Fundus photograph of moderate age-related macular degeneration (AMD) with numerous drusen
National Eye Institute, National Institutes of Health. Intermediate age-related macular degeneration fundus photograph. Figure 1. Source ID: commons.wikimedia.org/wiki/File:Intermediate_age_related_macular_degeneration.jpg. License: CC BY (Public Domain, U.S. federal government work).
Numerous medium to large drusen (yellow-white deposits) scattered in the macula, showing typical fundus findings of moderate AMD. This corresponds to the drusen findings of moderate AMD (AREDS category 3) that were the subject of the AREDS study discussed in the section “1. Relationship Between Supplements and Eye Diseases.”
The field of examining scientific evidence for nutrients and supplements for the prevention and progression suppression of eye diseases is attracting attention. Large-scale randomized controlled trials (RCTs) have been conducted, particularly for three diseases: age-related macular degeneration (AMD), cataracts, and dry eye.
The largest source of evidence is the Age-Related Eye Disease Study (AREDS) led by the U.S. National Eye Institute (NEI). AREDS, conducted from 1992 to 2001, was a large-scale RCT involving 3,640 participants 1), and examined the “AREDS formulation” combining vitamin C 500 mg, vitamin E 400 IU, beta-carotene 15 mg, and zinc oxide 80 mg. It showed that the risk of AMD progression was reduced by approximately 25% in patients with moderate to advanced AMD (AREDS categories 3 and 4) 1).
In the AREDS2 study (4,203 participants) conducted from 2006 to 2012 2), the efficacy and safety of a new formulation replacing beta-carotene with lutein 10 mg + zeaxanthin 2 mg per day were verified. Replacing beta-carotene with lutein and zeaxanthin showed comparable AMD progression suppression effects to beta-carotene 2), while avoiding the increased risk of lung cancer in smokers associated with beta-carotene, making it the current standard formulation.
Importantly, the AREDS/AREDS2 formulation is intended for suppressing progression in patients with moderate to advanced AMD and has not been established for preventing onset in the general population without AMD. Supplements are an adjunct to ophthalmic management, and the foundation is early detection and early treatment through regular eye examinations.
Evidence has established that the AREDS formulation reduces the risk of progression of moderate to advanced AMD (AREDS categories 3 and 4) by approximately 25% 1). However, this is “progression suppression,” and the effect of “preventing onset” in healthy individuals without AMD has not been established at this time. There is no general recommendation for people without AMD risk; AREDS2 formulation should be considered for patients with confirmed moderate to advanced AMD.
Major supplement ingredients related to eye diseases can be broadly divided into five categories.
Lutein and Zeaxanthin
Role: Main components of macular pigment (macula: the most important central area of the retina). They function as filters that absorb blue light and scavenge reactive oxygen species (ROS) to protect the retina from photo-oxidative damage 3).
AREDS2 formulation dose: Lutein 10 mg + zeaxanthin 2 mg per day 2).
Association with cataracts: Epidemiological studies have shown an inverse association between dietary intake of lutein and zeaxanthin and the risk of nuclear cataracts 5).
Vitamin C and E
Role: Water-soluble (vitamin C) and fat-soluble (vitamin E) antioxidant vitamins. They reduce oxidative stress in the retinal pigment epithelium (RPE).
AREDS formulation dose: Vitamin C 500 mg + vitamin E 400 IU per day 1).
Cataract prevention: A Cochrane review (Mathew 2012) concluded that the preventive effect of antioxidant supplements on cataracts is “not confirmed” 6). The AREDS trial also found no significant preventive effect on cataracts.
Zinc
Role: Supports the metabolism of the retinal pigment epithelium as a cofactor for antioxidant enzymes (Cu/Zn-SOD, catalase, etc.)1).
AREDS formulation dose: Zinc oxide 80 mg/day (combined with copper oxide 2 mg/day to prevent copper deficiency anemia)1).
Change in AREDS2: A reduction to 25 mg was considered, but no significant difference was found compared to the 80 mg group2).
Omega-3 Fatty Acids (EPA/DHA)
AMD: In AREDS2, no additional effect of omega-3 fatty acids (DHA 350 mg + EPA 650 mg/day) on AMD was observed2). Epidemiological studies have reported an association between fish intake and reduced AMD risk8).
