Julie A. Mares
INTRODUCTION
Food contains numerous bioactive molecules (vitamins, minerals, fatty acids, and other phytochemicals) that may modulate and attenuate the multifactorial pathogenetic processes that promote age-related macular degeneration (AMD), including oxidative stress, inflammation, phototoxicity, and ischemia. Nutrition may play an even larger role in preventing age-related degenerative changes as endogenous systems to manage these pathogenic processes become more challenged with age. Evidence that addresses the practical importance of nutrition on the common degenerative conditions that promote AMD has grown over the past three decades and is the focus of the current chapter.
Throughout the chapter, three general types of scientific evidence that inform us about nutrition and AMD will be discussed for each category of food component. One type of evidence comes from studies in animals and cell systems in which the short-term effects of nutrient deficiency or high-dose supplementation are tested. These experiments, which push the limits of physiological systems, elucidate the mechanisms by which particular nutrients can exert physiological or biochemical influences. These do not, however, provide insights about the influence of more moderate variations in intake, beyond overt deficiency states or pharmacological effects of nutrients under isolated conditions. The results of these experiments do not generally demonstrate the effect of a nutrient in the routine context where the nutrient is one of many components of foods consumed. Evidence for mechanisms by which nutrients may play a role in AMD is insufficient to predict the impact of food or supplement sources over decades.
Epidemiological studies in populations provide broader insights about relationships between the intake of foods and supplements under more relevant conditions in people and over the long term. These observations illustrate how diets that are rich in certain foods or nutrients relate to the development of early and late stages of AMD, usually over decades, in people possessing a variety of genetic predispositions, whose health is influenced by a variety of medical conditions, such as the presence of hypertension or diabetes and lifestyles such as the use of alcohol and cigarettes. The strength of evidence from observational studies lies in the strength and consistency of associations across many different samples of people who vary in the characteristics that might explain or confound these observations, rather from any single study.
While relationships with specific nutrients or food components to AMD are often the focus in such studies, the results are influenced by numerous other food components that are associated with the kind of diet that provided high levels of that specific nutrient. For example, people who eat high levels of the carotenoids lutein and zeaxanthin typically consume high levels of fruits and vegetables, particularly dark leafy greens. These foods, and foods often eaten along with them, are also high in vitamins C and E and other carotenoids that might also protect the retina. There is often an attempt to statistically adjust for these other aspects of diet in order for investigators to draw conclusions about a specific nutrient of interest. This statistical approach is unlikely to be sufficient to fully isolate the effects of one target nutrient with other related aspects of diet. This is because the intake of so many of the potentially protective ingredients in food is highly correlated, and study samples do not include large numbers of people who have high levels of one component and low levels of all other potentially protective components to reliably compare risks in these subgroups. For this reason, evidence of relationships of diets high in certain nutrients in the diet with AMD risk cannot be used to reliably predict the influence of supplements that contain the nutrient. The relationships of certain nutrients to AMD might also reflect the influence of other aspects of a health-conscious lifestyle, such as physical activity and use of protective sun gear, especially if not known or not measured well and adjusted for. Thus, while the observations made from epidemiological studies illustrate broad diet attributes that associate with lower risk for AMD, they do not permit us to generalize about the effects of single nutrients, either as distinct from the foods that contain them, or in nutritional supplements.
The attempt to understand the influence of particular nutrients when consumed in isolation and at high levels drove several decades of research using clinical trial designs. The appeal of the results of these trials is that a specific, short-term impact of a nutrient or combination of nutrients can be known with a high level of certainty, and not be confounded by the other food components or health behaviors that can influence the results of observational studies. These trials have provided insights about the potential for nutritional manipulation to impact the progression of AMD. Such trials aim to test the impact of food ingredients as medicines.
Given the limited medical approaches available to treat AMD, nutritional supplementation options have been valued. The specific nutrient doses and combination of ingredients is informed by a limited state of knowledge limiting the ability to generalize to the long-term influence of nutrients in foods or other supplement compositions.
Despite limitations of any one type of evidence, an integration of evidence from these three scientific approaches has provided much broader and deeper understanding with which to counsel both patients with AMD and their families, who, due to genetic predispositions, might themselves be at higher risk to develop the conditions some day. The current evidence, as well as gaps in our existing knowledge, will be described in the remainder of the chapter. We will conclude with a discussion of broad dietary patterns that show promise to lower the rate of AMD.
ANTIOXIDANTS
Oxidative damage occurs to macro molecules (such as proteins, lipids, and DNA) when reactive oxygen species (ROS) interact with them and compromise their function. The sources of ROS are many and can be the result of photooxidation of lipids from light exposure; they can also be the by-product of metabolic events, such as oxidative metabolism or enzyme reactions that use oxygen (such as xanthine oxidase). Alternatively, they may be produced directly as a mechanism for biological defense, as is the case when white blood cells respond immunologically to pathogens with an oxidant boost.
It is widely known that the retina is particularly susceptible to oxidative stress because of its high rates of oxidative metabolism and light exposure, and its high concentration of lipids with double bonds that are vulnerable to attack by free radicals. Multiple types of oxidative stress occur in cells, and the net damage is a function of the stressors themselves, as well as the ability to defend against them and repair the damage done.
Food contains numerous antioxidants, such as vitamins C and E and carotenoids, which are provided by fruits, vegetables, nuts, and nut or vegetable oils. These are chemicals that either directly neutralize ROS, or that are cofactors for enzyme systems that neutralize ROS, such as zinc and selenium, which are provided by meat, dairy, and some grains. These antioxidants work in different cell compartments, and often in complementary ways. Vitamin C is the most abundant dietary antioxidant in aqueous compartments of the cell, while vitamin E and vitamin E-related compounds are the most abundant lipid-phase antioxidants in foods. Other hydrocarbon plant compounds such as carotenoids are also active in lipid-soluble cell compartments, and may have unique function by virtue of their ability to align in biomembranes of cells or organelles. Foods can contain direct oxidants or substances which promote the production of ROS (including, potentially, residual herbicides and pesticides) but little is known about these effects on the eye and they will not be discussed here.
