Review

Received: 8 June 2009 Revised: 28 August 2009 Accepted: 8 September 2009 Published online in Wiley Interscience: 21 October 2009

(www.interscience.wiley.com) DOI 10.1002/jsfa.3785

Effects of lutein and zeaxanthin on aspects of eye health

Le Ma and Xiao-Ming Lin
Abstract
Lutein and zeaxanthin are members of the oxygenated carotenoids found particularly in egg yolks and dark-green leafy vegetables. A great deal of research has focused on their benecial roles in eye health. The present article summarises the current literature related to the bioactivity of these carotenoids, emphasising their effects and possible mechanisms of action in relation to human eye health. Available evidence demonstrates that lutein and zeaxanthin are widely distributed in a number of body tissues and are uniquely concentrated in the retina and lens, indicating that each has a possible specic function in these two vital ocular tissues. Most of epidemiological studies and clinical trials support the notion that lutein and zeaxanthin have a potential role in the prevention and treatment of certain eye diseases such as age-related macular degeneration, cataract and retinitis pigmentosa. The biological mechanisms for the protective effects of these carotenoids may include powerful blue-light ltering activities and antioxidant properties. Although most studies point towards signicant health benets from lutein and zeaxanthin, further large-scale randomised supplementation trials are needed to dene their effects on ocular function in health and disease. c 2009 Society of Chemical Industry Keywords: lutein; zeaxanthin; carotenoid; macular pigment; age-related macular degeneration; cataract

INTRODUCTION
Information has been accumulated indicating that a high dietary intake of carotenoid-rich foods is associated with a reduced incidence of several chronic diseases, including certain cancers, cardiovascular disease, and age-related macular degeneration (AMD).1 More than 600 carotenoids have been identied in nature up to date; about 40 of these are consumed in the typical human diet.2 Among them, lutein and zeaxanthin have been studied widely and proven to show diverse benecial effects on human health, particularly on optimising eye health. Lutein and its stereo isomer zeaxanthin, are xanthophyll carotenoids abundant in egg yolks and dark-green leafy vegetables such as spinach and kale.3 Although these carotenoids are similar in structure to - and -carotene, they do not have provitamin A activity.4 Absorption of these two carotenoids is inuenced by the same factors that affect dietary fat.5 Compared to other major dietary carotenoids, lutein and zeaxanthin are the principal carotenoids of serum in Asians, whereas they are the second most prevalent components in Americans.6 Despite the fairly ubiquitous presence throughout body tissues, they are the only carotenoids present in the lens and macular region of the retina, suggesting these compounds may play a protective role in these two vital ocular tissues.7 Although lutein and zeaxanthin are not essential nutrients for human health, they display biological activities that have attracted great attention on the prevention and reversal of certain serious eye diseases.8 11 A large number of epidemiological studies support the notion that high dietary intakes of xanthophylls are strongly associated with decreased risk of retinal degenerative diseases, especially AMD and cataract.8,9 Randomised clinical studies show that dietary supplementation with lutein and

zeaxanthin could result in increasing their serum concentrations and macular pigment optical density, and these ndings were suggestive of a possible benet of xanthophyll supplementation in preventing the onset and progression of certain eye diseases.10,11 Several studies have also indicated a potential contribution of lutein and zeaxanthin to the prevention of coronary heart disease and certain types of cancer.12,13 However, the results of these studies are somewhat conicting. Although the antioxidant properties are thought to be primarily responsible for their benecial properties, evidence is accumulating to suggest other mechanisms such as photoprotectants against blue light-induced damage in heavily exposed tissues may be involved as well.14,15 Even as the evidence that lutein and zeaxanthin have been strongly implicated as being protective against certain chronic diseases, there are no dened dietary reference intakes for them currently. The data available from population-based studies indicate that intake level of lutein has declined, particularly from dark-green leafy vegetables.16 Therefore, it is worth noting that increasing intakes of food sources rich in xanthophylls should be warranted. The following comprehensive review summarises the background information about lutein and zeaxanthin, presents the most current knowledge with respect to their roles in human eye health and disease, and discusses some of the mechanisms

Correspondence to: Xiao-Ming Lin, Department of Nutrition and Food Hygiene, School of Public Health, Peking University, 38 Xueyuan Road, Beijing 100191, China. E-mail: linbjmu@bjmu.edu.cn Department of Nutrition and Food Hygiene, School of Public Health, Peking University, 38 Xueyuan Road, Beijing 100191, China

