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Interconnecting the Mediterranean Diet and Age-Related Macular Degeneration
26 Interconnecting the Mediterranean Diet and Age-Related Macular Degeneration Jayne V Woodside, Damian Cole, Ruth E Hogg CENT RE FOR PUBLIC H EALTH, QUEEN’ S UNIVERS IT Y BE LFAST , I NSTI TUTE OF CLI NI CAL SCI ENCE A, B ELFAST, I RELAND
CHAPTER OUTLINE Introduction .................................................................................................................................. 425 Diet, Dietary Patterns, and AMD Risk ......................................................................................... 426 The Mediterranean Diet .............................................................................................................. 428 Measuring Adherence to a MD: The MD Score (MDS) .............................................................. 429 Epidemiologic Evidence Linking Adherence to a Med Diet and AMD Risk .............................. 432 Conclusion .................................................................................................................................... 434 Summary Points ........................................................................................................................... 434 References .................................................................................................................................... 435
Introduction In the developed world, as life expectancy increases and the birth rate declines, the proportion of older people is increasing. The number of people aged over 60 years is expected to rise from 605 million in 2000 to 2 billion in 2050, accounting for approximately one-fifth of the worldwide population in 2050.1 As the proportion of older people increases, so will the incidence of chronic diseases and the proportion of the population living with disability. Strategies that reduce age-related morbidity and reduce chronic disease prevalence are therefore important for healthy or successful aging, and any such strategies, which are successful, are likely to have financial and societal benefits. The avoidance of malnutrition is known to contribute to the health of older people and helps recovery from illness.2 Dietary factors have also been suggested to play a role in chronic disease prevention3,4 and to promote healthy aging, and are therefore the focus of much interest among researchers and policy makers with an interest in the primary and secondary prevention of chronic disease and the promotion of lifestyle factors that will encourage healthy aging. The increasing prevalence of age-related macular degeneration (AMD) and the impact on healthcare systems are major concern as the population ages. In 2014, it was estimated Handbook of Nutrition, Diet, and the Eye. https://doi.org/10.1016/B978-0-12-815245-4.00026-0 © 2019 Elsevier Inc. All rights reserved.
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that the pooled prevalence (mapped to an age range of 45–85 years) of early, late, and any AMD was 8%, 0.4%, and 9%, respectively.5 Within the same analyses, the projected number of people with AMD globally in 2020 was 196 million, increasing to 288 million by 2040.5 In an analysis focused on 14 population-based European cohorts, prevalence of early AMD increased from 3.5% in those aged 55–59 years to 17.6% in those aged 85 years; for late AMD these figures were 0.1% and 9.8%, respectively. However, decreasing prevalence of late AMD was observed after 2006, which became most prominent after age 70. Projections of AMD showed an almost doubling of affected persons despite a decreasing prevalence due to changes in population structure. By 2040, between 14.9 and 21.5 million individuals in Europe are likely to have early AMD according to the analysis, and for late AMD between 3.9 and 4.8 million. The authors suggested that the decreasing prevalence of late AMD was most likely explained by healthier lifestyles and changes in the population structure while the reduction in sight impairment was due to the implementation of antivascular endothelial growth factor treatment. Nevertheless, the numbers of affected subjects will increase considerably in the next two decades, and the authors concluded that AMD continues to remain a significant public health problem among elderly Europeans.6 AMD manifests initially as pigmentary irregularities of the retina and deposits of extracellular material called drusen that collect at the retinal pigment epithelial/choroidal interface. These features are not associated with overt sight loss and are termed early AMD or intermediate AMD depending on the size and extent of the drusen and pigmentary irregularities. Approximately one in two persons with extensive macular drusen will progress within 5 years to sight threatening geographic atrophy (GA) and/or neovascularization (nvAMD),7 which are late-stage manifestations of the condition.8,9 GA is currently untreatable and although nvAMD may now be controlled with antiangiogenic agents, the majority of patients so treated have residual visual disability due to varying degrees of retinal tissue disruption, scarring, and/or atrophy. Treatments with antiangiogenic agents is also a costly and time-intensive process as a series of monthly intraocular injections are given followed by regular check-ups, with periods of disease inactivity punctuated by reactivation followed by more injections (Fig. 1). As described, AMD is the predominant cause of blindness in high income countries,10 and is of growing importance in other settings, in association with increasing longevity.11 AMD is considered to be a complex multifactorial disorder, involving an interplay between genetic, environmental, and lifestyle factors, such as smoking,12 obesity,13 cardiovascular disease,14 macular pigment,15 sunlight exposure,16 dietary factors,17 high BMI,18 and physical activity.19
Diet, Dietary Patterns, and AMD Risk It has been known for some time that dietary factors can modulate AMD risk.20,21 Epidemiological studies have demonstrated that diets high in antioxidant nutrients (vitamins C and E, carotenoids such as lutein and zeaxanthin and fruit and vegetables rich in these nutrients) or zinc are associated with a decreased occurrence of AMD. Studies have also shown that a high dietary intake of trans fats is a risk factor for late AMD,22 while a higher
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FIG. 1 Features of age-related macular degeneration.
intake of fish or ω 3 fatty acids is protective against AMD.23 However, the evidence from clinical trials is less consistent. While high-dose multivitamin supplementation slowed the progression of AMD,24 similar trials of lutein and zeaxanthin supplements, with or without omega 3 fatty acids, showed no effect on AMD progression (AREDS2).25–27 Most studies to date have focused on individual food groups or nutrients, yet, in “real life” settings, individuals eat a combination of foods within a mixed diet rather than isolated foods and nutrients and it is known that diet is a multifactorial lifestyle behavior, with particular foods frequently consumed together, depending on the cultural, geographical, and economic context of the individual. Therefore, nutrition researchers are increasingly attempting to analyze relationships between dietary patterns or overall diet and disease, rather than specific foods or nutrients thus permitting the synergistic effects of food intake to be examined in relation to risk of disease.28 Dietary patterns rather than individual components are also increasingly being studied in relation to AMD.29–31 Various methodological approaches have been taken but tend to fall into two broad categories. The first are a posteriori approaches, including the use of factor and principal component analysis to identify patterns, which are then related to the disease under investigation.28–30 This is a data-driven approach, and requires no a priori hypothesis of what factors or food groups within the overall diet may be important. The second method uses a priori scores to assess an individual’s adherence to a specific diet such as the Mediterranean diet (MD)28,31 or a set of dietary recommendations,28 and therefore requires an a priori hypothesis of what may be important.
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One such dietary pattern that has generated much interest is the MD. Early observations in the Seven Countries study conducted in the 1960s reported lower cardiovascular disease mortality in populations in the Mediterranean region compared to Northern European or US populations, implying a cardioprotective effect of traditional MDs.32 Since then, numerous prospective studies have been published supporting a link between greater adherence to an MD and lower CVD and T2DM disease risk and overall mortality,33 with some studies, which have been meta-analyzed, also suggesting an association between increased adherence to the MD pattern and reduced risk of neurodegenerative disease, including Alzheimer’s Disease, and cancer outcomes.34 The traditional MD is increasingly being promoted as a model dietary pattern— particularly for disease prevention. In an overview of research on the MD, it has been suggested that >80% of CHD could be avoided by healthy food choices that are consistent with the traditional MD.35 Furthermore, in a systematic review of evidence supporting a causal link between dietary factors and CHD, evidence for a MD was rated as strong3 but further evaluation of dietary patterns in cohort studies and randomized trials was recommended. Seeing as the etiological profile for CVD and AMD is similar, and that they share a range of major risk factors, it is not surprising that there has also been some interest in the association between adherence to an MD pattern and risk of AMD, although research is at a much earlier stage than for CVD. This chapter will examine the food components of an MD and review the published evidence evaluating the MD for prevention of AMD.
