By Mark W. Roark, OD, FAAO
The macular carotenoids—lutein (L), zeaxanthin (Z), and meso-zeaxanthin (MZ)—are concentrated a hundred-fold in the central macula relative to other retinal tissue.(1) Since they effectively filter high-energy blue light,(2) exert strong antioxidant properties,(3) and improve retinal function in patients with or without age-related macular degeneration (AMD),(4-5) it is reasonable to consider their relationship to the incidence of AMD—i.e. their impact on the actual disease in addition to visual function.
Epidemiological studies of various designs have been used to investigate possible associations between dietary intake of carotenoids and AMD. Although observational research does not prove causation, it can still uncover valuable relationships when properly controlling for confounding factors.(6)
A well-known observational study used a multicenter case-control design with results published in 1994.(7) It compared 356 subjects recently diagnosed with advanced (wet) AMD to a similar group of 520 controls aged 55-80, while adjusting for smoking and other risk factors. Results indicated a 43% reduction in likelihood of advanced AMD for those reporting the highest versus the lowest dietary intake of carotenoids. Importantly, L and Z showed the strongest correlation.
The association between dietary antioxidants and AMD was also evaluated as part of the 15-year Blue Mountain Eye Study in Australia that began in 1992.(8) Repeat eye examinations that included fundus photography were performed after 5 years, 10 years, or both on more than 2,400 of the original 3,654 participants. An impressive 65% reduction in the risk of having wet AMD was found for subjects in the highest vs lowest tertile of dietary intake of L and Z. Those with above-average intake had a 34% lower risk of developing soft or reticular drusen.
A case-control study from 2001 compared 56 donor eyes diagnosed with AMD to 56 control eyes.(9) Three concentric areas of retinal tissue around the foveal center were found to have lower amounts of macular carotenoids when AMD was present. Statistical evaluation revealed that eyes with L and Z levels in the highest quartile had an 82% lower risk for AMD compared to eyes in the lowest quartile. A model created from this work suggested that the lower macular carotenoid concentrations identified were more likely the cause rather than the effect of the disease.
Randomized clinical trials (RCT) are often considered the gold standard in determining the effectiveness of a chosen intervention because they employ a masked approach and rigid protocol to control for bias.6The AREDS and AREDS2 studies are well-known RCTs that have convinced many clinicians of the link between nutrition and macular disease.
The original AREDS study released in 2001 did not find a reduced onset of early macular degeneration in those taking the AREDS formula.(10) However, none of the macular carotenoids were present in the original AREDS supplement. Therefore, no conclusions can be drawn from this research on the role of these specific nutrients in AMD.
The AREDS2 trial incorporated L and Z in some arms of the study and assessed outcomes in subjects with the intermediate stage of the disease.(11) The pre-planned secondary analysis revealed a significant benefit when L and Z were included, leading to an additional 10% reduction in the risk of conversion to wet AMD compared to the intervention arm with the original AREDS formula. Further, in participants with the lowest dietary intake of the macular carotenoids, reduction in disease progression improved to 26%, underscoring the impact of supplementation with these targeted macular nutrients.
Because it is now deemed unethical to withhold macular carotenoids in human clinical studies, we will likely never have complete knowledge of their association with AMD. However, adopting strategies to increase levels of L, Z, and MZ in the macula stands on solid scientific footing when considering their physical characteristics, strategic location, ability to improve visual function, and impact on study outcomes (as seen in CREST AMD5).
Whenever AMD is a concern, clinicians should recommend a healthy lifestyle that includes appropriate dietary choices along with a properly selected supplement that enhances the levels of macular carotenoids. Many practitioners confidently choose a formulation containing 10L, 2Z, and 10 MZ based on research showing its advantage over other supplements in maximizing macular tissue response.(12)
Special thanks to John Nolan, PhD, who gave valuable input for this article.
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Snodderly DM. Evidence for protection against age-related macular degeneration by carotenoids and antioxidant vitamins. Am J Clin Nutr. 1995;62(6):S1448-S1461.
Krinsky NI, Landrum JT, Bone RA. Biologic mechanisms of the protective role of lutein and zeaxanthin in the eye. Annu Rev Nutr. 2003;23:171–201
Nolan JM, Power R, Stringham J, et al. Enrichment of macular pigment enhances contrast sensitivity in subjects free of retinal disease: central retinal enrichment supplementation trials report 1. Investigative Ophthalmology & Visual Science2016;57(7):3429-3439.
Akuffo KO, Beatty S, Peto T, et al. The impact of supplemental antioxidants on visual function in nonadvanced age-related macular degeneration: a head-to-head randomized clinical trial. Invest Ophthalmol Vis Sci. 2017;58(12):5347-5360.
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Seddon JM, Ajani UA, Sperduto RD, et al. Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. Eye disease case-control study group. JAMA. 1994;272(18):1413–1420.
Tan JSL, Wang JJ, Flood V, et al. Dietary antioxidants and the long-term incidence of age-related macular degeneration. Ophthalmology. 2008;115(2):334–341.
Bone RA, Landrum JT, Mayne ST, Gomez CM, Tibor SE, Twaroska EE. Macular pigment in donor eyes with and without AMD: a case-control study. Invest Ophthalmol Vis Sci. 2001;42(1):235-240.
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 Research Group 2, Chew EY, Clemons TE, et al. Secondary analyses of the effects of lutein/zeaxanthin on age-related macular degeneration progression: AREDS2 report No. 3. JAMA Ophthalmol. 2014;132(2):142–149.
Akuffo KO, Nolan JM, Howard AN, et al. Sustained supplementation and monitored response with differing carotenoid formulations in early age-related degeneration, Eye (Lond). 2015;29(7):1-11.
Dr. Roark is the president of Allisonville Eye Care Center in Fishers, IN. He is a member of the American Optometric Association, the Indiana Optometric Association, and a Fellow of the American Academy of Optometry. Dr. Roark speaks frequently on the topics of contrast sensitivity and ocular nutrition. You may contact him firstname.lastname@example.org.