In studies with experimental animals, deficiencies of vitamins E and C, or nutrients such as zinc, which are components in enzymes that protect against oxidative stress, result in pathologic changes to the retina (as previously reviewed[1-3]). Yet, antioxidants can behave as pro-oxidants under some circumstances. Single or dual high-dose antioxidant supplements have not been associated with lower risk of progression of AMD.[4,5] This is consistent with evidence that oxidant defense is carried out by a highly complex system of mechanisms, in which antioxidant effects of several different individual antioxidant molecules have been found to be synergistic.[6-8] The type of oxidative stress that is most damaging depends on both the cell type and intracellular location. Retinal pigment epithelium cells, when cultured, demonstrate different vulnerabilities to the type of oxidant stress than do cells from other tissues, and the result of oxidants that target the cell surface and cytosol differs from that which targets specific organelles.[9]
In the Age-Related Eye Disease Study (AREDS), a 6.2 year randomized, placebo controlled clinical trial,[10] the administering of a high dose of the antioxidants (500 mg of vitamin C, 400 IU of vitamin E, 15 mg of beta-carotene, 80 mg of zinc along with 2 mg of copper), slowed the progression of AMD from intermediate to more advanced stages by 28%. There is also evidence that this treatment reduces the age-related oxidation of cysteine in the blood, which supports the possibility that the benefit is due to an improvement in oxidative stress.[11] A small short-term study of men with atrophic AMD, who received antioxidant supplements along with lutein, also reported improved visual function in this treatment group and not in randomized, placebo controls.[12]
Although the level of individual antioxidants in foods is usually much lower than levels provided by current high-dose antioxidant supplements, foods provide an even greater array of antioxidants than supplements, and the impact of decades of consuming dietary antioxidants on AMD may be substantial. In epidemiological studies, when associations with antioxidant nutrients are considered one at a time, low levels of one or more antioxidants in the blood or diet have often, but not always, been related to higher prevalence or incidence of certain age-related changes in the macula. Antioxidant nutrients related to lower occurrence of AMD include vitamin E[13-15] and/or one or more carotenoids or zinc.[14-20] The potential impact of a combination of dietary antioxidants was estimated in the Rotterdam Eye Study.[15]After adjusting for potential confounders, the 10% of participants who were consuming antioxidant-rich diets (i.e., diets with above the median intake of all four antioxidants in AREDS supplements) had a 35% lower risk of incident AMD than those with more average diets (diets with intakes of one to three antioxidants above the median). Risk in persons with antioxidant-poor diets (with all four antioxidant nutrients at levels below the median) was higher, although this was not statistically significant after adjustment for potential confounders, and larger samples would be needed to better evaluate this trend. Overall, there is a clear trajectory of lower risk for AMD that is associated with eating diets higher in several antioxidants. Lowering the prevalence of early or intermediate stages of AMD by eating antioxidant-rich foods has the potential to prevent even more cases of advanced AMD than does beginning supplements once intermediate AMD becomes manifest.
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Antioxidants and AMD |
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Summary of Evidence Oxidative stress or deficiency of dietary antioxidants in animals promotes degenerative changes in the retina. In people, there is broad evidence that supports the benefit of a combination of antioxidants in slowing early and late AMD:
Bottom Line and Unanswered Questions Foods rich in antioxidants (fruits, vegetables, and whole grains) are often associated with lower risk of early AMD.
One specific high-dose antioxidant supplement lowers risk for progression from intermediate to advanced AMD.
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The number of known and unknown antioxidants in foods exceeds that in most supplements, and foods high in antioxidants, such as vegetables, might lower oxidative stress to a greater degree than supplements. In a recent randomized, cross-over trial, eating two or more cups of Brassica vegetables (such as broccoli) lowered a urinary marker of oxidative stress, whereas moderate levels of supplementation with antioxidants in multivitamins did not.[21] However, it is not known whether the non-nutritive antioxidants in foods reach the retina (besides lutein and zeaxanthin, which are discussed next) or whether lowering the systemic level of oxidative stress by consuming such foods influences age-related macular degeneration.
LUTEIN AND ZEAXANTHIN
The specific carotenoids lutein, and its structural isomer zeaxanthin, may protect against the development of AMD, as previously reviewed.[22,23] These carotenoids, which comprise macular pigment[24,25] are responsible for the yellow color of the macula lutea and must be provided by the diet, since the body does not synthesize them. Their structure is similar to pro-vitamin A carotenoids, like beta-carotene, but with additional hydroxyl groups, which makes them more polar and unable to be used in vitamin A synthesis. Lutein and zeaxanthin are selectively concentrated into the retina and other ocular tissues over the five other carotenoids which predominate in human blood, and over the ?600 carotenoids present in nature. Evidence for the existence of specific xanthophyll-binding proteins in the vertebrate retina has been reported.[26,27]
Lutein and zeaxanthin may be obtained from many fruits and vegetables, from egg yolks,[28,29] or from supplements. Particularly rich sources include dark green leafy vegetables, such as spinach and kale, and green vegetables like broccoli, peas, green beans, and brussels sprouts. Americans, on average, consume 1-2 mg of these carotenoids daily.[30]
Lutein and zeaxanthin are found throughout the retina. The highest density occurs in the Henle fiber and inner plexiform layers.[31] At these locations, they are likely to function as an optical filter that absorbs short-wavelength visible (blue) light.[32] These features not only may block oxidative damage due to incident light energy, but may also improve visual resolution as previously reviewed.[33] One mechanism by which macular pigment could protect against the development and progression of AMD is by blocking light-induced formation of a toxic compound, A2E; this is the principal component of lipofuscin that accumulates in the RPE during phagocytosis of the rods and cones, and is taken up by the lysosomes. When a critical intracellular level of this compound has been reached, cell damage to DNA occurs, induced by blue light irradiation.[34] Because macular pigment can absorb 40-90% of incident blue light, it could reduce the amount of A2E formed. This possibility has not yet been tested.