The Mediterranean Diet The MD pattern describes eating habits of populations living in olive-growing regions of countries bordering the Mediterranean Sea, during the 1960s. The traditional MD is not a single dietary pattern as multiple differences, including sociocultural, economic, and religious variations, along the Mediterranean basin have influenced food intake.36 To facilitate research into the health properties of an MD, the traditional dietary pattern was first defined in 1993 at an International conference on diets of the Mediterranean37 and is characterized by the following: • • • • • •
high intake of plant foods comprising fruit and vegetables, wholegrain cereals, legumes, tree nuts and seeds high olive oil consumption moderate-to-high intake of fish with emphasis on oily fish moderate intake of poultry and low-fat dairy products (mostly as cheese and yogurts) low intake of meat and meat products moderate alcohol consumption, normally consumed as wine with meals.
The MD pattern is associated with greater intake of antioxidant vitamins and minerals, linoleic acid (LA), α-linolenic acid (ALA), and several other possibly beneficial nonnutrient constituents such as polyphenols.38 In contrast to a conventional low-fat diet (<30% total
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energy intake), the traditional MD advocates a moderate total fat intake (approximately 35%–40% energy intake) and is rich in monounsaturated (MUFA) and polyunsaturated (PUFA) fat and low in saturated fat (SFA) (<9%). Hence, the MD focuses on type rather than quantity of fat consumed and has been proposed as an alternative, palatable, beneficial lifestyle change.39 The traditional MD pyramid and healthy eating model is shown in Fig. 2.
Measuring Adherence to a MD: The MD Score (MDS) Since the 1990s, observational studies and clinical trials have published scoring systems to evaluate population adherence/compliance to a traditional MD. Adherence to a MD is most commonly measured through the use of a score (Mediterranean Diet Score (MDS)) and includes key foods consumed as part of the diet. The exact composition of the score used in epidemiological studies varies depending on the dietary data available, and the population studied.36,40,41 The original MDS was based on eight major food components (high intake of fruits, high intake of vegetables, high intake of legumes, high intake of cereals, low intake of meat, moderate intake of dairy products, high MUFA: SFA ratio, and moderate alcohol consumption)42 and was later updated to include moderate fish consumption as a ninth component.40 MDS is calculated as a composite score where a value of zero or one is assigned to each of the nine food components, of which the maximum MDS is nine and indicates greatest adherence to the traditional MD.40 Each food item score is calculated using gender-specific median value cut-off points for food consumption in the study population. Individual intake of healthful food components (e.g., fruits, vegetables, legumes, cereals, MUFA: SFA, and fish) are given a score of zero if they are below the population median consumption versus a score of one when intake is above the population median cut-off point. Conversely, intake of unhealthful food components (meat and dairy products) is assigned a score of one if intake is below the population median intake and zero if intake is above the population median intake.41 Since then, shorter dietary intake questionnaires have been developed, which assess the frequency of consumption for a typical serving of each specified food component and individual MDS is calculated as the sum score for included food components. Several variations of MDS systems have been published in different population groups with each MDS comprising a similar ordinal scale (mostly ranging from 9 to 18) measuring adherence to the traditional MD. An example used in a recent intervention study43 is shown in Table 1, while scoring systems, which give more points for each food item based on number of portions consumed, now exist.33 The main disadvantage of an a priori score approach is that the dietary pattern is defined on existing knowledge, which may be inconsistent and limited for a specific disease outcome and populations.44 The use of sample-specific medians to assign scores means that similar scores can be obtained by populations with very different dietary intake and actual adherence to the MD.41,45 Similarly, the multicomponent nature of
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FIG. 2 The Mediterranean Diet pyramid.
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Table 1 14-Item Mediterranean Diet Score (MDS) to Measure Adherence to a Med Diet in the PREDIMED Trial43 Questions
Criteria for 1 Point
1. Do you use olive oil as main culinary fat? 2. How much olive oil do you consume in a given day (including oil used for frying, salads, out-of-house meals, etc.)? 3. How many vegetable servings do you consume per day? (1 serving: 200 g [consider side dishes as half a serving]) 4. How many fruit units (including natural fruit juices) do you consume per day? 5. How many servings of red meat, hamburger, or meat products (ham, sausage, etc.) do you consume per day? (1 serving: 100–150 g) 6. How many servings of butter, margarine, or cream do you consume per day? (1 serving: 12 g) 7. How many sweet or carbonated beverages do you drink per day? 8. How much wine do you drink per week? 9. How many servings of legumes do you consume per week? (1 serving: 150 g) 10. How many servings of fish or shellfish do you consume per week? (1 serving 100–150 g of fish or 4–5 units or 200 g of shellfish) 11. How many times per week do you consume commercial sweets or pastries (not homemade), such as cakes, cookies, biscuits, or custard? 12. How many servings of nuts (including peanuts) do you consume per week? (1 serving 30 g) 13. Do you preferentially consume chicken, turkey, or rabbit meat instead of veal, pork, hamburger, or sausage? 14. How many times per week do you consume vegetables, pasta, rice, or other dishes seasoned with sofrito (sauce made with tomato and onion, leek, or garlic and simmered with olive oil)?
Yes 4 tbsp 2 (1 portion raw or as a salad) 3 <1 <1 <1 7 glasses 3 3 <3 3 Yes 2
From Martı´nez-Gonza´lez MA, Garcı´a-Arellano A, Toledo E, Salas-Salvado´ J, Buil-Cosiales P, et al. A 14-item Mediterranean Diet assessment tool and obesity indexes among high-risk subjects: the PREDIMED Trial. PLOS ONE 2012; 7(8): e43134. https://doi.org/10.1371/journal. pone.0043134.
the dietary score means that the same MDS can be obtained by individuals consuming quite different combinations of foods.41 It is still uncertain whether the MDS is appropriate for use in non-Mediterranean populations with contrasting social, cultural, and eating behaviours.38 In addition, the generation of a summary score implies that each component of the diet has an equal and additive effect on disease outcome and therefore effects of separate nutrients or foods are difficult to delineate using this approach.44 A final concern in the assessment of adherence to the MD concerns relates to the reliance of dietary assessment methods, such as the food frequency questionnaire or 24 h recall, on memory, which may make them inappropriate data collection tools to use with older populations, or on self-complete, which may be challenging for those with loss of visual function. A biomarker-based or biomarker/questionnaire combined approach to assess adherence to the MD may be more appropriate in such populations and would be a useful adjunct in epidemiological studies.
