Age-related macular degeneration (AMD) remains a leading cause of vision loss worldwide, and despite advances in imaging and anti-VEGF therapies, slowing disease progression is still a central goal in outpatient care. For the past two decades, the Age-Related Eye Disease Study (AREDS) formulations have played a key role in this effort. The AREDS2 formulation, in particular, is now widely recommended for patients with intermediate AMD or advanced disease in one eye, offering a modest but clinically meaningful reduction in risk of progression.1
At the same time, understanding of AMD has evolved significantly. The disease is no longer viewed as being driven purely by oxidative stress, but rather as a multifactorial process involving inflammation, complement dysregulation, mitochondrial dysfunction, and lipid metabolism.2 This shift has raised a reasonable question: while AREDS2 remains effective, is there room for a more optimal, next-generation formula?
How the AREDS Formula Was Developed
The original AREDS trial was built on the premise that oxidative stress contributes to retinal degeneration. The formulation—which includes vitamin C, vitamin E, beta-carotene, zinc, and copper—was designed to counteract this process. In a large randomized controlled trial, AREDS demonstrated a 25% reduction in progression to advanced AMD in high-risk patients, establishing supplementation as part of standard care.1
However, the formulation was not without limitations. Beta-carotene was associated with an increased risk of lung cancer in smokers, prompting concern about its safety profile.3 In addition, the biologic relevance of macular carotenoids such as lutein and zeaxanthin, which are known to concentrate in the retina, was not fully incorporated into the original formula.
AREDS2 was therefore designed to refine the approach. Beta-carotene was replaced with lutein and zeaxanthin, and omega-3 fatty acids were evaluated as potential additions. The updated formula maintained vitamins C and E, zinc, and copper, while improving safety and better aligning with retinal physiology.4
What AREDS2 Showed
AREDS2 confirmed that removing beta-carotene and substituting lutein and zeaxanthin preserved the protective effect of supplementation while eliminating the increased lung cancer risk seen in smokers.4 Notably, participants with low baseline dietary intake of lutein and zeaxanthin appeared to derive the greatest benefit, suggesting that carotenoid supplementation may be particularly important in specific patient populations.
Despite strong epidemiologic data, omega-3 fatty acids did not reduce progression to advanced AMD in the trial.4 Similarly, lowering the zinc dose did not significantly alter outcomes, leaving some uncertainty about optimal dosing while reinforcing that the overall formulation effect was robust.
Overall, AREDS2 solidified the role of targeted antioxidant and carotenoid supplementation. It also highlighted a plateau in benefit, suggesting that additional gains may require mechanisms beyond oxidative stress alone.
Need for an AREDS3
As understanding of AMD biology expands, several limitations of the current formulation have become more apparent.
First, AREDS2 does not address many of the pathways now known to be central to AMD pathogenesis. Chronic inflammation and complement dysregulation, for example, are key drivers of disease progression, yet are not directly targeted by current supplementation strategies.2 Genetic studies have also highlighted the role of complement factor variants, further emphasizing the importance of immune-mediated mechanisms.5
Second, carotenoid optimization remains an open question. Although lutein and zeaxanthin are included in AREDS2, meso-zeaxanthin—another macular carotenoid concentrated at the fovea—is not. Early studies suggest that supplementation with all 3 macular carotenoids (lutein, zeaxanthin, and meso-zeaxanthin) may improve macular pigment optical density and potentially visual function, although large-scale outcomes data are still limited.6
Third, mitochondrial dysfunction is increasingly recognized as a contributor to retinal aging and degeneration. The retina’s high metabolic demand makes it particularly vulnerable to energy failure and oxidative damage at the mitochondrial level. A study by Karunadharma et al showed that mitochondrial DNA is preferentially damaged with AMD progression compared with age-matched control subjects.7 Emerging interest in compounds such as coenzyme Q10 and nicotinamide (vitamin B3) reflects a broader shift toward supporting cellular energetics, though these approaches remain investigational in AMD.8,9
Finally, the current one-size-fits-all model may not reflect the heterogeneity of AMD. Differences in genetics, diet, disease stage, and systemic health likely influence response to supplementation. Future strategies may need to move toward more personalized approaches, rather than relying on a single standardized formula for all patients.
What Would AREDS3 Look Like?
