May/June 2019

All Eyes on Diet — Nutrition to Prevent and Treat Macular Degeneration
By KC Wright, MS, RDN, LD
Today’s Geriatric Medicine
Vol. 12 No. 3 P. 14

Consistent with longer lifespans, the prevalence of age-related macular degeneration (AMD) is rising globally and is a leading cause of visual impairment and blindness.1,2 AMD is a progressive chronic disease of the central retina, believed to advance along a continuum, from early AMD toward wet (neovascular) and/or dry (atrophic) AMD.3 It’s a complex disease that has numerous nonmodifiable risk factors, including genetics, increasing age, and light skin and iris color. Research also suggests that AMD is more prominent in females.1

Inflammation, oxidative stress, and endothelial dysfunction are among the many factors hypothesized to influence the incidence and progression of AMD.2 Research has focused on preventing or slowing the progression of AMD through pharmacological interventions,3 but considerable interest remains on the influences of modifiable risk factors—diet, smoking cessation, and physical activity—that may prevent or delay the onset of AMD.

The role of diet in AMD is significant, although nutrition education for health care professionals has been inadequate and practitioners’ nutrition knowledge is considered insufficient to allow them to offer dietary advice.4,5 As a modifiable risk factor, diet can be difficult to pinpoint because the progression of AMD is very gradual. Determining cause through randomized, multicenter clinical trials can also be a challenge, as they are time consuming and expensive. Fortunately, epidemiological studies have identified modifiable risk factors, including diet, as plausible biological mechanisms in the pathophysiology of the disease. Still, it’s difficult to make an association between an individual nutrient and an influence on AMD, and it’s impossible to dissociate the effect of a nutrient from that caused by other aspects of total dietary intake, but current research indicates that nutrition influences AMD and forms a basis for practical recommendations for patient care.

Antioxidants in AMD
The biological integrity of eye tissue is dependent on the balance between the production of free radicals and their destruction. With age, the production of free radicals that cause oxidative stress increases and some of the endogenous defenses decrease, which can create an imbalance leading to progressive damage of cellular structures. If there’s an imbalance in the retinal lipids, the photoreceptor degradation and accumulation may lead to the formation of drusen, yellow deposits of lipids under the retina.1

The retina possesses an antioxidant system with several components, the most important of which are vitamins C and E, along with the carotenoids lutein and zeaxanthin. Dietary antioxidants can act as a protective chain—with different antioxidants having a synergistic effect—and protect each other from direct destruction in the process of neutralizing free radicals.1 Thus, dietary antioxidants and supplements may help prevent and delay the progression of AMD due to the decrease of oxidative stress and reduction of inflammatory events.

A systematic review of prospective studies of dietary intake found no evidence that diets high in antioxidant vitamins prevent AMD. More specifically, there’s no evidence from randomized clinical trials that healthy people should take vitamin and antioxidant supplements to delay or prevent the onset of AMD.1 Rather, much of the current literature focuses on the analyses of dietary supplements based on the Age-Related Eye Disease Studies, AREDS and AREDS2, which are complex randomized clinical trials designed to evaluate the effects of antioxidant supplements on patients who already have AMD.

The AREDS supplements were formulated with vitamins C (500 mg) and E (400 IU), beta-carotene (15 mg), copper (2 mg), and with or without zinc (80 mg), in much higher concentrations than the recommended daily intake. Subjects aged 55¬–80 were categorized by the amount of drusen and visual acuity they possessed. Results showed that treatment with antioxidants reduced the risk of progression to advanced AMD in patients possessing extensive intermediate drusen or large drusen.6 The inclusion or exclusion of zinc in supplements had no bearing on the progression of AMD.

After publication of the AREDS report in 2001, its formulation became the standard of care, but due to concerns about beta-carotene increasing risk of lung cancer in smokers, it was replaced in AREDS2 by other carotenoids—lutein and zeaxanthin at daily doses substantially higher than those contained in a typical Western diet. In AREDS2, a controlled clinical trial, subjects aged 50–85 were at risk of progression to advanced AMD with bilateral large drusen or large drusen in one eye, and advanced AMD in the fellow eye. Omega-3 fatty acids eicosapentanoic acid (EPA) and docosahexanoic acid (DHA) were added to the original formulation. The expected 25% incremental improvement over the original AREDS supplement results was not obtained, although the evidence on beneficial and adverse effects from AREDS2 suggests that lutein (2 mg) and zeaxanthin (15 mg) could be an appropriate substitute to beta-carotene in the AREDS-type supplements, particularly for former or current smokers.7