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Epidemiologic Evidence Linking Adherence to a Med Diet and AMD Risk To date, only a limited number of studies have examined the associated between adherence to an MD and AMD risk. In 2011, Mares et al.46 conducted an investigation on the Carotenoids Age-Related Eye Disease Study (CAREDS) cohort. The study initially was established to examine the associations between the lifestyle behaviors of smoking, physical activity, and diet in relation to AMD. As part of this investigation, an alternative MDS (aMED), modified to suit the American population, was used. aMed adopted a nine-point scoring system allowing 1 point for the following food elements: whole grains, fruit, vegetables, fish, nuts, legumes, red meat, alcohol intake, and ratio of monounsaturated fat to saturated fat. Results indicated that those with a higher adherence to a Mediterranean style diet had lower risk of early AMD within this cohort, although this was not statistically significant (OR: 0.44 (95% CI: 0.10,1.27).46 More recently, Merle et al.31 used the same modified MDS to assess the associations between diet and progression to advanced AMD, while looking for links to genetic susceptibility in a portion of the Age-Related Eye Disease Study (AREDS) cohort.31 After adjustment for potential demographic, behavioral, ocular, and genetic confounders, this study found that higher adherence (aMedi score: 6–9) to a MD was associated with a 26% (HR: 0.74; 95%CI: 0.61,0.91) reduction in risk of progression to advanced AMD. While these participants were taking AREDS supplements, this factor did not affect the suggested protective outcomes of high MD adherence.31 Participants that were carrying the CFH Y402H nonrisk (T) allele were also less likely to progress to advanced AMD. The researchers in this study postulated that the effects of the MD are more pronounced with carriers of this allele, as the aMedi score was not associated with AMD in participants with the risk allele.31 In 2017, Hogg and collaborators published a paper detailing the associations between adherence to an MD and prevalence of AMD in a cross-section of the European Eye Study (EUREYE).47 The study included participants from seven different centers across Europe (UK, France, Italy, Estonia, Spain, Norway, and Greece). The MDS applied here was slightly different than the styles previously mentioned. This score was still based on a score of 0–9; however, the food group scores were slightly different. 1 point was awarded for set portions of olive oil, wine, fruit, vegetables or salad, legumes, low consumption of meat/meat products. One or more servings of both fruit and vegetables earned an extra point, while low consumption or white bread/rice or high consumption of whole-grain bread/rice earned the final point. Participants in the highest adherence group (>6 score) had 47% reduced odds of nvAMD, compared with those in the lowest adherence group (<4 score).47 This study investigated the links between MDS and GA; however, no significant associations were demonstrated. Analysis was carried out on potential links between MDS and early AMD but, as with GA, no relationship was found. The authors had pointed out that the classification process used to grade AMD involved color image grading, and one of the limitations of this technique is reduced ability to pick up some signs of early AMD. While this report carried out similar genetic analysis to that of Merle et al.,31 there was
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insufficient numbers of cases with nvAMD to fully investigate gene-diet interactions; therefore, the relationship between genetic susceptibility and late AMD could not be confirmed here.47 The association between MDS and nvAMD could not be explained by either lutein or zeaxanthin intake or status.47 More recently, a case-control study carried out on two populations (coastal and inland) with differing AMD prevalence in Portugal, aimed to investigate associations between nutritional risk profiles and AMD.48 A similar MDS (mediSCORE) was used to assess adherence to the diet. Overall, higher adherence to a MD (6 mediSCORE) was associated with reduced risk of AMD in this population, with a risk reduction of 27% (OR: 0.73; P ¼.009).48 This was confirmed in the subpopulation with the lower prevalence for AMD. In all but one (cereals) of the food groups that encompassed the mediSCORE, participants in this subpopulation reported higher levels of intake. Upon further analysis of the specific food groups, vegetables, fruit, and nuts showed a significant relationship with the no AMD outcome.48 This is consistent with a dietary pattern analysis carried out on The Melbourne Collaborative Cohort Study, those with a strong adherence to a dietary pattern with similar food groups to an MDS, with the addition of chicken, tended to have a lower prevalence of advanced AMD.29 These studies, although limited in number, do provide some evidence for the potential value of adhering to an MD on eye health, although there are not enough studies to comment in detail on the different forms and stages of AMD and whether analyses are consistent in terms of these outcomes. In support of the small number of MDS-specific analyses, many of the individual constituents of the MDS have previously been identified as associated with reduced prevalence of incidence of AMD, such as higher fruit and vegetable,49 olive oil,50 reduced red meat,51 lower glycemic index,52 and higher fish intake.23,53 Furthermore, there are plausible mechanisms, for example, metabolic, antioxidative, and antiinflammatory, by which an MD may affect AMD, including those which are common to vascular diseases, and those which are nonvascular.54 Thus, the limited observational evidence to date appears to support a possible protective effect association between greater adherence to MD and development of AMD, in both Mediterranean and non-Mediterranean populations. However, the independent effects of diet and lifestyle factors are difficult to disentangle in observational research and any observed effect can be challenged on the basis of residual confounding, partly due to inaccurate determination of confounders (which are inherently difficult to measure), and also due to inadequate adjustment for all potential confounders in multivariate analyses.55 A further difficulty with residual confounding in epidemiologic studies is that a causal relationship between diet and disease outcome is hard to establish. In this case, adherence to an MD may be a surrogate marker for an unmeasured dietary or lifestyle factor.55 Randomized controlled trials (RCT) would provide the most robust evidence of a causal effect of increased adherence to a MD on hard AMD end-points, but are difficult to conduct owing to the long progression of the disease process, which may take years to manifest as a clinical event. No such trials of MD and AMD currently exist.
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Conducting intervention studies with a whole diet pattern is more complex than a single nutrient intervention, which can, for example, in the case of micronutrients, be delivered in pill form using a placebo control for comparison. In food-based or whole diet studies, notable design issues include the selection of an appropriate control group, and determining whether the intervention can be blinded, or at least the endpoint assessment blinded. Giving careful consideration to methods to encourage and measure compliance is also important. Guidelines on the design, conduct, and reporting of food-based studies now exist,56 and these should be examined when developing such studies. The design of interventions will depend on whether the trials are of efficacy (which are certainly required initially), or, perhaps when the evidence base is more advanced, designed to develop and test interventions to promote long-term behavior change in the target group. A range of factors, including medical, physiological, psychological, social, and economic factors, can influence an older person’s diet,57 and interventions to change behaviors must consider the impact of these factors on the likely success of any intervention, including one promoting MD adherence.
Conclusion Strategies to encourage healthy aging are becoming increasingly important to public health. The MD has been proposed as a healthy eating model for disease prevention. Limited observational evidence supports this assertion to date for AMD; therefore, further well-designed analyses of observational studies are required. Clinical trial evidence confirming the effectiveness of an MD for AMD prevention are so far entirely lacking. Such studies need to be well designed, adequately powered, with careful choice of participants, study duration, outcomes to be assessed, and strategies to maximize compliance. Alongside these studies, consideration has to be given to how best promote and encourage dietary change in older people in general.
Summary Points The increasing prevalence of AMD, and the impact on healthcare systems is a major concern as the population ages, the projected number of people with AMD globally in 2020 was 196 million, with that set to increase to 288 million by 2040. The Mediterranean Diet is rich in fruit, vegetables, wholegrains, nuts and olive oil and low in red meat and is promoted as a healthy eating model for prevention of diseases such as cardiovascular disease and type 2 diabetes. There is growing interest in the role of the Mediterranean Diet in age-related macular degeneration, although evidence is limited and confined to epidemiologic studies with no evidence from clinical trials at present. It is thought that the high antioxidant capacity and anti-inflammatory properties of the diet reduce oxidative damage and low-grade inflammation, which is compatible with agerelated macular degeneration aetiology.
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While, foods and nutrients which predominate within the dietary pattern have previously been independently associated with risk of the condition, further epidemiological studies and clinical trials are required to confirm the benefit of a Mediterranean Diet for the prevention of age-related macular degeneration.