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Lutein and zeaxanthin and eye health through which these carotenoids may be involved in the prevention of AMD and other eye diseases. References for this review were identied through a literature search of the PubMed database and the Web of Science database published up to April 2009. The literature search was not conned to the English language, and relevant nonEnglish language publications were translated. Further articles, abstracts, and textbook references were selected from reviewing the bibliographies of the articles generated from the above search. The following key words and combinations of these words were used to perform the search: lutein, zeaxanthin, xanthophylls, carotenoid, macular pigment, eye disease, age-related macular degeneration, cataract, retinitis pigmentosa.

www.soci.org dietary sources of these compounds. Lutein is present in a wide variety of plant foods, especially in dark-green leafy vegetables. The two foods that have the highest amount are spinach and kale.19 Other major sources include broccoli, peas, turnip greens, summer squash, and Brussels sprouts. Dietary sources of zeaxanthin are limited to green, certain yelloworange fruits and vegetables, most abundantly in corn, nectarine, orange and papaya.3 Eggs, though not the richest dietary source of lutein and zeaxanthin, are considered a good source of these carotenoids due probably to the high bioavailability of lutein and zeaxanthin from the lipid matrix of the yolks.23 Currently, most reports and databases frequently provide combined data for lutein plus zeaxanthin in foods, partly because lutein is the principal component of most foods that are high in these two carotenoids, and the very similar polarities of lutein and zeaxanthin have made it difcult to distinguish them analytically. However, it leads to an overestimation of the true content of lutein in several foods, especially in some fruits frequently consumed where equal or higher amounts of zeaxanthin are present.24

CHEMICAL STRUCTURE OF LUTEIN AND ZEAXANTHIN

The chemical feature common to all carotenoids is the polyene chain, a long conjugated double-bond system, which determines their colours we see in nature as well as other major physicochemical and biochemical functions.17 Lutein and zeaxanthin are oxygenated carotenoids that consist of 40-carbon compounds with nine conjugated double bonds in the polyene chain. Their structures are characterised by the presence of two hydroxyl groups at the terminal rings of the molecule on the basic C40 H56 carotene structure, and thus are referred to as xanthophylls. Zeaxanthin is a stereoisomer of lutein, differing only in the location of one double bond in one of the hydroxyl groups. The hydroxyl groups are believed to provide unique biological function of these two xanthophylls.18,19 Relative to hydrocarbon carotenoids, lutein and zeaxanthin are more hydrophilic and polar in blood and tissues. The hydrophilic properties allow them to react with singlet oxygen generated in water phase more efciently than nonpolar carotenoids.20 Additionally, the relatively higher polarity partly determines distinctive characteristics during their metabolism, light absorption, capture and stabilisation in tissues, and potential orientations in a bilayer membrane.21 They possess absorption bands near the blue to violet end of the visible spectrum, making them ideal lters of blue light, and uorescence emission studies have conrmed their ability to act in such a capacity.22 Both lutein and zeaxanthin could adopt a roughly perpendicular orientation to the plane of the membrane. They span cell membranes with the lipophilic hydrocarbon chain inside the lipid bilayer and the hydrophilic hydroxyl groups encourage a membrane spanning conguration in lipid bilayers, especially in the case of zeaxanthin. This positioning optimises contact with the highly oxidisable cell membrane lipids, while also increasing membrane stability. Lutein could be oriented in parallel direction within the plane of the membrane as well.17,22 Unlike some carotenoids, such as - and -carotene, lutein and zeaxanthin can not be cleaved at the 1515 bond by the specic cleavage enzyme to generate vitamin A aldehyde, due to the presence of oxygenated groups in terminal ionone rings. Thus, they are not precursors of vitamin A.

