An ideal ocular nutritional supplement?*

The role of nutritional supplementation in prevention of onset or progression of ocular disease is of interest to health care professionals and patients. The aim of this review is to identify those antioxidants most appropriate for inclusion in an ideal ocular nutritional supplement, suitable for those with a family history of glaucoma, cataract, or age-related macular disease, or lifestyle factors predisposing onset of these conditions, such as smoking, poor nutritional status, or high levels of sunlight exposure. It would also be suitable for those with early stages of age-related ocular disease. Literature searches were carried out on Web of Science and PubMed for articles relating to the use of nutrients in ocular disease. Those highlighted for possible inclusion were vitamins A, B, C and E, carotenoids beta-carotene, lutein, and zeaxanthin, minerals selenium and zinc, and the herb, Ginkgo biloba. Conflicting evidence is presented for vitamins A and E in prevention of ocular disease; these vitamins have roles in the production of rhodopsin and prevention of lipid peroxidation respectively. B vitamins have been linked with a reduced risk of cataract and studies have provided evidence supporting a protective role of vitamin C in cataract prevention. Beta-carotene is active in the prevention of free radical formation, but has been linked with an increased risk of lung cancer in smokers. Improvements in visual function in patients with age-related macular disease have been noted with lutein and zeaxanthin supplementation. Selenium has been linked with a reduced risk of cataract and activates the antioxidant enzyme glutathione peroxidase, protecting cell membranes from oxidative damage while zinc, although an essential component of antioxidant enzymes, has been highlighted for risk of adverse effects. As well as reducing platelet aggregation and increasing vasodilation, Gingko biloba has been linked with improvements in pre-existing field damage in some patients with normal tension glaucoma. We advocate that vitamins C and E, and lutein/zeaxanthin should be included in our theoretically ideal ocular nutritional supplement.     

The potential role of nutrition on lens pathology: a systematic review and meta-analysis

Oxidative stress is one of the main mechanisms of lens opacification, and certain nutritional antioxidants are suspected to have a protective effect. To examine the role of these nutritional antioxidants on cataract prevention, we searched major databases and reviewed current evidence regarding the protective effect of nutritive antioxidants. We included observational studies that investigate the association between one or more of the following micronutrients and cataract: vitamin A, vitamin C, vitamin E, lutein, zeaxanthin, α- and β-carotene. Two independent authors extracted data and assessed their quality. We pooled results for overall cataract incidence for all types of cataract and separately for nuclear, cortical, and posterior subcapsular cataract. We did not perform sensitivity analysis. Twenty-five studies were included in the qualitative and 24 in the quantitative part of the study, with a total of 295,821 participants over 30 years old. Results from pooled analysis showed a protective effect of antioxidants on cataract, but not all of them reached statistical significance. Statistically significant results were reached for vitamin C (odds ratio [OR] = 0.88, 95% confidence interval [CI] [0.81, 0.97]), beta-carotene (OR = 0.89, 95% CI [0.83, 0.95]), and lutein and zeaxanthin (OR = 0.92, 95% CI [0.85, 0.99]). We did not find statistically significant results for vitamin E (OR = 0.84, 95% CI [0.70, 1.01]), vitamin A (OR = 0.90, 95% CI [0.80, 1.00]), or alpha-carotene (OR = 0.92, 95% CI [0.85, 1.00]). The present study shows a relation between certain antioxidants and cataract, but further studies, especially interventional, are needed to confirm this hypothesis.     

The macular xanthophylls

The macular pigments are predominantly composed of three carotenoids: lutein, zeaxanthin, and meso-zeaxanthin. These carotenoids are concentrated and distributed in a selective manner. The properties of these pigments are further explored along with their methods of uptake, stabilization, and storage. The dual nature of these pigments as filters and antioxidants are elaborated upon in relation to their protective effects upon the macula, specifically in age-related macular degeneration. Evidence suggests that increased levels of macular pigment are correlated with a decreased risk of age-related macular degeneration. Many have sought to exploit this therapeutic relation. Studies reveal that oral supplementation with lutein and zeaxanthin can increase the levels of macular pigments in the retina and plasma. The effects of such supplementation on actual ocular function have yet to be fully addressed. New and standardized methods of assessing macular pigment density are discussed and future areas of research to further our understanding of macular xanthophylls as they pertain to age-related macular degeneration are highlighted.     

