitamins and zinc reduced the risk of progression to advanced AMD in individuals at elevated risk, and AREDS2 subsequently refined the formulation by adding lutein and zeaxanthin, testing omega-3 fatty acids, and removing beta-carotene in certain formulations. According to the review, AREDS-based supplementation reduces progression from intermediate to advanced AMD by roughly 25 percent, and newer analyses support benefit even in some cases of late dry AMD. The authors emphasize that this remains the only nutritional intervention supported by large randomized trials showing a clear reduction in progression to advanced AMD.

From the broader field of more than 40 identified supplements, the review selected four candidates for focused analysis: NAD+ boosters, citicoline, pyruvate, and omega-3 fatty acids. The selection was guided by four considerations: these agents converge mechanistically on core pathways shared by retinal neurodegeneration and aging; they target aging hallmarks particularly relevant to the retina, including reduced mitochondrial resilience, altered lipid composition, and chronic low-grade inflammation; each shows a coherent translational trajectory from preclinical models to early human evidence; and each aligns with recent trends in registered clinical trials. Compounds such as alpha-lipoic acid, palmitoylethanolamide, carotenoids, and polyphenols were identified in the search but not selected for focused review because their evidence is either disease-specific or lacks a coherent trajectory across all three conditions.

Nicotinamide adenine dinucleotide (NAD+) supplementation emerges as one of the most mechanistically grounded candidate strategies, especially for glaucoma. NAD+ is an essential coenzyme fueling mitochondrial oxidative phosphorylation and ATP generation, processes critical for the retina’s exceptionally high energy demand. In most tissues, including the retina, the salvage pathway—which recycles nicotinamide (NAM) and nicotinamide riboside (NR) through nicotinamide mononucleotide—supplies roughly 80 percent of cellular NAD+. Retinal ganglion cells operate on a narrow metabolic margin, and the review describes how loss of axonal NMNAT2 raises the NMN/NAD+ ratio, activating SARM1, the central executioner of programmed axonal degeneration, which rapidly depletes NAD+ and triggers metabolic collapse and axonal fragmentation. Human donor retinae from glaucomatous eyes show marked NMNAT2 loss, consistent with this pathway’s activation.

The preclinical glaucoma evidence is striking. In the DBA/2J mouse model, nicotinamide supplementation provided robust, dose-dependent neuroprotection, preserving retinal ganglion cell structure and function in up to 70 percent of eyes at lower doses and 93 percent at higher doses, independent of intraocular pressure reduction. Combining NAM with the Wallerian degeneration slow allele achieved 94 percent protection against glaucomatous degeneration while maintaining axoplasmic transport and visual function on electroretinography. On the clinical side, patients with primary open-angle glaucoma show significantly reduced plasma NAM levels, and in the NHANES 2005–2008 cohort of 5,780 participants, higher dietary niacin intake of approximately 28 milligrams per day was associated with lower risk of developing glaucoma. A phase 2 randomized, double-blind, placebo-controlled trial in POAG patients tested ascending doses of oral NAM (1,000–3,000 mg/day) combined with pyruvate (1,500–3,000 mg/day); treatment significantly increased the number of improving visual field locations and improved pattern standard deviation over roughly two months, with no serious adverse events reported. The authors caution, however, that these short-term functional improvements may represent neuroenhancement rather than clinical neuroprotection, which would require longitudinal demonstration of slower structural or functional progression. A multicenter trial of NR at 300 mg/day for 24 months, with retinal nerve fiber layer thinning as the primary endpoint, is underway.

Safety considerations temper the enthusiasm. NAD+ precursors are generally well tolerated at standard doses—NR up to 2,000 mg/day over 8 to 12 weeks, NMN up to 900 mg/day for 60 days in randomized trials, and NAM generally well tolerated up to 3,000 mg/day in chronic use. But pharmacological doses of NAM at or above 3 g/day raise concerns: two cases of drug-induced liver injury have been reported at that dose, prompting the American Glaucoma Society and the American Academy of Ophthalmology to issue a joint position statement emphasizing that NAM is not FDA-approved for glaucoma, that high doses should be restricted to controlled clinical trials, and that niacin should not be substituted for NAM because of its higher liver toxicity risk. The review also flags a hypothesis-generating vascular safety signal: terminal NAM catabolites 2PY and 4PY were associated with cardiovascular events and soluble VCAM-1 in one report, and experimental exposure to 4PY—but not 2PY—increased endothelial VCAM-1 expression and leukocyte adhesion, although retinal accumulation and dose thresholds have not been established.