Dietary Nitrates in Green Leafy Vegetables and Beets
The Blue Mountain Eye Study is the first population-based study of adults aged 49 and older that demonstrated an inverse association between dietary nitrate intake and incidence of early, but not late, AMD.2 In other research, nitrate intake from vegetable sources was previously shown to improve endothelial function and minimize oxidative stress, suggesting a potential pathway by which dietary nitrate intake could protect against early AMD.8 Dietary nitrates are also shown to positively influence cardiovascular function, and since AMD and CVD share pathophysiologic pathways, this may explain the process whereby nitrate intake prevents the development of early AMD.2 Green leafy vegetables, including spinach, kale, Swiss chard, collard, arugula, and watercress, along with beets, are significant sources of dietary nitrate, precursors of nitric oxide.

Zinc
Zinc is the most abundant trace mineral in the retina.1 Seafood, particularly oysters, are the most nutrient-dense food sources of zinc, although beef, poultry, and pork generally provide sufficient amounts. Zinc is also found in beans, cereals, and nuts, although plant-based phytates may inhibit its absorption. The body does not store zinc, so if the diet is low in seafood and meat, zinc intake may not be adequate.

Zinc is a cofactor in many ocular enzymes and also binds complement factor H, inducing large multimeric forms that can help suppress the chronic inflammatory events in the retina that can lead to AMD.1 A systematic review of zinc trials in AMD analyzed the effect of zinc intake, both from supplements and/or foods in the treatment and primary prevention, and concluded that the current evidence on zinc intake for the prevention of AMD is inconclusive.9 However, AREDS revealed that 80 mg of zinc oxide, alone or in combination with antioxidants, significantly reduced the risk of progression to advanced AMD in individuals with moderate AMD.6 The risk of visual acuity loss was of similar magnitude, but not statistically significant.

Two other randomized clinical trials showed a statistically significant increase in visual acuity in early AMD patients, while another revealed no effect of zinc treatment on visual acuity in advanced AMD patients.9 The authors of the systematic review concluded, based on the strength of AREDS, that zinc treatment may be effective in preventing progression to advanced AMD, but that zinc supplementation alone may not be sufficient to produce clinically meaningful changes in visual acuity.

In a 2016 study, a diet high in zinc; vitamins D, E, and C; omega-3 fats; and beta-carotene was associated with a 60% to 90% reduction in the odds of developing neovascular AMD compared with a low intake of these nutrients.10 The results of this case-control study showed a greater reduction in odds compared with the AREDS supplement. This reinforces that the absorption of selective, extracted, or synthesized micronutrients from supplements is likely to be different from absorption of such compounds intact from whole foods.

Lutein and Zeaxanthin Supplementation
Lutein and zeaxanthin are major carotenoids found in fruits, green vegetables, corn, and egg yolks. Lutein and zeaxanthin foods have been shown to increase pigment macular density, but this capacity varies among individuals.1 Despite the strong biological plausibility, AREDS2 failed to demonstrate in the primary analyses the protective effects of lutein and zeaxanthin. However, there was a 26% risk reduction when the analysis was restricted to a subgroup of participants at the lowest 20% of the dietary intake of lutein/zeaxanthin.7 This supports the hypothesis that supplements may be more effective when the baseline dietary intake is below a sufficient threshold. It should also be noted that the intake of lutein/zeaxanthin in Western diets is far below the recommended level.1

A meta-analysis of eight randomized clinical trials of AMD subjects compared lutein/zeaxanthin with a placebo and found that lutein/zeaxanthin improved visual acuity and contrast sensitivity of the patients, and, more significantly, there was a dose-response relationship.11 Therefore, it’s advisable to recommend either food or supplement sources of lutein/zeaxanthin, especially for AMD patients. Results of the TOZAL (Taurine, Omega-3 Fatty Acids, Zinc, Antioxidant, Lutein) study demonstrated that AMD patients need at least six months of dietary intake to have a positive outcome.12

In 2016, a large prospective cohort study reported that high dietary intake of folate was associated with a decreased risk of progression of geographic atrophy.13 Folate is found in green vegetables, fruits, nuts, beans, and peas—the same food sources as those for lutein/zeaxanthin.