References 1. World Health Organisation. Ageing and Life Course Available from: http://www.who.int/ageing/en/ Accessed 1 June 2018. 2. Ahmed T, Haboubi N. Assessment and management of nutrition in older people and its importance to health. Clin Interv Aging. 2010;5:207–216. 3. Mente A, de Koning L, Shannon HS, Anand SS. A systematic review of the evidence supporting a causal link between dietary factors and coronary heart disease. Arch Intern Med. 2009;169:659–669. 4. World Cancer Research Fund. Diet and cancer report. https://wcrf.org/dietandcancer Accessed 1 June 2018. 5. Wong WL, Su X, Li X, 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:e106–e116. 6. Colijn JM, GHS B, Prokofyeva E, et al. European Eye Epidemiology (E3) consortium. Prevalence of age-related macular degeneration in Europe: The past and the future. Ophthalmology. 2017;124:1753–1763. 7. Davis MD, Gangnon RE, Lee LY, et al. The Age-Related Eye Disease Study severity scale for age-related macular degeneration: AREDS Report No. 17. Arch Ophthalmol. 2005;123:1484–1498. 8. Wong TY, Chakravarthy U, Klein R, et al. The natural history and prognosis of neovascular age-related macular degeneration: a systematic review of the literature and meta-analysis. Ophthalmology. 2008;115:116–126. 9. Sunness JS, Gonzalez-Baron J, Applegate CA, et al. Enlargement of atrophy and visual acuity loss in the geographic atrophy form of age-related macular degeneration. Ophthalmol. 1999;106:1768–1779. 10. Evans JR, Fletcher AE, Wormald RP. Age-related macular degeneration causing visual impairment in people 75 years or older in Britain: an add-on study to the Medical Research Council Trial of Assessment and Management of Older People in the Community. Ophthalmol. 2004;111:513–517. 11. Krishnan T, Ravindran RD, Murthy GV, et al. Prevalence of early and late age-related macular degeneration in India: the INDEYE study. Invest Ophthalmol Vis Sci. 2010;51:701–707. 12. Smith W, Assink J, Klein R, et al. Risk factors for age-related macular degeneration: Pooled findings from three continents. Ophthalmology. 2001;108:697–704. 13. Clemons TE, Milton RC, Klein R, Seddon JM, Ferris 3rd FL, Age-Related Eye Disease Study Research Group. Risk factors for the incidence of Advanced Age-Related Macular Degeneration in the Age-Related Eye Disease Study (AREDS) AREDS report no. 19. Ophthalmology. 2005;112:533–539. 14. Hogg RE, Woodside JV, Gilchrist SE, et al. Cardiovascular disease and hypertension are strong risk factors for choroidal neovascularization. Ophthalmology. 2008;115:1046–1052 [e2]. 15. Beatty S, Murray IJ, Henson DB, Carden D, Koh H, Boulton ME. Macular pigment and risk for age-related macular degeneration in subjects from a Northern European population. Invest Ophthalmol Vis Sci. 2001;42:439–446. 16. Fletcher AE, Bentham GC, Agnew M, et al. Sunlight exposure, antioxidants, and age-related macular degeneration. Arch Ophthalmol. 2008;126:1396–1403.
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17. VandenLangenberg GM, Mares-Perlman JA, Klein R, Klein BE, Brady WE, Palta M. Associations between antioxidant and zinc intake and the 5-year incidence of early age-related maculopathy in the Beaver Dam Eye Study. Am J Epidemiol. 1998;148:204–214. 18. Seddon JM, Cote J, Davis N, Rosner B. Progression of age-related macular degeneration: association with body mass index, waist circumference, and waist-hip ratio. Arch Ophthalmol. 2003;121:785–792. 19. Knudtson MD, Klein R, Klein BE. Physical activity and the 15-year cumulative incidence of age-related macular degeneration: The Beaver Dam Eye Study. Br J Ophthalmol. 2006;90:1461–1463. 20. Broadhead GK, Grigg JR, Chang AA, McCluskey P. Dietary modification and supplementation for the treatment of age-related macular degeneration. Nutr Rev. 2015;73:448–462. 21. Evans JR, Lawrenson JG. A review of the evidence for dietary interventions in preventing or slowing the progression of age-related macular degeneration. Ophthalmic Physiol Opt. 2014;34:390–396. 22. Chong EW, Robman LD, Simpson JA, et al. Fat consumption and its association with age-related macular degeneration. Arch Ophthalmol. 2009;127:674–680. 23. Zhu W, Wu Y, Meng YF, Xing Q, Tao JJ, Lu J. Fish consumption and age-related macular degeneration incidence: A meta-analysis and systematic review of prospective cohort studies. Nutrients. 2016;8E743. 24. Chew EY, Lindblad AS, Clemons T, Age-Related Eye Disease Study Group. Summary results and recommendations from the age-related eye disease study. Arch Ophthalmol. 2009;127:1678–1679. 25. van Leeuwen R, Boekhoorn S, Vingerling JR, et al. Dietary intake of antioxidants and risk of age-related macular degeneration. JAMA. 2005;294:3101–3107. 26. Age-Related Eye Disease Study 2 Research G. 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;309:2005–2015. 27. Ma L, Dou HL, Wu YQ, et al. Lutein and zeaxanthin intake and the risk of age-related macular degeneration: a systematic review and meta-analysis. Br J Nutr. 2012;107:350–359. 28. Hu FB. Dietary pattern analysis: A new direction in nutritional epidemiology. Curr Opin Lipidol. 2002;13:3–9. 29. Islam FMA, Chong EW, Hodge AM, et al. Dietary patterns and their associations with age-related macular degeneration. Ophthalmology. 2014;121:1428–1434. 30. Chiu CJ, Chang ML, Zhang FF, et al. The relationship of major American dietary patterns to age-related macular degeneration. Am J Ophthalmol. 2014;158:118–127. 31. 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;102:1196–1206. 32. Keys A, Menotti A, Karvonen MJ, et al. The diet and 15-year death rate in the seven countries study. Am J Epidemiol. 1986;124:903–915. 33. Sofi F, Macchi C, Abbate R, Gensini GF, Casini A. Mediterranean diet and health status: an updated meta-analysis and a proposal for a literature-based adherence score. Public Health Nutr. 2014;17:2769–2782. 34. Sofi F, Abbate R, Gensini GF, Casini A. Accruing evidence on benefits of adherence to the mediterranean diet on health: an updated systematic review and meta-analysis. Am J Clin Nutr. 2010;92:1189–1196. 35. Willett WC. The Mediterranean Diet: science and practice. Public Health Nutr. 2006;9:105–110.
