AREDS2 as a Retinal Geroprotective Strategy: A Literature Review Through a Geroscience Lens
Literature Review
DOI:
https://doi.org/10.55175/cdk.v53i08.2130Keywords:
Age-related macular degeneration, AMD, AREDS2, geroscience, precision geromedicine, retinal geroprotectionAbstract
Introduction: Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss among the elderly population. The Age-Related Eye Disease Study 2 (AREDS2) supplementation was developed as an evidence-based nutraceutical strategy to slow the progression of AMD. This review aims to evaluate the clinical evidence and potential application of AREDS2 as a geroprotective retinal intervention within the framework of precision geromedicine. Methods: A narrative review of recent AREDS and AREDS2 studies was conducted, integrating concepts from geroscience related to retinal aging. Results: The AREDS2 formulation, which replaced beta-carotene with lutein and zeaxanthin, demonstrated an 18% reduction in AMD progression risk without increasing lung cancer risk among smokers. AREDS2 components target key aging pathways, including oxidative stress, mitochondrial dysfunction, chronic inflammation, and dysregulated autophagy. In addition, potential modulation of mTOR and AMPK signaling suggests a role in extending retinal healthspan. Conclusion: AREDS2 represents a promising nutraceutical approach as a retinal gerotherapy within the paradigm of precision geromedicine. Its clinical implications include preventing AMD progression, optimizing visual function in older adults, and enabling integration into precision-based ophthalmologic practice. Further research is warranted to validate the molecular mechanisms and assess the cross-population effectiveness, thereby strengthening its role in broader age-related ocular health interventions.
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References
Kashi AK, Souied E, Fares S, Borrelli E, Capuano V, Jung C, et al. The spectrum of central choriocapillaris abnormalities on swept-source optical coherence tomography angiography in the fellow eye of unilateral exudative age-related macular degeneration patients: from flow deficits to subclinical non-exudative neovascularization. J Clin Med. 2021;10(12):2658. doi: 10.3390/JCM10122658.
Rein DB, Wittenborn JS, Zhang X, Honeycutt AA, Lesesne SB, Saaddine J. Forecasting age-related macular degeneration through the year 2050: the potential impact of new treatments. Arch Ophthalmol. 2009;127(4):533–40. doi: 10.1001/ARCHOPHTHALMOL.2009.58.
Pennington KL, DeAngelis MM. Epidemiology of age-related macular degeneration (AMD): associations with cardiovascular disease phenotypes and lipid factors. Eye and vision (London, England) 2016;3:34. https://doi.org/10.1186/s40662-016-0063-5.
Vyawahare H, Shinde,P. Age-related macular degeneration: epidemiology, pathophysiology, diagnosis, and treatment. Cureus 2022;14(9):e29583. https://doi.org/10.7759/cureus.29583.
Guo J, Huang X, Dou L, Yan M, Shen T, Tang W, et al. Aging and aging-related diseases: from molecular mechanisms to interventions and treatments. Signal Transduction Targeted Ther. 2022;7(1):1–40. https://doi.org/10.1038/s41392-022-01251-0.
Iakovou E, Kourti M. A comprehensive overview of the complex role of oxidative stress in aging, the contributing environmental stressors and emerging antioxidant therapeutic interventions. Front Aging Neurosci. 2022;14:827900. https://doi.org/10.3389/fnagi.2022.827900.
Upadhyay M, Bonilha V. Analysis of oxidative stress-mediated degeneration in retina and RPE using sodium iodate (NaIO3) model. Free Radic Biol Med. 2018;128:S128. doi: 10.1016/J.FREERADBIOMED.2018.10.318.
Prea SM Chan, EC, Dusting GJ, Vingrys AJ, Bui BV, Liu GS, et al. Gene therapy with endogenous inhibitors of angiogenesis for neovascular age-related macular degeneration: beyond anti-VEGF therapy. J Ophthalmol. 2015;1:201726. https://doi.org/10.1155/2015/201726.
