Efficacy of -3 Fatty Acids in Preventing Age-Related Macular Degeneration A Systematic Review William G. Hodge, MD, PhD, 1,2 Howard M. Schachter, PhD, 2 David Barnes, MD, 2 Yi Pan, MSc, 1 Elizabeth C. Lowcock, BScH, 1 Li Zhang, BSc, 2 Margaret Sampson, MLIS, 2 Andra Morrison, BSc, 2 Khai Tran, PhD, 2 Maia Miguelez, PhD, 2 Gabriela Lewin, MD 2 Topic: What is the evidence for efficacy of dietary and/or supplemental -3 fatty acids in preventing age-related macular degeneration (AMD)? Clinical Relevance: Age-related macular degeneration is the leading cause of blindness and vision impair- ment in persons older than 50 years living in North America. There is no cure for AMD, and treatment does not usually restore vision but only prevents disease progression to a modest degree. -3 fatty acids are considered potentially important antioxidants and are being considered as an arm of the Age-Related Eye Disease Study II clinical trial. Methods/Literature Reviewed: Keywords were searched in Medline, Pre-Medline, Embase, and the Co- chrane Library on Ovid. There was no restriction on the year or language of publication. Results: There were 6 observational studies found, but the specific outcomes, exposures, and covariates studied all varied greatly. Conclusion: There is some clinical evidence for protection of AMD from -3 fatty acids. However, the results are not consistent. Hence, our conclusion is that this issue is neither clearly supported nor refuted by the present world literature. This is an intriguing and extremely important question but needs further study first with prospective cohort designs and, if positive, randomized clinical trials. Ophthalmology 2006;113: 1165–1173 © 2006 by the American Academy of Ophthalmology. Polyunsaturated fatty acids are classified based on their chemical structure into 2 groups: -3 fatty acids and -6 fatty acids. The -3 notation means that the first double bond in this family of polyunsaturated fatty acids is 3 carbons from the methyl end of the molecule. Age-related macular degeneration (AMD) is the leading cause of blindness and vision loss in North Americans older than 50 years. 1 Very high levels of the omega-3 fatty acid docosahexaenoic acid are present in the retina—specifically, in the disk membranes of photoreceptor cells’ outer segments. 2 The high docosahexaenoic acid content and its specific and consistent tissue distribution suggest that docosahexaenoic acid has an important functional role in the retina. 3 The purpose of our systematic review is to evaluate the current world literature on the topic of -3 fatty acids and preven- tion of AMD. Docosahexaenoic acid accounts for over half the total fatty acyl groups present in the phospholipids of rod outer segment membranes, a proportion that is higher than what is found in any other tissue. 4 Its specific role, however, is not exactly known. The role of docosahexaenoic acid may be related to its biophysical effects on the cell membrane. Docosahexaenoic acid influences the membranes’ biophys- ical properties by polyunsaturation and may help to create a membrane that accommodates the dynamic behavior of rho- dopsin during the photoreceptive process. 5–7 In addition, do- cosahexaenoic acid may modulate the activity of membrane- bound enzymes and receptors and the kinetics of membrane transport systems, as well as be a precursor for the synthesis of other biologically active molecules. Docosahexaenoic acid also may play a role in modulating G protein– coupled signaling pathways that are involved in visual transduction. 7 The importance of docosahexaenoic acid in photoreceptor membrane anatomy and physiology gives basic science support for a possible beneficial role in retinal disease such as AMD. Furthermore, the -3 fatty acid eicosapentaenoic acid affects lipoprotein metabolism and decreases the production of other compounds, including cytokines, interleukin 1, Originally received: August 5, 2005. Accepted: February 14, 2006. Manuscript no. 2005-731. 1 Department of Ophthalmology, University of Ottawa Eye Institute, Ot- tawa, Canada. 2 Chalmers Systematic Review Research Group, CHEO Research Institute, Ottawa, Canada. This study was requested and funded by the Office of Dietary Supplements, National Institutes of Health, Bethesda, Maryland, through the Evidence- Based Practice Center program at the Agency for Healthcare Research and Quality, Rockville, Maryland. Correspondence to William G. Hodge, MD, PhD, University of Ottawa Eye Institute, 501 Smyth Road, Ottawa Ontario K1H 8L6, Canada.E-mail: whodge@ottawahospital.on.ca. 1165 © 2006 by the American Academy of Ophthalmology ISSN 0161-6420/06/$–see front matter Published by Elsevier Inc. doi:10.1016/j.ophtha.2006.02.043