Associations between Nutrition and Cataract

Associations between Nutrition and Cataract

Allen Taylor, Ph.D.

Blindness due to opacification of the lens, or cataract, afflicts 50 million persons worldwide, In the United States over 541,000 cataract extractions are done annually at a cost of over $3.8 billion. Conservative estimates indicate that the prevalences of cataracts in Americans aged 65- 75 and 75-85 years are 18% and 46%, respectively. Cataracts are even more prevalent in some other populations. It is estimated that the need for cataract extractions would be diminished by half if onset of cataract could be delayed by only ten years. Hypotheses regarding the etiology of cataract include oxidative perturbations of protein metabolism, diverse pathologic conditions, and perhaps glycation of lens proteins. Epidemiologic data indicate that elevated plasma levels of specific nutrients (i.e., carotenoids, ascorbate, tocopherol, and taurine) are associated with diminished incidence of certain types of cataract. Biochemical evidence suggests that each of these compounds can delay photooxidative damage to lens proteins. Roles in lens metabolism for selenium and tryptophan have been suggested. Elucidation of mechanisms by which caloric restriction delays cataract development is a promising area of current research.

Key Words: ascorbic acid, vitamin C, vitamin E , carotenoids, cataracts, nutrition, antioxidants, diabetes, aging

The ocular lens is the only transparent organ in the body (Figures 1 and 2). It must remain so in order to focus light on the ret- ina. Approximately 35% of the lens is protein, and 63% is water. In contrast to the rapid rate of protein turnover in many organs, the proteins in the lens exist in situ for decades. Exposure to light, oxygen, and products of normal aging; pathology; and adverse environmental conditions’ subject the proteins of the lens to myriad and extensive postsynthetic modification^.^-^ These include (photo)oxidation, racemiza- tion, glycosylation, and/or glycation (non- enzymatic glycosylation), aggregation, and eventual polymerization and precipitation to form opacities, or senile cataracts (Fig-

Dr. Taylor is Director of the Laboratory for Nu- trition and Cataract Research at the USDA Human Nutrition Research Center on Aging at Tufts University, 71 1 Washington Street, Boston, MA 02111.

ure 3 ) . * s 3 The term “senile cataract” is used to distinguish this major form of cataract, which affects the elderly, from cataract induced by trauma or associated with diabetes mellitus. Despite differences in no- menclature, the various forms of cataract share some similarities in biochemistry, pathology, and impact on vision.

Approximately 50 million persons in the

dmrrr l er. Figure 1. The eye. The lens is an avascular tissue that derives its nutriture primarily from the aqueous humor.

NUTRITION REVlEWSlVOL 47, NO WAUGUST 1989 225

Figure 2. Picture of a clear lens.

world are blind from cataracts, and more 52-64, 65-74, and 75-85 years, respec- than 541,000 cataract extractions are per- tively.6 If early lens changes are also in- formed annually in the United States5 The cluded in the calculation, the prevalence of Framingham Eye Study found that the cataract is twice as high.6 The annual costs prevalences of senile cataract were 4.5%, for these extractions and associated physi- l8%, and 45.9% among persons aged cian visits are over $3.5 billion.’

Normal image Image with central opacification

Figure 3. left: View through a clear lens. Note that the image is crisp. right: View through aged and cataractous lens. The image is partially obscured, and the background is darkened, indicating age-related browning of the lens.

226 NUTRITION REVIEWSlVOL 47, NO BIAUGUST 1989

However, it has been estimated that if cataracts could be delayed by only ten years, the need for lens extractions could be diminished by half.5 In addition to considerable savings on healthcare, delay in the onset of cataract would lead to gains in productivity and enhancement in the life quality of our elderly. Laboratory experi- mentation suggests that this goal may be achieved. In this review of results of current research on the relationship between nutrition and development of cataracts, particu- lar emphasis will be placed on correlations gleaned from epidemiologic studies that are supported by laboratory experimenta- tion. Readers are referred to other re- viewsB-l0 for topics that can be considered only superficially here.

Hypotheses Regarding Cataract Formation Some epidemiologic studies have indi-

cated a higher prevalence of certain types of cataract in persons who live in the tropics as compared with those living in more temperate climates; the difference may be due to greater exposure to sunlight in the tropics.11a12 An injurious role of excess light was corroborated by experiments showing the formation of cataract- like protein aggregates in lens preparations exposed to light with a high ultraviolet component similar to that of sunlight.13-15 Thus, it would appear that light is a photooxidative cataractogenic insult, and that protection of eyes against exposure to in- tense light or protection of lens constitu- ents with antioxidants might be useful. It should be noted, however, that the light- exposure hypothesis has not received uni- versal acceptance. Hardingl relegated the increased incidence in the tropical populations to bouts with dehydration and diar- rhea.