The macular pigment density reduces about twofold between the central macula, where the zeaxanthin isomer predominates, and the periphery where the lutein isomer predominates.[24] The highest density of xanthophyll carotenoids in the peripheral retina is in the rod outer segment membranes,[35] where their concentration is consistent with a role in oxidant defense. An antioxidant role is supported by the presence of oxidation products of lutein and zeaxanthin in the retina.[36] These carotenoids may also influence membrane stability by their unique alignment in biological membranes.[37]
Animal models to study the impact of macular pigment on AMD or related photoreceptor health are limited to species that accumulate these carotenoids in their ocular tissues: primates, and some birds such as quail. Primates fed diets deficient in these xanthophyll carotenoids[38,39] suffer a loss of retinal pigment epithelial (RPE) cells and increased photoreceptor cell death.[40] Retinal zeaxanthin has been demonstrated to prevent light-induced photoreceptor death in quail.[41]
Lower levels of lutein and zeaxanthin have been found in autopsy specimens of donor eyes with AMD.[42] Similarly, in two cross-sectional studies, people with AMD have lower concentrations of these carotenoids in their macula compared to those without AMD.[43,44] In contrast, in the largest such cross-sectional study, which involved about 1700 women, macular pigment was actually higher in those with intermediate and advanced AMD.[45] However, evidence in subgroups of women from this study is consistent with the possibility of a protective effect in the youngest two-thirds of the sample with stable diets. Prospective studies of the relationships of macular pigment to the onset of AMD are needed in order to understand whether low macular pigment is a consequence of, or a contributor to, AMD.
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Lutein and Zeaxanthin and AMD |
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Summary of Evidence In vitro and animal studies indicate that the oxygenated carotenoids lutein and zeaxanthin may lower oxidative stress in the retina directly or by lowering blue light that reaches the photoreceptor outer segments or RPE. Lutein and/or zeaxanthin supplementation in animals lowers light-induced damage to the retina. The long-term intake of diets rich in lutein and zeaxanthin is often, but not consistently, related to lower risk for AMD. Bottom Line and Unanswered Questions Foods rich in lutein and zeaxanthin are high in antioxidants, which are associated with lower risk of AMD.
The benefit of diets or supplements rich in lutein and zeaxanthin or high macular pigment levels on incidence and progression of AMD has not been adequately studied.
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Results from observational studies indicate inconsistent associations between the intake and blood levels of lutein and zeaxanthin and the occurrence of age-related macular degeneration. In two case-control studies, higher serum levels[46,47] and dietary intake of lutein and zeaxanthin[48] were associated with a statistically significant reduction in the risk of neovascular/exudative AMD. Higher levels of dietary lutein and zeaxanthin were also associated with lower prevalence of retinal pigmentary abnormalities among Americans 40-59 years of age, and lower rates of advanced AMD in Americans 60-79 years of age, in the Third National Health and Nutrition Examination Survey.[49] Low levels of plasma zeaxanthin[19] in one study, and both lutein and zeaxanthin in another study,[16] were associated with a higher prevalence of early and late AMD. Other studies have either failed to find an association, or associations did not reach statistical significance.[14,50-54] It is too early to draw conclusions from population studies because the inconsistent observations are likely to be biased by recent diet change, selective mortality bias or competing risk factors, or limited to certain stages of AMD (discussed previously[55]). In the recent Carotenoids in Age-Related Eye Disease Study (CAREDS), high intake of lutein and zeaxanthin was associated with lower odds for intermediate AMD only after excluding persons who were likely to have had unstable diets,[20] suggesting that dietary changes contribute to inconsistent results in epidemiological studies of AMD. A bias of selective mortality might also explain the inconsistent results in population studies. For example, older participants in observational studies may be more likely to have eaten diets rich in fruits and vegetables over their adult lifetime than people in their birth cohort who are no longer living, making it more difficult to discern the effects of those diets on disease outcomes. Longer-term prospective studies, particularly of the youngest persons at risk for AMD, will provide more insights in years to come.
The benefits of lutein and zeaxanthin supplements on preventing or slowing AMD are unknown. One reason is that the ability to accumulate carotenoids with supplements appears to be variable across individuals. Between 20% and 50% of subjects in previous investigations have low serum and/or retinal response to oral supplementation with these carotenoids.[56-58] In general, blood responses to oral carotenoids vary in different people, as well.[59,60] The influences on the ability to take up carotenoids by the intestinal tract and the eye are largely unknown. Having high levels of body fat and diabetes is related to lower macular density.[61] These conditions might reflect levels of oxidative stress or lipoprotein distributions, which could, in turn, influence the ability to accumulate carotenoids.
The benefit of taking lutein and zeaxanthin supplements has not been studied in prospective studies or clinical trials. There was, however, one very small and short-term trial in which visual acuity improved slightly in the fewer than 30 subjects who received exclusively lutein supplements.[12] Further information about the benefits of supplementation with lutein and zeaxanthin (and omega-3 fatty acids) on progression of advanced AMD may come from a large set of multicenter clinical trials (AREDS II) that is currently underway.