Dry eye: In the DREAM study (535 patients, RCT), omega-3 supplementation (EPA 2,000 mg + DHA 1,000 mg/day) showed no significant difference in dry eye improvement compared to olive oil placebo7).
Anthocyanins found in blueberries and bilberries have been reported at the basic research level to improve dark adaptation and retinal blood flow. However, evidence of efficacy from RCTs is limited9), and currently the evidence is insufficient to recommend them in clinical practice.
For patients diagnosed with moderate to advanced AMD (AREDS categories 3 and 4), taking the AREDS2 formulation (including lutein 10 mg + zeaxanthin 2 mg/day) is recommended 2). On the other hand, there is no general recommendation for healthy individuals without AMD risk; dietary intake from green leafy vegetables such as spinach and kale is the foundation. It is important to decide after consulting an ophthalmologist.
Key change: Replacement of beta-carotene with lutein 10 mg + zeaxanthin 2 mg/day
Results: Showed non-inferiority in slowing AMD progression after substitution. In former smokers, the risk of progression to exudative AMD was further reduced in the lutein/zeaxanthin group.
Long-term follow-up of AREDS2 (2022, 10-year data)10):
The lutein/zeaxanthin group showed a further long-term reduction in the risk of progression to exudative AMD.
The AREDS formulation was not confirmed to prevent cataracts 1). On the other hand, multiple epidemiological studies have shown an inverse association between dietary intake of lutein and zeaxanthin and the risk of nuclear cataract5), suggesting that dietary intake may reduce the risk of cataract development. However, there are no large-scale RCTs proving the interventional effect of supplements.
A Cochrane review (Mathew 2012, 21 RCTs) concluded that there is no high-quality evidence that supplementation with antioxidant vitamins (A, C, E), lutein, and zeaxanthin delays the onset or progression of cataracts 6).
The DREAM trial (2018) was an RCT comparing the efficacy of omega-3 fatty acids (EPA 2,000 mg + DHA 1,000 mg/day for 12 months) with olive oil placebo in 535 patients with chronic dry eye. There was no significant difference between the two groups in the primary endpoint (OSDI score) 7), and the efficacy of omega-3 supplements for dry eye was negative. Although a meta-analysis (Giannaccare 2019) reported some efficacy 11), omega-3 supplements are not included in the standard treatment for dry eye due to the high quality of the DREAM trial.
Target: Patients diagnosed with moderate to advanced AMD in one eye (AREDS categories 3 and 4) 2)
Limited effect on early AMD: No significant progression inhibition has been shown for AREDS categories 1 and 2 (small drusen). Unnecessary supplement use carries a risk of excessive intake, so caution is needed.
Confirmation of smoking status: For smokers, choose the AREDS2 formulation without beta-carotene.
Spinach leaves (green-yellow vegetables rich in lutein and zeaxanthin)
Nillerdk. Spinach leaves (1 kg, separated from stems). Wikimedia Commons. 2008. Figure 1. Source ID: commons.wikimedia.org/wiki/File:Spinach_leaves.jpg. License: CC BY 3.0.
Spinach leaves without stems, a representative source of lutein and zeaxanthin containing about 12 mg lutein/100 g. This corresponds to dietary intake from green-yellow vegetables (spinach, kale) rich in lutein, discussed in the section “4. Dietary intake.”
Green-yellow vegetables are excellent sources of lutein and zeaxanthin4).
Spinach: about 12 mg lutein/100 g, about 1.1 mg zeaxanthin/100 g4)
Kale: about 22 mg lutein/100 g (highest level among foods)4)
Broccoli: about 1.4 mg lutein/100 g4)
Egg yolk: high bioavailability of lutein and zeaxanthin (3 to 4 times that of vegetables)4)
Fish (mackerel, Pacific saury, sardines, etc.) consumed twice or more per week is useful as a source of EPA/DHA8), and epidemiological studies have reported an association between fish intake and reduced risk of AMD.
Supplements are not medicines but are classified as foods. Under the Consumer Affairs Agency’s Foods with Function Claims System (2015), certain scientific evidence-based functional claims are allowed 12), but they have not undergone national review for efficacy and safety like pharmaceuticals. When selecting products equivalent to the AREDS2 formulation, check the ingredient content and be careful not to exceed the recommended intake.
QWhat foods are high in lutein?