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36. Mila-Villarroel R, Bach-Faig A, Puig J, et al. Comparison and evaluation of the reliability of indexes of adherence to the Mediterranean Diet. Public Health Nutr. 2011;14:2338–2345. 37. Willett WC, Sacks F, Trichopoulou A, et al. Mediterranean diet pyramid: a cultural model for healthy eating. Am J Clin Nutr. 1995;61:1402S–1406S. 38. McKeown PP, Logan K, McKinley MC, Young IS, Woodside JV. CVD, diabetes and cancer: Evidence for the use of the Mediterranean Diet in patients with CHD. Proc Nutr Soc. 2010;69:45–60. 39. Kris-Etherton P, Eckel RH, Howard BV, St Jeor S, Bazzarre TL, Nutrition Committee Population Science Committee and Clinical Science Committee of the American Heart Association. AHA Science Advisory: Lyon Diet Heart Study: Benefits of a Mediterranean-style, National Cholesterol Education Program/American Heart Association step I dietary pattern on cardiovascular disease. Circulation. 2001;103:1823–1825. 40. Trichopoulou A, Costacou T, Bamia C, Trichopoulos D. Adherence to a Mediterranean diet and survival in a Greek population. N Engl J Med. 2003;348:2599–2608. art C, Samieri C, Alle`s B, Barberger-Gateau P. Potential benefits of adherence to the Mediterranean 41. Fe diet on cognitive health. Proc Nutr Soc. 2013;72:140–152. 42. Trichopoulou A, Kouris-Blazos A, Wahlqvist ML, et al. Diet and overall survival in elderly people. BMJ. 1995;311:1457–1460. 43. Martı´nez-Gonza´lez MA, Garcia-Arellano A, Toledo E, Salas-Salvado J, Buil-Cosiales P, Corella D. A 14-item Mediterranean Diet assessment tool and obesity indexes among high-risk subjects: The PREDIMED trial. PLoS ONE. 2012;7:e43134. 44. Kant AK. Dietary patterns: Biomarkers and chronic disease risk. Appl Physiol Nutr Metab. 2010;35:199–206. art C, Jutand MA, Laurin D, Barberger-Gateau P. Dietary patterns: a novel 45. Alle`s B, Samieri C, Fe approach to examine the link between nutrition and cognitive function in older individuals. Nutr Res Rev. 2012;25:207–222. 46. Mares JA, Voland RP, Sondel SA, et al. Healthy lifestyles related to subsequent prevalence of age-related macular degeneration. Arch Ophthalmol. 2011;129:470–480. 47. Hogg RE, Woodside JV, McGrath A, et al. Mediterranean diet score and its association with age-related macular degeneration: The European eye study. Ophthalmology. 2017;124:82–89. 48. Nunes S, Alves D, Barreto P, et al. Adherence to a Mediterranean diet and its association with age-related macular degeneration. The Coimbra eye study-report 4. Nutrition. 2018;51-52:6–12. 49. Cho E, Seddon JM, Rosner B, Willett WC, Hankinson SE. Prospective study of intake of fruits, vegetables, vitamins, and carotenoids and risk of age-related maculopathy. Arch Ophthalmol. 2004; 122:883–892. goire A, Merle BM, Korobelnik JF, et al. Olive oil consumption and age-related macular 50. Cougnard-Gre degeneration: The Alienor study. PLoS One. 2016;11:e0160240. 51. 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;169:867–876. 52. Kaushik S, Wang JJ, Flood V, et al. Dietary glycemic index and the risk of age-related macular degeneration. Am J Clin Nutr. 2008;88:1104–1110. 53. Augood C, Chakravarthy U, Young I, et al. Oily fish consumption, dietary docosahexaenoic acid and eicosapentaenoic acid intakes, and associations with neovascular age-related macular degeneration. Am J Clin Nutr. 2008;88:398–406. 54. Koushan K, Rusovici R, Li W, Ferguson LR, Chalam KV. The role of lutein in eye-related disease. Nutrients. 2013;5:1823–1839.
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55. Dauchet L, Amouyel P, Dallongeville J. Fruits, vegetables and coronary heart disease. Nat Rev Cardiol. 2009;6:599–608. 56. Welch RW, Antoine JM, Berta JL, et al. Guidelines for the design, conduct and reporting of human intervention studies to evaluate the health benefits of foods. Br J Nutr. 2011;106:S3–15. 57. de Morais C, Oliveira B, Afonso C, Lumbers M, Raats M, de Almeida MD. Nutritional risk of European elderly. Eur J Clin Nutr. 2013;67:1215–1219.
Further Reading 58. Bach-Faig A, Berry EM, Lairon D, et al. Mediterranean diet pyramid today. Science and cultural updates. Public Health Nutr. 2011;14:2274–2284.
CHAPTER OUTLINE Introduction .................................................................................................................................. 425 Diet, Dietary Patterns, and AMD Risk ......................................................................................... 426 The Mediterranean Diet .............................................................................................................. 428 Measuring Adherence to a MD: The MD Score (MDS) .............................................................. 429 Epidemiologic Evidence Linking Adherence to a Med Diet and AMD Risk .............................. 432 Conclusion .................................................................................................................................... 434 Summary Points ........................................................................................................................... 434 References .................................................................................................................................... 435
Introduction In the developed world, as life expectancy increases and the birth rate declines, the proportion of older people is increasing. The number of people aged over 60 years is expected to rise from 605 million in 2000 to 2 billion in 2050, accounting for approximately one-fifth of the worldwide population in 2050.1 As the proportion of older people increases, so will the incidence of chronic diseases and the proportion of the population living with disability. Strategies that reduce age-related morbidity and reduce chronic disease prevalence are therefore important for healthy or successful aging, and any such strategies, which are successful, are likely to have financial and societal benefits. The avoidance of malnutrition is known to contribute to the health of older people and helps recovery from illness.2 Dietary factors have also been suggested to play a role in chronic disease prevention3,4 and to promote healthy aging, and are therefore the focus of much interest among researchers and policy makers with an interest in the primary and secondary prevention of chronic disease and the promotion of lifestyle factors that will encourage healthy aging. The increasing prevalence of age-related macular degeneration (AMD) and the impact on healthcare systems are major concern as the population ages. In 2014, it was estimated Handbook of Nutrition, Diet, and the Eye. https://doi.org/10.1016/B978-0-12-815245-4.00026-0 © 2019 Elsevier Inc. All rights reserved.
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that the pooled prevalence (mapped to an age range of 45–85 years) of early, late, and any AMD was 8%, 0.4%, and 9%, respectively.5 Within the same analyses, the projected number of people with AMD globally in 2020 was 196 million, increasing to 288 million by 2040.5 In an analysis focused on 14 population-based European cohorts, prevalence of early AMD increased from 3.5% in those aged 55–59 years to 17.6% in those aged 85 years; for late AMD these figures were 0.1% and 9.8%, respectively. However, decreasing prevalence of late AMD was observed after 2006, which became most prominent after age 70. Projections of AMD showed an almost doubling of affected persons despite a decreasing prevalence due to changes in population structure. By 2040, between 14.9 and 21.5 million individuals in Europe are likely to have early AMD according to the analysis, and for late AMD between 3.9 and 4.8 million. The authors suggested that the decreasing prevalence of late AMD was most likely explained by healthier lifestyles and changes in the population structure while the reduction in sight impairment was due to the implementation of antivascular endothelial growth factor treatment. Nevertheless, the numbers of affected subjects will increase considerably in the next two decades, and the authors concluded that AMD continues to remain a significant public health problem among elderly Europeans.6 AMD manifests initially as pigmentary irregularities of the retina and deposits of extracellular material called drusen that collect at the retinal pigment epithelial/choroidal interface. These features are not associated with overt sight loss and are termed early AMD or intermediate AMD depending on the size and extent of the drusen and pigmentary irregularities. Approximately one in two persons with extensive macular drusen will progress within 5 years to sight threatening geographic atrophy (GA) and/or neovascularization (nvAMD),7 which are late-stage manifestations of the condition.8,9 GA is currently untreatable and although nvAMD may now be controlled with antiangiogenic agents, the majority of patients so treated have residual visual disability due to varying degrees of retinal tissue disruption, scarring, and/or atrophy. Treatments with antiangiogenic agents is also a costly and time-intensive process as a series of monthly intraocular injections are given followed by regular check-ups, with periods of disease inactivity punctuated by reactivation followed by more injections (Fig. 1). As described, AMD is the predominant cause of blindness in high income countries,10 and is of growing importance in other settings, in association with increasing longevity.11 AMD is considered to be a complex multifactorial disorder, involving an interplay between genetic, environmental, and lifestyle factors, such as smoking,12 obesity,13 cardiovascular disease,14 macular pigment,15 sunlight exposure,16 dietary factors,17 high BMI,18 and physical activity.19
Diet, Dietary Patterns, and AMD Risk It has been known for some time that dietary factors can modulate AMD risk.20,21 Epidemiological studies have demonstrated that diets high in antioxidant nutrients (vitamins C and E, carotenoids such as lutein and zeaxanthin and fruit and vegetables rich in these nutrients) or zinc are associated with a decreased occurrence of AMD. Studies have also shown that a high dietary intake of trans fats is a risk factor for late AMD,22 while a higher
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FIG. 1 Features of age-related macular degeneration.
