BEYOND AREDS2: NEXT-GENERATION NUTRITIONAL SUPPLEMENTS FOR AGE-RELATED MACULAR DEGENERATION
Abstract
Background: Age-related macular degeneration (AMD) remains the leading cause of irreversible vision loss in older adults worldwide. While the AREDS2 formula has represented the standard of care for nutritional supplementation in intermediate AMD, emerging evidence suggests that newer compounds may offer enhanced protection against disease progression.
Methods: This systematic review evaluates literature identified in PubMed, Scopus, and Web of Science up to July 2024. The analysis concentrates on clinical trials, observational research, and mechanistic studies concerning next-generation supplements for AMD, such as astaxanthin, resveratrol, flavonoids, and apocarotenoids.
Results: We identified 42 relevant studies demonstrating that novel compounds address limitations of the current AREDS2 formulation through superior antioxidant properties (astaxanthin exhibits 10-100 times greater potency than lutein), enhanced anti-inflammatory effects (resveratrol reduces mtROS by 50%), and improved mitochondrial protection. Apocarotenoids like crocetin and norbixin show enhanced bioavailability and retinal protection compared to traditional carotenoids. Combination approaches targeting multiple AMD pathways simultaneously appear most promising.
Conclusion: Current evidence indicates that these novel compounds, particularly when combined with specific carotenoids, may represent a significant advancement beyond the current AREDS2 formulation. Further clinical validation is necessary to establish optimal dosing protocols and long-term safety profiles, but the emerging evidence supports a shift toward personalized, mechanism-based supplementation strategies for AMD management.
References
Wong WL, Su X, Li X, Cheung CMG, Klein R, Cheng C-Y, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. *Lancet Glob Health*. 2014;2(2):e106–16.
Bhutto I, Lutty G. Understanding age-related macular degeneration (AMD): relationships between the photoreceptor/retinal pigment epithelium/Bruch’s membrane/choriocapillaris complex. *Mol Aspects Med*. 2012;33(4):295–317.
Fleckenstein M, Keenan TDL, Guymer RH, Chakravarthy U, Schmitz-Valckenberg S, Klaver CC, et al. Age-related macular degeneration. *Nat Rev Dis Primers*. 2021;7(1):31.
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):2005–15.
Chew EY, Clemons TE, Sangiovanni JP, Danis RP, Ferris FL, Elman MJ, 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):142–9.
Fakhri S, Pesce M, Patra F, De Zio R, D’Onofrio MF, D’Amico M, et al. Beyond AREDS formulations, what is next for age-related macular degeneration? *J Ophthalmol*. 2020;2020:4984927.
Rasmussen HM, Johnson EJ. Nutrient supplementation for age-related macular degeneration. *Curr Opin Ophthalmol*. 2014;25(3):186–90.
Tisi A, Feligioni M, Passacantando M, Ciancaglini M, Maccarone R. The impact of oxidative stress on blood-retinal barrier physiology in age-related macular degeneration. *Cells*. 2021;10(1):64.
Abokyi S, To C-H, Lam TT, Tse DY. Central role of oxidative stress in age-related macular degeneration: evidence from a review of the molecular mechanisms and animal models. *Oxid Med Cell Longev*. 2020;2020:7901270.
Kaarniranta K, Kauppinen A, Blasiak J, Salminen A. Role of mitochondrial dysfunction and oxidative stress in the pathogenesis of age-related macular degeneration. *Antioxidants (Basel)*. 2023;12(3):574.
Beatty S, Koh H, Phil M, Henson D, Boulton M. The role of oxidative stress in the pathogenesis of age-related macular degeneration. *Surv Ophthalmol*. 2000;45(2):115–34.
Keenan TDL, Agrón E, Domalpally A, Clemons TE, van Asten F, Myers CE, et al. Progression of geographic atrophy in age-related macular degeneration: AREDS2 report number 16. *Ophthalmology*. 2018;125(12):1913–28.
Age-Related Eye Disease Study Research Group. The Age-Related Eye Disease Study (AREDS): design implications. AREDS report no. 1. *Control Clin Trials*. 1999;20(6):573–600.
Advani J, Mehta P, Hamel AR, Raghunathan A, Iyengar S, Chévez-Barrios P, et al. QTL mapping of human retina DNA methylation identifies 87 gene-epigenome interactions in age-related macular degeneration. *Nat Commun*. 2024;15(1):1972.
Natoli R, Fernando N, Jiao H, Racic T, Madigan M, Barnett NL, et al. Retinal macrophages synthesize C3 and activate complement in AMD and in models of focal retinal degeneration. *Invest Ophthalmol Vis Sci*. 2017;58(9):3827–36.