DIETARY ALLOWANCE AND SAFETY OF LUTEIN AND ZEAXANTHIN

Currently, no recommended dietary allowances for xanthophyll carotenoids exist worldwide. Using the Third National Health and Nutrition Examination Survey (NHANES III) data, Americans consume approximately 2.4 mg day1 of lutein and zeaxanthin combined.25 The most recent report indicates that mean dietary intakes of lutein and zeaxanthin in Australia are 0.8 mg day1 .26 Levels of intake vary hugely between different individuals and population subgroups. For example, dietary intakes of these carotenoids are markedly higher among non-Hispanic Blacks, compared with non-Hispanic Whites and MexicanAmericans.27 No toxic side effects attributable to lutein and zeaxanthin supplements were observed at doses of up to 40 mg daily for 9 weeks or 30 mg daily for 140 days.11,28 No changes in the biochemical and haematological parameters were reported with respect to increased intake of those carotenoids. Moreover, the results of teratogenicity and mutagenicity studies conducted also showed no irreversible adverse effects at comparable dosages, suggesting that lutein and zeaxanthin are safe for human consumption.29 Lutein has been generally recognised as safe, which means that lutein can be formulated into certain food and dietary supplement applications. Although lutein and zeaxanthin are considered to be major carotenoids in normal Western diet, the data available from population-based studies showed that lutein intake tended to decline in both the US and Europe, particularly from dark-green leafy vegetables.16,30 Therefore, it is worth noting that increasing intakes of food sources rich in xanthophylls should be warranted.

HUMAN ABSORPTION, METABOLISM, AND DISTRIBUTION OF LUTEIN AND ZEAXANTHIN

Virtually little is known regarding the biology of dietary lutein and zeaxanthin in the human gastrointestinal tract. Absorption of these carotenoids is assumed to follow a similar route of other lipophilic compounds. It is affected by the same factors that inuence fat absorption.5 It is likely, therefore, that lutein and zeaxanthin released from their food matrix are digested and absorbed in a pattern of events one would expect of conjugated bile acids or

DIETARY SOURCES OF LUTEIN AND ZEAXANTHIN

Humans and primates do not have the capacity for de novo biosynthesis of lutein and zeaxanthin, and therefore depend entirely on

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www.soci.org lipid, being acted upon by bile salts and pancreatic lipases and incorporated into micelles that are absorbed into the mucosal cells of the small intestine via passive diffusion.31 Thereafter, they are transported from the intestinal mucosa by chylomicrons and are later taken up by hepatocytes, entering the hepatic circulation where the bulk of them are repackaged as plasma lipoproteins for subsequent release into the systemic circulation.32 Because of their polarity, they are assumed to be located at the lipoprotein surface and are more readily transferred among the different classes of lipoproteins.32 Unlike non-polar carotenoids such as carotene and lycopene which tend to be localised primarily in very low-density lipoprotein (VLDL) and low-density lipoproteins (LDL), lutein and zeaxanthin are evenly distributed between high density lipoproteins (HDL) and LDL in fasting blood.33 The association between lipoprotein and xanthophylls is relatively non-specic but mutually benecial. Chylomicron levels of xanthophylls increase early, with a peak at approximately 2 h after ingestion,34 while peak blood concentrations were observed at about 16 h postingestion.35,36 The blood xanthophyll level may vary considerably across individuals and population. Lutein and zeaxanthin are major carotenoids in the blood and account for about 53% of the total blood carotenoids in Asians compared with 23% in Americans.6,37 This likely reects the relative differences in intakes of xanthophyll carotenoids in these sample populations. Lutein and zeaxanthin are widely distributed in a number of human tissues; however, distributions of these carotenoids are eccentric among different bodily tissues and organs. They are the only carotenoids normally present in the macular and lens.38 The concentration of lutein and zeaxanthin at the macula represents the most conspicuous accumulation of carotenoids in the body, so both of them are referred to as macular pigments. The estimated concentration rises to almost 1 mmol L1 within the Henle bre layer of the macula, three orders of magnitude above that existing in normal human serum, suggesting the uptake, stabilisation and storage of these xanthophylls at the macula appears to be extraordinarily specic and efcient.24 Studies of tissue-specic distribution of macular xanthophylls showed that zeaxanthin was preferentially accumulated in the foveal region of macula, whereas lutein became the dominant carotenoid with increasing radial distance from the fovea.38,39 The observed differences in capture of these compounds indicated that tissue-specic xanthophyll binding proteins might mediate lutein and zeaxanthin capture. Tubulin, present in abundance within the axonal layer of the fovea, was initially identied as a possible binding protein for the deposition and stabilisation of the high concentrations of xanthophylls.40 Tubulin exhibits carotenoid-binding properties, but with a relatively weak, non-specic binding afnity. In a recent report, a Pi isoform of glutathione S-transferase (GSTP1), as a specic xanthophyll binding protein, was puried and isolated from the Henle bre region of the fovea, with high afnity and specicity for both forms of macular zeaxanthin.41 Functionally, the complex of the GSTP1 and zeaxanthin can enhance antioxidant properties of zeaxanthin in a model lipid oxidation system by inhibiting free radical mediated degradation.42