Langford-Smith A, Keenan TDL, Clark SJ, Bishop PN, Day AJ. The role of complement in age-related macular degeneration: Heparan sulphate,a ZIP code for complement factor H?. J Innate Immun. 2014;6(4):407–16. doi: 10.1159/000356513.
Suzumura A, Terao R, Kaneko H. Protective effects and molecular signaling of n-3 fatty acids on oxidative stress and inflammation in retinal diseases. Antioxidants. 2020;9(10):920. doi: 10.3390/ANTIOX9100920.
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. doi: 10.1016/J.OPHTHA.2013.07.039.
Wang L, Chen Y, Sternberg P, Cai J. Essential roles of the PI3 kinase/akt pathway in regulating Nrf2-dependent antioxidant functions in the RPE. Invest Ophthalmol Vis Sci. 2008;49(4):1671–8. doi: 10.1167/IOVS.07-1099.
Wang D, Chen Y, Li J, Wu E, Tang T, Singla RK, et al. Natural products for the treatment of age-related macular degeneration. Phytomedicine. 2024;130:155522. https://doi.org/10.1016/j.phymed.2024.155522.
Iakovou E, Kourti M. A comprehensive overview of the complex role of oxidative stress in aging, the contributing environmental stressors and emerging antioxidant therapeutic interventions. Front Aging Neurosc. 2022;14:827900. https://doi.org/10.3389/fnagi.2022.827900.
Reinisalo M, Karlund A, Koskela A, Kaarniranta K, Karjalainen RO. Polyphenol stilbenes: molecular mechanisms of defence against oxidative stress and aging-related diseases. Oxidative Med Cell Longevity. 2015;2015:340520. https://doi.org/10.1155/2015/340520.
Wessels I, Maywald M, Rink L. Zinc as a gatekeeper of immune function. Nutrients 2017;9(12):1286. https://doi.org/10.3390/nu9121286.
Basyal D, Lee S, Kim HJ. Antioxidants and mechanistic insights for managing dry age-related macular degeneration. Antioxidants (Basel). 2024;13(5):568. https://doi.org/10.3390/antiox13050568.
Marino N, Putignano G, Cappilli S, Chersoni E, Santuccione A, Calabrese G, et al. Towards AI-driven longevity research: a overview. Front Aging. 2023;4:1057204. https://doi.org/10.3389/fragi.2023.1057204.
Shanaida M, Mykhailenko O, Lysiuk R, Hudz N, Balwierz R, Shulhai A, et al. Carotenoids for antiaging: nutraceutical, pharmaceutical, and cosmeceutical applications. Pharmaceuticals 2025;18(3):403. https://doi.org/10.3390/ph18030403.
Parmar UPS, Surico PL, Mori T, Singh RB, Cutrupi F, Premkishore P, et al. Antioxidants in age-related macular degeneration: lights and shadows. Antioxidants (Basel). 2025;14(2):152. https://doi.org/10.3390/antiox14020152.
Alugoju P, Krishna Swamy VKD, Anthikapalli NVA, Tencomnao T. Health benefits of astaxanthin against age-related diseases of multiple organs: a comprehensive review. Crit Rev Food Sci Nutr. 2023;63(31):10709–74. doi:10.1080/10408398.2022.2084600.
Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: an expanding universe. Cell. 2023;186(2):243–78. doi:10.1016/J.CELL.2022.11.001.
Kennedy BK, Berger SL, Brunet A, Campisi J, Cuervo AM, Epel ES, et al. Geroscience: linking aging to chronic disease. Cell. 2014;159(4):709–13. doi: 10.1016/J.CELL.2014.10.039.
Campisi J, Kapahi P, Lithgow GJ, Melov S, Newman JC, Verdin E. From discoveries in ageing research to therapeutics for healthy ageing. Nature. 2019;571(7764):183–92. doi: 10.1038/S41586-019-1365-2.