Whether or not light is involved, a pleth- ora of analytical and experimental da- ta3,l4-l6 leave little doubt that oxidation of lens proteins is highly correlated with cata- r a ~ t . ~ . ~ This relationship is not unexpected, since high-energy oxygen species are gen- erated in the lens, and activities of antioxidant enzymes are diminished, particularly

in the oldest lens tissue (Figure 4). This diminished anti oxidant capabi I ity leaves the long-lived proteins and other constitu- ents vulnerable. Evidence to support a role for oxidation includes the following observations. 1) Nuclear cataract was observed in patients who underwent hyperbaric oxygen therapy.” 2) There were markedly enhanced rates of mature cataract in mice that survived exposure to 100% oxygen twice weekly for 3 h.18 3) A higher incidence of cataract development was noted in hyperbaric oxygen-treated lenses in vitro.19 In this work19 the decline in glutathione and increase in glutathione disulfide- changes normally related to aging or cataract formation-were also observed. 4) Proteins in the aged and cataractous lens are extensively o x i d i ~ e d . ~ , ~ 5) The industrial antioxidant 0.4% butylated hydroxytoluene depressed formation of cataracts, which were induced by feeding rats 50% galactose.20

Almost immediately upon the discovery that nutrients might be antioxidants, the search was begun for antioxidants in the lens.21-22 However, only recently have epidemiologic studies been of sufficient scale to suggest correlations between systemic antioxidant status and incidence of cataract .23,24

Individual Nutrients and Cataract

Carotenoids In persons without extensive nuclear cat-

aract, Jacques et al.24 found that elevated levels of carotenoids in plasma were strongly correlated with lower incidence of cataract. Carotenoids, i.e., p-carotene, are good free-radical traps in tissues such as lens that have low partial pressures of oxy- g e r ~ . * ~ Thus, serum levels of >1.7 pmol of carotenoids/L seemed to afford some protection against most forms of cataract. However, a serum level of 3.3 pmol/L did not offer significantly greater protection. Given that p-carotene levels were most highly correlated with the delay of cataract, it would appear that future effort should pursue the utility of this nutrient.

NUTRITION RNlEWSlVOL 47, NO 8IAUGUST 1989 227

Figure 4. Anatomy of the lens, which can be divided into three developmental zones. The outer epithelial cells are the most recently elaborated and contain organelles and an active protein synthetic capacity but do not produce substantial amounts of the major lens gene products, or crystallins. These cells differentiate to form the middle layer or cortex. Cells in the outer cortex also contain nuclei and active synthetic capabilities; however, in contrast with the epithelium, crystallins comprise the majority of the cellular proteins. In the mature lens, crystallins account for -98% of the dry mass. Cells in the lens nucleus do not contain organelles. They are synthetically quiescent, light-transmitting fibers. Thus, any changes that occur to the proteins in the inner cortex and nucleus must be due to age-related postsynthetic events.

Ascorbic Acid Most research aimed at identification of

antioxidant nutrients or systems that might affect protein stability in the lens has con- centrated on ascorbate, tocopherol, and glutathione. These three antioxidants appear to work in concert with each other.26-29 It is plausible that the sparing effect on serum tocopherol caused by elevated serum ascorbate might also exist in the l e n ~ . ’ ~ , ~ ’

Ascorbic acid is probably one of the most effective, least toxic antioxidants identified in mammalian systems to date.30-37 Interest in the function of ascorbate in the lens was prompted by teleologic arguments based on the observation that ascorbate concentrations in the lens can be as much as 30 times those in plasma (particularly in diur- nal and that in the aged and cataractous human lens ascorbate concentrations are lower than in normal lenses.36 This is particularly true in the oldest part or nucleus of the lens, where the concentration of ascorbate is 25% of that in

the cortex and where most senile cataracts originate.% A critical role for ascorbate in maintaining the clarity of the lens was suggested in early experiments indicating that guinea pigs reared on ascorbate-deficient diets showed earlier cataract develop- ~ n e n t . ~ ~ From a nutritional vantage point, work reported in much of the earlier literature lacks much methodologic rigor. None- theless, important lessons and possibilities for future research were indicated. Signifi- cant, cell-free experiments were performed to corroborate the circumstantial and teleologic arguments. Many of these showed protective effects of ascorbate, particularly when physiologic conditions were ap- p ro ac h ed. 1 4 p 1 5,28 T h u s, as co r ba t e was shown to have protective effects against ultraviolet light damage to lens proteins, pro- teases, lipids, and the Na+/K+ p ~ r n p . ’ ~ , ~ ~