L Ma, X-M Lin

LUTEIN AND ZEAXANTHIN AND EYE HEALTH

Age-related macular degereration Age-related macular degereration (AMD) is the leading cause of irreversible vision loss in people over the age of 65 years in industrialised countries.43 Two types of AMD exist: early (or dry)

and late (or wet). Early AMD is characterised clinically by yellowish deposits known as soft drusen accumulations, patchy atrophy and pigmentary abnormalities in the retinal pigment epithelial (RPE) and Bruchs membrane, while late-stage manifestations encompass choroidal neovascularisation (CNV), subretinal haemorrhage, detachment of RPE, and retinal scarring.44,45 Although the pathophysiology of AMD continues to elude, there is a growing body of evidence implicating oxidative stress and cumulative blue light damage in the process.46 As the major components of macular pigment, it comes as no surprise that lutein and zeaxanthin have the benecial effects on preventing the onset and progression of AMD. Results from epidemiological studies that evaluated the relationship between dietary intake and/or blood levels of xanthophyll carotenoids and AMD were not consistent; however, most indicated a protective relationship (Table 1). Using the Eye Disease CaseControl Study (EDCCS) data, Seddon et al. reported that a high dietary intake of carotenoids was associated with a reduced risk for AMD adjusting for other risk factors for AMD.47 Those subjects in the highest quintile of lutein and zeaxanthin intake had a 57% lower risk for AMD than those in the lowest quintile, whereas preformed vitamin A, vitamin E, or total vitamin C consumption was not associated with a statistically signicant reduced risk for AMD. The subsequent analysis of consumption of specic foods showed that subjects in the highest quintile for consumption of spinach had 86% lower odds of advanced or exudative AMD. This is noteworthy, given that spinach is a particularly rich source of lutein and zeaxanthin. Likewise, a smaller study that carried out by Snellen et al. was in accord with the EDCCS ndings.48 Nonetheless, it was noteworthy that this study found a clear inverse doseresponse relationship between intake of lutein plus zeaxanthin and occurrence of neovascular AMD. Similarly, Moeller and colleagues evaluated dietary intake lutein and zeaxanthin in relation to the incidence of intermediate AMD in the CAREDS cohort of 1787 participants, and found a signicant risk reduction of AMD by 43% in women younger than 75 years with a high dietary intake of xanthophyll carotenoids.49 Data from the Age-Related Eye Disease Study (AREDS) involving 4519 participants aged 60 to 80 years were also consistent with the hypotheses that a reduced risk of AMD was inversely associated with intakes levels of lutein and zeaxanthin. Those individuals in the highest quintile of dietary intake of lutein and zeaxanthin had a 27%, 35% or 55% lower probability of developing large or extensive intermediate drusen, neovascular AMD, or geographic atrophy, respectively.8 In the most recent Blue Mountains Eye Study (BMES), Tan et al. assessed prospectively the relationship between the frequency of intake of different types of antioxidants and the long-term risk of incident AMD in Australia, and suggested a 65% reduced rate of neovascular AMD between subjects with the highest and lowest intake of lutein and zeaxanthin.26 In addition, those subjects with above median intakes also had a reduced risk of indistinct soft or reticular drusen. The rst epidemiological study to show a direct relationship between blood levels of xanthophyll carotenoids and AMD risk was EDCCS.50 Results from this study indicated that the risk of neovascular AMD was lower in subjects with the highest level of serum lutein and zeaxanthin than those with the lowest level. Subsequently, Gale et al. investigated relations of lutein and zeaxanthin in the plasma to AMD in a cross-sectional study of 380 elderly men and women in UK.51 They found that the plasma zeaxanthin, but not lutein or lutein plus zeaxanthin, was signicantly lower in individuals with AMD compared to those without the disease after adjustment for age and other risk factors. These studies were consistent with work by

