By Lynn Keegan, RN, PhD, HNC, FAAN
Macular degeneration (MD), also termed age-related macular degeneration (ARMD), is the leading cause of deteriorating vision and blindness in people older than age 60 in the United States. It affects 25-30 million people worldwide. As Americans age, the incidence rate is expected to triple by 2025.1
Signs, Symptoms, and Disease Process
Macular degeneration begins with the loss of central vision. There are several theories used to explain the origin and progression of the disease process. The simplest theory is that in individuals who are susceptible on the basis of pre-existing genetic, environmental, or metabolic conditions, light entering the eye sets up a process of rapid oxidation that destroys the pigment of the retinal cells, and the resulting buildup of debris causes damage to vision. Table 1 lists the most common risk factors for ARMD.
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Common changes as normal eyes age include: changes in color perception, floaters, dry or burning eyes, and/or difficulty adjusting to changes in light. Early symptoms of ARMD include difficulty reading print because the pages appear to be distorted in the center, difficulty recognizing familiar faces, problems with depth perception, and difficulty finding personal objects even in a familiar environment. There are two types of ARMD, wet and dry, with the less severe, slower-progressing, dry-type occurring 85-90% of the time.1
Symptoms of macular degeneration can be mistaken for psychiatric disease. Charles Bonnett syndrome, manifested by visual hallucinations such as purple flowers on khaki pants or little girls in white dress playing in the yard, may occur in 10% of ARMD patients.1 Also, some ARMD patients may be labeled as having early dementia because of the inability to recognize familiar faces.
The physical findings include drusen on the retina. Drusen are small yellow deposits that contain complex lipids, fatty wastes of the photoreceptor cells, and calcium. Drusen are used as markers for ARMD, but their presence alone does not indicate that the patient has ARMD.
Epidemiological studies of dietary, environmental, and behavioral risk factors suggest that oxidative stress is a contributing factor to ARMD. Pathology studies indicate that damage to the retinal pigment epithelium (RPE) is an early event in ARMD. In vitro studies show that oxidant-treated RPE cells undergo apoptosis, a possible mechanism by which RPE cells are lost during the early phase of ARMD.2
Dietary Phytochemicals, Minerals, and Macular Degeneration
At one time, researchers believed that all antioxidants served the same function. Now there is evidence that individual antioxidants may be used by the body for specific purposes. Lutein and zeaxanthin, naturally occurring fat-soluble antioxidant carotenoid biochemicals that are found in green leafy vegetables such as spinach, kale, collard greens, romaine lettuce, leeks, and peas, have been found to be helpful in preventing the progression of ARMD.
Lutein is the primary carotenoid in the retina of humans. Lutein in the retina acts to filter and shield harmful blue light from the eye and protect against ARMD. One study indicated that adults with the highest dietary intake of lutein had a 57% decreased risk of macular degeneration compared to those with the lowest intake. The roles played by zinc and copper also will be explored in this article.
Animal Studies
Research into the mechanisms underlying the development of ARMD has been limited by the lack of animal models for this disease. Studies have been done assessing the severity of macular drusen in elderly rhesus monkeys and comparing these findings to circulat-ing levels of select components of the free radical defense system and levels of thiobarbituric acid reactive substances (TBARS), the latter being a measure of lipid peroxidase activity. The monkeys with the most severe drusen were found to have alterations in the enzymes associated with copper and had higher plasma levels of TBARS. This research supports the concept that excessive oxidative lipid damage contributes to ARMD.3
The role of copper in the development of ARMD is not entirely clear. Copper is a promoter of angiogenesis, a process that appears to play a prominent role in ARMD.4 Studies have been undertaken utilizing agents that block copper to see if this can prevent the neovascularization prominent in some ARMD.5 In the neovascular form of ARMD, extensive studies are being undertaken to elucidate the growth factors underlying the progression of the disease.6 Several approaches are being developed in animal models to prevent ocular angio-genesis by blocking the key steps in the angiogenic cascade.7
As noted above, the xanthophyll carotenoids (lutein and zeaxanthin) are hypothesized to delay the progression of ARMD. An investigation on quail determined that diets enriched with zeaxanthin could alter zeaxanthin or lutein concentrations in the retina, serum, liver, and fat tissues. Xanthophyll profiles in quail mimic those in primates. Thus, the quail is a good animal model for further exploration of factors regulating delivery of dietary carotenoids to the retina.8
Genetic Factors
A number of specific genetic abnormalities recently have been described. The phenotype of a premature form of autosomal dominant macular degeneration has been characterized. This disease is manifested by a spectrum of retinal pigment epithelium (RPE) changes from mild to marked atrophy. Drusen-like deposits are present and subretinal neovascular membrane is an established complication. The locus for this disease has been found on chromosome 5.9
A study from the University of Michigan’s Kellogg Eye Center demonstrated a relationship between gene mutations on the X chromosome and MD. The mutation (Tyr141Cys) is a gene called RDS that causes an inherited eye disease that mimics MD. The suspicion is that some individuals with ARMD might also harbor the RDS mutation.10
A recent ground-breaking discovery confirms not only the association of genetic abnormalities of ARMD, but in a large family also confirmed the age-related penetrance of the disease.11
Human Studies
In an effort to explore the pathogenesis of ARMD to facilitate early detection and prevention, scientists in China studied the enzymes in red blood cells and levels of serum minerals and antiretinal antibodies in ARMD patents, and in controls, comparing electron microscopy and immunohistochemical surveys of the ARMD subretinal neovascular membrane. Their findings showed that the levels of superoxide dismutase and catalase as well as serum zinc were decreased in ARMD patients, and that the ratio of copper to zinc was increased.12