intake of fish or ω 3 fatty acids is protective against AMD.23 However, the evidence from clinical trials is less consistent. While high-dose multivitamin supplementation slowed the progression of AMD,24 similar trials of lutein and zeaxanthin supplements, with or without omega 3 fatty acids, showed no effect on AMD progression (AREDS2).25–27 Most studies to date have focused on individual food groups or nutrients, yet, in “real life” settings, individuals eat a combination of foods within a mixed diet rather than isolated foods and nutrients and it is known that diet is a multifactorial lifestyle behavior, with particular foods frequently consumed together, depending on the cultural, geographical, and economic context of the individual. Therefore, nutrition researchers are increasingly attempting to analyze relationships between dietary patterns or overall diet and disease, rather than specific foods or nutrients thus permitting the synergistic effects of food intake to be examined in relation to risk of disease.28 Dietary patterns rather than individual components are also increasingly being studied in relation to AMD.29–31 Various methodological approaches have been taken but tend to fall into two broad categories. The first are a posteriori approaches, including the use of factor and principal component analysis to identify patterns, which are then related to the disease under investigation.28–30 This is a data-driven approach, and requires no a priori hypothesis of what factors or food groups within the overall diet may be important. The second method uses a priori scores to assess an individual’s adherence to a specific diet such as the Mediterranean diet (MD)28,31 or a set of dietary recommendations,28 and therefore requires an a priori hypothesis of what may be important.
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One such dietary pattern that has generated much interest is the MD. Early observations in the Seven Countries study conducted in the 1960s reported lower cardiovascular disease mortality in populations in the Mediterranean region compared to Northern European or US populations, implying a cardioprotective effect of traditional MDs.32 Since then, numerous prospective studies have been published supporting a link between greater adherence to an MD and lower CVD and T2DM disease risk and overall mortality,33 with some studies, which have been meta-analyzed, also suggesting an association between increased adherence to the MD pattern and reduced risk of neurodegenerative disease, including Alzheimer’s Disease, and cancer outcomes.34 The traditional MD is increasingly being promoted as a model dietary pattern— particularly for disease prevention. In an overview of research on the MD, it has been suggested that >80% of CHD could be avoided by healthy food choices that are consistent with the traditional MD.35 Furthermore, in a systematic review of evidence supporting a causal link between dietary factors and CHD, evidence for a MD was rated as strong3 but further evaluation of dietary patterns in cohort studies and randomized trials was recommended. Seeing as the etiological profile for CVD and AMD is similar, and that they share a range of major risk factors, it is not surprising that there has also been some interest in the association between adherence to an MD pattern and risk of AMD, although research is at a much earlier stage than for CVD. This chapter will examine the food components of an MD and review the published evidence evaluating the MD for prevention of AMD.
The Mediterranean Diet The MD pattern describes eating habits of populations living in olive-growing regions of countries bordering the Mediterranean Sea, during the 1960s. The traditional MD is not a single dietary pattern as multiple differences, including sociocultural, economic, and religious variations, along the Mediterranean basin have influenced food intake.36 To facilitate research into the health properties of an MD, the traditional dietary pattern was first defined in 1993 at an International conference on diets of the Mediterranean37 and is characterized by the following: • • • • • •
high intake of plant foods comprising fruit and vegetables, wholegrain cereals, legumes, tree nuts and seeds high olive oil consumption moderate-to-high intake of fish with emphasis on oily fish moderate intake of poultry and low-fat dairy products (mostly as cheese and yogurts) low intake of meat and meat products moderate alcohol consumption, normally consumed as wine with meals.
The MD pattern is associated with greater intake of antioxidant vitamins and minerals, linoleic acid (LA), α-linolenic acid (ALA), and several other possibly beneficial nonnutrient constituents such as polyphenols.38 In contrast to a conventional low-fat diet (<30% total
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energy intake), the traditional MD advocates a moderate total fat intake (approximately 35%–40% energy intake) and is rich in monounsaturated (MUFA) and polyunsaturated (PUFA) fat and low in saturated fat (SFA) (<9%). Hence, the MD focuses on type rather than quantity of fat consumed and has been proposed as an alternative, palatable, beneficial lifestyle change.39 The traditional MD pyramid and healthy eating model is shown in Fig. 2.
Measuring Adherence to a MD: The MD Score (MDS) Since the 1990s, observational studies and clinical trials have published scoring systems to evaluate population adherence/compliance to a traditional MD. Adherence to a MD is most commonly measured through the use of a score (Mediterranean Diet Score (MDS)) and includes key foods consumed as part of the diet. The exact composition of the score used in epidemiological studies varies depending on the dietary data available, and the population studied.36,40,41 The original MDS was based on eight major food components (high intake of fruits, high intake of vegetables, high intake of legumes, high intake of cereals, low intake of meat, moderate intake of dairy products, high MUFA: SFA ratio, and moderate alcohol consumption)42 and was later updated to include moderate fish consumption as a ninth component.40 MDS is calculated as a composite score where a value of zero or one is assigned to each of the nine food components, of which the maximum MDS is nine and indicates greatest adherence to the traditional MD.40 Each food item score is calculated using gender-specific median value cut-off points for food consumption in the study population. Individual intake of healthful food components (e.g., fruits, vegetables, legumes, cereals, MUFA: SFA, and fish) are given a score of zero if they are below the population median consumption versus a score of one when intake is above the population median cut-off point. Conversely, intake of unhealthful food components (meat and dairy products) is assigned a score of one if intake is below the population median intake and zero if intake is above the population median intake.41 Since then, shorter dietary intake questionnaires have been developed, which assess the frequency of consumption for a typical serving of each specified food component and individual MDS is calculated as the sum score for included food components. Several variations of MDS systems have been published in different population groups with each MDS comprising a similar ordinal scale (mostly ranging from 9 to 18) measuring adherence to the traditional MD. An example used in a recent intervention study43 is shown in Table 1, while scoring systems, which give more points for each food item based on number of portions consumed, now exist.33 The main disadvantage of an a priori score approach is that the dietary pattern is defined on existing knowledge, which may be inconsistent and limited for a specific disease outcome and populations.44 The use of sample-specific medians to assign scores means that similar scores can be obtained by populations with very different dietary intake and actual adherence to the MD.41,45 Similarly, the multicomponent nature of
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FIG. 2 The Mediterranean Diet pyramid.