Recent epidemiologic investigations also corroborate the protective effect of ascorbate, particularly in subcapsular cataracts, and several studies in progress are at-

228 NUTRITION REVIEWSIVOL 47. NO 8IAUGUST 1989

tempting to determine the dietary level of this nutrient that offers maximal protection in delaying the onset or progress of cataract. The data provided by Jacques et suggest that when compared with persons with 40 pmol of ascorbate/L of plasma, those with 90 pmol of ascorbate/L of plasma have less chance of developing ad- vanced cataract. This observation was statistically significant, however, only for subcapsular cataract. From the work of Jacob et a1.,26 it would appear that in order to achieve this level of plasma ascorbate, in- gesting pharmacologic doses ( X O O mg of ascorbate per day) may be necessary. These observations are consistent with the suggestion of Garry et al.40 that the recommended dietary allowance (RDA) of ascorbate should be increased; the authors are at odds, however, with Olson’s41 opinion that such elevated doses of ascorbate do not increase the body pool to levels that enhance health.

Other doubts regarding the use of ascorbate to delay cataract were suggested from observations that 1) scorbutics are not known to get cataracts; 2) when combined with iron and oxygen in vitro, ascorbate can participate in oxidative reactions; and 3) elevated concentrations of ascorbate, which is itself a carbohydrate, can cause glycation of proteins.28

Although the utility of a high intake of ascorbate remains to be established, some of these concerns can be addressed. First, most scorbutics do not live long enough to get cataracts, but scorbutic guinea pigs that did live long enough did show an increased incidence of cataract.39 Second, our recent studies showed no differences in sodium dodecyl sulfate-polyacrylamide gel electrophoresis protein profiles of lenses from animals fed three times the sat- urating dose of ascorbate as compared with animals fed marginal amounts (only 4% of the high level) of ascorbate. An absence of protein modification was also established in mice maintained on 8.3% a s c ~ r b a t e . ~ ~ If glycation were significant in our experiment^,'^ it probably would have been detected in lenses of animals fed

such high levels of ascorbate. The data also suggest that metal levels in lens are too low to be a factor in generation of oxidized ascorbate under physiologic conditions. Apparently, only when glutathione or other substances that can reduce dehydroascorbate to ascorbate are depleted can ascorbate become a glycating re- agent.21r28 Indeed, dehydroascorbate levels in the lens are less than 5% of the ascorbate leve1.22~34.35~43

Aging may result in slightly lower concentrations of ascorbate in the lens,35 pre- sumably in both genders. It appears that mean plasma ascorbate levels are slightly higher in women than in men26,40 and higher in leaner and nonsmoking persons than in heavier persons or smokers. Per- haps future studies will determine relationships between cataract, dietary or lens ascorbate content, body mass, and smok- ing.

Tocopherol Whereas ascorbate is water-soluble, to-

copherol is lipid-soluble and is thought to be one of the best lipid-soluble antioxidants. As noted earlier, in some systems tocopherol functions as long as there is sufficient ascorbate present to keep it in a reduced state.29 Like other cells, lens cells have lipid-containing cell membranes, and the integrity of such membranes must be preserved to maintain function. Accord- ingly, research has sought to determine whether vitamin E could delay a variety of biochemical dysfunctions in lens cells and frank cataract in a few animal models. In humans, enhanced levels of tocopherol in the diet were associated with delayed progress of certain forms of senile cataracts, but the relationship was not of a level of statistical significance that would permit identification of vitamin E, as opposed to the triad of vitamins C and E and carotenoids, as the protective

Associations regarding the beneficial aspects of vitamin E were also investigated in various biochemical and in-vivo animal experiments. Using cultured lenses, Varma15 and Trevithick et al.44-45 noted that

NUTRfTlON REVIEWSIVOL 47. NO BIAUGUST 1989 229

M tocopherol prevented 1) an increase in lipid oxidation products caused by light exposure, and 2) sugar-induced os- motic cataract in vitro, respectively. How- ever, when a diet containing 50% galactose was fed to rats, a dietary supplement of 5 g of vitamin E/kg of diet (about 100 times the usual level) failed to prevent the appear- ance of dense nuclear opacities.46 Similar results were obtained by Libondi et al.47 in their attempts to alleviate galactose-induced cataract and the usually observed decrease in nonprotein sulfhydryl groups in the cataractous lenses in rats.47 In contrast, vitamin E appeared to reduce lens damage in rabbits treated with the oxidant am i notriazol .48

Thus, vitamin E may be useful in delaying a number of cataract-like insults. However, epidemiologic investigations to date have been unable to ascertain statistically significant relationships that independently es- tablish the utility of this vitamin as an anticataract nutrient.

