Current Opinion in Ophthalmology:Volume 19(1)January 2008p 66-70
Nutrition and the prevention of cataracts
[Cataract surgery and lens implantation: Edited by Mark Packer, Drs Fine, Hoffman & Packer]
Fernandez, Mark M; Afshari, Natalie A
Duke University Eye Center, Durham, North Carolina, USA
Correspondence to Dr Natalie Afshari, MD, Duke University Eye Center, DUMC Box 3802, Durham, NC 27710, USA Tel: +1 919 684 3799; fax: +1 919 681 7661; e-mail: natalie.afshari@duke.edu
Purpose of review: Oxidative stress is a major cause of cataract development. Numerous studies have been published regarding the effects of nutritional supplementation on cataract progression.
Recent findings: Basic science research has demonstrated a protective effect of antioxidants on lens tissue, and supplementation with vitamin C and lutein/zeaxanthin has been associated with a decreased risk of cataract formation in multiple observational studies. One large interventional trial demonstrated a significant difference in participants treated with high-dose vitamin C versus placebo, but a more recent interventional study did not replicate these findings. In a review of the carotenoids lutein and zeaxanthin, the Food and Drug Administration concluded there is insufficient evidence to suggest that supplementation with these carotenoids lowers the risk of cataract formation. While high doses of multivitamins, antioxidants, or lutein and zeaxanthin are unlikely to be of significant ophthalmic benefit to the general public, these nutrients may help individuals exposed to high oxidative stress, such as heavy smokers, and those with poor nutrition.
Summary: Supplementation with vitamin C, lutein, zeaxanthin, or a multivitamin may help certain populations, but is unlikely to affect the progression of cataracts in most patients.
Cataracts are the leading cause of blindness in the world [1], responsible for 48% of blindness worldwide [2,3•]. Cataract-related care is a significant public health burden in the United States, as it constitutes the largest Medicare expenditure among ophthalmic conditions [4]. Although phacoemulsification with intraocular lens placement is a well refined procedure that offers excellent refractive outcomes in developed countries, good surgical outcomes and access to care are limited for people of lower socioeconomic status and in parts of the developing world, where 90% of cataract blindness occurs [3•,5]. The ability to delay cataract extraction by 10 years has been estimated to lower the total number of procedures necessary by 50% [6], significantly lowering medical expenditures for this disease. The past several years have seen multiple basic science and epidemiological studies seeking to correlate dietary intake of micronutrients and macronutrients with the risk of cataract formation.
The human lens has approximately 1.6 million lens fiber cells at birth, which increases to 3 million by age 20 and to 3.5 million by age 80. Lens fiber cells have a very high protein concentration in order to enable transparency, and there is no protein turnover. The proteins at the center of the lens are those that were created during embryogenesis [7]. This absence of protein recycling means that processes causing opacity are very difficult, if at all possible, to reverse.
Multiple forms of cataracts exist and the pathophysiology of cataract formation is not completely understood, but a putative cause for age-related nuclear cataracts is oxidative stress [8]. By weight, the protein content of the adult lens is approximately 35%; the nucleus itself is 50% protein. One lens protein of particular interest is α-crystallin, which comprises the majority of the lens protein. α-Crystallin is a small chaperone protein that binds selectively to misfolded proteins to prevent them from aggregation, thus helping to maintain the optical clarity of the lens. The concentration of this protein decreases significantly with age, and the activity of existing α-crystallins themselves may also decrease [7].
The lens also contains a high concentration of glutathione compared with other tissues, and glutathione is considered the first line of defense against reactive oxygen species. When antioxidant concentrations are inadequate and the redox balance in the lens is shifted toward a state of oxidation, sulfhydryl groups are oxidized, resulting in protein cross-linking and lipid peroxidation. Protein aggregates form within the lens, and these theoretically begin to scatter light when they become larger then 5 × 107 Da [8]. Indeed, the worsening of age-related nuclear cataracts is correlated with a dramatic decrease in the concentration of glutathione in the lens [9].