Oxidation of lipids, nucleic acids, or proteins has been suggested to be involved in the etiology of several chronic diseases including ARMD, and even aging in general. A large body of research has investigated the potential role of antioxidant nutrients in the prevention of chronic diseases.13 Among the supplements studied has been zinc because of its effect as a catalyst in multiple enzymatic processes. Extensive research as part of the Age-Related Eye Disease Study (AREDS) found no difference between the baseline dietary zinc intake of the general population as compared with the intake of those with AREDS.14
A study conducted in Alberta, Canada, reported significant reduction in the progression of certain categories of ARMD with the use of high-dose antioxidant and zinc supplementation. Recommendations were that people not taking in adequate amounts of beta-carotene, vitamins C and E, and zinc be counseled to better meet recommended dosages by using some combination of currently available over-the-counter supplements: ICAPS, TR, Ocuvite, and Vitalux, as well as Centrum multivitamins and individual supplements.15
On the other hand, a population-based cohort study in Australia found no association between baseline intake of antioxidant vitamins and zinc (apart from vitamin C) and the five-year incidence of early ARMD.16 Taken together, most of these studies suggest that although the baseline plasma levels of ARMD and normal patients may be identical, the ARMD patient, who is genetically or environmentally susceptible to the disease, is likely benefited in preventing further deterioration of ARMD by the use of antioxidant and mineral supplements, especially zinc.
One Dutch study found the prevalence of ARMD in patients with low antioxidant and lutein intake to be approximately twice as high as that in patients with high intakes.17 An Italian investigation found that a deficiency of antioxidants (vitamins C and E and carotenoids) seems to be associated with ARMD, particularly in the advanced form.18
The classic study that awakened interest in the possible contribution of nutrient deficiencies to this condition evaluated the relationships between dietary intake of carotenoids and vitamins A, C, and E and the risk of ARMD.19 At five ophthalmology centers in the United States a total of 356 subjects, ages 55-80 years, who were diagnosed with the advanced stage of ARMD within one year prior to their enrollment were studied. The 520 control subjects had other ocular diseases, and were frequency-matched to cases according to age and sex. The relative risk for ARMD was estimated according to dietary indicators of antioxidant status, controlling for smoking and other risk factors. Analysis found that higher dietary intake of carotenoids was associated with a lower risk for ARMD. Adjusting for other risk factors for ARMD, those in the highest quintile of carotenoid intake had a 43% lower risk for ARMD compared with those in the lowest quintile.
Among the specific carotenoids, lutein and zeaxanthin, which are primarily obtained from dark green, leafy vegetables, were most strongly associated with a reduced risk for ARMD. Several food items rich in carotenoids were inversely associated with ARMD. In particular, a higher frequency of intake of spinach or collard greens was associated with a substantially lower risk for ARMD. The intake of preformed vitamin A (retinol) was not appreciably related to ARMD. Neither vitamin E nor total vitamin C consumption was associated with a statistically significant reduced risk for ARMD, although a trend toward a lower risk for ARMD was identified among those with higher intakes of vitamin C, particularly from foods.
Inverse associations have been reported between the incidence of advanced, neovascular ARMD, the combined intake of dietary lutein and zeaxanthin, and lutein and zeaxanthin concentration in the blood serum. Research data suggest that people with high levels of lutein and zeaxanthin in either the diet or serum would likely have, in addition, relatively high densities of these carotenoids in the macula (the central area of the retina), the so-called "macular pigment." Several lines of evidence point to a potential protective effect by the macular pigment against ARMD.20
One study examined the relationship between dietary intake of lutein and zeaxanthin using a food-frequency questionnaire, concentration of lutein and zeaxanthin in the serum, and macular pigment optical density. The researchers also analyzed the serum and retinas from 23 tissue donors in order to obtain the concentration of lutein and zeaxanthin in these tissues. The results reveal positive, albeit weak, associations between dietary intake of lutein and zeaxanthin and serum concentrations of lutein and zeaxanthin, and between serum concentrations of lutein and zeaxanthin and macular pigment density. The authors estimated that approximately one-half of the variability in the subjects’ serum concentration of lutein and zeaxanthin can be explained by their dietary intake of lutein and zeaxanthin, and about one-third of the variability in their macular pigment density can be attributed to their serum concentrations of lutein and zeaxanthin. These results, together with the reported associations between risk of ARMD and dietary and serum lutein and zeaxanthin, support the hypothesis that low concentrations of macular pigment may be associated with an increased risk of ARMD.20
A Japanese study evaluated the relationship between fatty acids and ARMD. Findings indicate that polyunsaturated fatty acids, vulnerable to free radicals and reactive oxygen species and easily peroxidized, may be related to ARMD induction.21
Another study assessed whether dietary intake of fat or fish is associated with age-related maculopathy (ARM) prevalence.22 People (n = 3,654) ages 49 years or older with ARM were identified from masked grading of retinal photographs. A self-administered, semi-quantitative food-frequency questionnaire was completed adequately by 88.8% of participants and used to assess dietary intakes of fat and fish. A higher frequency of fish consumption was associated with decreased risk of late ARM. Subjects with higher energy-adjusted intakes of cholesterol were significantly more likely to have late ARM. Thus, the amount and type of dietary fat intake may be associated with ARM.
