Given both the extent of disability caused by age-related cataract and its costs, $5 to $6 billion per year²⁶ (Congressional Testimony of S.J. Ryan, May 5, 1993) in the United States, it is urgent that we elucidate causes of cataract and identify strategies to slow the development of this disorder. It is estimated that a delay in cataract formation of approximately 10 years would reduce the prevalence of visually disabling cataract by approximately 45%.¹² Such a delay would enhance the quality of life for much of the world's older population and substantially reduce the economic burden due to cataract-related disability and cataract surgery. It is such data that provide the impetus for this research.

In addition, as the lens ages, the proteins are photo-oxidatively damaged, aggregate, and accumulate in lens opacities. Dysfunction of the lens due to opacification is called cataract. The term age-related cataract is used to distinguish lens opacification associated with old age from opacification associated with other causes, such as congenital and metabolic disorders or trauma.²⁸

LIGHT EXPOSURE AS A RISK FACTOR FOR CATARACT

Various epidemiologic studies show associations between elevated risk of various forms of cataract and exposure to higher intensities of incident or reflected ultraviolet light or both (Table 1).^15,32–40 Greater light exposure was (weakly) associated with an increased risk for cortical opacity in Chesapeake Bay watermen³² and in men (but not women) in Wisconsin.³⁶ Light-related risk for cataract alsowas increased among Italians but not among resi-dents of Massachusetts.³⁷ Risk for posterior subcapsular cataract was weakly related to light exposure in Chesapeake Bay watermen and (nonsignificantly) in residents of Wisconsin. Other studies (Massachusetts and Italy) did not find associations between posterior subcapsular cataract risk and light exposure. Nuclear cataract appears unrelated to risk for cataract in most studies.

Geographic data provide some support for purported relationships between light exposure and cataract risk.⁴¹ Persons living closer to the equator⁴² and living at higher elevations appear to have anelevated risk of various forms of cataract.^{35,38–41,43} Indeed, one of the strongest predictors of cataract surgery likelihood in a Medicare beneficiary is a person's latitude of residence.⁴⁰ Although not a uniform observation,^2,44,45 these epidemiologic data have been corroborated or anticipated by exposure of squirrels to ultraviolet light in vivo⁴⁶ and in many experiments in vitro^{6–8,42,47–52} and references cited within. As an aggregate, the latter references indicate that exposure of lens constituents to various wavelengths of light results in alterations that are quite similar to those found in cataract.

HIGH-ENERGY RADIATION AS A RISK FACTOR FOR CATARACT

Cataractogenesis is also clearly related to exposure to high-energy radiation. Taylor and associates showed a dose-response relationship betweenx-irradiation and risk for cataract in rats.⁵³ In a study with 99 patients, the 89 who received whole-body irradiation (10 g) had cataract develop in less than 4 years.⁵⁴ The 10 patients who were treated for aplastic anemia and did not receive radiation treatment did not show evidence of cataractogenesis.

EXPOSURE TO HIGH LEVELS OF OXYGEN AS A RISK FACTOR FOR CATARACT

Perhaps the clearest causal association between oxidative stress and cataract comes from experiences involving elevated levels of oxygen. Nuclear cataract was observed in patients treated with hyperbaric oxygen therapy,⁵⁵ and markedly elevated levels of mature cataract were observed in mice that survived exposure to 100% oxygen twice weekly for 3 hours.⁵⁶ A decline in glutathione (GSH) and an increase in glutathione disulfide (oxidative changes normally related to aging or cataract) also were noted. A higher incidence of cataract was noted in lenses exposed to hyperbaric oxygen in vitro,⁵⁷ and Giblin also noted very early stages of cataract in guinea pigs exposed to hyperbaric oxygen.⁵⁸ However, there was difficulty in repeating these results (Taylor and coworkers, unpublished data). Oxidative damage to membrane lipids in fiber cells also is associated with lens opacities.⁵⁹

SMOKING AS A RISK FACTOR FOR CATARACT

Smoking and tobacco chewing appear to induce oxidative stress and have been associated with both diminished levels of antioxidants, ascorbate, and carotenoids^60–65 and with enhanced cataract at a younger age.^66–69 Of interest are the following recent observations:

1. For male smokers, there appears to be an inverse relationship between serum levels of α-carotene, 13-cryptoxanthin, lutein, and severity of nuclear sclerosis⁷⁰ (but the reverse may be true for women).
   