Many basic science studies have explored the role of antioxidants in lens health.
Small molecules that aid in the defense against reactive oxygen species include vitamin C, vitamin E, and the carotenoids. Enzymatic sources within the lens include glutathione peroxidase, superoxide dismutase, and catalase [8]. Early animal studies linked deficiencies of vitamin E with cataract formation in juvenile rabbits [10], as well as with accelerated cataract progression in the setting of vitamin C deficiency in guinea pigs exposed to UVB light [11]. Subsequently, investigators seeking an experimental model for nuclear cataracts found that incubating lens tissue with peroxide results in protein changes similar to those seen in cataractous lenses [12]. More recent studies [13] have revealed that overexpression of superoxide dismutase (via incubation with a plasmid vector) prevents cataract formation in rat lenses exposed to this peroxide model of cataractogenesis.
A number of animal studies have recently further correlated the use of antioxidants with decreased cataract progression. Bayer et al. [14] reported that supplementation with hazelnut prevented the formation of cataracts in rats treated with doxorubicin. Doxorubicin is a chemotherapeutic agent that uses oxidative stress to destroy cancer cells, so supplementation with hazelnuts could also lower the therapeutic effect of this drug. Regardless, the report highlights the capacity of antioxidants such as this one to protect against cataracts.
Kumar et al. [15] reported a decrease in the chaperone function of α-crystallin when rats were made chronically hyperglycemic, and they further reported that this decrease in chaperone function could be avoided by supplementation with curcumin (turmeric). Curcumin-supplemented animals did not develop cataracts. Curcumin also has antioxidant properties, and therefore it was proposed that curcumin modulates α-crystallin by decreasing oxidative stress in the setting of hyperglycemia [15].
Other nutrients of interest are the xanthophylls lutein and zeaxanthin. Lutein, like its stereo isomer zeaxanthin, is believed to act primarily as a filter of blue light [16], but is also a free radical scavenger because of the presence of an easily oxidizable hydroxyl group [17]. These combined effects of lutein have been found to significantly decrease UVB-induced peroxidation in human lens epithelial cells [18]. Lutein and zeaxanthin are also the only carotenoids that occur naturally in the lens and macula [19]. Dietary lutein is present in dark, leafy vegetables such as spinach and kale as well as yellow-colored foods like corn and egg yolks [20]. A recent study in quail [21] suggests that lens concentrations of lutein and zeaxanthin can be modulated by dietary supplementation in carotenoid-deficient vertebrates; however, the study did not report on the incidence of cataract in these animals.
Interestingly, the key to delaying the onset of cataracts may not be in dietary supplementation but in dietary restriction. In a small study of calorically restricted rats, Wang et al. [22] noted a lower incidence of protein aggregation in the lenses of older animals with diets that were nutritionally complete but with 40% fewer calories than rats fed ad libitum. Lenses from the calorically restricted rats were also less susceptible to oxidative damage in vitro. Miller et al. [23] found that mice fed diets restricted in the amino acid methionine had longer lifespans with significantly fewer lens opacities than control mice.
Clinical trials have also correlated nutrition intake with the appearance of cataracts.
