Table 3.

Effects of some carotenoids on age-related eye diseases.

Carotenoid	Characteristics of the study	Cell type/animal model	Effects in chronic eye diseases	Ref.
Lutein and zeaxanthin	Multicenter, randomized, double-masked, placebo-controlled phase 3 study with a 2 × 2 factorial design (2006–2012) Participants were randomized to receive lutein 10 mg + zeaxanthin 2 mg, DHA 350 mg + EPA 650 mg, lutein + zeaxanthin and DHA + EPA, or placebo All participants were also asked to take the original AREDS formulation or accept a secondary randomization to 4 variations of the AREDS formulation, including elimination of beta-carotene, lowering of zinc dose, or both	4203 human patients, age 50-85 years	Median follow-up: 5 years, with 1940 study eyes, 1608 participants, progressing to advanced AMD Kaplan-Meier probabilities of progression to advanced AMD by 5 years were 31% (493 eyes, 406 participants), for placebo, 29% (468 eyes, 399 participants), for lutein + zeaxanthin, 31% (507 eyes, 416 participants), for DHA + EPA, and for lutein + zeaxanthin and DHA + EPA, 30% (472 eyes, 387 participants) Comparison with placebo demonstrated no statistically significant reduction in progression to advanced AMD (hazard ratio 0.90 (98.7% CI, 0.76-1.07); p = 0.12 for lutein + zeaxanthin; 0.97 (98.7% CI, 0.82-1.16); p = 0.70 for DHA + EPA; 0.89 (98.7% CI, 0.75-1.06); p = 0.10 for lutein + zeaxanthin and DHA + EPA) No apparent effect of beta-carotene elimination or lower-dose zinc on progression to advanced AMD More lung cancers were noted in the beta-carotene vs no beta-carotene groups (23 (2.0%) vs 11 (0.9%), nominal p = 0.04), mostly in former smokers Addition of lutein + zeaxanthin, DHA + EPA, or both to the AREDS formulation did not further reduce risk of progression to advanced AMD Because of potential increased incidence of lung cancer in former smokers, lutein + zeaxanthin could be an appropriate carotenoid substitute in the AREDS formulation	[152]
	Prospective study, in 1980 Repeated administration of a food frequency questionnaire during 12 years of follow-up	Human patients (female), age 45-71 years	Decrease the risk of cataracts, p = 0.04, foods rich in these carotenoids may decrease the risk of cataracts severe enough to require extraction	[155]
	Prospective study, in 1986 Repeated administration of carotenoids and other nutrients—frequency questionnaire during 8 years of follow-up	36644 human patients (male), age 45-75 years	May decrease the risk of cataracts severe enough to require extraction; this relation appears modest in magnitude As recommendations—to consume vegetables/fruit high in carotenoids daily; p = 0.03	[156]
	1354 people eligible, 246 developed a nuclear cataract (level 4 or 5 opacity) Nuclear opacity was assessed on a 5-point ordinal scale using lens photographs taken at baseline (1988-1990) and at follow-up (1993-1995) Food frequency questionnaire	Human patients, adults aged 43-84 years	Decrease the risk of nuclear cataracts Possible protective influence of lutein and vitamins E and C on the development of nuclear cataracts; the evidence provides weak support for these associations	[157]
	Usual nutrient intake = average intake from 5 food frequency questionnaires (were collected during a 13- to 15-year period before the evaluation of lens opacities). The duration of vitamin supplement use was determined from 7 questionnaires collected during this same period	478 human patients (nondiabetic female), aged 53-73 years	Prevention of age-related cataract The prevalence of nuclear opacities was significantly lower (p = 0.04) for women who used a vitamin C supplement for ≥10 years relative to women who never used vitamin C supplements (odds ratio, 0.36; 95% confidence interval, 0.18-0.72) Plasma measures of vitamins C and E taken at the eye examination were inversely associated with the prevalence of nuclear opacities	[158]
	Study for individual carotenoids and tocopherols in serum, quality-controlled HPLC method One-way ANOVA analysis and logistic regression analysis were applied	138 human patients with senile cataracts	No association The relation carotenoids-cataracts is biologically plausible; serum carotenoid levels are highly dependent on dietary intake and may not be clinically relevant biomarkers for cataract risk	[160]
Macular pigments	The optical density of MP was measured psychophysically	46 subjects, age 21-81 years with healthy maculae and in 9 healthy eyes known to be at high risk of AMD	Decrease the risk of AMD age-related decline (optical density of MP) at volunteers with no ocular disease (right eye: r(2) = 0.29, p = 0.0006; left eye: r(2) = 0.29, p < 0.0001) Healthy eyes (predisposed to AMD) had significantly less MP than healthy eyes at no such risk (Wilcoxon's signed rank test: p = 0.015) Supplemental lutein and zeaxanthin may delay, avert, or modify the course of this disease	[162]