Despite inconsistent data for these specific carotenoids to date, lutein and zeaxanthin may be two of the many components in fruits and vegetables that may slow earlier stages of AMD. It is possible there are combinations of foods that provide the optimal mix of nutrients that protect against AMD. Americans who reported high intakes of vitamin A-rich fruits and vegetables had lower prevalence of AMD.[62]Low fruit and vegetable consumption was associated with higher 5 year incidence of large drusen in the Beaver Dam Eye Study.[14] In CAREDS, there was a strong inverse relationship between intermediate AMD and the intake of vegetables in general, and green vegetables, specifically, in women under 75 years of age with stable intakes. One small study in Lithuania reported that the consumption of fresh, uncooked vegetables at least twice per week (compared to less than twice per week during the winter/spring months) was inversely associated with AMD, in women of ages age 65-74 years.[63] Inverse associations with intakes of vegetables and fruits throughout the rest of the year were also observed, but did not reach statistical significance. In a large prospective follow-up study of women in the Nurses' Health Study, and men in the Health Professionals Follow-up Study, fruit intake was inversely associated with the risk of neovascular AMD, while overall fruit and vegetable intake were not associated with AMD.[50] Better diets and overall health habits might explain different associations with vegetable intake from those study samples.
In summary, while there is strong biological plausibility that macular carotenoids might protect against AMD, the results of existing epidemiological studies are inconsistent, and have not addressed relationships of macular pigment, specifically, to the progression of AMD. A large clinical trial (AREDS II) is underway to determine the impact of lutein and zeaxanthin supplements on the progression of advanced AMD.
The possibility that lutein and zeaxanthin are some of the many components of fruits and vegetables that could protect against the development of AMD seems strong. However, many older patients who have been prescribed warfarin treatment to prevent blood clotting have been unnecessarily advised to avoid the intake of root and leafy green vegetables because they contain vitamin K. Vitamin K is necessary for blood clotting by its action on the formation prothrombin, or clotting factor II. A sudden increase in vitamin K intake can increase blood prothrombin levels. However, patients can be advised to consult with the physician who manages the treatment to adjust the warfarin dose to the highest daily green vegetable intake that the patient can consistently eat.
ZINC
Zinc may be particularly important to the retina because concentrations of zinc in the retina exceed those elsewhere in the body, with the exception of the prostate.[64] Deficiency of zinc in both animals and people impairs retinal functioning, as previously reviewed.[1] The mechanisms by which zinc could influence AMD are numerous and fall into three general categories: catalytic, regulatory, and structural.[65]Zinc catalyzes enzymatic reactions, and is a cofactor of over 100 enzymes, some of which are involved in oxidant defense. Zinc depletion in RPE cells has reduced levels of catalase, glutathione peroxidase, and metallothionein, and has reduced ability to phagocytize photoreceptor outer segments.[66] Zinc performs structural roles; its presence facilitates protein folding to produce biologically active molecules that organize into zinc finger-like structures. Zinc is also necessary for the DNA binding capability of over 400 nuclear regulatory units and plays a role in cellular signaling.[67] It is involved in many homeostatic mechanisms, including immune responses, previously reviewed.[67,68] Evidence can be found that both zinc deficiency and excesses impair immunity.[68] Zinc depletion may also trigger apoptosis of RPE cells, or increase the vulnerability of RPE cells to photic injury.[69] However, zinc supplementation can also enhance stress-induced effects in RPE cells.[70] Thus, there is evidence for numerous mechanisms by which zinc could influence retinal systems that are involved in the development of AMD.
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Zinc and AMD |
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Summary of Evidence Zinc availability influences retinal function in animals and humans. Observational studies report inconsistent relationships between moderate variation in long-term zinc intake and AMD. High-dose zinc supplementation in one large clinical trial lowered the progression of intermediate to late AMD. (Results of smaller and shorter trials were inconsistent.) Bottom Line and Unanswered Questions Moderate intake of foods rich in zinc (dairy, meat, shellfish) might lower risk for AMD, by virtue of the zinc they provide or because they also contain other protective vitamins that are poorly studied.
High-dose zinc supplementation may modestly slow progression of AMD among persons who already have intermediate AMD.
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The longer-term benefit of zinc on risk for AMD is not clear from observational studies. In the Beaver Dam Eye Study[18] high intake of zinc from foods and supplements was related to lower prevalence of early AMD, compared to low intake. The association for the incidence of early AMD in that population pointed in the same direction, but was statistically significant only for the incidence of retinal pigment abnormalities, a less common and more intermediate stage of AMD.[14] In a longer-term prospective study in the Netherlands, zinc intake was related to lower risk for incident AMD.[15] In an Australian study with a similar distribution of zinc intake, early AMD was less prevalent among people with high zinc intake as compared to low zinc intake, but this was not statistically significant.[71] Incident AMD in the same population was unrelated to zinc intake.[51] The power to evaluate associations between the intake of zinc and late AMD was low in these three populations. However, zinc intake was unrelated to self-reported incident AMD (a combination of early and late AMD) in two other large study samples.[72]
By contrast, the use of high-dose zinc supplements (80 mg as zinc oxide, along with 2 mg of cupric oxide) for 6 years, with or without antioxidants, was associated with modestly lower progression from intermediate to advanced AMD in the AREDS.[10] One smaller zinc supplementation trial had previously reported a benefit of zinc supplementation on vision loss in patients with AMD,[73] while another did not.[74] No serious safety issues with zinc supplementation were identified in the 6 year AREDS study (aside from more frequent hospitalization for genitourinary problems in men and more frequent anemia, unsupported by differences in hematocrit) and zinc supplementation was related to lower mortality in this sample.[75] However, the longer-term benefits and risks of zinc supplementation at the high levels tested in AREDS are unknown. While an enhanced immune response has been noted in institutionalized elderly who were supplemented for 1 or 2 years with moderate levels of zinc,[76] in combination with one or more other nutrients, controversy about the long-term safety of high-dose zinc supplementation exists[77] and can only be addressed with longer-term studies.