Sulfhydryl-Containing Compounds Glutathione (gamma glutamylcysteinyl-

glycine) acts on a variety of biomolecules to maintain them in a reduced state. It can act as an antioxidant directly by maintaining the reduced state of protein sulfhydryl groups, or it can act indirectly by nonenzy- matic reduction of dehydroascorbate to ascorbate. The young lens is equipped with levels of enzymes sufficient to regenerate glutathione from oxidized glutathione and to synthesize glutathione de novo. Glutathi- one has clearly been implicated in antioxidant defense mechanisms in the lens, and its value is corroborated by the observation that the glutathione levels are lower in lens nucleus (oldest tissue) and in cataracts than in normal lens. However, the absence of a correlation between glutathione nutriture and the concentration of glutathione in lens suggests that a significant amount of fundamental work will have to be done before the utility of dietary glutathione can be considered further. Nevertheless, a number of sulfhydryl-containing agents, in-

cluding glutathione, are being investigated for their anticataractogenic potential.49

Taurine Highly associated with the delay of cata-

ract formation are elevated plasma levels of the nonessential amino acid taurine (P. Jacques, personal communication). Tau- rine is one of the major (-0.5 mM) free amino acids in the lens.1° It appears to be synthesized there and to be transported into the lens by a taurine-specific trans- porter. Whereas dietary insufficiency and retinal dysfunction in primates, including humans, have been noted,50 literature regarding the function of taurine in the lens is scanty at best. The few reports available indicate that a dearth of dietary cysteine or methionine, both precursors of taurine, result in taurine insufficiency. Since taurine appears to have antioxidant and anticataract capabilities, studies of its biologic ac- tion in the lens could be productive.

Selenium Selenium is an integral part of the en-

zyme glutathione peroxidase, which de- stroys peroxides derived from fatty acids. Both excess and deficiency of selenium have been associated with pathologic states. Excess selenium causes cataract in rats,6 and Jacques et al.24 noted that of the minerals tested (zinc, selenium, calcium, and magnesium), only selenium at elevated concentrations (>1.27 pmol/L) was associated with a significantly increased incidence of cataract in humans. Elevated levels of calcium are found in cataractous lens, but it appears that the elevation of lens calcium is subsequent to cataract formation.6 Assuming the importance of the selen i um-dependen t gl utath ione peroxidase, populations with low and high in- takes of selenium were tested for glutathione peroxidase activity in blood.51 Average glutathione peroxidase activity was lower in the group whose blood selenium level was 0.76 pmol/L than in persons with a level of >2.6 pmol/L. Since there was no further increase in glutathione peroxidase activity in persons who had >2.6 pmol of

230 NUTRITION REVIEWSIVOL 47, NO 8IAUGUST 1989

selenium/L of blood, a saturation model with respect to blood selenium level and glutathione peroxidase activity was suggested. Whanger et al.51 also indicated that tissue saturation with selenium occurs at selenium intake levels greater than that re- quired to achieve maximal glutathione peroxidase activity. They also noted, however, that there was no attempt to control the sample for age, sex, duration of residence in the study area, diet, or use of mineral and/or vitamin supplements. It seems rea- sonable to assume that a similar saturation model exists in the lens; thus, further study on the effect of selenium intake on incidence of cataract appears to be warranted.