Terluk MR, Kapphahn RJ, Soukup LM, Gong H, Gallardo C, Montezuma SR, et al. Investigating mitochondria as a target for treating age-related macular degeneration. *J Neurosci*. 2015;35(18):7304–11.
Sparrow JR, Wu Y, Kim CY, Zhou J. Phospholipid meets all-trans-retinal: the making of RPE bisretinoids. *J Lipid Res*. 2010;51(2):247–61.
Grimmig B, Kim SH, Nash K, Bickford PC, Douglas Shytle R. Neuroprotective mechanisms of astaxanthin: a potential therapeutic role in preserving cognitive function in age and neurodegeneration. *GeroScience*. 2017;39(1):19–32.
Nakajima Y, Inokuchi Y, Shimazawa M, Otsubo K, Ishibashi T, Hara H. Astaxanthin, a dietary carotenoid, protects retinal cells against oxidative stress in-vitro and in mice in-vivo. *J Pharm Pharmacol*. 2008;60(10):1365–74.
Pintea A, Rugină D, Pop R, Moşoarcă C, Socaciu C, Bele C. Antioxidant effect of trans-resveratrol in cultured human retinal pigment epithelial cells. *J Ocul Pharmacol Ther*. 2011;27(2):315–21.
Kubota S, Kurihara T, Ebinuma M, Kubota M, Yuki K, Sasaki M, et al. Resveratrol prevents light-induced retinal degeneration via suppressing activator protein-1 activation. *Am J Pathol*. 2010;177(4):1725–31.
Mimura T, Kaji Y, Noma H, Funatsu H, Okamoto S. The role of SIRT1 in ocular aging. *Exp Eye Res*. 2013;116:17–26.
Kode A, Rajendrasozhan S, Caito S, Yang SR, Megson IL, Rahman I. Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells. *Am J Physiol Lung Cell Mol Physiol*. 2008;294(3):L478–88.
Nagineni CN, Raju R, Nagineni KK, Kommineni VK, Cherukuri A, Sinha D, et al. Resveratrol suppresses expression of VEGF by human retinal pigment epithelial cells: potential nutraceutical for age-related macular degeneration. *Aging Dis*. 2014;5(2):88–100.
Musiał C, Gdańska P, Kolasa-Wołosiuk A, Grabowska M, Łukowicz M, Urbański M, et al. The influence of dietary polyphenols on AMD from the perspective of their mechanisms of action. *Nutrients*. 2024;16(10):1510.
Middleton E Jr, Kandaswami C, Theoharides TC. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. *Pharmacol Rev*. 2000;52(4):673–751.
Larson AJ, Symons JD, Jalili T. Therapeutic potential of quercetin to decrease blood pressure: review of efficacy and mechanisms. *Adv Nutr*. 2012;3(1):39–46.
Gopinath B, Flood VM, Rochtchina E, Wang JJ, Mitchell P. Consumption of polyphenol-rich fruits and risk of age-related macular degeneration. *Br J Nutr*. 2018;120(5):527–33.
Gomes dos Santos AL, Bochot A, Tsapis N, Artzner F, Bejjani RA, Thillaye-Goldenberg B, et al. Liposomes and bioinspired nanoparticles for drug delivery in age-related macular degeneration. *J Control Release*. 2020;326:1–19.
Puglia C, Santonocito D. Nanocarriers for topical administration of resveratrol: a comparative study. *Int J Pharm*. 2019;567:118466.
Parisi V, Tedeschi M, Gallinaro G, Varano M, Saviano S, Piermarocchi S, CARMA Study Group. Carotenoids and antioxidant nutrients in age-related macular degeneration. *Nutrients*. 2024;16(3):454.
Marangoni D, Falsini B, Piccardi M, Ambrosio L, Minnella AM, Savastano MC, et al. Functional effect of saffron supplementation and risk genotypes in early age-related macular degeneration: a preliminary report. *J Transl Med*. 2013;11:228.
Sparrow JR, Gregory-Roberts E, Yamamoto K, Blonska A, Ghosh SK, Ueda K, et al. The bisretinoids of retinal pigment epithelium. *Prog Retin Eye Res*. 2012;31(2):121–35.
Asai A, Nakano T, Takahashi M, Nagao A. Orally administered crocetin and crocins are absorbed into blood plasma as crocetin and its glucuronide conjugates in mice. *J Agric Food Chem*. 2005;53(18):7302–6.
Bazan NG. Cellular and molecular events mediated by docosahexaenoic acid-derived neuroprotectin D1 signaling in photoreceptor cell survival and brain protection. *Prostaglandins Leukot Essent Fatty Acids*. 2009;81(2-3):205–11.
Serhan CN. Pro-resolving lipid mediators are leads for resolution physiology. *Nature*. 2014;510(7503):92–101.