DIETARY FAT
There are at least three broad mechanisms by which dietary fats might enhance or slow age-related macular degeneration. First, because of the high caloric density of fats, eating high-fat foods can displace other foods in the diet which have high nutrient density that may have otherwise lowered oxidative stress, or enhanced macular pigment or immunity. Second, eating high-fat and low-nutrient dense foods may contribute to high body mass, which is sometimes reported to be a risk factor for AMD.[78-80] Third, fatty acids themselves have numerous biological effects as components of biological membranes and regulators of biochemical pathways. Dietary fats could promote AMD by promoting atherosclerosis, which is related to AMD risk in some studies[81,82] or parallel atherosclerosis-like processes which result in lipid enrichment and mineralization of the retina. Certain fatty acids can also have direct physiological effects on the retina by modulating oxidative stress, or by the inflammatory response which can promote AMD pathogenesis (discussed below).
OVERALL LEVELS OF FAT
In laboratory studies of mouse models of atherosclerosis, feeding high-fat diets resulted in the accumulation of lipid-like droplets in the retina and degenerative changes in RPE cells and Bruch's membrane.[83-86] In epidemiological studies, there is a consistent relationship of high dietary fat levels to risk for early and late AMD in observational studies. High total levels of dietary fat have been related to higher prevalence,[87-89] incidence,[78,90,91] or progression[92] of both early and advanced AMD in several different study samples, even though not always statistically significant. Some exceptions to this trend include prevalence or short-term incidence studies with low power to evaluate associations with either early AMD[91] or advanced AMD.[87-89] In one short-term prospective study, persons with low, compared to moderate, levels of dietary fat were at higher risk for the 5 year incidence of early AMD.[91]
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Dietary Fat and AMD |
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Summary of Evidence High-fat diets in mouse models of AMD induce retinal pathology thought to contribute to AMD in humans. In population studies:
The body of evidence from in vitro and in vivo animal and clinical experiments suggest there is evidence that a protective effect of omega-3 fatty acids in the body, in general, may involve one or more of the following:
Bottom Line Avoidance of excess fats in foods that provide few micronutrients (processed sweet and salty snacks, and high-fat desserts) and favoring omega-3 fatty acids over omega-6 in the diet by eating fatty fish, leafy green vegetables, and whole grains, may lower risk and progression of AMD. Unanswered Questions The benefit and safety of supplementing with fish oils to slow early or advanced AMD is unknown. |
SPECIFIC FATS
There is inconsistency across studies in the type of fat that was most related to AMD. This suggests that these relationships may reflect, in part, the caloric density of dietary fats that replace other micronutrients. In some samples, high intake of saturated fats was more strongly related to risk for AMD or similarly to other types of fat,[88-90,93] while in other studies total intake of polyunsaturated fatty acids or monounsaturated fatty acids[78,92] was more strongly related. The intake of trans fatty acids, provided in diets by margarines and other processed foods, was related to higher risk for AMD in two studies.[78,92] Because fat intake often changes, particularly in relation to diagnosis for cardiovascular diseases, which can be related to AMD, these relationships are difficult to interpret. Moreover, there is limited ability in such studies to adjust for the numerous other protective aspects of diet that accompany a more moderate, as compared to high, intake of fat.
In contrast, there is more consistency in epidemiological studies that report lower risk for AMD among people with high intakes of fish or long-chain omega-3 polyunsaturated fatty acids (LC omega-3 PUFAs).[90-92,94] The protective influence of omega-3 fatty acids could be somewhat dependent on the omega-6 content of the diet. A higher ratio of omega-3 to -6 fatty acids could increase formation of antiinflammatory eiscosanoids from omega-3 fatty acids, because the omega-6 fatty acids compete for the desaturase enzyme that creates them[95] or replace the omega-6 content of membranes. In one past study, LC omega-3 PUFA intake was stronger among subjects who had low intake of omega-6 PUFAs.[78]
There has been interest in the health benefits of omega-3 fatty acids since the 1970s, when it was observed that Greenland Inuit who ingested high levels of fatty fish that contain them, had low rates of cardiovascular disease. Omega-3 fatty acids are one of two major classes of polyunsaturated fatty acids. Alpha linolenic acid, an omega-3 fatty acid, is one of two essential fatty acids that must be obtained from the diet because they cannot be synthesized by the body. In the body, this fatty acid which is contained in leafy green vegetables and in larger proportion in some vegetable oils (canola, soy, and flaxseed) can be elongated to make the two major LC omega-3 PUFAs: eicosapentaenoic acid (EPA) and docosopentaenic acid (DPA); however, the efficiency of conversion is not well understood. Fatty fish (salmon, tuna, mackerel, and herring) which concentrate EPA and docosahexaenoic acid (DHA) from algae, the primary producers of these fatty acids in the ecosystem, are concentrated dietary sources of these LC omega-3 PUFAs. These fatty acids are also more concentrated in meat of animals fed grass-based diets than grain-based diets.[96]
There is general agreement that the American diet has changed over the last century, so that the ratio of omega-6 fatty acids (found in meat, vegetable oils such as corn, safflower, and soy, and processed foods made with these oils) to omega-3 fatty acids has increased. American diets provide about 10 times the amount of omega-6 to -3 fatty acids, and there is a general consensus that consuming more omega-3 fatty acids and less omega-6 would be optimal for health.
LC omega-3 PUFAs, such as DHA, may be particularly important to the health of the retina. The pathogenesis of AMD may be influenced by atherosclerosis or involve parallel processes.[97] There is a large body of evidence to suggest that EPA and DHA lower CVD mortality by several mechanisms: by an improvement of blood lipids by lowering blood triglycerides, decreasing inflammation, blood pressure, and platelet aggregation and by improving vascular reactivity (recently reviewed).[98] These may influence AMD pathogenesis directly or indirectly.
DHA is the most abundant LC omega-3 PUFA in rod outer segment membranes[99,100] at a concentration that exceeds levels found elsewhere in the body.[101] Its presence in membranes affects their biophysical properties and may influence membrane-bound enzymes, receptors, and transport. This is important in visual transduction,[102] but may also influence the pathogenesis of AMD. LC omega-3 PUFAs may protect against AMD by direct influence on retinal cell survival.[103] DHA has also been demonstrated to protect RPE cells from oxidative stress.[103,104] However, high intake of this type of fat might also lower risk for AMD because of its antiinflammatory properties.[95] Numerous cell culture studies provide clues for possible mechanisms by which LC omega-3 PUFAs could enhance the integrity of vascular and basement membranes and prevent neovascularization (recently reviewed[105]).