Nutritional Supplementation and Age-Related Macular Degeneration

The prevalence of Age-related macular degeneration (AMD) is increasing as the population of elderly in the United States grows. Currently the pathogenesis is not fully understood, however oxidative injury is felt to play a significant role. The Age-Related Eye Disease Study (AREDS) established that a supplemental combination of dietary antioxidants of zinc, β-carotene, vitamin C and vitamin E slowed progression of AMD. Recently lutein, zeaxanthin, B vitamins, and omega-3 fatty acids have also been reported to decrease AMD progression, while vitamin E and β-carotene where found to increase the risk of late AMD. AREDS2 is currently underway, further examining the effects of omega-3 fatty acids, carotenoids, and the original AREDS formulation. While awaiting the results of AREDS2, it is important to understand the evidence currently available, so that physicians can safely advise patients today. This review examines the most current literature available exploring nutritional supplementation in age-related macular degeneration.     

Nutritional supplementation and age-related macular degeneration

The prevalence of Age-related macular degeneration (AMD) is increasing as the population of elderly in the United States grows. Currently the pathogenesis is not fully understood, however oxidative injury is felt to play a significant role. The Age-Related Eye Disease Study (AREDS) established that a supplemental combination of dietary antioxidants of zinc, β-carotene, vitamin C and vitamin E slowed progression of AMD. Recently lutein, zeaxanthin, B vitamins, and omega-3 fatty acids have also been reported to decrease AMD progression, while vitamin E and β-carotene where found to increase the risk of late AMD. AREDS2 is currently underway, further examining the effects of omega-3 fatty acids, carotenoids, and the original AREDS formulation. While awaiting the results of AREDS2, it is important to understand the evidence currently available, so that physicians can safely advise patients today. This review examines the most current literature available exploring nutritional supplementation in age-related macular degeneration.     

The effect of lutein and zeaxanthin supplementation on metabolites of these carotenoids in the serum of persons aged 60 or older

PURPOSE: To investigate the effect of lutein supplementation at doses of 2.5, 5.0, and 10 mg/d for 6 months on distribution of these carotenoids and their metabolites in the serum of elderly human subjects, with and without age-related macular degeneration. To determine whether supplementation with lutein can interact with the serum levels of other dietary carotenoids, retinol, and alpha-tocopherol. METHODS: Forty-five subjects received daily supplements of lutein (containing 5% zeaxanthin) for 6 months and were followed up for another 6 months after supplementation. Blood was collected at various intervals and lutein, zeaxanthin, and their metabolites in the sera were quantified by normal-phase high-performance liquid chromatography (HPLC)-UV/visible detection. Other dietary carotenoids, retinol, and alpha-tocopherol were identified and quantified on a C18 reversed phase HPLC column. RESULTS: After 6 months of supplementation with 10 mg of lutein, the increases in the mean serum levels from baseline were: 210 to 1000 nM/L (P < 0.0001) for lutein and 56 to 95 nM/L (P < 0.0001) for zeaxanthin. Similarly, the mean concentrations (nM/L) of carotenoid metabolites increased from 49 to 98 (P < 0.0001) for 3-hydroxy-beta,epsilon-caroten-3'-one (3'-oxolutein); 31 to 80 (P < 0.0001) for 3'-hydroxy-epsilon,epsilon-caroten-3-one; and 19 to 25 (P < 0.0001) for epsilon,epsilon-carotene-3,3'-dione. The serum levels of these carotenoids gradually decline within 6 months after supplementation. CONCLUSIONS: The increase in the serum levels of lutein/zeaxanthin correlates with increases in the serum levels of their metabolites that have previously been identified in the ocular tissues. Elderly human subjects with and without AMD can safely take supplements of lutein up to 10 mg/d for 6 months with no apparent toxicity or side effects.     