Sivaprasad S, Chong N V. The complement system and age-related macular degeneration. Eye. 2006;20(8):867–72. doi: 10.1038/SJ.EYE.6702176.
Wong KH, Nam HY, Lew SY, Naidu M, David P, Kamalden TA, et al. Discovering the potential of natural antioxidants in age-related macular degeneration: a review. Pharmaceuticals (Basel). 2022 Jan 14;15(1):101. doi: 10.3390/ph15010101.
Buonfiglio F, Korb CA, Stoffelns B, Pfeiffer N, Gericke A. Recent advances in our understanding of age-related macular degeneration: mitochondrial dysfunction, redox signaling, and the complement system. Aging Dis. 2024;16(3):1535–75. doi: 10.14336/AD.2024.0124.
Chew EY, Clemons T, SanGiovanni JP, Danis R, Domalpally A, McBee W, et al. The Age-Related Eye Disease Study 2 (AREDS2): study design and baseline characteristics (AREDS2 report no 1). Ophthalmology. 2012;119(11):2282–9. doi: 10.1016/J.OPHTHA.2012.05.027.
Suzumura A, Terao R, Kaneko H. Protective effects and molecular signaling of n-3 fatty acids on oxidative stress and inflammation in retinal diseases. Antioxidants (Basel). 2020;9(10):920. doi: 10.3390/ANTIOX9100920.
Mrowicka M, Mrowicki J, Kucharska,E, Majsterek I. Lutein and zeaxanthin and their roles in age-related macular degeneration-neurodegenerative disease. Nutrients 2022;14(4):827. https://doi.org/10.3390/nu14040827.
Wong KH, Nam HY, Lew SY, Naidu M, David P, Kamalden TA, et al. Discovering the potential of natural antioxidants in age-related macular degeneration: a review. Pharmaceuticals (Basel, Switzerland) 2022;15(1):01. https://doi.org/10.3390/ph15010101.
Fingar DC, Blenis J. Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression. Oncogene. 2004;23(18):3151–71. doi:10.1038/SJ.ONC.1207542.
Lambert NG, ElShelmani H, Singh MK, Mansergh FC, Wride MA, Padilla M, et al. Risk factors and biomarkers of age-related macular degeneration. Prog Retin Eye Res. 2016;54:64–102. doi: 10.1016/J.PRETEYERES.2016.04.003.
Bian Q, Gao S, Zhou J, Qin J, Taylor A, Johnson EJ, et al. Lutein and zeaxanthin supplementation reduces photooxidative damage and modulates the expression of inflammation-related genes in retinal pigment epithelial cells. Free Radic Biol Med. 2012;53(6):1298–307. doi:10.1016/J.FREERADBIOMED.2012.06.024.
Tuo J, Ross RJ, Herzlich AA, Shen D, Ding X, Zhou M, et al. A high omega-3 fatty acid diet reduces retinal lesions in a murine model of macular degeneration. Am J Pathol. 2009;175(2):799–807. doi: 10.2353/AJPATH.2009.090089.
Detaram DH, Mitchell P, Russell J, Burlutsky G, Liew G, Gopinath B. Dietary zinc intake is associated with macular fluid in neovascular agerelated macular degeneration. Clin Exp Ophthalmol. 2020;48(1):61–8. doi: 10.1111/CEO.13644.
Gemenetzi M, Lotery AJ. Complement pathway biomarkers and age-related macular degeneration. Eye (Lond). 2016;30(1):1–14. doi:10.1038/EYE.2015.203.
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Copyright (c) 2026 Bhirau Wilaksono, Enno Elfandari, Rayhani Ichsan, A. Dhini Alfiandari, Nurul Muf'idah Damry, Andi Makkawaru Chairul, Nurul Mutiah Aminuddin, Novi Safitri Nurdin, Aida Ayu Chandrawati, Nurussyariah Hammado

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