Unfortunately, none of the over 100 clinical trials of LC omega-3 PUFAs in medical research has evaluated its impact on AMD. However, despite lack of proof of effectiveness in treating AMD, previous clinical trials provide a large body of evidence to support the notion that omega-3 fatty acids are potent antiinflammatory agents and reduce the need for medications for the chronic inflammatory disease of rheumatoid arthritis.[106] Also, past clinical trials provide a history about the potential safety of long-chain, omega-3 supplements in about 10,000 subjects of previous studies. In past studies (previously reviewed[107] in which 0.3-8 g of DHA and EPA per day was supplemented for periods of 1 week to 7 years, no side effects were reported in 52% of the studies. Overall, side effects were reported in fewer than 7% of subjects and involved minor gastrointestinal disturbances (such as diarrhea) and several cases of bleeding in trials where patients took warfarin or aspirin daily.
In summary, at this time, most population studies to date suggest lower early and late AMD among people who eat high levels of fish or LC omega-3 PUFAs. The evidence for antioxidant and antiinflammatory properties of these fatty acids is also supportive of this possibility. However, results of population studies may reflect other benefits of diets that are high in fish. For example, fatty fish also provide vitamin D, which also has antiinflammatory properties, and was recently reported to be associated with lower risk for early AMD in one population (discussed below). The current evidence supports the possibility that reducing intake of omega-6 PUFAs and increasing omega-3 PUFAs of the diet may lower risk for AMD with little health risk. This can be achieved by eating leafy green vegetables and fatty fish, substituting canola and olive oils for corn and safflower oils, and avoiding processed foods, selecting fish with low potential to contain heavy metals (for example, by choosing wild caught rather than farm-raised fish) can minimize potential harmful effects.
The benefit of supplementing with 1 g per day of LC omega-3 PUFAS is currently being tested in a large clinical trial (AREDS II).
POSSIBLE PROTECTION BY ASPECTS OF DIET LESS WELL INVESTIGATED
VITAMIN D
Newly emerging evidence for the high prevalence of complement H-polymorphisms among people with AMD suggests that inflammation may play an important role in the development of AMD.[108-110] High levels of C-reactive protein (a systemic marker of inflammation)[111,112] and the use of antiinflammatory medications[113] were significantly related to AMD, independent of other established risk factors, in some but not all[114,115] previous studies. Proteins associated with inflammation including C-reactive protein, fibrinogen, and complement components, as well as transcripts of these proteins, have been observed to be entrapped within drusen, suggesting the involvement of immunocompetent cells in drusen biogenesis.[116] Nutrients which attenuate the inflammatory response or enhance immunity to pathogens might protect against AMD. Vitamin D is an example of one such food component with antiinflammatory properties.[117]
One form of the vitamin, vitamin D3 (cholecalciferol), is synthesized in the skin when exposed to sufficient ultraviolet light. The amount of ultraviolet exposure needed to elevate blood vitamin D to recommended levels is small, ?5-15 min per day with face and hands exposed three times per week in the summer or on any available sunny days in the winter. However, aging and sunscreen use can reduce synthesis.[118,119] Vitamin D2 (ergocalciferol) is also provided by some foods: fortified cows milk or soy-milk, cheese, eggs, and fatty fish. However, it has recently been recognized that many older people obtain inadequate levels of vitamin D, because they neither consume the foods that contain it nor get adequate sun exposure to manufacture it in sufficient quantities. Thirty percent of elderly Caucasians sampled in Boston were found to be deficient in vitamin D; the intake of this vitamin is particularly low among men and women over 51 years of age in the United States.[120] Vitamin D intake reduces C-reactive protein, a marker of systemic inflammation.[121] Low vitamin D status has been associated with the occurrence of common chronic diseases that are suspected to be promoted by inflammatory mechanisms such as cancers, diabetes, and cardiovascular disease.[117]
Higher blood levels of vitamin D were recently reported to be associated with lower risk for early AMD in the Third National Health and Nutrition Examination Survey.[122] Consistent findings in other samples are required to better evaluate this as one of many food components that could protect against AMD. There were too few cases of advanced AMD to reliably evaluate relationships with blood vitamin D in this study, but vitamin D might protect against neovascular AMD by virtue of its antiangiogenic properties in endothelial cells.[123,124] This remains to be investigated.
In summary, vitamin D might be another of the food components that protects the aging retina. Because this vitamin is provided in milk and fatty fish, it might explain, in part, relationships of these foods to AMD in past studies. There is currently insufficient evidence to reliably determine whether vitamin D status contributes significantly to protection against AMD.
Glycemic Index
The glycemic index of foods was recently introduced to be another possible aspect of diet that could influence the development of AMD.[125] While advanced glycation end products have been found in drusen, it is not yet known whether they are a cause or consequence of degenerative changes. Degeneration of the retinal vasculature is a well-known complication of diabetes mellitus, yet, the presence of diabetes has sometimes, but not always, been related to AMD in epidemiological studies. The biological plausibility that elevations in blood sugar promote AMD, particularly in the absence of diabetes, remains untested. Nevertheless, diets with a low glycemic index often include few refined grains and sugars and plenty of fruits, vegetables, whole grains, legumes, and milk which have numerous ingredients that could protect against AMD. Thus, high-glycemic-index diets, like high-fat diets, may be related to higher rates of AMD, in part or in whole, because they are poorer in a wide variety of protective nutrients and other diet components.
HERBAL SUPPLEMENTS
The use of herbal supplements has increased in the United States. Several herbal supplements such as those containing ginkgo biloba and bilberry have been promoted to benefit the health of the retina. However, there are no scientific studies that support their benefit, except one very small (20 persons) study of ginko biloba in patients with AMD, in which improvement in visual acuity was indicated in a preliminary report (recently reviewed[126]).