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Table 1 14-Item Mediterranean Diet Score (MDS) to Measure Adherence to a Med Diet in the PREDIMED Trial43 Questions
Criteria for 1 Point
1. Do you use olive oil as main culinary fat? 2. How much olive oil do you consume in a given day (including oil used for frying, salads, out-of-house meals, etc.)? 3. How many vegetable servings do you consume per day? (1 serving: 200 g [consider side dishes as half a serving]) 4. How many fruit units (including natural fruit juices) do you consume per day? 5. How many servings of red meat, hamburger, or meat products (ham, sausage, etc.) do you consume per day? (1 serving: 100–150 g) 6. How many servings of butter, margarine, or cream do you consume per day? (1 serving: 12 g) 7. How many sweet or carbonated beverages do you drink per day? 8. How much wine do you drink per week? 9. How many servings of legumes do you consume per week? (1 serving: 150 g) 10. How many servings of fish or shellfish do you consume per week? (1 serving 100–150 g of fish or 4–5 units or 200 g of shellfish) 11. How many times per week do you consume commercial sweets or pastries (not homemade), such as cakes, cookies, biscuits, or custard? 12. How many servings of nuts (including peanuts) do you consume per week? (1 serving 30 g) 13. Do you preferentially consume chicken, turkey, or rabbit meat instead of veal, pork, hamburger, or sausage? 14. How many times per week do you consume vegetables, pasta, rice, or other dishes seasoned with sofrito (sauce made with tomato and onion, leek, or garlic and simmered with olive oil)?
Yes 4 tbsp 2 (1 portion raw or as a salad) 3 <1 <1 <1 7 glasses 3 3 <3 3 Yes 2
From Martı´nez-Gonza´lez MA, Garcı´a-Arellano A, Toledo E, Salas-Salvado´ J, Buil-Cosiales P, et al. A 14-item Mediterranean Diet assessment tool and obesity indexes among high-risk subjects: the PREDIMED Trial. PLOS ONE 2012; 7(8): e43134. https://doi.org/10.1371/journal. pone.0043134.
the dietary score means that the same MDS can be obtained by individuals consuming quite different combinations of foods.41 It is still uncertain whether the MDS is appropriate for use in non-Mediterranean populations with contrasting social, cultural, and eating behaviours.38 In addition, the generation of a summary score implies that each component of the diet has an equal and additive effect on disease outcome and therefore effects of separate nutrients or foods are difficult to delineate using this approach.44 A final concern in the assessment of adherence to the MD concerns relates to the reliance of dietary assessment methods, such as the food frequency questionnaire or 24 h recall, on memory, which may make them inappropriate data collection tools to use with older populations, or on self-complete, which may be challenging for those with loss of visual function. A biomarker-based or biomarker/questionnaire combined approach to assess adherence to the MD may be more appropriate in such populations and would be a useful adjunct in epidemiological studies.
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Epidemiologic Evidence Linking Adherence to a Med Diet and AMD Risk To date, only a limited number of studies have examined the associated between adherence to an MD and AMD risk. In 2011, Mares et al.46 conducted an investigation on the Carotenoids Age-Related Eye Disease Study (CAREDS) cohort. The study initially was established to examine the associations between the lifestyle behaviors of smoking, physical activity, and diet in relation to AMD. As part of this investigation, an alternative MDS (aMED), modified to suit the American population, was used. aMed adopted a nine-point scoring system allowing 1 point for the following food elements: whole grains, fruit, vegetables, fish, nuts, legumes, red meat, alcohol intake, and ratio of monounsaturated fat to saturated fat. Results indicated that those with a higher adherence to a Mediterranean style diet had lower risk of early AMD within this cohort, although this was not statistically significant (OR: 0.44 (95% CI: 0.10,1.27).46 More recently, Merle et al.31 used the same modified MDS to assess the associations between diet and progression to advanced AMD, while looking for links to genetic susceptibility in a portion of the Age-Related Eye Disease Study (AREDS) cohort.31 After adjustment for potential demographic, behavioral, ocular, and genetic confounders, this study found that higher adherence (aMedi score: 6–9) to a MD was associated with a 26% (HR: 0.74; 95%CI: 0.61,0.91) reduction in risk of progression to advanced AMD. While these participants were taking AREDS supplements, this factor did not affect the suggested protective outcomes of high MD adherence.31 Participants that were carrying the CFH Y402H nonrisk (T) allele were also less likely to progress to advanced AMD. The researchers in this study postulated that the effects of the MD are more pronounced with carriers of this allele, as the aMedi score was not associated with AMD in participants with the risk allele.31 In 2017, Hogg and collaborators published a paper detailing the associations between adherence to an MD and prevalence of AMD in a cross-section of the European Eye Study (EUREYE).47 The study included participants from seven different centers across Europe (UK, France, Italy, Estonia, Spain, Norway, and Greece). The MDS applied here was slightly different than the styles previously mentioned. This score was still based on a score of 0–9; however, the food group scores were slightly different. 1 point was awarded for set portions of olive oil, wine, fruit, vegetables or salad, legumes, low consumption of meat/meat products. One or more servings of both fruit and vegetables earned an extra point, while low consumption or white bread/rice or high consumption of whole-grain bread/rice earned the final point. Participants in the highest adherence group (>6 score) had 47% reduced odds of nvAMD, compared with those in the lowest adherence group (<4 score).47 This study investigated the links between MDS and GA; however, no significant associations were demonstrated. Analysis was carried out on potential links between MDS and early AMD but, as with GA, no relationship was found. The authors had pointed out that the classification process used to grade AMD involved color image grading, and one of the limitations of this technique is reduced ability to pick up some signs of early AMD. While this report carried out similar genetic analysis to that of Merle et al.,31 there was
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insufficient numbers of cases with nvAMD to fully investigate gene-diet interactions; therefore, the relationship between genetic susceptibility and late AMD could not be confirmed here.47 The association between MDS and nvAMD could not be explained by either lutein or zeaxanthin intake or status.47 More recently, a case-control study carried out on two populations (coastal and inland) with differing AMD prevalence in Portugal, aimed to investigate associations between nutritional risk profiles and AMD.48 A similar MDS (mediSCORE) was used to assess adherence to the diet. Overall, higher adherence to a MD (6 mediSCORE) was associated with reduced risk of AMD in this population, with a risk reduction of 27% (OR: 0.73; P ¼.009).48 This was confirmed in the subpopulation with the lower prevalence for AMD. In all but one (cereals) of the food groups that encompassed the mediSCORE, participants in this subpopulation reported higher levels of intake. Upon further analysis of the specific food groups, vegetables, fruit, and nuts showed a significant relationship with the no AMD outcome.48 This is consistent with a dietary pattern analysis carried out on The Melbourne Collaborative Cohort Study, those with a strong adherence to a dietary pattern with similar food groups to an MDS, with the addition of chicken, tended to have a lower prevalence of advanced AMD.29 These studies, although limited in number, do provide some evidence for the potential value of adhering to an MD on eye health, although there are not enough studies to comment in detail on the different forms and stages of AMD and whether analyses are consistent in terms of these outcomes. In support of the small number of MDS-specific analyses, many of the individual constituents of the MDS have previously been identified as associated with reduced prevalence of incidence of AMD, such as higher fruit and vegetable,49 olive oil,50 reduced red meat,51 lower glycemic index,52 and higher fish intake.23,53 Furthermore, there are plausible mechanisms, for example, metabolic, antioxidative, and antiinflammatory, by which an MD may affect AMD, including those which are common to vascular diseases, and those which are nonvascular.54 Thus, the limited observational evidence to date appears to support a possible protective effect association between greater adherence to MD and development of AMD, in both Mediterranean and non-Mediterranean populations. However, the independent effects of diet and lifestyle factors are difficult to disentangle in observational research and any observed effect can be challenged on the basis of residual confounding, partly due to inaccurate determination of confounders (which are inherently difficult to measure), and also due to inadequate adjustment for all potential confounders in multivariate analyses.55 A further difficulty with residual confounding in epidemiologic studies is that a causal relationship between diet and disease outcome is hard to establish. In this case, adherence to an MD may be a surrogate marker for an unmeasured dietary or lifestyle factor.55 Randomized controlled trials (RCT) would provide the most robust evidence of a causal effect of increased adherence to a MD on hard AMD end-points, but are difficult to conduct owing to the long progression of the disease process, which may take years to manifest as a clinical event. No such trials of MD and AMD currently exist.