Omega-3 Supplementation
EPA and DHA, essential polyunsaturated fatty acids (PUFAs), are required for metabolism and must be obtained from the diet. EPA and DHA can also be synthesized from the 18-carbon fat alpha-linolenic acid (ALA), although the conversion rate to omega-3 PUFAs is relatively low. Still, food sources of ALA, such as seeds, nuts, and vegetable oils, have nutritional merit. Only the combined high intake of all three omega-3 fats has been associated with a reduction in the odds of developing early AMD compared with low intake.3

The addition of EPA and DHA in AREDS2 to the original AREDS formula failed to show additional AMD risk reduction—an unexpected finding, as epidemiological studies had pointed to the prophylactic effect of omega-3 for AMD.1 However, there is consistent evidence that high doses of DHA from oily fish are associated with a decreased risk of neovascular (wet) AMD. Five studies in a systematic review showed that a high intake of omega-3 fats and fish had statistically significant associations with the decreased development of intermediate and late AMD.3 Prospective data from the Women’s Health Study, a large cohort without AMD, indicated that regular consumption of DHA and EPA fish was associated with a significantly decreased risk of incidence of AMD and may be of benefit in primary prevention.14 In addition, this research showed a marked increase in the risk of developing AMD when the balance of omega-6 fatty acids was high. Omega-6 fats are sourced from vegetable oils and animal fats and are known to be proinflammatory. A high consumption of trans fats was associated with an increased risk of developing late AMD.3 The major source of trans fats in the diet is partially hydrogenated vegetable oils used in some fried and processed foods.

In general, the majority of evidence suggesting a positive effect of dietary omega-3 intake on the development and progression of AMD comes from observational studies, but remains to be demonstrated in randomized clinical trials.1 Given the current evidence, it’s reasonable to advise AMD patients to consume dietary fatty fish—salmon, tuna, sardines, mackerel, trout, anchovies, and swordfish—or take fish oil supplements, with the understanding that doubts remain as to its efficacy. A typical dosage of fish oil is 3 g to 9 g daily. A registered dietitian or pharmacist should recommend a reputable source.

Carbohydrates
Refined carbohydrates, such as white bread, white rice, white pasta, and refined sugar, and potatoes, have a high glycemic index (GI) that can stimulate a rapid increase in blood glucose. Low-GI foods—such as whole fruits, vegetables, whole grain bread, oats, bran, and legumes—have been shown to improve glycemic control and reduce postprandial hyperglycemia when an increase in intracellular oxidative stress (by hypothesized hyperglycemic pathway mechanisms) stimulates high concentrations in blood glucose.15 Studies show that a high-GI diet compared with a low-GI diet was associated with an increased risk of developing early AMD.3 A high-GI diet was associated with a 17% increased risk of progression to advanced AMD.16

The Mediterranean Diet
Inspired by the traditional diet followed by people living in the countries that border the Mediterranean Sea, the Mediterranean diet (Med diet) refers to a way of eating that’s rich in vegetables, fruits, whole grains, legumes, nuts, seeds, and extra virgin olive oil (EVOO). Fish, poultry, and dairy are consumed in low to moderate amounts, and red and processed meats are limited. Wine, particularly red, is consumed with meals in low to moderate amounts. Existing knowledge about nutrition and health suggest that the incidence or risk of major chronic disease in older adults, such as coronary heart disease, stroke, metabolic syndrome and diabetes, cognitive impairment, and certain cancers, can be reduced and even prevented with healthy, lifelong dietary habits in line with the Med diet.17

A systematic review of the role of diet and food intake in AMD showed that a high adherence to the Med diet was beneficial in late AMD.3 A high consumption of red meat has been shown to increase the odds of developing AMD, while processed meat such as salami and sausage has been associated with developing late AMD.18

The Carotenoids Age-Related Eye Disease Study demonstrated that a high adherence to the Med diet was associated with a lower prevalence of early AMD.19 Data from AREDS were compared with dietary information collected from food-frequency questionnaires and the alternate Med diet score, comprising intake of vegetables, fruits, legumes, whole grains, nuts, fish, red and processed meats, alcohol, and the ratio of monounsaturated to saturated fats.1 Analysis showed that a high score was associated with a 26% reduced risk of progression to advanced AMD, and that the consumption of fish and vegetables was associated with a lower risk of progression to advanced AMD. The administration of AREDS supplements did not change the protective effect of the Med diet on the risk of progression. In the Coimbra Eye Study, a high Med diet score appears to confer protection against the development of AMD, driven by increased consumption of fruits and some antioxidant micronutrients, which emerged as statistically significant protective factors.20

The biological plausibility of the benefits of the Med diet involves a decrease in oxidative stress and inflammation. In fact, those who have a greater adherence to the Med diet have higher plasma concentrations of some important and beneficial biomarkers for oxidative stress.1 The benefits of the Med diet appear to be due to the synergistic and interactive combinations of nutrients rather than to the isolated nutrients themselves.