Plasma antioxidant vitamins and carotenoids and age-related cataract.

OBJECTIVE: To investigate the relationships between plasma concentrations of antioxidant vitamins and carotenoids and nuclear, cortical, and posterior subcapsular cataracts in a group of elderly men and women. DESIGN: Cross-sectional survey. PARTICIPANTS: Three hundred seventy-two men and women, aged 66 to 75 years, born and still living in Sheffield, England. METHODS: The Lens Opacities Classification System (LOCS) III was used to grade nuclear, cortical, and posterior subcapsular lens opacities. Fasting blood samples were taken to assess plasma concentrations of vitamin C, vitamin E, alpha-carotene, beta-carotene, lycopene, lutein, zeaxanthin, and beta-cryptoxanthin. MAIN OUTCOME MEASURES: Logistic regression analyses of the associations between plasma vitamin concentrations and cataract subtype, adjusting for age, gender, and other risk factors. RESULTS: After adjustment for age, gender, and other risk factors, risk of nuclear cataract was lowest in people with the highest plasma concentrations of alpha-carotene (odds ratio [OR], 0.5; 95% confidence interval [CI], 0.3-0.9, P for trend 0.006) or beta-carotene (OR, 0.7; 95% CI, 0.4-1.4, P for trend 0.033). Risk of cortical cataract was lowest in people with the highest plasma concentrations of lycopene (OR, 0.4; 95% CI, 0.2-0.8, P for trend 0.003), and risk of posterior subcapsular cataract was lowest in those with higher concentrations of lutein (OR, 0.5; 95% CI, 0.2-1.0, P for trend 0.012). High plasma concentrations of vitamin C, vitamin E, or the carotenoids zeaxanthin and beta-cryptoxanthin were not associated with decreased risk. CONCLUSIONS: These findings suggest that a diet rich in carotenoids may protect against cataract development, but because they are based on observational data, they need to be confirmed in randomized controlled trials.     

Lutein and antioxidants in the prevention of age-related macular degeneration

Demographic developments in Europe and North America are causing an increase of age-related diseases. Age-related macular degeneration (AMD) is one of the leading causes of severe central visual acuity loss in elderly people and seems to be an economic problem, too. There is evidence that oxidative damage is an important factor for exacerbation of AMD. Macular pigment with its antioxidative effect may serve as"natural sunglasses" filtering the blue light acting as a possible source of photooxidative damage to the neurosensory retina. The macular pigment consists mostly of lutein and zeaxanthin. These micronutrients from the group of carotenoids, as is the case for vitamins (vitamins C, E, and beta-carotene), cannot be synthesized in mammals and that is the reason why the role of micronutrition or its supplementation and its correlation to AMD progression has been discussed for years.The results of currently published studies are often contradictory. At present there are no results from randomized controlled studies confirming that supplementation of lutein and zeaxanthin can reduce the risk for AMD. Several epidemiological studies investigating the impact of antioxidants and omega-3 fatty acids on the incidence of AMD provided conflicting results.Up to now, AREDS is the largest randomized controlled study investigating the effect of supplementation of antioxidants, zinc, and copper on the progression of AMD. AREDS showed a significant effect of this supplementation in some particular groups of patients with AMD. The supplementation of lutein and omega-3 fatty acids is not toxic but a positive effect has not been proven by randomized studies.     