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Conducting intervention studies with a whole diet pattern is more complex than a single nutrient intervention, which can, for example, in the case of micronutrients, be delivered in pill form using a placebo control for comparison. In food-based or whole diet studies, notable design issues include the selection of an appropriate control group, and determining whether the intervention can be blinded, or at least the endpoint assessment blinded. Giving careful consideration to methods to encourage and measure compliance is also important. Guidelines on the design, conduct, and reporting of food-based studies now exist,56 and these should be examined when developing such studies. The design of interventions will depend on whether the trials are of efficacy (which are certainly required initially), or, perhaps when the evidence base is more advanced, designed to develop and test interventions to promote long-term behavior change in the target group. A range of factors, including medical, physiological, psychological, social, and economic factors, can influence an older person’s diet,57 and interventions to change behaviors must consider the impact of these factors on the likely success of any intervention, including one promoting MD adherence.
Conclusion Strategies to encourage healthy aging are becoming increasingly important to public health. The MD has been proposed as a healthy eating model for disease prevention. Limited observational evidence supports this assertion to date for AMD; therefore, further well-designed analyses of observational studies are required. Clinical trial evidence confirming the effectiveness of an MD for AMD prevention are so far entirely lacking. Such studies need to be well designed, adequately powered, with careful choice of participants, study duration, outcomes to be assessed, and strategies to maximize compliance. Alongside these studies, consideration has to be given to how best promote and encourage dietary change in older people in general.
Summary Points The increasing prevalence of AMD, and the impact on healthcare systems is a major concern as the population ages, the projected number of people with AMD globally in 2020 was 196 million, with that set to increase to 288 million by 2040. The Mediterranean Diet is rich in fruit, vegetables, wholegrains, nuts and olive oil and low in red meat and is promoted as a healthy eating model for prevention of diseases such as cardiovascular disease and type 2 diabetes. There is growing interest in the role of the Mediterranean Diet in age-related macular degeneration, although evidence is limited and confined to epidemiologic studies with no evidence from clinical trials at present. It is thought that the high antioxidant capacity and anti-inflammatory properties of the diet reduce oxidative damage and low-grade inflammation, which is compatible with agerelated macular degeneration aetiology.
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While, foods and nutrients which predominate within the dietary pattern have previously been independently associated with risk of the condition, further epidemiological studies and clinical trials are required to confirm the benefit of a Mediterranean Diet for the prevention of age-related macular degeneration.
References 1. World Health Organisation. Ageing and Life Course Available from: http://www.who.int/ageing/en/ Accessed 1 June 2018. 2. Ahmed T, Haboubi N. Assessment and management of nutrition in older people and its importance to health. Clin Interv Aging. 2010;5:207–216. 3. Mente A, de Koning L, Shannon HS, Anand SS. A systematic review of the evidence supporting a causal link between dietary factors and coronary heart disease. Arch Intern Med. 2009;169:659–669. 4. World Cancer Research Fund. Diet and cancer report. https://wcrf.org/dietandcancer Accessed 1 June 2018. 5. Wong WL, Su X, Li X, 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:e106–e116. 6. Colijn JM, GHS B, Prokofyeva E, et al. European Eye Epidemiology (E3) consortium. Prevalence of age-related macular degeneration in Europe: The past and the future. Ophthalmology. 2017;124:1753–1763. 7. Davis MD, Gangnon RE, Lee LY, et al. The Age-Related Eye Disease Study severity scale for age-related macular degeneration: AREDS Report No. 17. Arch Ophthalmol. 2005;123:1484–1498. 8. Wong TY, Chakravarthy U, Klein R, et al. The natural history and prognosis of neovascular age-related macular degeneration: a systematic review of the literature and meta-analysis. Ophthalmology. 2008;115:116–126. 9. Sunness JS, Gonzalez-Baron J, Applegate CA, et al. Enlargement of atrophy and visual acuity loss in the geographic atrophy form of age-related macular degeneration. Ophthalmol. 1999;106:1768–1779. 10. Evans JR, Fletcher AE, Wormald RP. Age-related macular degeneration causing visual impairment in people 75 years or older in Britain: an add-on study to the Medical Research Council Trial of Assessment and Management of Older People in the Community. Ophthalmol. 2004;111:513–517. 11. Krishnan T, Ravindran RD, Murthy GV, et al. Prevalence of early and late age-related macular degeneration in India: the INDEYE study. Invest Ophthalmol Vis Sci. 2010;51:701–707. 12. Smith W, Assink J, Klein R, et al. Risk factors for age-related macular degeneration: Pooled findings from three continents. Ophthalmology. 2001;108:697–704. 13. Clemons TE, Milton RC, Klein R, Seddon JM, Ferris 3rd FL, Age-Related Eye Disease Study Research Group. Risk factors for the incidence of Advanced Age-Related Macular Degeneration in the Age-Related Eye Disease Study (AREDS) AREDS report no. 19. Ophthalmology. 2005;112:533–539. 14. Hogg RE, Woodside JV, Gilchrist SE, et al. Cardiovascular disease and hypertension are strong risk factors for choroidal neovascularization. Ophthalmology. 2008;115:1046–1052 [e2]. 15. Beatty S, Murray IJ, Henson DB, Carden D, Koh H, Boulton ME. Macular pigment and risk for age-related macular degeneration in subjects from a Northern European population. Invest Ophthalmol Vis Sci. 2001;42:439–446. 16. Fletcher AE, Bentham GC, Agnew M, et al. Sunlight exposure, antioxidants, and age-related macular degeneration. Arch Ophthalmol. 2008;126:1396–1403.
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55. Dauchet L, Amouyel P, Dallongeville J. Fruits, vegetables and coronary heart disease. Nat Rev Cardiol. 2009;6:599–608. 56. Welch RW, Antoine JM, Berta JL, et al. Guidelines for the design, conduct and reporting of human intervention studies to evaluate the health benefits of foods. Br J Nutr. 2011;106:S3–15. 57. de Morais C, Oliveira B, Afonso C, Lumbers M, Raats M, de Almeida MD. Nutritional risk of European elderly. Eur J Clin Nutr. 2013;67:1215–1219.
Further Reading 58. Bach-Faig A, Berry EM, Lairon D, et al. Mediterranean diet pyramid today. Science and cultural updates. Public Health Nutr. 2011;14:2274–2284.