An Asian diet pattern, representing a higher intake of fruit, vegetables, legumes, whole grains, tomatoes, and seafood, has also been shown to have a protective role in both early and advanced AMD. A significantly reduced risk of AMD was seen with one to five servings of fish consumption per week (compared with less than one serving.)21 By contrast, the Western diet, defined as having a higher intake of red meat, processed meat, high-fat dairy products, fried potatoes, refined grains, and eggs, demonstrated increased odds for both early and advanced AMD in a systematic review.3

Data from a population-based study suggests a protective role of EVOO consumption for late AMD in elderly subjects, yet no association was found between EVOO consumption and early AMD, nor was the use of other types of fat associated with any stage of AMD.22 However, the use of EVOO was found to be beneficial in reducing the odds of developing late AMD in two reported studies.3 EVOO contains monounsaturated fatty acids and polyphenols that also have antioxidant and anti-inflammatory properties.

To reduce the risk of developing early AMD, alcohol consumption for both men and women should be limited to fewer than two standard drinks per day.3 However, other research suggests a significant risk when one to two servings of alcohol were consumed compared with less than one serving daily.21

Genetic Influences
Epidemiological studies suggest that a healthy diet combined with the absence of smoking and physical activity were associated with reduced occurrence of both early and advanced AMD, although genetic risk may modify the benefits of a healthful lifestyle. CFH is one of the main genes implicated in AMD, and the risk allele leads to complement activation of increasing the AMD risk.1 In the previously cited 2016 prospective cohort study, the Med diet score was associated with a lower risk of advanced AMD among individuals carrying the CFH Y402H nonrisk (T) allele.13 Thus, it would be prudent for physicians to recommend to individuals who have a family history of AMD to follow a healthy lifestyle including adoption of the Med diet.

AMD Diet Prescription
As diet is a modifiable risk factor for AMD, nutrition should be an intervention priority for older adults to both prevent and delay the disease. A plant-based diet, abundant in micronutrients, tends to have greater bioavailability of nutrients than do dietary supplements, which are poorly regulated.

In general, there are adequate amounts of vitamins, carotenoids, and essential fatty acids in the American diet to supply the health needs of individuals. And many of these nutrients share the same rich food sources: nuts and seeds, whole grains, dark leafy vegetables, and fruits. New research suggests that a minimum of 1.25 to 1.5 cups of vegetables and two servings of fruit daily, along with fish consumption twice weekly, significantly reduces the risk of developing AMD.23

When nutrient requirements are not met through diet alone and dietary supplements are warranted, the American Academy of Ophthalmology recommends physicians consider antioxidant vitamin and mineral supplementation as per the AREDS trials for patients with intermediate or advanced AMD to slow progression of the disease.24 Both the AREDS (containing beta-carotene) and AREDS2 (containing lutein/zeaxanthin) formulations are available on the market. Supplement choice should be based on cigarette smoking status, as beta-carotene is associated with an increased risk of lung cancer among smokers as well as former smokers.

Improved patient education by health professionals along with improved strategies for patient adherence are needed in the nutrition management of AMD. Even a modest protective effect on the prevention and progression of AMD could have a significant impact on patient welfare and burden to society.

— KC Wright, MS, RDN, LD, works on telehealth wellness research for older adults at Dartmouth Medical Center. She advocates for sustainable food systems at www.wildberrycommunications.com.

References
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2. Gopinath B, Liew G, Kifley A, et al. Association of dietary nitrate intake with the 15-year incidence of age-related macular degeneration. J Acad Nutr Diet. 2018;118(12):2311-2314.

3. Chapman NA, Jacobs RJ, Braakhuis AJ. Role of diet and food intake in age-related macular degeneration: a systematic review. Clin Exp Ophthalmol. 2019;47(1):106-127.