Lutein und Antioxidantien zur Prävention der AMD

Demographic developments in Europe and North America are causing an increase of age-related diseases. Age-related macular degeneration (AMD) is one of the leading causes of severe central visual acuity loss in elderly people and seems to be an economic problem, too. There is evidence that oxidative damage is an important factor for exacerbation of AMD. Macular pigment with its antioxidative effect may serve as“natural sunglasses” filtering the blue light acting as a possible source of photooxidative damage to the neurosensory retina. The macular pigment consists mostly of lutein and zeaxanthin. These micronutrients from the group of carotenoids, as is the case for vitamins (vitamins C, E, and β-carotene), cannot be synthesized in mammals and that is the reason why the role of micronutrition or its supplementation and its correlation to AMD progression has been discussed for years. The results of currently published studies are often contradictory. At present there are no results from randomized controlled studies confirming that supplementation of lutein and zeaxanthin can reduce the risk for AMD. Several epidemiological studies investigating the impact of antioxidants and ω-3 fatty acids on the incidence of AMD provided conflicting results. Up to now, AREDS is the largest randomized controlled study investigating the effect of supplementation of antioxidants, zinc, and copper on the progression of AMD. AREDS showed a significant effect of this supplementation in some particular groups of patients with AMD. The supplementation of lutein and ω-3 fatty acids is not toxic but a positive effect has not been proven by randomized studies.     

Effect of dietary zeaxanthin on tissue distribution of zeaxanthin and lutein in quail

PURPOSE: The xanthophyll carotenoids (lutein and zeaxanthin) are hypothesized to delay progression of age-related macular degeneration. The quail has a cone-dominant retina that accumulates carotenoids. The purpose of these experiments was to characterize the carotenoid composition of retina, serum, liver, and fat in quail and to determine whether dietary enrichment with zeaxanthin alters zeaxanthin or lutein concentrations in these tissues. METHODS: Quail were fed for 6 months with a commercial turkey diet (T group; n = 8), carotenoid-deficient diet (C- group; n = 8), or a carotenoid-deficient diet supplemented with 35 mg 3R,3'R-zeaxanthin per kilogram of food, (Z+ group; n = 8). Zeaxanthin was derived from Sphingobacterium multivorum (basonym Flavobacterium). Carotenoids in serum, retina, liver, and fat were analyzed by HPLC. RESULTS: As in the primate fovea, the retina accumulated zeaxanthin, lutein, and cryptoxanthin, and preferentially absorbed zeaxanthin (P < 0.005). In contrast, lutein was preferentially absorbed by liver (P < 0.01) and fat (P < 0.0001). In supplemented females, zeaxanthin increased approximately 4-fold in retina, and 74-, 63- and 22-fold in serum, liver, and fat, respectively. In males, zeaxanthin was elevated approximately 3-fold in retina, and 42-, 17-, and 12-fold in serum, liver, and fat, respectively. Birds fed the Z+ diet absorbed a higher fraction of dietary lutein into serum, but lutein was reduced in the retina (P < 0.05). CONCLUSIONS: Xanthophyll profiles in quail mimic those in primates. Dietary supplements of zeaxanthin effectively increased zeaxanthin concentrations in serum, retina, liver, and fat. The robust response to zeaxanthin supplementation identifies the quail as an animal model for exploration of factors regulating delivery of dietary carotenoids to the retina.     