	Lutein (L) and zeaxanthin (Z) extracted from each tissue sample were determined by HPLC	56 donors with AMD and 56 controls were cut into 3 concentric regions centered on the fovea	The results are inconsistent with a model that attributes a loss of L and Z in the retina to the destructive effects of AMD	[163]
	The relative risk for AMD—estimated according to dietary indicators of antioxidant status, controlling risk factors (smoking), by using multiple logistic regression analyses	356 case subjects, diagnosed with the advanced stage of AMD within 1 year prior to their enrollment, aged 55-80 years 520 control subjects	Increasing the consumption of foods rich in certain carotenoids (dark-green, leafy vegetables) may decrease the risk of developing advanced or exudative AMD	[165]
Lutein	Measuring macular pigment optical density (MPOD) and retinal sensitivity Vitamin supplementation (lutein 10 mg/day, zeaxanthin 2 mg/day), 3 months later—repeated ophthalmological examination	20 patients with medium/large drusen, 19 with RPD, and 15 control subjects	The mean MPOD significantly increased in RPD (p = 0.002), showing no more difference compared with controls (p = 0.3); no significant changes were found in mean retinal sensitivity and BCVA (p = 0.3 and p = 0.7) Medium/large drusen did not show significant changes on MPOD, retinal sensitivity, and BCVA (p = 0.5, p = 0.7, and p = 0.7, respectively) Different pathophysiology for RPD as compared with medium/large drusen	[168]
Lutein and zeaxanthin	Dietary intake	People over age 40 years (n = 8222)	No association with AMD Higher levels of lutein and zeaxanthin in the diet were related to lower odds for pigmentary abnormalities, one sign of early ARM (odds ratio among persons in high vs low quintiles = 0.1, 95% confidence interval: 0.1, 0.3) and of late ARM (odds ratio = 0.1, 95% confidence interval: 0.0, 0.9)	[170]
	Dietary intake + supplement intake of antioxidant vitamins and zinc at baseline and the 5-year incidence of early age-related maculopathy A 145-item food frequency questionnaire (FFQ) was used to assess nutrient intakes	During 1992-1994, 3654 people, aged > 49 years (82% of those are eligible) were examined for the Blue Mountains Eye Study baseline 5 years later, 2335 persons (75% of known survivors) were reexamined	No evidence of protection associated with dietary antioxidant or zinc intakes	[171]
Lutein + lycopene	Dietary intake Cross-sectional study Photodocumented retinal status and HPLC to measure plasma carotenoid concentrations	111 individuals with type 2 diabetes in a community-based study	Modulation of retinopathy risk A higher concentration of PVA carotenoids was associated with greater odds of diabetic retinopathy, after adjustment for risk factors (p = 0.049)	[172]
Zeaxanthin	Diet supplemented with 0.02% or 0.1% Zx	Age-matched normal rats	Inhibits diabetic retinopathy Zx supplementation has the potential to inhibit the development of retinopathy in diabetic patients	[173]
Lutein	Lutein, lutein + insulin 12 weeks	Streptozotocin-induced diabetic rats	Preventing the development of cataracts Treatment is useful in preventing the development of cataracts in streptozotocin-induced diabetic rats	[174]
Carotenoids and vitamins A, C, and E	Multicenter (5 ophthalmology centers in the USA) eye disease case control study	356 case subjects, diagnosed with an advanced stage of AMD within 1 year prior to their enrollment, aged 55 to 80 years, and residing near a participating clinical center The 520 control subjects were from the same geographic areas as case subjects, had other ocular diseases, and were frequency matched to cases according to age and sex	Dietary intake of carotenoids associated with a lower risk for AMD Adjusting for other risk factors for AMD—those in the highest quintile of carotenoid intake had a 43% lower risk for AMD compared with those in the lowest quintile (odds ratio, 0.57; 95% confidence interval, 0.35 to 0.92; p for trend = 0.02) 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 AMD (p for trend = 0.001) Several food items rich in carotenoids were inversely associated with AMD A higher frequency of intake of spinach or collard greens was associated with a substantially lower risk for AMD (p for trend < 0.001) The intake of preformed vitamin A (retinol) was not appreciably related to AMD Neither vitamin E nor total vitamin C consumption was associated with a statistically significant reduced risk for AMD; a possibly lower risk for AMD was suggested among those with higher intake of vitamin C from foods Increasing the consumption of foods rich in certain carotenoids (dark-green, leafy vegetables) may decrease the risk of developing advanced or exudative AMD	[153]