4. Adams KM, Kohlmeier M, Zeisel SH. Nutrition education in U.S. medical schools: latest update of a national survey. Acad Med. 2010;85(9):1537-1542.

5. Mowe M, Bosaeus I, Rasmussen HH, et al. Insufficient nutritional knowledge among health care workers? Clin Nutr. 2008;27(2):196-202.

6. 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.

7. Age-Related Eye Disease Study 2 Research Group. Lutein + zexanthin 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.

8. Bondonno CP, Croft KD, Hodgson JM. Dietary nitrate, nitric oxide, and cardiovascular health. Crit Rev Food Sci Nutr. 2016;56(12):2036-2052.

9. Vishwanathan R, Chung M, Johnson EJ. A systematic review on zinc for the prevention and treatment of age-related macular degeneration. Invest Ophthal Vis Sci. 2013;54(6):3985-3998.

10. Aoki A, Inoue M, Nguyen E, et al. Dietary n-3 fatty acid, α-tocopherol, zinc, vitamin D, vitamin C, and β-carotene are associated with age-related macular degeneration in Japan. Sci Rep. 2016;6:20723.

11. Liu R, Wang T, Zhang B, et al. Lutein and zeaxanthin supplementation and association with visual function in age-related macular degeneration. Invest Ophthal Vis Sci. 2014;56(1):252-258.

12. Cangemi FE. TOZAL study: an open case control study of an oral antioxidant and omega-3 supplement for dry AMD. BMC Ophthal. 2007;7:3.

13. Merle BM, Silver RE, Rosner B, Seddon JM. Dietary folate, B vitamins, genetic susceptibility and progression to advanced nonexudative age-related macular degeneration with geographic atrophy: a prospective cohort study. Am J Clin Nutr. 2016;103(4):1135-1144.

14. Christen WG, Schaumberg DA, Glynn RJ, Buring JE. Dietary ω-3 fatty acid and fish intake and incident age-related macular degeneration in women. Arch Ophthalmol. 2011;129(7):921-929.

15. Chiu CJ, Taylor A. Dietary hyperglycemia, glycemic index and metabolic retinal diseases. Prog Retin Eye Res. 2011;30(1):18-53.

16. Chiu CJ, Milton RC, Klein R, Genser G, Taylor A. Dietary carbohydrate and the progression of age-related macular degeneration: a prospective study from the Age-Related Eye Disease Study. Am J Clin Nutr. 2007;86(4):1210-1218.

17. Boccardi V, Calvani R, Limongi F, et al. Consensus paper on the “executive summary of the international conference on Mediterranean diet and health: a lifelong approach” an Italian initiative supported by the Mediterranean Diet Foundation and the Menarini Foundation. Nutrition. 2018;51-52:38-45.

18. Chong EW, Simpson JA, Robman LD, et al. Red meat and chicken consumption and its association with age-related macular degeneration. Am J Epidemiol. 2009;169(7):867-876.

19. Merle BM, Silver RE, Rosner B, Seddon JM. Adherence to a Mediterranean diet, genetic susceptibility, and progression to advanced macular degeneration: a prospective cohort study. Am J Clin Nutr. 2015;102(5):1196-1206.

20. Raimundo M, Mira F, Cachulo MDL, et al. Adherence to a Mediterranean diet, lifestyle and age-related macular degeneration: the Coimbra Eye Study — report 3. Acta Ophthalmol. 2018;96(8):926-932.

21. Dinu M, Pagliai G, Casini A, Sofi F. Food groups and risk of age-related macular degeneration: a systematic review with meta-analysis [published online July 5, 2018]. Eur J Nutr. doi: 10.1007/s00394-018-1771-5.

22. Cougnard-Grégoire A, Merle BM, Rougier JK, et al. Olive oil consumption and age-related macular degeneration: the Alienor Study. PLoS ONE. 2016;11(7):e0160240.

23. De Koning-Backus APM, Buitendijk GHS, Kiefte-de Jong JC, et al. Intake of vegetables, fruit, and fish is beneficial for age-related macular degeneration. Am J Ophthalmol. 2019;198:70-79.

24. Age-related macular degeneration PPP — updated 2015. American Academy of Ophthalmology website. https://www.aao.org/preferred-practice-pattern/age-related-macular-degeneration-ppp-2015. Updated January 2015. Accessed January 15, 2019.