If AREDS2 reflects an oxidative stress–focused model of AMD, a next-generation formulation would ideally expand to address the broader, multifactorial nature of AMD pathophysiology. Although no formal AREDS3 trial has yet been published, the National Eye Institute is currently developing a prospective AREDS3 study to evaluate whether additional supplemental strategies may provide benefit beyond the current AREDS2 formulation, particularly in patients with extrafoveal geographic atrophy (GA). Recent post hoc analyses from AREDS and AREDS2 demonstrated that antioxidant and lutein/zeaxanthin supplementation may slow progression of noncentral GA toward the fovea, potentially prolonging foveal sparing and preservation of central vision. These findings require prospective validation, but they provide an important clinical rationale for continued refinement of AMD supplementation strategies.10
Several candidate components are already being explored in the literature and could plausibly form the basis of an updated approach. One potential extension would involve optimization of macular carotenoids. Adding meso-zeaxanthin to lutein and zeaxanthin could more closely replicate the natural composition of macular pigment. Early studies suggest that this combination may enhance macular pigment optical density and improve visual performance, although definitive outcomes data are still lacking.11 This would be a relatively low-risk modification with a strong physiologic rationale.
A second area of interest is mitochondrial support. Given the high metabolic demands of photoreceptors and retinal pigment epithelial cells (RPEs), compounds such as coenzyme Q10 and nicotinamide have been proposed as potential additions to future formulations. Increasing evidence suggests that mitochondrial dysfunction and impaired cellular energetics contribute to AMD progression, making metabolic support an appealing therapeutic target.7 Recent research has also highlighted the potential role of vitamin B–related pathways and NAD+ metabolism in retinal aging and degeneration. Data from large longitudinal studies have demonstrated an association between higher vitamin B intake and reduced risk of AMD development and progression.12 These findings further support the growing interest in B vitamins and other NAD+ precursors as potential additions to future AMD supplementation strategies.
These agents may improve cellular energy production and resilience to oxidative injury, addressing a component of AMD pathogenesis not targeted by current formulations.7 The addition of mitochondrial/NAD+ precursors (nicotinamide, nicotinamide mononucleotide, and nicotinamide riboside) could provide compelling protective effects against retinal degeneration, as reduced NAD+ levels have been observed in AMD.9 A recent study showed the efficacy of coenzyme Q10 to be effective in preventing apoptosis and mitochondrial stress-related damage to RPEs in an in vitro model.8 Robust clinical trials evaluating its efficacy in preventing AMD are yet to be performed, making this addition merely hypothesis-driven at present.
Third, an AREDS3-type formulation might begin to address chronic inflammation and complement activation, which are now recognized as central drivers of AMD progression. Although direct complement inhibitors are being developed as pharmacologic therapies, nutritional approaches, such as omega-3 derivatives or other anti-inflammatory compounds, could play an adjunctive role. Although the AREDS2 trial showed that adding omega-3 fatty acids had no overall effect on risk of advanced AMD, future anti-inflammatory nutritional strategies may prove more biologically targeted than traditional antioxidant approaches.
Finally, future formulations may need to be more personalized from patient to patient, because genetic variations in complement pathways have been shown to influence AMD risk and may also affect response to supplementation.5 Although genotype-guided supplementation is not yet standard practice, it represents a potential direction for future research and clinical application. A holistic personalized approach would ideally integrate genetics, nutritional supplementation, diet, and associated disease processes.
Looking Ahead
AREDS2 remains the standard of care and should continue to be recommended for appropriate patients. Its benefits are well supported, and no alternative formulation has yet demonstrated superior outcomes in large randomized trials.
That said, it is increasingly clear that AREDS2 represents a foundation rather than a final answer. As research continues to clarify the roles of inflammation, mitochondrial function, and macular pigment biology, future formulations may expand beyond antioxidant supplementation alone to incorporate a more comprehensive approach reflecting a deeper understanding of AMD pathophysiology. RP
References
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2. Ambati J, Fowler BJ. Mechanisms of age-related macular degeneration. Neuron. 2012;75(1):26-39. doi:10.1016/j.neuron.2012.06.018
3. Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med. 1994;330(15):1029-1035. doi:10.1056/NEJM199404143301501
4. Age-Related Eye Disease Study 2 Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA. 2013;309(19):2005-2015. doi:10.1001/jama.2013.4997
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8. Hernandez M, Recalde S, Bezunartea J, et al. The scavenging activity of coenzyme Q10 plus a nutritional complex on human retinal pigment epithelial cells. Int J Mol Sci. 2024;25(15):8070. doi:10.3390/ijms25158070
9. Saini JS, Corneo B, Miller JD, et al. Nicotinamide ameliorates disease phenotypes in a human iPSC model of age-related macular degeneration. Cell Stem Cell. 2017;20(5):635-647.e7. doi:10.1016/j.stem.2016.12.015
10. Keenan TDL, Hébert M, Chew EY, Johnson MW. What should patients with age-related macular degeneration eat? Am J Ophthalmol. Published online April 14, 2026. doi:10.1016/j.ajo.2026.04.003
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12. Poteet J, Koetting C, Vakharia PS. Role of B vitamins in preventing the development and progression of age-related macular degeneration. Ophthalmol Ther. 2026;15(1):1-19. doi:10.1007/s40123-025-01281-1