2. There is diminished risk for cataract in smokers who use multivitamins.²⁵
   

CELLULAR ANTIOXIDANTS AS PRIMARY DEFENSES AGAINST LENS DAMAGE

Protection against photo-oxidative insult can be conceived as due to two interrelated processes. Primary defenses offer protection of proteins and other constituents by lens antioxidants and antioxidant enzymes (see Fig. 3). Secondary defenses include proteolytic and repair processes, which degrade and eliminate damaged proteins and other biomolecules in a timely fashion.⁷¹

The major aqueous antioxidants in the lens are ascorbate⁷² and GSH.^3,73–75 Both are present in the lens at millimolar concentrations.^76–78 Ascorbate is probably the most effective, least toxic antioxidant identified in mammalian systems.^79,80 Interest in the function of ascorbate in the lens was prompted by teleologic arguments, which suggested age-related compromises in ascorbate and compromises in lens function might be related. Thus, the following observations were noted:

1. The lens and aqueous concentrate ascorbate greater than 10-fold the level was found in guinea pig and human plasma^72,73,81,82 (Fig. 4).
   
2. In the lens core (see Fig. 2b), the oldest part of the lens, and the region involved in much senile cataract, the concentration of ascorbate is only 25% of the surrounding cortex.⁸³
   
3. Lens ascorbate concentrations are lower in cataract than in the normal lens.⁸⁴
   
4. Ascorbate levels in the lens are significantly lower in old guinea pigs than in young animals with the same dietary intake of ascorbate.^72,81 The same pertains in Emory mice.⁷⁸
   

These data suggest either that there is age-related depletion of ascorbate in the lens or that the bioavailability of this compound changes with age. Enthusiasm for nutrient antioxidants has been fueled by observations that ocular levels of ascorbate are related to dietary intake in humans and animals that require exogenous ascorbate (see Fig. 4).^72,81,82 Thus, the concentration of vitamin C in the lens was increased with dietary supplements beyond levels achieved in persons who already consumed more than two times the recommended daily allowance (60 mg/day) for vitamin C.^72,73

Feeding elevated ascorbate delayed progress of, or prevented galactose cataract in guinea pigs⁸⁵ and rats,⁸⁶ selenite-induced cataracts in rats,⁸⁷ lens opacification in GSH-depleted chick embryos,⁸⁸ and delayed UV-induced protein and protease damage in guinea pig lenses.^7–9,89 Increasing lens ascorbate concentrations by only twofold is associated with protection against cataract-like damage.⁸

Because ascorbate is a carbohydrate, it is biochemically plausible that vitamin C induces damage in the lens in vivo.^90,91 However, there currently are no data to support this as a medical concern. Mice fed 8% of the weight of their diet as ascorbate did not develop cataract.⁹² If glycation induces pathologic lens damage, antiglycating agents such as phenacylthiazoliums may be useful.⁹³ It is interesting that comparable compounds have been tried as anticataractogens and were assumed to act as reducing cysteine prodrug agents.⁹⁴

GSH levels are several-fold the levels found in whole blood and orders of magnitude greater than the concentration observed in the plasma. GSHlevels also diminish in the older and cataractouslens.⁷⁴ There have been several attempts to exploitthe reducing capabilities of GSH. Injection ofGSH-OMe was associated with delayed buthioninesulfoxamine-induced⁹⁵ and naphthalene cataract.^74,96,97Preliminary evidence from studies with galactose-induced cataract also indicates some advantage of maintaining elevated GSH status in rats.⁷⁶ However, it is not clear that feeding GSH is associated with higher ocular levels of this antioxidant.⁷⁶ Other compounds, such as pantetheine, which also includes sulfhydryls, are under investigation as anticataractogenic agents.⁹⁸ However, the efficacy of this compound in later-life cataract remains to be established.⁹⁹

Pharmacologic opportunities are suggested by observations that incorporating the industrial antioxidant 0.4% butylated hydroxytoluene in diets of galactose-fed (50% of diet) rats diminished prevalence of cataract.¹⁰⁰

Tocopherols and carotenoids are lipid-soluble antioxidants^101,102 with probable roles in maintaining membrane integrity¹⁰³ and GSH recycling.¹⁰⁴ Concentrations of tocopherol in the whole lens are in the micrometer range¹⁰⁵ (Table 2), but it appears that lens and dietary levels of tocopherol are unrelated.¹⁰⁶ Because most of the compound is found in the membranes, particularly in the younger tissues (Taylor and coworkers, unpublished data), the concentrations can be orders of magnitude higher. Age-related changes in levels of tocopherol and carotenoids have not been documented. Tocopherol is reported to be effective in delaying a variety of induced cataracts in animals, including galactose^28,107,108 and aminotriazole-induced cataracts in rabbits.¹⁰⁹

Elevated carotenoid intake frequently is associated with health benefits. However, little experimental work has been done regarding lens changes in response to variations in levels of this nutrient. It is intriguing that β-carotene levels in the human lenses are limited¹⁰⁵ (see Table 2). Instead, major lens carotenoids are lutein/zeaxanthin. These also are the major carotenoids in the macula.¹¹⁰ Also present are retinol and retinol ester, and tocopherols. In beef, β-carotene occasionally was observed in lenses. This apparent quixotic appearance of the β-carotene appears to be caused by seasonal and dietary availability.