A
Spinach (about 12 mg/100 g), kale (about 22 mg/100 g), broccoli, and other green-yellow vegetables are major dietary sources of lutein 4). Egg yolks are not as high in lutein content as vegetables, but because lutein is fat-soluble, absorption efficiency is high. A dietary intake of 6–10 mg/day of lutein is recommended. Actively eating green-yellow vegetables every day is the basis for obtaining lutein from food.
If supplements are not used properly, they can cause side effects and risks. The following points require attention.
Beta-carotene and lung cancer risk in smokers:
The ATBC study (1994) found that beta-carotene supplementation (20 mg/day) in 29,133 male smokers increased lung cancer incidence by 18% 13)
The CARET study also showed increased lung cancer risk with beta-carotene supplementation in smokers and asbestos-exposed individuals
Based on these findings, AREDS2 replaced beta-carotene with lutein/zeaxanthin 2)
Do not use AREDS formulations containing beta-carotene in smokers or those with a history of smoking, even after quitting
Excessive zinc intake:
Copper deficiency anemia has been reported with long-term use of AREDS formulation containing 80 mg/day zinc oxide 1)
The AREDS formulation includes 2 mg copper oxide to prevent copper deficiency, but regular blood tests are recommended during long-term use.
Tolerable upper intake level of zinc for general adults (Dietary Reference Intakes for Japanese 2020): 45 mg/day for men, 35 mg/day for women
High-dose vitamin E:
Schürk et al. (2010, meta-analysis) suggested an association between high-dose vitamin E intake and increased risk of hemorrhagic stroke14)
Caution is needed for long-term use of high doses (400 IU/day)
Drug interactions:
Vitamin E and omega-3 fatty acids have anticoagulant effects; caution is needed for interactions with anticoagulants such as warfarin
Consult your doctor about discontinuing use before surgery
QDo eye supplements have side effects?
A
Beta-carotene in the AREDS formula increases the risk of lung cancer in smokers, so it is contraindicated for smokers and those with a history of smoking13). The AREDS2 formula replaces beta-carotene with lutein/zeaxanthin to avoid this risk. Additionally, long-term use of 80 mg/day zinc oxide can cause copper deficiency anemia, so the formula always includes 2 mg copper oxide1). High-dose long-term intake of vitamin E has been associated with an increased risk of hemorrhagic stroke14), requiring caution.
The macula is at high risk for light-induced oxidative stress, and ultraviolet and blue light can generate reactive oxygen species (ROS). Oxidative stress is involved in the onset and progression of AMD3).
ROS production: Photooxidation of lipofuscin (waste product) due to light reactions is a major cause of RPE damage
Drusen formation: Reduced RPE processing capacity leads to deposition of lipoproteins and complement in the extracellular matrix
Progression to exudative AMD: Oxidative stress and RPE damage induce complement activation and VEGF signaling, leading to neovascularization
Pseudo-color map of macular pigment optical density (MPOD) (comparison before and after ERM peeling)
Imanishi H, Takaoka M, Sonoda S, Oishi A, Yoshimura N. Multimodal imaging showing macular pigment optical density changes before and after ERM peeling. PLOS ONE. 2018. Figure 1. DOI: 10.1371/journal.pone.0197034. License: CC BY 4.0.
A pseudo-color visualization map of macular pigment optical density (MPOD), showing high-density (warm colors) pigment distribution at the fovea. This corresponds to the photoprotective and antioxidant functions of MPOD formed by lutein and zeaxanthin, discussed in section “6. Pathophysiology and Antioxidant Mechanisms.”
Lutein and zeaxanthin selectively accumulate in the macula, forming macular pigment optical density (MPOD)3).
Light filter function: Selectively absorbs blue light (400–500 nm), attenuating its reach to photoreceptors
Antioxidant function: Acts as a ROS scavenger by directly quenching singlet oxygen and peroxyl radicals
meso-zeaxanthin: A third macular pigment enzymatically converted from lutein in the retina, with the highest concentration in the fovea3)
Role of Zinc as a Cofactor for Antioxidant Enzymes
Zinc functions as an essential cofactor in the active site of the antioxidant enzyme Cu/Zn-SOD (copper-zinc superoxide dismutase)1). SOD converts superoxide anions, a type of ROS, into harmless hydrogen peroxide. It also works in concert with catalase and glutathione peroxidase to maintain the overall antioxidant defense system. The RPE is a highly metabolic tissue that processes phagosomes shed from photoreceptors, and adequate zinc supply is important for maintaining normal function.