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Table 1. Summary of epidemiological studies examining lutein and zeaxanthin and AMD Study and year EDCCS, 1993 Reference 50 Study design, follow-up Casecontrol Study population Men and women, US Men and women, US Men and women, US Men and women, US Men and women, Netherlands Men and women, UK Sample size 421 cases, 615 controls 356 cases, 520 controls 167 cases, 167 controls 56 cases, 56 controls 72 cases, 66 controls 380 Exposure measure Serum lutein and zeaxanthin Lutein and zeaxanthin intake Serum lutein and zeaxanthin Retinal lutein and zeaxanthin Lutein and zeaxanthin intake Plasma lutein Plasma zeaxanthin Plasma lutein and zeaxanthin Lutein and zeaxanthin intake Plasma lutein Comparison 0.668 vs 0.247 mol L1 Quintile 5 vs 1 OR/RR (95% CI) 0.3 (0.20.6)

EDCCS, Seddon et al., 1994 BDES, Mares-Perlman et al., 1995 Bone et al., 1997

47

Casecontrol

0.43 (0.20.7)

54

Nested casecontrol Casecontrol

Quintile 5 vs 1

1.4 (0.72.5)

53

Quartile 4 vs 1

0.18 (0.050.64)

Snellen et al., 2002 Gale et al., 2003

48

Casecontrol

Quartile 4 vs 1

0.4 (0.20.9)

51

Cross-sectional

Tertile 3 vs 1

0.59 (0.301.11) 0.50 (0.241.00) 0.53 (0.291.11)

CAREDS, Moeller et al., 2006 POLA, Delcourt et al., 2006

49

Cohort, 7 years

Women, US

1787

Quintile 5 vs 1

0.57 (0.340.95)

52

Cross-sectional

Men and women, France

899

Quintile 5 vs 1

0.31 (0.091.07)

AREDS, 2007

Casecontrol

Men and women, US

1568 casesa , 1115 controls 118 casesb , 1115 controls 658 casesc , 1115 controls 254

Plasma zeaxanthin Plasma lutein and zeaxanthin Lutein and zeaxanthin intake

0.07 (0.010.58) 0.21 (0.050.79)

Quintile 5 vs 1

0.73 (0.560.96)

0.45 (0.240.86) 0.65 (0.450.93) Lutein and zeaxanthin intake Lutein and zeaxanthin intake Lutein and zeaxanthin intake Quintile 5 vs 1 2.65 (1.136.22)

Robman et al., 2007 Cho et al., 2008

56

Cohort, 7 years

55

Cohort, 18 years Cohort, 10 years

Men and women, Australia Men and women, US Men and women, Australia

113 058

Quintile 5 vs 1

1.18 (0.642.17)

BMES, Tan et al., 2008

26

3654

Tertile 3 vs 1

0.35 (0.130.92)

AMD, age-related macular degeneration; AREDS, Age-Related Eye Disease Study; BDES, Beaver Dam Eye Study; BMES, Blue Mountain Eye Study; CAREDS, Carotenoids in the Age-Related Eye Disease Study; CI, condence interval; EDCCS, Eye Disease Case Control Study Group; OR, odds ratio; POLA, Pathologies Oculaires Liees a lAge study; RR, relative risk. a Cases with extensive intermediate or large drusen. b Cases with geographic atrophy. c Cases with neovascular AMD.

Delcourt and co-workers, who noted that AMD was signicantly associated with plasma zeaxanthin and lutein plus zeaxanthin, and tended to be associated with plasma lutein after multivariate adjustment.52 A comparative study of lutein and zeaxanthin levels in human donor retina both with and without AMD conrms the above

correlation.53 In this casecontrol study, Bone et al. measured the actual amounts of lutein and zeaxanthin in autopsy retinas from 56 donors diagnosed with AMD and from 56 controls without the disease, using high-performance liquid chromatography (HPLC). The retinal levels of lutein and zeaxanthin in three concentric regions centred on the fovea were signicantly lower in eyes with