LARGER DIETARY PATTERNS
There is evidence that the pathogenesis of AMD, like many other chronic diseases of aging, is likely to involve a complex interaction of cellular and vascular factors, which may be promoted by light damage, oxidative stress, and inflammation.[127] Therefore, it comes as no surprise that numerous nutrients and other dietary components may play multiple roles which could be additive or complementary. In many recent studies, specific dietary patterns, which include a high density of fruits and vegetables and whole grains, moderate or low fat levels, and low-fat dairy foods, such as the Mediterranean diet and Dietary Approaches to Stop Hypertension (DASH) diet, have been related to reduced occurrence or progression of many chronic diseases of aging,[128-132] and results support the idea that the small effects of many individual nutrients or compounds could add up to a stronger effect when the overall diet is examined. For example, it was recently demonstrated that the combination of high-fruit and -vegetable diets and low-saturated-fat diets were more protective against coronary heart disease mortality than was either alone.[133]
The possibility that certain specific diet patterns slow the development of early or advanced AMD has not yet been studied. There does exist evidence in mice for the cooperative influence of dietary nutrients on the retina in mice: the deposition of basal laminar deposits that are stimulated by diets high in polyunsaturated fatty acids is minimized by treatment with vitamin E.[85] Because many aspects of diet have the potential to protect against ARM, there may be important insights to be gained by considering overall diet patterns and their relationships to the occurrence of AMD. Certainly, the body of evidence about specific nutrients and foods that are related to lower occurrence of AMD support the possibility that Mediterranean diets or DASH diets could also lower risk for early or advanced AMD.
CONSIDERATIONS IN USING SUPPLEMENTS TO TREAT AMD
There has been a substantial upswing in the marketing of vitamin and mineral supplements for aging eyes. This prompts questions from patients who have AMD about the use of these supplements to slow progression of this condition and about whether their family members who may be at greater risk will benefit from beginning supplementation to prevent or delay getting the condition themselves. It is interesting to note that while regular supplement use has been practiced by more than half of Americans for decades, the prevalence of early AMD in one primarily Caucasian American community (in Beaver Dam, Wisconsin) was similar to the prevalence among similar, primarily Caucasian, communities in Australia and the Netherlands,[134] where the frequency of supplement use is about one-third that in the US community. In fact, rates of neovascular AMD were lowest in the Dutch community. The use of multivitamin supplements is consistently unrelated to AMD in past epidemiological studies (previously reviewed[77,126]).
The evidence for benefit of supplements in treating AMD is limited to one study (previously reviewed[77,126,135]). The AREDS demonstrated that taking a high-dose combination antioxidant supplement for 6 years resulted in a 28% reduction of risk for progression to advanced AMD among subjects who already had intermediate AMD.[10] Given the limited treatment options for AMD, this may have value for individual persons. It may be that supplement use is more or less helpful in people who are genetically prone to AMD, but this has not been tested. A considerable public health benefit of taking the AREDS supplements has been estimated.[136] However, it is not yet possible to weigh the costs, in terms of health risks of long-term use and whether there would be similar or greater overall health benefit relative to an equal amount of money spent on consuming food sources of antioxidants. It is unknown whether a similar benefit would accrue by the consumption of lower levels of antioxidants. While greater benefit might be achieved in slowing AMD with even higher doses of antioxidants, this is not recommended because higher doses have the potential to pose greater health risks. Results of a recent meta-analysis suggested that intakes of vitamin E higher than the amount in AREDS supplements (above 400 IU) was associated with higher risk for mortality in clinical trials.[137] A larger impact might be possible with intakes over longer periods. Intakes of beta-carotene above 20 mg have been associated with higher risk of cancer in smokers.[138,139]
It is also unclear whether the results can be generalized to other populations who are less-healthy or consume better or worse diets. People with less nutritious diets might benefit more, but may also be at higher risk for side effects of pharmacological doses of nutrients if diet imbalances already exist. Insufficient numbers of people in the AREDS, or in all trials combined, exist to determine whether the benefit (or risk) is greater in subgroups that have other risk factors for AMD or for specific types of AMD. There were too few people who developed early stages of AMD to determine whether these high-dose antioxidants had value in slowing progression of earlier stages.
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The Bottom Line: Summary of Recommendations to Patients with Intermediate or Late AMD |
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Supplements Taking the AREDS tested supplement containing 500 IU vitamin E, 1405 mg beta-carotene, 500 mg vitamin C, and 80 mg zinc with 2 mg copper may reduce progression. Caveats
Foods The overall body of current research suggests that healthy eating may slow the progression of AMD. (See recommendations for patients who are at risk for AMD because of a family history of AMD.) |
SUMMARY AND CONSIDERATIONS IN RECOMMENDING DIETS TO LOWER RISK OR PROGRESSION OF AMD
The knowledge base available to suggest foods that may slow AMD at early or late stages is currently greater than for supplements. The results of the AREDS confirmed that nutrition is important to the health of the aging macula.
Thus, both patients who have AMD and people who might be at high risk for AMD (perhaps because of a family history of AMD) who inquire about what they can do to slow AMD, can be appropriately advised by their physicians to 'eat well', just as they might be cautioned to stop smoking. A full discussion of the details of 'eating well' is beyond the scope of this chapter, but suggestions in the following section summarize recommendations, as relevant to what we currently know about AMD, and the role of nutrition in chronic diseases of aging.