Yet another study used a large cross-sectional survey to evaluate the association between dietary fat and ARMD, and found that ARMD was not significantly associated with dietary fat.23
Mechanism of Action
The RPE is a monolayer of cuboidal cells that is strategically placed between the rod and cone photoreceptors and the vascular bed of the choriocapillaris. The RPE has many important functions, including phagocytic uptake and breakdown of the sloughed photoreceptor membranes. The RPE also is responsible for the uptake, processing, transport, and release of vitamin A (retinol), and setting up the ion gradients within the interphotoreceptor matrix. In addition, the RPE acts as the blood-retina barrier and provides all transport of substances from blood to the retina and vice versa. The RPE contains pigment granules that seem to be involved in many important functions, such as protection from oxidative stress, detoxification of peroxides, and binding of zinc and drugs.
Recent research shows that melanin granules are connected to the lysosomal degradation pathway. Deficiency of melanin pigment is associated with ARMD.24 Studies have tested the hypothesis that neovascular-related ARMD is directly associated with oxidative stress involving the macular RPE. In one study, whole surgically removed eyes were studied with a variety of techniques including electron microscopy, immunological studies, and quantitation of enzymes thought to protect from oxidative stress. The authors found that copper and zinc superoxide dismutase immunoreactivity (an immunological measurement of enzyme activity) increased and catalase decreased with age in the cytoplasm and lysosomes from both macular RPE of normal eyes and eyes with ARMD. Both heme oxygenase-1 (HOG1) and heme oxygenase-2 (HOG2) had a highly significant greater immunoreactivity in the RPE cell lysosomes that decreased with age, especially in patients with RPE. The authors concluded that the high HOG1 and HOG2 lysosomal enzyme antigen levels in macular RPE cells of eyes with neovascular ARMD represented an upregulation of these enzymes in response to oxidative stress, and that the protective mechanism of enzymatic upregulation diminished with age. The much higher HOG1 and HOG2 levels in macular RPE cells from younger individuals confirm that the protective mechanisms against oxidation, and consequentially the development of ARMD, decreases with age.25
As briefly mentioned above, the body responds to oxidative damage by producing new blood vessels (neovascularization) under the effect of vascular endothelial growth factor (VEGF), leading to further damage. There are studies currently under way evaluating anti-VEGF substances (antibodies and oligonucleotides) in the prevention of the neovascular damage.26
All of these studies emphasize the importance of optimizing antioxidant protection during the process of aging well before the onset of neovascularization.
Conclusion
The impact of positive dietary changes has profound consequences for optimizing health and well being for the mature years. It appears that increasing the consumption of foods rich in certain carotenoids, in particular dark green, leafy vegetables, may decrease the risk of developing advanced or exudative ARMD, the most visually disabling form of macular degeneration among older people. The role of the antioxidants lutein and zeaxanthin (as well as vitamins A, C, and E) in the prevention of ARMD support the almost universal dietary guideline to maximize intake of fruits and vegetables. Future dietary guidelines for the elderly need to take into account protective food patterns, rather than target specific foods.27 Presently, there is little chance of reversing ARMD, but recent advances in the areas of early detection and nutritional intervention, including proprietary supplements containing zinc (see Table 2 for food sources of zinc), may slow the progression of ARMD.
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Dietary Recommendations
Recent studies indicate that preventive measures and dietary changes implemented early in life can reduce an individual’s risk of ARMD (see Table 3). There is ample epidemiological evidence that the amount of macular pigment is inversely associated with the incidence of ARMD. Macular pigment can be increased in primates by either increasing the intake of foods that are rich in lutein and zeaxanthin, such as dark green leafy vegetables, or by supplementation with lutein or zeaxanthin.28
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Structural and clinical studies have shown that these carotenoids are concentrated in the retinal macular pigment and that such accumulation is dependent on dietary intake. Consumption of dark green leafy vegetables has been shown in clinical studies to reduce the risk of ARMD.
Studies indicate that the density of the macular pigment is related to preservation of visual sensitivity and (possibly) protection from ARMD.29 While lifestyle modifications such as smoking cessation, reduction of alcohol consumption, and the wearing of sunglasses may reduce the risk of ARMD, it is likely that consumption of specific dietary components (i.e., fruits and vegetables) can reduce the risk further.
Dr. Keegan is Director, Holistic Nursing Consultants, Port Angeles, WA.
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Keegan L. Age-related macular degeneration and nutrition. Altern Med Alert 2004;7(2):16-21.
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