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www.soci.org AMD than control eyes. Logistic regression analysis indicated that those in the highest quartile of retinal xanthophyll levels had an 82% lower risk for AMD compared with those in the lowest quartile. This study is the rst of its kind to specically evaluate the possible association between lutein and zeaxanthin concentrations in the retina and risk of AMD, and the importance of this study rests on directly supporting the hypothesis that macular xanthophylls protects against AMD. The above studies lend support to the view that the level of lutein and zeaxanthin in the diet, blood, or retina is related to the risk for AMD. However, these observations were not conrmed by other investigators.54,55 For example, Mares-Perlman et al. failed to conrm the inverse relationship of lutein and zeaxanthin in the serum to AMD.54 A population-based cohort study also found no inverse association between early AMD and dietary intake of lutein and zeaxanthin.55 Rather, the study conducted by Robman et al found indications that higher intakes of dietary lutein and zeaxanthin were related with increased rate of progression of AMD.56 These inconsistencies may reect differences in the study design and methods used to dene the range of xanthophyll intakes, limitations of the protection to certain stages of the disease, and particular types of people. Therefore, further larger epidemiologic studies are needed to determine the associations of these carotenoids with AMD. Although the epidemiological evidence in relation to AMD could not be interpreted as conclusive for showing cause and effect, it has triggered the considerable interest in assessing the effects of lutein and zeaxanthin supplementation on preventing or delaying the progression of AMD. Several intervention trials showed that dietary supplementation with lutein and zeaxanthin resulted in a measurable increase both in blood xanthophyll level and macular pigment optical density (MPOD) (Table 2). Landrum et al. supplemented two subjects with lutein esters equivalent to 30 mg of free lutein day1 for 140 days. Serum level of lutein increased by 10-fold within 20 days, and MPOD increased by 21% and 39%.28 Subsequently, Rosenthal et al. reported that lutein supplementation for 6 months led to twofold, 2.9-fold and 4-fold increase in serum lutein concentrations of the 2.5 mg, 5 mg and 10 mg groups, respectively.57 These results were consistent with the study by Huang et al.58 In this 9 month intervention with lutein and zeaxanthin, a two-fold to three-fold increase in serum xanthophyll level was found at month 6. It is noteworthy that participants with AMD had a lower increase in serum lutein concentration than did those without AMD. In the recent LUNA study, 108 subjects received a daily supplement consisting of 12 mg lutein and 1 mg zeaxanthin over a period of 6 months. MPOD signicantly increased in the intervention group.59 Subjects with low baseline MPOD were more likely to exhibit a dramatic rise in MPOD, or to exhibit no rise in MPOD, in response to supplements than subjects with medium to high baseline MPOD values, suggesting that intestinal malabsorption of these carotenoids was not responsible for the lack of a macular response to such supplements and saturable mechanisms might have effects on the retinal capture and/or stabilisation of the macular carotenoids. Furthermore, recent studies have suggested that supplementation with lutein and zeaxanthin may improve visual function in AMD patients as well. Richer et al. investigated the effects of antioxidant supplementation (including lutein) on visual performance in a double-blind placebo-controlled study of 90 patients known to have atrophic AMD who were followed for 1 year.10 Results showed that daily supplementation with 10 mg of lutein

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or 10 mg of lutein plus antioxidant supplementation led to signicant improvements in visual acuity, contrast sensitivity and glare recovery. Likewise, Parisi et al. evaluated the inuence of supplementation on retinal function in non-advanced AMD patients and in healthy control subjects by recording multifocal electroretinograms.60 A signicant increase in response amplitude densities of the focal electroretinograms was observed in patients with AMD taking daily supplements of 10 mg lutein and 1 mg zeaxanthin, suggesting that a selective dysfunction in the central retina could be improved by the supplementation with these carotenoids. Similarly, the results of the TOZAL study agreed with the earlier studies and were predictive for positive visual acuity outcomes which could be required supplementation for longer than 6 months.61 Cataract Cataract is an opacication of the lens in the eye which obstructs the passage of light, often resulting in impaired vision or blindness.62 Within two decades, cataract becomes more common with increasing age and is an important cause of disability among the elderly population throughout the world. More than one million cataract extractions are performed annually in the US.63 It is anticipated that the prevalence of cataract will increase by 50% as the number of elderly Americans increases.64 Meanwhile, cataract is prevalent in approximately 37% for Chinese adults over the age of 50.65 It has been postulated that dietary antioxidants, especially lutein and zeaxanthin, play a crucial role in the prevention of the oxidation of lens proteins and the formation of cataract. Epidemiological studies examining the relation of dietary intakes or blood levels of lutein plus zeaxanthin with the risk of cataract suggest a trend toward a protective relation (Table 3). In the Beaver Dam Eye Study (BDES) cohort of adults aged 43 to 84 years, lutein was the only examined carotenoid associated with incident nuclear cataract.66 Intake of lutein at baseline decreased the risk of nuclear opacities only among persons younger than 65 but not among older persons. Likewise, the results of the Nurse Health Study (NHS) and the US Health Professionals Follow-up Study (HPFS) showed that, compared with those in the lowest quintile, subjects with the highest intake of lutein and zeaxanthin had a 22% or 19% decreased risk of cataract extraction in women or men, respectively.67,68 Increasing intake of foods rich in lutein such as spinach and kale was most consistently associated with a lower risk of cataract, while cataract was not strongly associated with consumption of carotene-rich foods. Similarly, data from Gale et al. were suggestive of a 50% reduced rate of posterior subcapsular cataract in subjects with higher plasma lutein concentration in a retrospective study of 372 subjects, whereas high plasma vitamin C, vitamin E, zeaxanthin and -cryptoxanthin were not associated with decreased risk.69 This is corroborated by observations of Vu et al. that suggest a 36% reduced rate of nuclear cataract in those with the top quintile of intake of lutein plus zeaxanthin in a population-based study of 3271 Australians.70 However, cortical and posterior subcapsular cataracts were not signicantly associated with intake of lutein plus zeaxanthin. The published data from the POLA study showed only plasma zeaxanthin, but not lutein, was signicantly associated with reduced nuclear cataract.52 Recently, CAREDS reported a 23% lower prevalence of nuclear cataract with the intake of lutein and zeaxanthin over the seven years of follow-up.71 Serum levels of these carotenoids were also moderately associated with decreased prevalence of nuclear cataract in older women. In a 10 year prospective study conducted among 35 551 participants, women in the highest