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The Bottom Line: Recommendations for Patients Who Are at Risk for AMD Because of a Family History of AMD |
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Supplements There is no evidence from population studies or clinical trials that supplement use of any kind will lower risk for developing AMD. Foods Current scientific evidence supports the possibility that healthy eating is the most promising means known (besides avoiding smoking) to lower risk for developing AMD. Because of the broad evidence for benefits of numerous food components, a focus on a balanced diet, rather than food supplements, is more likely to lower risk. Diets which show promise to lower risk for AMD include:
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The last five decades of medical research have demonstrated the wisdom of refraining from providing patients with bifurcated lists of 'good' or 'bad' foods or nutrients. Over that time, the results of studies (influenced by market forces), have been enlisted to extol the benefits of some (margarine, beta-carotene, vitamin E) and admonished against indulgence in others (eggs, red meats, whole-fat dairy, high-cholesterol shellfish) to prevent chronic diseases like cardiovascular disease and cancer. Currently, there is a better understanding of the complexity of roles of foods in the development of chronic diseases and the value of traditional diets, such as the 'Mediterranean diet' are being considered by the medical community. The process of adaptation has resulted in traditional diets, specific to the availability of foods in different regions of the world that have promoted health and longevity over thousands of years. Evidence is mounting that certain diet patterns, such as the Mediterranean diet, have more potential to slow the onset, progression, and recurrence of cardiovascular disease and this may be true for eye disease, as well. The current consensus of medical research, together with specific knowledge of relationships of foods and nutrients to AMD, as reviewed in this chapter, suggests the following as recommendations to patients to slow early and late AMD.
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1. |
Eat an abundance of fruits and vegetables of varying colors. Currently, the US Dietary Guidelines suggest eating three to five vegetables per day and two to four servings of fruit to minimize risk for a variety of chronic diseases. This translates into ?3/4 to 1 cup of vegetables and 1/2 cup of fruit three times a day. Choosing a variety of colors naturally varies the nutrients supplied by them. Dark green leafy vegetables are rich in lutein and zeaxanthin, but are also rich in a wide variety of micronutrients such as vitamins E, C, and other carotenoids. Yellow and orange fruits and vegetables are often sources of vitamin A and sources of the carotenoids beta-carotene, lutein, and cryptoxanthin. Red fruits and vegetables often contain not only vitamin C, but also other carotenoids, such as lycopene. Blue and purple fruits supply other phytochemicals such as flavonoids and anthocyanins that have antioxidant and antiinflammatory properties. |
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2. |
Eat whole grains at most meals, as breads, cereals, or pasta. These provide many more B vitamins, vitamin E, and minerals (such as selenium) than refined grains. They are also higher in fiber which can cause one to feel satisfied sooner. The current US guidelines suggest eating from 6 to 11 servings of grains per day, depending on the calories needed. Some controversy exists over the optimal amount and frequency of grains needed in diets. However, there is no controversy about the fact that whole grains are nutritionally superior to refined grains. |
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3. |
Eat a variety of protein sources daily. Daily high-quality protein sources are necessary. US Dietary guidelines suggest that one should eat two to three servings of meat or alternate protein sources (meat, fish, poultry, eggs, nuts or legumes) and three servings of dairy each day. Many of these have ingredients that may slow AMD, dairy products (milk, cheese, yogurt) are one of two main sources of zinc in the American diet and many are fortified with vitamin D, as well. If dairy foods are not eaten, calcium and many vitamins can be obtained from beans and other plant foods, instead. If further research confirms a role of vitamin D in slowing AMD, as early findings suggest, then people not eating dairy foods can receive vitamin D by eating eggs, fatty fish from cold waters, small frequent (three or more times/week) exposure to sunlight, or taking multivitamins. |
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4. |
Eat moderate amounts of fat, reducing processed fats and omega-6 fats and increasing omega-3 fatty acids. Excess fat in the diet lowers the overall nutrient density because high-fat foods (such as from high-fat desserts and salty snacks) are typically low in vitamins and minerals and replace nutrient-dense foods. However, some fat may be part of a healthy diet for people with or at risk for AMD. Fat is not only important in enhancing the natural flavor of foods but also aids digestion of fat-soluble plant pigments. For example, salads to which full-fat salad dressings or avocados have been added raise blood carotenoids more than eating fat-free salads that are equally high in carotenoids.[140,141] Current recommendations to lower omega-6 and increase omega-3 fats in the diet can be achieved by reducing processed foods, replacing corn oils and margarines with canola, nut, and olive oils, and increasing the intake of cold-water fish, which provide LC omega-3 PUFAs. Substituting meat that has increasingly come from grain-fed animals, with meat from traditional grass-fed animals, is another option to increase omega-3 PUFA intake. Avoiding processed foods will lower trans-fat intake; since processed foods and oils provide ?80% of trans fats in the diet, compared to 20%, that occur naturally in food from animal sources. |
IMPORTANCE OF FOOD TO AMD PATIENTS BEYOND NUTRIENTS
Foods nourish patients with AMD by providing numerous bioactive chemicals that directly or indirectly slow the pathogenesis of AMD. Additionally, the likelihood that foods that they eat (or perhaps supplements they take if eating healthy foods is not possible) can slow the progression of their condition may provide a sense of hope, optimism, and self-empowerment that cannot come from the limited medical treatments that are currently available. The overall current body of scientific evidence provides solid support for this, whether or not the long-term impact of isolated components is possible or practical to determine conclusively.
Foods can also stimulate the senses. This may be particularly nourishing to the patient with AMD who is becoming aware of diminished sense of sight. The role of food in connecting the person to his or her surroundings is heightened in patients with AMD (or any significant vision loss). Since food lies at the center of many of the activities and rituals that bring meaning and joy to one's life, the smells and tastes of traditional foods can reinforce connections to cherished past experiences. Physicians might consider supplementing their recommendations, based on evidence for the pharmacological impact of food components on the pathogenetic process that promote AMD, with encouragement toward a focus on enjoying healthful eating.
Decades of medical research both inform us of the large number of vitamins, minerals, and phytochemicals that are currently known to contribute to retinal health, and foster within us an appreciation of the probability that others, of which we may not be presently aware, are likely to be elucidated in the near future.
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