Souied EH, Aslam T, Garcia-Layana A, Holz FG, Leys A, Silva R, et al. Omega-3 fatty acids and age-related macular degeneration. *Ophthalmic Res*. 2015;55(2):62–9.
Merle BMJ, Benlian P, Puche N, Bassols A, Delcourt C, Souied EH, Nutritional AMD Treatment 2 Study Group. Circulating omega-3 Fatty acids and neovascular age-related macular degeneration. *Invest Ophthalmol Vis Sci*. 2014;55(3):2010–9.
Liu X, Machado GC, Eyles JP, Ravi V, Hunter DJ. Dietary supplements for treating osteoarthritis: a systematic review and meta-analysis. *Br J Sports Med*. 2018;52(3):167–75.
Bone RA, Landrum JT, Guerra LH, Ruiz CA. Lutein and zeaxanthin dietary supplements raise macular pigment density and serum concentrations of these carotenoids in humans. *J Nutr*. 2003;133(4):992–8.
Chew EY, Clemons TE, Agrón E, Sperduto RD, Sangiovanni JP, Kurinij N, 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):692–9.
Hussein G, Sankawa U, Goto H, Matsumoto K, Watanabe H. Astaxanthin, a carotenoid with potential in human health and nutrition. *J Nat Prod*. 2006;69(3):443–9.
Del Amo EM, Rimpelä AK, Heikkinen E, Kari OK, Ramsay E, Lajunen T, et al. Pharmacokinetic aspects of retinal drug delivery. *Prog Retin Eye Res*. 2017;57:134–85.
Awh CC, Lane AM, Hawken S, Zanke B, Kim IK. CFH and ARMS2 genetic polymorphisms predict response to antioxidants and zinc in patients with age-related macular degeneration. *Ophthalmology*. 2013;120(11):2317–23.
Richer S, Stiles W, Statkute L, Pulido J, Frankowski J, Rudy D, et al. Double-masked, placebo-controlled, randomized trial of lutein and antioxidant supplementation in the intervention of atrophic age-related macular degeneration: the Veterans LAST study (Lutein Antioxidant Supplementation Trial). *Optometry*. 2004;75(4):216–30.
Csaky K, Ferris F 3rd, Chew EY, Nair P, Chew CC, Murphy R, et al. Report from the NEI/FDA Endpoints Workshop on Age-Related Macular Degeneration and Inherited Retinal Diseases. *Invest Ophthalmol Vis Sci*. 2017;58(9):3456–63.
Sunness JS, Rubin GS, Applegate CA, Bressler NM, Marsh MJ, Hawkins BS, et al. Visual function abnormalities and prognosis in eyes with age-related geographic atrophy of the macula and good visual acuity. *Ophthalmology*. 1997;104(10):1677–91.
Sadda SR, Guymer R, Holz FG, Schmitz-Valckenberg S, Curcio CA, Bird AC, et al. Consensus definition for atrophy associated with age-related macular degeneration on OCT: Classification of Atrophy Report 3. *Ophthalmology*. 2018;125(4):537–48.
Schmidt-Erfurth U, Sadeghipour A, Gerendas BS, Waldstein SM, Bogunović H. Artificial intelligence in retina. *Prog Retin Eye Res*. 2018;67:1–29.
Thomas CN, Purslow C, Basu H, Murdoch I, Hart PM, Ghanchi F, et al. Evaluation of a self-management intervention for dry age-related macular degeneration in a randomized clinical trial. *JAMA Ophthalmol*. 2021;139(7):758–66.
Jaffe GJ, Westby K, Csaky KG, Monés J, Pearlman JA, Patel SS, et al. C5 Inhibitor Avacincaptad Pegol for Geographic Atrophy Due to Age-Related Macular Degeneration: A Randomized Pivotal Phase 2/3 Trial. *Ophthalmology*. 2021;128(4):576–86.
Liao DS, Grossi FV, El Mehdi D, Gerber MR, Brown DM, Heier JS, et al. Complement C3 Inhibitor Pegcetacoplan for Geographic Atrophy Secondary to Age-Related Macular Degeneration: A Randomized Phase 2 Trial. *Ophthalmology*. 2020;127(2):186–95.
Views:
7
Downloads:
6
Copyright (c) 2025 Maja Ćwiek, Amin Omidi, Bartosz Krawiec, Bartosz Zarębski, Olaf Jadanowski, Jakub Sójka, Maksymilian Szombara, Michał Mokrzyński, Piotr Szyszka, Klaudia Malec
This work is licensed under a Creative Commons Attribution 4.0 International License.
All articles are published in open-access and licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). Hence, authors retain copyright to the content of the articles.
CC BY 4.0 License allows content to be copied, adapted, displayed, distributed, re-published or otherwise re-used for any purpose including for adaptation and commercial use provided the content is attributed.