The lens also contains the following antioxidant enzymes: glutathione peroxidase/reductase, catalase, and superoxidase dismutase and enzymes of the glutathione redox cycle.^{47,48,96,111,112} These interact via the forms of oxygen, as well as with the antioxidants (i.e., GSH is a substrate for glutathione peroxidase). The activities of many antioxidant enzymes are compromised on development, aging, and cataract formation.⁵⁹

PROTEASES AS SECONDARY DEFENSES

Proteolytic systems can be considered secondary defense capabilities that remove cytotoxic damaged or obsolete proteins from lenses and other eye tissues.^{2,71,85,113–124} Such proteolytic systems exist in young lens tissue, and damaged proteins usually are maintained at harmless levels by primary and secondary defense systems in younger lenses and in younger lens tissues within older lenses.

Two studies indicate interactions between primary and secondary defense systems. A direct sparing effect of ascorbate on a photo-oxidatively induced compromise of proteolytic function has been shown.⁷ GSH also spares activity of enzymes involved in the conjugation of ubiquitin to substrates.^115,122 Ubiquitin conjugation is required for selective targeting of substrates for degradation. However, on aging or oxidative stress, most of these enzymatic capabilities are found in a state of reduced activity⁷¹ (Table 3). The observed accumulation of oxidized (and/or otherwise modified) proteins in older lenses is consistent with the failure of these protective systems to keep pace with the insults that damage lens proteins. This occurs in part because, like bulk proteins, enzymes that comprise some of the protective systems are damaged by photo-oxidation.^{2,7,115,122,125} From these data, it is clear that the young lens has significant primary and secondary protection. However, age-related compromises in the activity of antioxidant enzymes, con-centrations of the antioxidants, and activities ofsecondary defenses may lead to diminished protection against oxidative insults.¹²³ This diminished protection leaves the long-lived proteins and other constituents vulnerable. Lens opacities develop as the damaged proteins aggregate and precipitate.² Current data predict that elevated antioxidant intake can be exploited to extend the function of some of these proteolytic capabilities.

Nine of the studies were retrospective case-controlor cross-sectional studies in which levels of cataract patients were compared with levels of individuals with clear lenses.^{37,101,126–128,130,131,133,136} Our ability to interpret data from retrospective studies, such as these, is limited by the concurrent assessment of lens status and levels. Prior diagnosis of cataract might influence behavior of cases including diet, and it also might bias reporting of usual diet.

Seven studies^{25,132,135,137–140} assessed levels or supplement use or both and then followed individuals with intact lenses for up to 8 years. Prospective studies, such as these, are less prone to bias because assessment of exposure is performed before the outcome is present. Some of these studies^25,132,135 did not directly assess lens status, but used cataract extraction or reported diagnosis of patients with cataract as a measure of cataract risk. Extraction may not be a good measure of cataract incidence (i.e., development of new cataract), because it incorporates components of both incidence and progression in severity of existing cataract. However, extraction is the result of visually disabling cataract and is the endpoint that we wish to prevent.

The length of time that dietary intake of nutrients is measured also may affect the accuracy of these analyses since cataract develops over many years; one measure may not provide as accurate an assessment of usual intake. Instead, multiple measures over time may offer a better nutritional correlate of cataract.

Hankinson and coworkers¹³² measured intake several times over a 4-year period, whereas other studies used only one measure of serum antioxidant status, dietary intake, or supplement use. Jacques and associates¹⁴¹ measured supplement intake for more than 10 years and found different risk ratios (RRs) for cataract in persons who took vitamin C supplements for different periods of time (see section A below).

In addition to the different study designs noted above, various studies used different lens classification schemes, different definitions of high and low levels of nutrients, and different age groups of subjects. A study (n = 367) that monitored cataract in vivo and cataract extraction but did not find associations between nutriture and cataract is not described further because the cataract classifications do not match those used on other work.³⁴

ASCORBATE

As noted above, dietary ascorbate intake is related to eye tissue ascorbate levels. Given potential anti-cataractogenic and putative procataractogenic roles for ascorbate, the available epidemiologic data regarding ascorbate intake and risk for cataract are particularly intriguing.

Vitamin C was considered in 9 published studies^{37,127,128,130–133,139,141} and observed to be inversely associated with at least one type of cataract in 8 of these studies (Fig. 5).

Several studies found correlations between vitamin C supplement use and risk of cataract. In our nutrition and vision project,¹⁴¹ age-adjusted analyses based on 165 women with high vitamin C intake (mean, 294 mg/day) and 136 women with low vitamin C intake (mean, 77 mg/day) indicated that the women who took vitamin C supplements for 10 years or longer had over 70% lower prevalence of early opacities (RR, 0.23; CI, 0.09–0.60; see Fig. 5A) and greater than 80% lower risk of moderate opacities (RR, 0.17; CI, 0.03–0.87) at any site compared with women who did not use vitamin C supplements.¹⁴¹ Recent reexamination of 600 of the members of the same cohort indicates that comparable data can be anticipated. This corroborated work by Hankinson and associates,¹³² who noted that women who consumed vitamin C supplements for more than 10 years had a 45% reduction in rate of cataract surgery (RR, 0.55; CI, 0.32–0.96; see Fig. 5G). However, after controlling for nine potential confounders, including age, diabetes, smoking, and energy intake, they did not observe an association between total vitamin C intake and rate of cataract surgery (see below).