Nutritional influences on visual development and function

Experiments conducted on many different species reveal a fundamental paradox about the vertebrate eye; it is damaged by its own operation. This vulnerability stems from the need to respond to visible light, often actinic, but also from the intrinsic metabolic and structural state of the eye's internal structures. Photoreceptor outer segments, for instance, have high concentrations of diet-derived long-chain polyunsaturated fatty acids and these membrane lipids are highly prone to peroxidation due to the high oxygen tension of the outer retina. Such a high diathesis for damage would be catastrophic if it were not balanced by an equally impressive system for responding to such stressors. The retina (and to a lesser extent the crystalline lens), for instance, is especially rich in dietary antioxidants such as vitamin E, vitamin C and the macular carotenoids (lutein and zeaxanthin) putatively to retard light-induced oxidative damage. The nutrients that support both essential function (e.g., retinal, the vitamin form of vitamin A, in photopigment) and protection operate in a highly integrated manner. For instance, Vitamin E is a lipophillic chain-breaking anti-oxidant (protecting DHA-rich outer segment membranes) that regenerates itself through reaction with vitamin C (a primary anti-oxidant against aqueous radicals) and is spatially distributed in complement with the carotenoids lutein and zeaxanthin. Nor are these interactions relegated to simply providing protection and the basic elements needed for transduction. Macular lutein and zeaxanthin, for example, improve visual performance (e.g., reduce glare disability and discomfort, speed photostress recovery, and enhance chromatic contrast) through purely optical means (by absorbing short-wave light anterior to the foveal cones). The vulnerability of the eye to exogenous insult, and the sensitivity of the eye to dietary components, is not static: infants have more vulnerable retinas due to clearer lenses and higher metabolic activity; the elderly are more vulnerable due to such factors as increased inflammatory stress and a higher content of photosensitizers (such as lipofuscin) creating cascading oxidative effects. Hence, optimal dietary prophylaxis changes as the eye ages. The eye, perhaps more than most other biological structures, has evolved an exquisite and shifting sensitivity to dietary intake throughout the lifespan, not just for its basic operation (e.g., Vitamin A for transduction), but also for its very preservation.     

Nutrition and age-related macular degeneration

Age-related macular degeneration is a growing burden disease with a high prevalence in elderly: it is the first cause of blindness in developped countries. It is a multifactorial disease with genetic factors and nutritional factors. Carotenoids, lutein and zeaxanthin are components of macular pigment and they have a filter role for blue light and an antioxidant role. Other nutritional factors might play a role as antioxidants: zinc, selenium, vitamin E, vitamin C… which lead to the ARED Study. It is the only one study with proven positive effects on the disease progression (stages 3 and 4). A high glycemic index increases oxidative stress. Long chain omega-3 polyunsaturated fatty acids have a protective effect. Available data are presented and discussed. These are new preventive issues.     

Plasma lutein and zeaxanthin and other carotenoids as modifiable risk factors for age-related maculopathy and cataract: the POLA Study

PURPOSE: To assess the associations of plasma lutein and zeaxanthin and other carotenoids with the risk of age-related maculopathy (ARM) and cataract in the population-based Pathologies Oculaires Liées à l'Age (POLA) Study. METHODS: Retinal photographs were graded according to the international classification. ARM was defined by the presence of late ARM (neovascular ARM, geographic atrophy) and/or soft indistinct drusen (>125 microm) and/or soft distinct drusen (>125 microm) associated with pigmentary abnormalities. Cataract classification was based on a direct standardized lens examination at the slit lamp, according to Lens Opacities Classification System III. Plasma carotenoids were measured by high-performance liquid chromatography (HPLC), in 899 subjects of the cohort. RESULTS: After multivariate adjustment, the highest quintile of plasma zeaxanthin was significantly associated with reduced risk of ARM (OR=0.07; 95% CI: 0.01-0.58; P for trend=0.005), nuclear cataract (OR=0.23; 95% CI: 0.08-0.68; P for trend=0.003) and any cataract (OR=0.53; 95% CI: 0.31-0.89; P for trend=0.01). ARM was significantly associated with combined plasma lutein and zeaxanthin (OR=0.21; 95% CI: 0.05-0.79; P for trend=0.01), and tended to be associated with plasma lutein (OR=0.31; 95% CI: 0.09-1.07; P for trend=0.04), whereas cataract showed no such associations. Among other carotenoids, only beta-carotene showed a significant negative association with nuclear cataract, but not ARM. CONCLUSIONS: These results are strongly suggestive of a protective role of the xanthophylls, in particular zeaxanthin, for the protection against ARM and cataract.     