Riboflavin Riboflavin is a precursor for flavin ade-

nine dinucleotide (FAD) synthesis. FAD is a cofactor for glutathione reductase, an en- zyme involved in regeneration of glutathione. Recent research by Horwitz et indicated that lens epithelia of patients (n = 8) taking thyroxine or riboflavin supplements showed higher glutathione reductase activity than did lens epithelia of noncon- sumers of these supplement^.^^ Thyroxine (and possibly insulin) enhances glutathione reductase by stimulating the enzymatic conversion of riboflavin to FAD. However, despite these positive correlations between riboflavin status and glutathione reductase activity, no significant difference in the mean activity of glutathione reductase in cataractous lenses as opposed to nonca- taractous lenses has been observed. Al- though some laboratory studies indicated that riboflavin is necessary to maintain lens ~ l a r i t y , ~ a correlation between riboflavin nutriture or status and incidence of cata- r a ~ t ~ ~ has not been firmly established for human population^.^^,^^

Only one clinical study of humans appeared to support the use of riboflavin supplementation. Thus, BhaP4 observed riboflavin deficiency in erythrocytes of 81% of patients with cataract and in 12% of the controls. However, the study subjects did not constitute a random sample population, and thiamine and pyridoxine deficien-

I

cies were more prevalent in the controls than in the subjects with cataract, a finding indicating fairly severe malnutrition in both groups.

Tryptophan Tryptophan deficiency is a well-docu-

mented cause of cataract in animals.8 How- ever, such dietary insufficiency, as distinct from malnutrition, has not been observed in humans. Serum tryptophan concentrations (1 1.8 k 2.5 pg/mL) are insignificantly different in patients with cataract as compared with nonaffected individual^.^^ This observation is interesting because it relates to mechanisms by which aspirin use may affect c a t a r a c t . l ~ ~ ~ - ~ ~ Use of aspirin dimin- ishes tryptophan levels in serum. Thus, if aspirin is useful to delay cataract, then the beneficial effect does not appear to involve altering tryptophan levels. The relationships between both aspirin or tryptophan use and cataract promise to be areas of lively debate.

Socioeconomic Considerations This article has dealt with relationships

between cataract and nutrition primarily from a biochemical perspective and with the implicit assumption that adequate nutriture would be available. Although this perspective is a valid one for most of the developed world, less affluent populations frequently confront malnutrition and its de- bilities. Thus, in affluent populations only a minor fraction may be poorly nourished (i.e., 1-3% have insufficient levels of ascorbate or riboflavin in the diet),26 and appro- priate nutrition or supplementation pro- vides a long, useful life for the lens. However, the vision of malnourished chil- dren or young adults may be jeopardized because of their disadvantaged socioeconomic position.'as This often-neglected socioeconomic cause of cataract and other abnormalities may contribute to the large number of cases of cataract throughout the world.

Future Directions The data presented allow optimism that

means may be available to delay the onset

NUTRITION REVlEWSlVOL 47. NO BIAUGUST 1989 231

of cataract in underdeveloped countries. Even where available nutrition is adequate but suboptimal, it may be possible to im- pede further the rate at which cataract de- velops by optimizing nutrition and suitably protecting the eye. Several areas of study have been suggested. Many of these ideas share a common need to define better the bioavailability and use of nutrients during aging.

A recent approach to delaying a variety of age-related syndromes that has received considerable attention is dietary caloric restriction, the only known way to extend mean and total lifespan and to delay the onset of many diseases of late life. Leveille et aL60 introduced the concept that dietary caloric restriction might delay some of the insolubilization of lens crystallin that ac- companies aging and/or cataract, and we recently demonstrated that caloric restriction may offer a way to delay senile-type cataract.61 Although caloric restriction may not be applicable to many humans, elucidation of the underlying mechanisms may provide a promising area of biochemical or genetic research to ophthalmologists, nu- tritionists, and gerontologists. Thus, recent observations that caloric restriction may result in a lower concentration of glucose in blood6* and diminish age-related glycation of proteins or other cellular constitu- ents are most interesting, because glycation is one of the age-related postsynthetic modifications of proteins that has been related to cataract. However, these possibilities are also intriguing in that they reflect on a mechanism by which aspirin mediates its putative anticataract effects, i.e., it has been suggested that aspirin consumption may be involved in depressing blood glucose levels and that this effect may spare the lens.5e-59 Clearly, these areas of research deserve considerable attention.

The author thanks Dr. George Edwin Bunce for generously sharing his original references and a preprint of his review article in this field. Ms. Esther Epstein and Dr. Paul Jacques helped with final preparation and editing of the text. This work was supported in part by grants from USDA contract no. 53-3KO6-5-10, the Daniel and

Florence Guggenheim Foundation, the Massa- chusetts Lions Eye Research Fund, Inc., and Hoffmann-La Roche, Inc.

Figures 1, 3, and 4: Copyright 1974 CIBA- GElGY Corporation. Reproduced with permis- sion from Clinical Symposia by John Craig, M.D. All rights reserved.

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Associations between Nutrition and Cataract