In comparison to the data noted above, Mares-Perlman and coworkers¹²⁶ report that past use of supplements containing vitamin C was associated with a reduced prevalence of nuclear cataract (RR, 0.7; CI, 0.5–1.0; see Fig. 5C) but an increased prevalence of cortical cataract (adjusted RR, 1.8; CI, 1.2–2.9) after controlling for age, sex, smoking, and history of heavy alcohol consumption (see Fig. 5D).

The inverse relationship is corroborated by data from other studies. Robertson and coworkers¹²⁷ compared cases (with cataracts that impaired vision) to age and sex-matched control subjects who were either free of cataract or had minimal opacities that did not impair vision. The prevalence of cataract in consumers of daily vitamin C supplements of greater than 300 mg/day was approximately one third the prevalence in persons who did not consume vitamin C supplements (RR, 0.30; CI, 0.24–0.77; see Fig. 5B).

Elevated dietary ascorbate also was related to benefit with respect to cataract in some studies. Leske and coworkers¹²⁸ observed that persons with vitamin C intake in the highest 20% of their population group had a 52% lower prevalence for nuclear cataract (RR, 0.48; CI, 0.24–0.99) compared with persons who had intakes among the lowest 20% after controlling for age and sex (see Fig. 5C). Weaker inverse associations were noted for other types of cataract (see Fig. 5F). Jacques andChylack¹³⁰ observed that among persons with higher vitamin C intakes (over 490 mg/day), the prevalence of cataract was 25% of the prevalence among persons with lower intakes (less than 125 mg/day; RR, 0.25; CI, 0.06–1.09; see Fig. 5A).

However, Vitale and coworkers¹³³ observed no differences in cataract prevalence between per-sons with high (over 261 mg/day) and low (lessthan 115 mg/day) vitamin C intakes. The Italian-American Studies group³⁷ also failed to observe any association between prevalence of cataract and vitamin C intake. In addition, in a large prospective study, comparison of women with high intakes (median, 705 mg/day) to women with low intakes (median, 70 mg/day) failed to show any significant correlation with risk for cataract extraction (RR, 0.98; CI, 0.72–1.32).¹³²

Attempts to corroborate the above inverse associations between cataract risk and intake using plasma vitamin C levels generally were frustrating. Jacques and Chylack¹³⁰ observed that persons with high plasma vitamin C levels (greater than 90 μmol/L) had less than one-third the prevalence of early cataract as did persons with low plasma vitamin C (less than 40 μmol/L), although this difference was not statistically significant (RR, 0.29; 95% CI, 0.06–1.32) after adjustment for age, sex, race, and history of diabetes (see Fig. 5A). Mohan and associates¹³¹ noted an 87% (RR, 1.87; CI, 1.29–2.69) increased prevalence of mixed cataract (posterior subcapsular and nuclear involvement) for each standard deviation increase in plasma vitamin C levels. Vitale and coworkers¹³³ observed that persons with plasma levels greater than 80 μmol/L and less than 60 μmol/L had similar prevalences of both nuclear (RR, 1.31; CI, 0.61–2.39) and cortical (RR, 1.01; CI, 0.45–2.26) cataract after controlling for age, sex, and diabetes. Results from one intervention trial have been published and are described below.¹⁴²

VITAMIN E

Vitamin E, a natural lipid-soluble antioxidant, can inhibit lipid peroxidation¹⁰³ and appears to stabilize lens cell membranes.¹⁴³ The efficacy of vitamin E as an antioxidant may be affected by ascorbate (see legend to Fig. 3) and also enhances glutathione recycling, perhaps helping to maintain reduced glutathione levels in the lens and aqueous humor.¹⁰⁴

Consumption of vitamin E supplements was inversely correlated with cataract risk in two studies (Fig. 6). Robertson and coworkers¹²⁷ found among age- and sex-matched case and control subjects that the prevalence of advanced cataract was 56% lower (RR, 0.44; CI, 0.24–0.77; see Fig. 6B) in persons who consumed vitamin E supplements (greater than 400 IU/day) than in persons not consuming supplements. Jacques and Chylack (unpublished data) observed a 67% (RR, 0.33; CI, 0.12–0.96) reduction in prevalence of cataract for vitamin E supplement users after adjusting for age, sex, race, and diabetes. Mares-Perlman and coworkers¹²⁶ observed only weak, nonsignificant associations between vitamin E supplement use and nuclear (RR, 0.9; CI, 0.6–1.5; see Fig. 6C) and cortical (RR, 1.2; CI, 0.6–2.3; see Fig. 6D) cataract.