Identification and quantitation of carotenoids and their metabolites in the tissues of the human eye

There is increasing evidence that the macular pigment carotenoids, lutein and zeaxanthin, may play an important role in the prevention of age-related macular degeneration, cataract, and other blinding disorders. Although it is well known that the retina and lens are enriched in these carotenoids, relatively little is known about carotenoid levels in the uveal tract and in other ocular tissues. Also, the oxidative metabolism and physiological functions of the ocular carotenoids are not fully understood. Thus, we have set out to identify and quantify the complete spectrum of dietary carotenoids and their oxidative metabolites in a systematic manner in all tissues of the human eye in order to gain better insight into their ocular physiology.Human donor eyes were dissected, and carotenoid extracts from ocular tissues [retinal pigment epithelium/choroid (RPE/choroid), macula, peripheral retina, ciliary body, iris, lens, vitreous, cornea, and sclera] were analysed by high-performance liquid chromatography (HPLC). Carotenoids were identified and quantified by comparing their chromatographic and spectral profiles with those of authentic standards.Nearly all ocular structures examined with the exception of vitreous, cornea, and sclera had quantifiable levels of dietary (3R,3'R,6'R)-lutein, zeaxanthin, their geometrical (E / Z) isomers, as well as their metabolites, (3R,3'S,6'R)-lutein (3'-epilutein) and 3-hydroxy-beta,epsilon-caroten-3'-one. In addition, human ciliary body revealed the presence of monohydroxycarotenoids and hydrocarbon carotenoids, while only the latter group was detected in human RPE/choroid. Uveal structures (iris, ciliary body, and RPE/choroid) account for approximately 50% of the eye's total carotenoids and approximately 30% of the lutein and zeaxanthin. In the iris, these pigments are likely to play a role in filtering out phototoxic short-wavelength visible light, while they are more likely to act as antioxidants in the ciliary body. Both mechanisms, light screening and antioxidant, may be operative in the RPE/choroid in addition to a possible function of this tissue in the transport of dihydroxycarotenoids from the circulating blood to the retina. This report lends further support for the critical role of lutein, zeaxanthin, and other ocular carotenoids in protecting the eye from light-induced oxidative damage and aging.     

抗氧化剂治疗年龄相关性黄斑变性的研究

年龄相关性黄斑变性（AMD）是西方55岁以上老年人低视力和盲的首要原因,发病机制尚不明确,缺乏可靠的预防和治疗方法。近年来国内外很多学者就AMD早期药物防治进行了广泛的实验与临床研究,重点是抗氧化剂的作用。就锌制剂,维生素A、C、E,多聚不饱和脂肪酸,类胡萝卜素（主要是叶黄素和玉米黄质）等的研究现状进行综述。     

HPLC measurement of ocular carotenoid levels in human donor eyes in the lutein supplementation era

PURPOSE: A substantial proportion of the population at risk for visual loss from age-related macular degeneration consumes supplements containing high doses of lutein, but clinical studies to date have shown only modest and variable increases in macular carotenoid pigments in response to supplementation. To determine whether lutein supplementation can indeed alter ocular carotenoid levels, the authors chemically measured levels of lutein, zeaxanthin, and their metabolites in the macula, peripheral retina, and lens of 228 eyes from 147 human donors and correlated these results with retrospective supplement histories from families of selected members of the study population. METHODS: Lenses and circular punches of macula (4-mm diameter) and equatorial peripheral retina (8-mm diameter) were dissected from donor eyes free of ocular disease procured from the local eye bank. The amounts of lutein, zeaxanthin, meso-zeaxanthin, and 3'-oxolutein were determined by HPLC with photodiode array and mass spectral detection. RESULTS: Eighteen percent of eyes from donors age 48 and older had unusually high levels (66.3 +/- 15.1 ng) of macular carotenoids that were three times the rest of the older population's mean level (23.0 + 12.1 ng; P < 0.001). Carotenoid levels in these outliers were also unusually high in the lens and in the peripheral retina. Similar outliers were not present in donors younger than 48. Most of these outliers regularly consumed high-dose lutein supplements before death. Lutein supplementation was uncommon in older donors whose macular carotenoids were in the normal range. CONCLUSIONS: The presence of unusually high levels of macular carotenoids in older donors who were regularly consuming high-dose lutein supplements supports the hypothesis that long-term lutein supplementation can raise levels of macular pigment. Elevated carotenoid levels in the peripheral retina and lens in these same donors could have important implications for understanding why some clinical methods of macular pigment measurement have had difficulty detecting robust and consistent responses in carotenoid supplementation trials.     