Early animal studies indicated that dietary deficiencies of antioxidants like vitamin C and vitamin E, as well as amino acids including tryptophan and histidine, resulted in cataract formation [24]. These indications prompted multiple large epidemiological studies seeking to correlate intake of vitamins, specifically antioxidants, with the onset of cataracts. An early report with promising results was the Linxian cataract study [25] - a randomized, double-masked trial of multiple supplement combinations in 2141 nutritionally deprived residents of two communes in Linxian, China. The trial included a daily multivitamin or four different daily vitamin/mineral combinations, which included retinol/zinc, riboflavin/niacin, ascorbic acid/molybdenum, and selenium/α-tocopherol/β-carotene. Participants aged 65-74 treated with a daily multivitamin for approximately 6 years enjoyed a 36% reduction in the prevalence of nuclear cataracts. The multivitamin contained 26 vitamins and minerals, including 180 mg ascorbic acid, 40 mg niacin, and 60 IU α-tocopherol but no lutein or zeaxanthin. Daily riboflavin (3 mg) and niacin (40 mg) also appeared to have a significant protective effect for nuclear cataracts but increased the risk for posterior subcapsular cataracts [25]. The other vitamin/mineral combinations did not significantly improve clinical outcomes. More recent results from the observational Age Related Eye Disease Study [26] also indicated that taking a daily multivitamin (Centrum) had a protective effect against nuclear opacities. Data mined from the Beaver Dam Eye Study cohort [27] suggested a 60% lower 5-year risk of nuclear and cortical cataracts in participants who reported the use of multivitamins or any supplement containing vitamin C or vitamin E for 10 years. One interventional study also produced somewhat promising results. The Roche European-American Cataract Trial [28] was a randomized, double-blind, placebo-controlled study wherein 158 participants from the United States and the United Kingdom were given a daily multivitamin for 3 years. There was a small but statistically significant decrease in cataract progression in the US participants, but not in the UK participants [28].
These studies may simply indicate that a good general nutritional status lowers the risk of cataract. Interestingly, Moeller et al. [29] reported that participants in the Nurses Health Study who adhered to the Dietary Guidelines for Americans and had diets rich in fruits and vegetables also had a lower prevalence of nuclear opacities.
Another finding of interest was reported by Taylor et al. from data collected in the Nurses Health Study's Nutrition and Vision Project [30]. Results from this prospective, observational study indicated that vitamin C intake at or above 362 mg/day for 10 years or longer in women below the age of 60 was associated with a 57% lower incidence of nuclear cataracts. Similar observational results were reported by Chesan-Taber et al. [31], who correlated 10 years or more of vitamin C supplementation with a 28% lower incidence of cataract extraction in women. This agreed with the 2005 report by Ferrigno et al. [32], of the Italian-American Clinical Trial of Nutrition Supplements, that higher plasma levels of vitamin C were associated with a lower prevalence of nuclear and posterior subcapsular cataracts. The National Health and Nutrition Examination Survey II [33] (another observational study) also correlated a 1-mg/dl increase in plasma ascorbate with a 26% decreased risk of cataracts in older (62-70 years old) Americans.
Unfortunately, many studies of selective supplementation with high-dose antioxidants such as vitamin C have not shown a significant protective effect against cataracts. The Age Related Eye Disease Study trial [34], which did find a beneficial effect in participants using multivitamins, found no significant benefit in participants using high doses of vitamin C, vitamin E, or β-carotene in a large, relatively well nourished, older cohort. The Blue Mountains Eye Study [35] also found no association between vitamin C intake and cataracts, and the Beaver Dam Eye Study [36] only found an inverse correlation between vitamin C intake and cataracts for participants who were hypertensive or were heavy smokers.
The majority of trials reporting an inverse correlation between high antioxidant intake and cataract progression were observational studies [37,38••]. The Linxian study [25] remains the only randomized control trial that reported a significant correlation, and these results were not replicated in the more recent Antioxidants in Prevention of Cataract study [39] - a 5-year randomized control trial of vitamin A, vitamin C, vitamin E and β-carotene in residents of South India. The results of these studies indicate that supplementation with vitamin C and/or other antioxidants for many years may provide some benefit to individuals suffering from nutritional deficiencies or whose systems are exposed to high oxidative stress and have compromised antioxidant activity, like heavy smokers [40]. It may also be of benefit to use a daily multivitamin, but this appears to be helpful only if it is continued for many years and is initiated at a younger age. There is not, however, strong enough evidence to warrant high-dose antioxidant supplementation in the general population.