The inverse association between vitamin E intake and risk for cataract was corroborated by Leske and associates.¹²⁸ They observed that after controlling for age and sex, persons with vitamin E intakes among the highest 20% had an approximately 40% lower prevalence of cortical (RR, 0.59; CI, 0.36–0.97; see Fig. 6D) and mixed (RR, 0.58; CI, 0.37–0.93; see Fig. 6F) cataract relative to personswith intakes among the lowest 20%. Jacques andChylack¹³⁰ observed a nonsignificant inverse association when they related total vitamin E intake (i.e., combined dietary and supplemental intake) to cataract prevalence. Persons with vitamin E intake over 35.7 mg/day had a 55% lower prevalence of early cataract (RR, 0.45; CI, 0.12–1.79) than did per-sons with intakes less than 8.4 mg/day.¹³⁰ However,Hankinson and coworkers¹³² found no association between vitamin E intake and cataract surgery. Women with high vitamin E intakes (median,210 mg/day) had a similar rate of cataract surgery (RR, 0.96; CI, 0.72–1.29) as did women with low intakes (median, 3.3 mg/day). In partial contrast with their positive correlations between serumα-tocopherol levels and cataract, Mares-Perlman and coworkers¹²⁹ found that dietary vitamin E was associated (nonsignificantly) with diminished risk of nuclear cataract in men but not in women (see Fig. 6C).

Four studies assessing plasma vitamin E levels also reported significant inverse associations with cataract. Knekt and coworkers¹³⁵ followed a cohort of 1419 Finns for 15 years and identified 47 patients admitted to ophthalmologic wards for mature cataract. They selected two controls per patient matched for age, sex, and municipality. These investigators reported that persons with serum vitamin E concentrations above approximately 20 μmol/L had approximately half the rate of subsequent cataract surgery (RR, 0.53; CI, 0.24–1.1; see Fig. 6G) compared with persons with vitamin E concentrations below this concentration. Vitale and coworkers¹³³ observed the age-, sex-, and diabetes-adjusted prevalence of nuclear cataract to be approximately 50% less (RR, 0.52; CI, 0.27–0.99; see Fig. 6C) among persons with plasma vitamin E concentrations greater than 29.7 μmol/L compared with persons with levels less than 18.6 μmol/L. A similar comparison showed that the prevalence of cortical cataract did not differ between those with high and low plasma vitamin E levels (RR, 0.96; CI, 0.52–0.1.78; see Fig. 6D). Jacques and Chylack¹³⁰ also observed the prevalence of posterior subcapsular cataract to be 67% (RR, 0.33; CI, 0.03–4.13; see Fig. 6E) lower among persons with plasma vitamin E levels above 35 μmol/L relative to persons with levels below21 μmol/L after adjustment for age, sex, race, anddiabetes; however, the effect was not statistically significant. Prevalence of any early cataract (RR, 0.83; CI, 0.20–3.40; see Fig. 6A) or cortical cataract (RR, 0.84; CI, 0.20–3.60; see Fig. 6D) did not differ between those with high and low plasma levels. Plasma vitamin E also was inversely associated with prevalence of cataract in a large Italian study after adjusting for age and sex, but the relationship was no longer statistically significant after adjusting for other factors such as education, sunlight exposure, and family history of cataract.³⁷ Leske and coworkers¹⁰¹ also showed that individuals with high plasma vitamin E levels had significantly lower prevalence of nuclear cataract (RR, 0.44; CI, 0.21–0.90), but vitamin E was not associated with cataracts at other lens sites.

Mares-Perlman and coworkers noted a significant elevated prevalence of nuclear cataract in men with high serum vitamin E (RR, 3.74; CI, 1.25–11.2) but not in women (RR, 1.47; CI, 0.57–3.82; see Fig. 6C).⁷⁰ One other study failed to observe any association between cataract and plasma vitamin E levels.¹³¹

Mares-Perlman and coworkers⁷⁰ observed an inverse (nonsignificant) relationship (RR, 0.61; CI, 0.32–1.19) between serum γ-tocopherol, which has lower biologic vitamin E activity compared toα-tocopherol (Fig. 7B), and severity of nuclear sclerosis, but a positive, significant relationship between elevated serum α-tocopherol levels and severity of nuclear cataract (RR, 2.13; CI, 1.05–4.34; see Fig. 6C).

Whereas serum α-tocopherol appeared to be associated with nonsignificant increases in risk for cortical or any cataract, serum γ-tocopherol was not significantly associated with cortical or any cataract in these studies.