Citicoline, a naturally occurring endogenous compound hydrolyzed after oral administration into choline and cytidine, which feed the Kennedy pathway for phosphatidylcholine synthesis, has accumulated the most extensive clinical trial experience, particularly in glaucoma. A 3-year randomized, double-blind trial in 78 open-angle glaucoma patients with controlled intraocular pressure found that topical citicoline slowed progression in 10-2 visual field mean deviation and retinal nerve fiber layer thinning. Oral citicoline studies reported stabilized visual field indices and preserved RNFL and ganglion cell layer thickness over 24 months in 60 patients, and a multicenter European crossover trial of 500 mg/day showed significantly improved vision-related quality of life, the first placebo-controlled evidence of such an effect in glaucoma. In diabetic retinopathy, evidence is thinner: a 3-year study of 20 patients with type 1 diabetes and mild non-proliferative DR treated with citicoline 2 percent eye drops plus vitamin B12 showed reduced microvascular damage and neuro-retinal degeneration compared with untreated controls, and preclinical work in diabetic mice showed reduced reactive gliosis and apoptosis. The review concludes that citicoline currently occupies a disease-specific role, with insufficient evidence for AMD or DR.

Pyruvate, a central glycolytic intermediate that supports oxidative phosphorylation and can non-enzymatically scavenge hydrogen peroxide, remains largely preclinical in ophthalmology. Across rat and mouse ocular-hypertension models, pyruvate administered alone or with NAM preserved ganglion-cell somas and axons and improved pattern electroretinography and optomotor readouts. Human metabolomic analyses from large biobanks report that higher circulating levels of pyruvate-related energetic metabolites associate with lower glaucoma risk, offering modest incremental predictive value over polygenic risk scores. No randomized clinical trials have evaluated pyruvate supplementation in AMD or DR, and no long-term safety or efficacy data exist in retinal disease populations, leaving it an experimental candidate despite its biological plausibility.

Omega-3 fatty acids present the clearest divergence between evidence types. DHA is highly enriched in photoreceptor membranes and gives rise to neuroprotectin D1, a potent anti-inflammatory and anti-apoptotic mediator in human RPE and neural retina. Observational data support an association: in a pre-specified analysis of the PREDIMED population, higher intake of long-chain omega-3 polyunsaturated fatty acids—at least approximately 500 mg per day—was associated with reduced incidence of sight-threatening diabetic retinopathy in older adults with type 2 diabetes. Yet randomized supplementation has repeatedly fallen short. AREDS2 showed no additional benefit of DHA plus EPA (350 mg plus 650 mg daily) on progression to advanced AMD, a null result that persisted across severity levels, genetic subgroups, and long-term follow-up. The NAT-2 trial of 840 mg/day DHA for 3 years in unilateral neovascular AMD found no significant effect on drusen number, area, or remodeling, and the ASCEND-Eye randomized analysis did not demonstrate a significant protective effect against diabetic retinopathy. The review attributes the discrepancy to timing, since trials enrolled patients with established disease; tightly regulated retinal DHA incorporation; possible ceiling effects from modern diets; and disease complexity beyond inflammation alone.

The review’s bottom line is measured. Current evidence supports biological plausibility and early functional or biomarker signals for NAD+ boosters, citicoline, pyruvate, and omega-3 fatty acids, particularly in glaucoma and diabetic retinal disease, but does not yet establish disease-modifying efficacy for any of the four. None should be considered a substitute for established standard-of-care treatment, and the authors stress that high-dose nicotinamide investigated in glaucoma trials represents a pharmacological intervention that should not be equated with routine vitamin B3 supplementation. They call for adequately powered randomized trials with standardized formulations, clinically meaningful ophthalmic outcomes, pharmacokinetic and lipidomic endpoints, and biomarker-guided approaches to identify which patients might benefit—positioning metabolic supplementation as a promising but still developing strategy whose potential to preserve retinal function awaits confirmation in longitudinal clinical trials.

Subject of Research: Nutritional and metabolic supplements targeting aging-related pathways in retinal neurodegeneration across AMD, diabetic retinopathy, and glaucoma

Article Title: Retinal neurodegeneration as accelerated ocular aging: a review of nutritional and metabolic supplements

Article References: Moshtaghion, S. M., Shayan, M., Ramakrishnan, S., Ham, A., Gharehkoshan, A. S., Morley, M. G., Zebardast, N., Díaz-Corrales, F. J., Rodríguez de la Rúa, E., Husain, D., Sobrin, L., Elze, T., Friedman, D. S., & Eslami, M. (2026). Retinal neurodegeneration as accelerated ocular aging: a review of nutritional and metabolic supplements. Frontiers in Aging, 7, Article 1912337. https://doi.org/10.3389/fragi.2026.1912337

Image Credits: AI Generated

DOI: 10.3389/fragi.2026.1912337

Keywords: retinal neurodegeneration, ocular aging, NAD+ boosters, nicotinamide, citicoline, pyruvate, omega-3 fatty acids, glaucoma, age-related macular degeneration, diabetic retinopathy, AREDS2, mitochondrial dysfunction