Two encouraging reports regarding xanthophylls and cataracts have recently been published. Vu et al. [41], of the Melbourne Visual Impairment project - an observational study of over 3000 residents of Melbourne over the age of 40 - reported an inverse correlation between high lutein and zeaxanthin intake and the risk of nuclear cataracts. Delcort et al. [42] noted a 75% lower risk of nuclear cataracts among individuals with high plasma zeaxanthin in a prospective study of 899 residents of southern France. There was not a significant association for plasma levels of lutein in this study. These results are in agreement with a small double-blind interventional study [43] of patients supplemented for 2 years with thrice-weekly lutein (15 mg), α-tocopherol (100 mg), or a placebo. Participants given lutein supplements displayed better visual acuity and had serum lutein levels approximating that of individuals with diets rich in dark, leafy greens, although there was no comment on the appearance of lens opacities [43].
These results echo those of earlier studies. In the Beaver Dam Study [36], participants in the highest quintile of lutein intake had significantly fewer cataracts than those in the lowest quintile. The authors also noted that the association was stronger for lutein intake in the distant past - an association not found for α-carotene or β-carotene. Women in the Nurses Health Study [30,44] with the highest intake of lutein and zeaxanthine also had a 22% lower risk of cataracts needing extraction when compared with those with the lowest intake. The Male Health Professionals trial [45] also reported that those with the highest lutein/zeaxanthin intake had a risk ratio for cataracts of 0.81 compared with those with the lowest intake.
Enthusiasm should be tempered, however, as there is not yet sufficient evidence to recommend regular lutein/zeaxanthine supplementation [46]. Serum levels of lutein above 1.05 μmol/l have been associated with carotenodermia [47], so supplementation should be in moderation. Furthermore, the US Food and Drug Administration recently conducted an exhaustive review of the interventional and observational studies published regarding lutein and cataracts, concluding that there is no credible scientific evidence that these xanthophylls lower the risk of cataract or slow their progression [48••]. The Food and Drug Administration review noted that observational studies suffer from recall bias, and that estimates of lutein intake were made that may have been inaccurate because of variation in food preparation techniques, participant recall errors, and the presence of other nutrients in the foods consumed. The observational studies examined also revealed a poor association between lutein intake and plasma concentrations of the nutrient [48••]. An association between lutein/zeaxanthine and cataracts may exist, but this has not been adequately proven.
Cataracts constitute an immense public health burden, and it would be very useful to identify dietary supplements that could delay the onset of this disease. Most research to date has focused on high-dose antioxidant supplementation, as oxidative stress is the most probable cause of vision-impairing damage to the lens. Many of these nutrients have been shown to protect the lens from oxidative damage in in-vitro models of cataractogenesis, and vitamin C as well as lutein and zeaxanthin have been correlated with decreased risk of cataract in vitro in a number of observational studies. These benefits appear to be most significant for participants who maintain a high intake of each nutrient for a number of years earlier in life. Patients exposed to excessive oxidative stress, like heavy smokers, may enjoy a more significant benefit. The results are inconsistent, however, and there is a lack of interventional data supporting the use of nutrient supplementation to prevent cataracts. Many studies have also associated multivitamins and a healthy diet with reduced risk of cataracts, and more interventional studies in the future could strengthen this association. Perhaps more important than supplementation is dietary discretion, as a few studies have correlated increased body mass index and waist-to-hip ratio with an increased risk of incident cataracts [49]. Nutritional supplementation is clearly not a quick fix for cataracts, but maintaining a healthy lifestyle with a diet rich in fruits and vegetables may be the best nutritional advice we can give to patients wishing to delay the onset of this disease.
N.A.A. receives a grant from Research to Prevent Blindness.
Papers of particular interest, published within the annual period of review, have been highlighted as: TOP
• of special interest TOP
•• of outstanding interestTOP
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 75). TOP
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Keywords:
antioxidant; cataract; lutein; multivitamin; nutrition; xanthophyll