Two prospective studies showed a reduced risk for cataract progress among individuals with higher plasma vitamin E. Rouhiainen and coworkers¹³⁸ found a 73% reduction in risk for cortical cataract progression (RR, 0.27; CI, 0.08–0.83; see Fig. 6D), whereas Leske and coworkers¹³⁹ reported a 42% reduction in risk for nuclear cataract progression (RR, 0.58; CI, 0.36–0.94; see Fig. 6C). Vitamin E supplementation was related to a lower risk for progress of nuclear opacity (RR, 0.43; CI, 0.19–0.99).¹³⁹

CAROTENOIDS

The carotenoids, like vitamin E, also are natural lipid-soluble antioxidants.¹⁰³ β-carotene is the best-known carotenoid because of its importance as a vitamin A precursor. It exhibits particularly strong antioxidant activity at low partial pressures of oxygen (15 torr).¹⁴⁴ This is similar to the -20 torr partial pressure of oxygen in the core of the lens.¹⁴⁵ However, it is only one of approximately 400 naturally occurring carotenoids,¹⁴⁶ and other carotenoidsmay have similar or greater antioxidant potential.^{102,103,147,148} In addition to β-carotene, α-carotene, lutein, and lycopene are important carotenoid components of the human diet.¹⁴⁹ Carotenoids have been identified in the lens in 10 ng/g or greater net weight concentrations (see Table 1).^105,150 There are a dearth of laboratory data that relate carotenoids to cataract formation, and there also are no data that relate carotenoid supplement use to risk for cataracts.

Jacques and Chylack¹³⁰ were the first to ob-serve that persons with carotene intakes above18,700 IU/day had the same prevalence of cataract as those with intakes below 5677 IU/day (RR, 0.91; CI, 0.23–3.78; Fig. 8A). Hankinson and associates¹³² followed this report with a study that specified that the multivariate-adjusted rate of cataract surgery was approximately 30% lower (RR, 0.73; CI, 0.55–0.97) for women with high carotene intakes (median, 14,558 IU/day) compared with women with low intakes of this nutrient (median, 2935 IU/day; see Fig. 8E). However, although cataract surgery was inversely associated with total carotene intake, it was not strongly associated with consumption of carotene-rich foods, such as carrots. Rather, cataract surgery was associated with lower intakes of foods, such as spinach, that are rich in lutein and xanthin carotenoids rather than β-carotene. This would appear to be consistent with our observation that the human lens contains lutein and zeaxanthin but not β-carotene. Unfortunately, cataract surgery was not an endpoint in other studies that considered xanthaphylls.^70,126

Jacques and Chylack¹³⁰ also noted that persons with high plasma total carotenoid concentrations (over 3.3 μmol/L) had less than one fifth the prevalence of cataract compared with persons with low plasma carotenoid levels (less than 1.7 μmol/L; RR, 0.18; CI, 0.03–1.03) after adjustment for age, sex, race, and diabetes (see Fig. 8A). However, they were unable to observe an association between carotene intake and cataract prevalence. Knekt and coworkers¹³⁵ reported that among age- and sex-matched case and control subjects, persons with serum β-carotene concentrations above approximately 0.1 AM had a 40% reduction in the rate of cataract surgery compared with persons with concentrations below this level (RR, 0.59; CI, 0.261.25).

The most recent study that correlated serum carotenoids and severity of nuclear and conical opaci-ties⁷⁰ indicates that higher levels of individual or total carotenoids in the serum were not associated with less-severe nuclear or cortical cataract overall, although same sex-related differences in risk were noted. Associations between risk for some forms of cataract and nutriture differed between men and women (e.g., nuclear cataract and α-carotene intake; Fig. 9B).¹²⁹ Other nutrients for which cataract risk in women versus men showed opposing relationships to include serum β-carotene (Fig. 10) and serum lycopene (Fig. 11). A marginally significant trend for lower RR for cortical opacity with increasing serum levels of β-carotene was observed in men but not women. Higher serum levels of α-carotene, β-cryptoxanthin, and lutein were significantly related to lower risk for nuclear sclerosis only in men who smoked. In contrast, higher levels of some carotenoids often were directly associated with elevated risk for nuclear sclerosis and cortical cataract (see Figs. 10 and 12), particularly in women.

Vitale and colleagues¹³³ also examined the relationships between plasma β-carotene levels and age-, sex-, and diabetes-adjusted prevalence of cortical and nuclear cataract (see Fig. 10B and C). Although the data suggested a weak inverse association between plasma β-carotene and cortical cataract and a weak positive association between this and nuclear cataract, neither association was statistically significant. Persons with plasma β-carotene concentrations above 0.88 μmol/L had a 28% lower prevalence of cortical cataract (RR, 0.72; CI, 0.37–1.42) and a 57% (RR, 1.57; CI, 0.84–2.93) higher prevalence of nuclear cataract compared with persons with levels below 0.33 μmol/L (Fig. 13).

Hankinson and coworkers¹³² observed correlations between β-carotene intake but not intake of β-carotene-containing foods and risk for cataract extraction. Instead, they saw an inverse relation be-tween risk for cataract extraction and intake of lutein and zeaxanthin-containing foods such as spinach (Fig. 14). This observation would appear to be consistent with observations that lutein and zeaxanthin are the most prevalent carotenoids in lens (see Table 2). However, Mares-Perlman^126,129 did not detect significantly altered risk for cataract among consumers of these nutrients.