DHA (docosahexaenoic acid) is an omega-3 long-chain polyunsaturated fatty acid abundantly present in the outer segment membranes of retinal photoreceptors. Together with EPA (eicosapentaenoic acid), it serves as a precursor for the anti-inflammatory lipid mediators resolvins and protectins 7). These mediators promote the resolution of inflammation, but clinical effects on dry eye in RCTs are considered insufficient.
The 10-year long-term follow-up data of AREDS2 (Report 28: Chew 2022) 10) confirmed that the lutein/zeaxanthin group further reduced the risk of progression to exudative AMD in the long term. No long-term safety issues were identified, and the benefit of beta-carotene-free formulations for smokers was reaffirmed.
Use of macular pigment optical density (MPOD) as a biomarker
MPOD measurement is being studied as an indicator of macular carotenoid content 3). Evaluation methods such as heterochromatic flicker photometry, resonance Raman spectroscopy, and fundus autofluorescence are being investigated as objective measures of supplement efficacy.
Personalized nutritional guidance based on genetic polymorphisms
Research is exploring whether the effect of the AREDS formulation may differ depending on polymorphisms in AMD susceptibility genes (CFH Y402H, ARMS2 A69S) 15). It has been suggested that individuals with CFH polymorphisms may have different responsiveness to zinc 15), and in the future, personalized supplement prescriptions based on genetic profiles may become possible.
Accumulating basic research indicates that the composition of the gut microbiota influences the absorption efficiency and blood levels of lutein and zeaxanthin. It is known that even with the same dietary and supplement intake, there are large inter-individual differences in blood lutein levels. Combining with gut environment improvement (e.g., probiotics) to enhance absorption efficiency is being explored.
Ongoing research on nutritional interventions for dry eye
Although the DREAM study negated the effect of omega-3 7), research on the association between overall dietary patterns (e.g., Mediterranean diet) and dry eye risk is progressing 11). The involvement of other nutrients such as polyphenols and vitamin D in dry eye is also being investigated, and new RCTs are being conducted.
Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001;119(10):1417-1436.
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.
Bernstein PS, Li B, Vachali PP, et al. Lutein, zeaxanthin, and meso-zeaxanthin: the basic and clinical science underlying carotenoid-based nutritional interventions against ocular disease. Prog Retin Eye Res. 2016;50:34-66.
Perry A, Rasmussen H, Johnson EJ. Xanthophyll (lutein, zeaxanthin) content in fruits, vegetables and corn and egg products. J Food Compos Anal. 2009;22(1):9-15.
Christen WG, Liu S, Glynn RJ, et al. Dietary carotenoids, vitamins C and E, and risk of cataract in women: a prospective study. Arch Ophthalmol. 2008;126(1):102-109.
Mathew MC, Ervin AM, Tao J, et al. Antioxidant vitamin supplementation for preventing and slowing the progression of age-related cataract. Cochrane Database Syst Rev. 2012;(6):CD004567.
Dry Eye Assessment and Management Study Research Group. n-3 Fatty acid supplementation for the treatment of dry eye disease. N Engl J Med. 2018;378(18):1681-1690.
SanGiovanni JP, Chew EY, Clemons TE, et al. The relationship of dietary lipid intake and age-related macular degeneration in a case-control study: AREDS report no. 20. Arch Ophthalmol. 2007;125(5):671-679.
Kalt W, Hanneken A, Milbury P, et al. Recent research on polyphenolics in vision and eye health. J Agric Food Chem. 2010;58(7):4001-4007.
Chew EY, Clemons TE, Agrón E, et al. Long-term outcomes of adding lutein/zeaxanthin and ω-3 fatty acids to the AREDS supplements on age-related macular degeneration progression: AREDS2 report 28. JAMA Ophthalmol. 2022;140(7):692-698.
Giannaccare G, Pellegrini M, Sebastiani S, et al. Efficacy of omega-3 fatty acid supplementation for treatment of dry eye disease: a meta-analysis of randomized clinical trials. Cornea. 2019;38(5):565-573.
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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.
Schürks M, Glynn RJ, Rist PM, et al. Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials. BMJ. 2010;341:c5702.
Seddon JM, Reynolds R, Yu Y, et al. Risk models for progression to advanced age-related macular degeneration using demographic, environmental, genetic, and ocular factors. Ophthalmology. 2011;118(11):2203-2211.
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