Chronic ingestion of (3R,3'R,6'R)-lutein and (3R,3'R)-zeaxanthin in the female rhesus macaque

PURPOSE: To investigate how supplementation of the monkey's diet with high doses of lutein (L), zeaxanthin (Z), or a combination of the two affects the plasma levels and ocular tissue deposition of these carotenoids and their metabolites over time and to determine whether these high doses can cause ocular toxicity. METHODS: Eighteen female rhesus monkeys were divided into groups of control (n = 3 control), L-treated (n = 5, 9.34 mg lutein/kg and 0.66 mg zeaxanthin/kg), Z-treated (n = 5, 10 mg zeaxanthin/kg), and L/Z-treated (n = 5, lutein and zeaxanthin, each 0.5 mg/kg). After 12 months of daily supplementation, one control animal, two L-treated animals, two Z-treated animals, and all the L/Z-treated animals were killed. The rest of the monkeys were killed after an additional six months without supplementation. Plasma and ocular tissue carotenoid analyses, fundus photography, and retina histopathology were performed on the animals. RESULTS: Supplementation of monkeys with L and/or Z increased the mean plasma and ocular tissue concentrations of these carotenoids and their metabolites. The mean levels of L and Z in the retinas of the L- and Z-treated animals after 1 year increased significantly over baseline. High dose supplementation of monkeys with L or Z did not cause ocular toxicity and had no effect on biomarkers associated with kidney toxicity. CONCLUSIONS: The mean levels of L and Z in plasma and ocular tissues of the rhesus monkeys increase with supplementation and in most cases correlate with the levels of their metabolites. Supplementation of monkeys with L or Z at high doses, or their combination does not cause ocular toxicity.     

Macular Pigment Imaging in AREDS2 Participants: An Ancillary Study of AREDS2 Subjects Enrolled at the Moran Eye Center

Purpose. Age-Related Eye Disease Study 2 (AREDS2) is a randomized, placebo-controlled study designed to determine whether supplementation with 10 mg of lutein and 2 mg of zeaxanthin per day can slow the rate of progression of age-related macular degeneration (AMD). Although some biomarkers of response to carotenoid supplementation such as serum concentrations are part of the AREDS2 protocol, measurement of carotenoid concentrations in the eye and other tissues is not. In this approved ancillary study, macular pigment optical density (MPOD), macular pigment distributions, and skin carotenoid levels at enrollment and at each annual visit were measured to assess baseline carotenoid status and to monitor response to assigned interventions. Methods. All subjects enrolled at the Moran Eye Center had MPOD and macular pigment spatial distributions measured by dual-wavelength autofluorescence imaging and total skin carotenoids measured by resonance Raman spectroscopy. Results. Baseline MPOD in enrolled subjects was unusually high relative to an age-matched control group that did not consume carotenoid supplements regularly, consistent with the high rate of habitual lutein and zeaxanthin consumption in Utah AREDS2 subjects prior to enrollment. MPOD did not correlate with serum or skin carotenoid measurements. Conclusions. Useful information is provided through this ancillary study on the ocular carotenoid status of AREDS2 participants in the target tissue of lutein and zeaxanthin supplementation: The macula. When treatment assignments are unmasked at the conclusion of the study, unique tissue-based insights will be provided on the progression of AMD in response to long-term, high-dose carotenoid supplementation versus diet alone. (ClinicalTrials.gov number, NCT00345176.).     