ANTIOXIDANT COMBINATIONS

To more closely approximate combined effects on cataract risk of the multiple antioxidants that are contained in food, this group was the first to adopt “antioxidant indices.” However, it is possible that single nutrients appear to have strong influences on the indices, and we now question the utility of theindices. Nevertheless, in an attempt to offer a complete summary, data regarding relationships between antioxidant indices and cataract risk are presented below (see Fig. 14). To be consistent with the earlier sections, we first describe effects of supplement use. Then the effects of intake, including foods, are summarized.

Robertson and coworkers¹²⁷ found no enhanced benefit to persons taking both vitamin E and vitamin C supplements compared with persons who only took either vitamin C or vitamin E. Leske and coworkers¹²⁸ found that the use of multivitamin supplements was associated with decreased prevalence for each type of cataract: 60%, 48%, 45%, and 30%, respectively, for posterior subcapsular (RR, 0.40; CI, 0.21–0.77), cortical (RR, 0.52; CI, 0.36–0.72), nuclear (RR, 0.55; CI, 0.33–0.92), and mixed (RR, 0.70; CI, 0.51–0.97) cataracts (see Figs. 14B-E). Luthra and coworkers¹³⁶ and Leske and coworkers¹⁵¹ reported that supplement consumption was associated with a slight reduction in risk of cortical cataract in a black population (RR, 0.77; CI, 0.61–0.98) in those younger than 70 years of age (see Fig. 14C).

Multivitamins also were reported to reduce the risk of incident cataracts, as well as progression of existing cataracts in several studies (see Fig. 14). Seddon and coworkers²⁵ observed a reduced risk for incident cataract for users of multivitamins (RR, 0.73; CI, 0.54–0.99). Mares-Perlman and coworkers¹³⁷ reported that multivitamin users had significant 20% (RR, 0.8; CI, 0.6–1.0) and 30% (RR, 0.7; CI, 0.5–1.0) reduction of cortical cataract progression and incidence, respectively (see Fig. 14C). Leske and coworkers¹³⁹ reported a 31% reduced risk for progression of nuclear cataract among users of multivitamins (RR, 0.69; CI, 0.48–0.99). Hankinson and coworkers¹³² found no relationship between multivitamin use and risk of cataract extraction. In these studies, it is not clear whether synergy between nutrients, with respect to conferring diminished risk for cataract, is indicated.

The first, and perhaps most important, study in terms of showing the utility of diet indicates that persons who consumed at least 1.5 servings of fruits or vegetables or both had only a 20% risk of having cataract develop as did those who did not (see Fig. 14A).¹³⁰ Hankinson and coworkers¹³² calculated an antioxidant score based on intakes of carotene, vitamin C, vitamin E, and riboflavin and observed a 24% reduction in the adjusted rate of cataract surgery among women with high antioxidant scores relative to women with low scores (RR, 0.76; CI, 0.57–1.03; see Fig. 14F).

Using a similar index based on combined antioxidant intakes (vitamin C, vitamin E, and carotene, as well as riboflavin), Leske and coworkers¹²⁸ found that persons with high scores had 60% lower adjusted prevalence of cortical (RR, 0.42; CI, 0.18–0.97; see Fig. 14C) and mixed (RR, 0.39; CI, 0.19–0.80; see Fig 14E) cataract compared with those who had low scores.

Jacques and Chylack¹³⁰ also found that the adjusted prevalence of all types of cataract was 40% (RR, 0.62; CI, 0.12–1.77) and 80% (RR, 0.16; CI, 0.04–0.82) lower for persons with moderate and high-antioxidant index scores (based on combined plasma vitamin C, vitamin E, and carotenoid lev-els) compared with persons with low scores (seeFig. 14A). Mohan and coworkers¹³¹ constructed asomewhat more complex antioxidant scale that in-cluded erythrocyte levels of glutathione peroxidase,glucose-6-phosphate dehydrogenase, and plasma levels of vitamin C and vitamin E. Even though Mohan and coworkers failed to see any protective associations with any of these individual factors and even reported a positive association between plasma vitamin C and prevalence of cataract, they found that persons with high antioxidant index scores had a substantially lower prevalence of cataracts involving the posterior subcapsular region (RR, 0.23; CI, 0.06–0.88; see Fig. 14D) or mixed cataract with posterior subcapsular and nuclear components (RR, 0.12; CI, 0.03–0.56) after multivariate adjustment (see Fig. 14E). Knekt and coworkers¹³⁵ observed that the rate of cataract surgery for persons with high levels of both serum vitamin E and β-carotene concentrations appeared lower than the rate for persons with either high vitamin E or high β-carotene levels (see Fig. 14F). Persons with high serum levels of either had a rate of cataract surgery that was 40% less than did persons with low levels of both nutrients (RR, 0.38; CI, 0.15–1.0).

Vitale and coworkers¹³³ also examined the relationship between antioxidant scores (based on plasma concentrations of vitamin C, vitamin E, and β-carotene) and prevalence of cataract, but did not see evidence of any association. The age-, sex-, and diabetes-adjusted RRs were close to one for both nuclear (RR, 0.96; CI, 0.54–1.70) and cortical (RR, 1.17; CI, 0.62–2.20) cataract.

INTERVENTION STUDIES

Only one intervention trial designed to assess the effect of vitamin supplements on cataract risk has been completed. Sperduto and coworkers¹⁴² took advantage of two ongoing, randomized, double-masked vitamin and cancer trials to assess the impact of vitamin supplements on cataract prevalence. The trials were conducted among almost 4000 participants aged 45 to 74 years from rural communes in Linxian, China. Participants in the first trial received either a multisupplement or placebo. In the second trial, a more complex factorial design was usedto evaluate the effects of four different vitamin/mineral combinations: retinol (5000 IU) and zinc(22 mg); riboflavin (3 mg) and niacin (40 mg); vitamin C (120 mg) and molybdenum (30 μg); and vitamin E (30 mg), β-carotene (15 mg), and selenium (50 μg). At the end of the 5- to 6-year follow-up, the investigators conducted eye examinations to determine the prevalence of cataract (Fig. 15).

In the first trial, there was a significant 43% reduction in the prevalence of nuclear cataract for persons aged 65 to 74 years receiving the multisupplement (RR, 0.57; CI, 0.36–0.90; see Fig. 15A). The second trial showed a significantly reduced prevalence of nuclear cataract in persons receiving the riboflavin/niacin supplement relative to those persons not receiving this supplement (RR, 0.59; CI, 0.45–0.79). The effect was strongest in those aged 65 to 74 years (RR, 0.45; CI, 0.31–0.64). However, the riboflavin/niacin supplement appeared to increase the riskof posterior subcapsular cataract (RR, 2.64; CI,1.31–5.35; see Fig. 15C). The results further sug-gested a protective effect of the retinol/zinc supple-ment (RR, 0.77; CI, 0.58–1.02) and the vitaminC/molybdenum supplement (RR, 0.78; CI, 0.59–1.04) on prevalence of nuclear cataract.

CALORIE RESTRICTION AND CONTROL OF BODY MASS INDEX AS A MEANS TO DELAY CATARACT

Restriction of caloric intake extends youth anddelays age-related cataract (as well as many other late-life diseases) in these animals (Fig. 16). The decrease in risk for cataract in calorie-restricted Emory mice has some parallels in a recent study, which indicates that well-fed male physicians with body mass index below 22 enjoyed less risk for cataract compared with physicians with body mass indices above 25.¹⁵² Because cataract is associated with oxidative stress, it might be anticipated that the delay in cataract would be accompanied by elevated ascorbate levels in the protected animals. Nevertheless, in young and old animals, plasma-ascorbate concentrations were lower than in the nonrestricted mice.^77,78,153

The impression created by the literature is that there is some benefit to enhanced antioxidant intake with respect to diminished risk for cataract. Optimal levels of ascorbate appear to be 250 mg/day; however, more information is essential before describing optimal nutriture vis à vis cataract. It is difficult to compare the various studies. That the correlations were not always with the same form of cataract may indicate, in addition to the conclusions reached, that the cataracts were graded differently or that there are common etiologic features of each of the forms of cataract described or both. Most of the studies noted above used case-control designs, and most assessed status only once. Because intake or status measures are highly variable and the effects of diet are likely to be cumulative, studies should be performed on populations for which long-term dietary records are available. It appears that intake studies are preferable to use for plasma measures if a single measure of status must be chosen. Longitudinal studies and more intervention studies are certainly essential to truly establish the value of antioxidants and to determine the extent to which cataract progress is affected by nutriture. More uniform methods of lens evaluation, diet recording, and blood testing, for example, would facilitate conclusions regarding the merits of antioxidants. Optimization of nutriture can be achieved through better diets and supplement use once appropriate levels of specifically beneficial nutrients are defined. In addition to quantifying optimal intake, it is essential to know for how long or when intake of the nutrients would be useful with respect to delaying cataract. It is possible to adjust normal dietary practice to obtain close-to-saturating levels of plasma ascorbate (less than 250 mg/day).^{72,132,141,154} Because the bioavailability of ascorbate may decrease with age, slightly higher intakes may be required in the elderly. Thus, the overall impression created by these data suggests that further research in this field will bring significant health benefits.

Poor education and lower socioeconomic status also markedly increase risk for these debili-ties.^{128,131,155,156} These are related to poor nutrition.Because cost-benefit analysis regarding remediation clearly indicates that cataract prevention is preferable (and essential where there is a dearth of surgeons) to surgery, it is not premature to contemplate the value of intervention for populations at risk. The work available, albeit preliminary, indicates that nutrition may provide the least costly and most practicable means to attempt the objectives of delaying cataract.

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