Lutein,zeaxanthin, and meso-zeaxanthin: The basic and clinical science underlying carotenoid-based nutritional interventions against ocular disease

The human macula uniquely concentrates three carotenoids: lutein, zeaxanthin, and meso-zeaxanthin. Lutein and zeaxanthin must be obtained from dietary sources such as green leafy vegetables and orange and yellow fruits and vegetables, while meso-zeaxanthin is rarely found in diet and is believed to be formed at the macula by metabolic transformations of ingested carotenoids. Epidemiological studies and large-scale clinical trials such as AREDS2 have brought attention to the potential ocular health and functional benefits of these three xanthophyll carotenoids consumed through the diet or supplements, but the basic science and clinical research underlying recommendations for nutritional interventions against age-related macular degeneration and other eye diseases are underappreciated by clinicians and vision researchers alike. In this review article, we first examine the chemistry, biochemistry, biophysics, and physiology of these yellow pigments that are specifically concentrated in the macula lutea through the means of high-affinity binding proteins and specialized transport and metabolic proteins where they play important roles as short-wavelength (blue) light-absorbers and localized, efficient antioxidants in a region at high risk for light-induced oxidative stress. Next, we turn to clinical evidence supporting functional benefits of these carotenoids in normal eyes and for their potential protective actions against ocular disease from infancy to old age.     

Dietary modulation of lens zeaxanthin in quail

Although higher dietary intake of lutein/zeaxanthin has been associated with reduced risk for cataracts, the impact of dietary supplements on lens lutein (L) or zeaxanthin (Z) has not been examined. If higher lens carotenoids do reduce risk for cataract, it would be essential to know whether dietary carotenoids can elevate carotenoids in the adult vertebrate lens. In this study, a covey of Japanese quail were hatched and raised 6 months on carotenoid-deficient diet, then switched to deficient diet supplemented with low or high 3R,3R'-zeaxanthin (5 or 35 mgkg(-1) food) or beta-carotene (50 mgkg(-1) food). Controls included a group of covey-mates that remained on the deficient diet and another raised from birth on the high Z (35 mg Zkg(-1)) diet. At 1 year of age, carotenoids and tocopherols in the lens and in the serum were analysed by HPLC, and compared by analysis of variance. Serum Z was significantly elevated in deficient birds fed the lower or higher Z supplement for 6 months (P<0.0001 for each). Serum Z in birds maintained on the higher Z supplement for 1 year was much higher than that in deficient birds (P<0.0001), but not different from deficient birds given the higher Z supplement. As in humans, the predominant lens carotenoids were lutein (L) and zeaxanthin (Z), and the total carotenoid concentration was of lower magnitude than the concentration of alpha-tocopherol. Responses to Z supplementation were sex-related. Female quail had 5-10 times higher serum concentrations of both Z and L than males (P<0.0001, <0.001), and they also had higher lens Z concentrations than males (P<0.0006); possible effects of estrogen on lens carotenoids are discussed. Lens Z concentration was strongly and positively correlated with serum Z in females (r=0.77; P<0.002). Deficient adult females supplemented with the 35 mgkg(-1) dose of Z for 6 months had a mean lens Z concentration (0.252+/-0.06 microgg(-1) protein) close to that in females fed with the supplement from birth (0.282+/-0.15 microgg(-1) protein). Birds fed with the higher dietary Z supplement for 6 or 12 months had significantly higher lens Z than birds fed lower or no dietary Z (P<0.0001). Lens L was not altered by dietary supplementation with either Z or beta-carotene. beta-Carotene supplements did not result in detectable lens beta-carotene, and had no effect on lens Z. Neither Z nor beta-carotene supplementation had a significant effect on serum or lens tocopherol concentrations. These studies in quail provide the first experimental evidence that lens carotenoids in adult vertebrates can be manipulated by dietary Z supplements.