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Table 2. Summary of supplementation trials with lutein and age-related macular degeneration Study and year Landrum et al., 1997 Reference number 28 Follow-up 140 days Study population Men, US Sample size 2 Supplement dose 30 mg lutein Results Signicant increase in serum lutein level and MPOD Signicant increase in serum lutein level and no effect on visual acuity Signicant increase in serum levels of lutein and zeaxanthin, and MPOD Signicant increase in serum level lutein and MPOD Signicant improvements in MPOD, visual acuity, contrast sensitivity, and glare recovery Signicant improvement in visual acuity

Rosenthal et al., 2006

57

6 months

Men and women, US

45

2.5 mg lutein; 5 mg lutein; 10 mg lutein

Huang et al., 2008

58

6 months

Men and women, US

40

10 mg lutein and 2 mg zeaxanthin

LUNA, Trieschmann et al., 2007

59

6 months

Men and women, Germany

136

12 mg lutein and 1 mg zeaxanthin

LAST, Richer et al., 2004

10

12 months

Men and women, US

90

10 mg lutein; 10 mg lutein plus antioxidants; placebo 8 mg lutein, 0.4 mg zeaxanthin plus antioxidants 10 mg lutein, 1 mg zeaxanthin plus antioxidants; placebo

TOZAL, Cangemi et al., 2007

61

6 months

Men and women, US

37

Parisi et al., 2008

60

12 months

Men and women, Italy

27

Signicant increases in multifocal electroretinogram N1P1 response amplitude densities of R1 and R2

LAST, Lutein Antioxidant Supplementation Trial; LUNA, LUtein Nutrition effects measured by Autouorescence study; MPOD, macular pigment optical density; TOZAL, the Taurine, Omega-3 Fatty Acids, Zinc, Antioxidant, Lutein study.

quintile of intake of lutein and zeaxanthin had an 18% lower risk of developing cataract compared to those in the lowest quintile.9 A signicant inverse trend was observed between lutein and zeaxanthin intakes and the risk of cataract after adjusted for other cataract risk factors. Olmedilla et al. designed a long-term supplementation with lutein to determine the effects of lutein on visual function of the cataract patients.72 Results showed serum levels of lutein and its metabolites increased signicantly, and visual performance indices such as visual acuity and glare sensitivity improved. Subsequently, in a randomised double-blind placebo-controlled study of dietary supplementation with lutein, -tocopherol or placebo in patients with cataract, Snellen visual acuity and glare sensitivity improved only in lutein-supplemented patients after the 2 year supplementation period, whereas there was a trend toward the maintenance of and decrease in visual acuity with -tocopherol and placebo supplementation, respectively.73

Retinitis pigmentosa Retinitis pigmentosa (RP) is a clinically heterogeneous group of inherited retinal degenerative diseases, characterised by degeneration of retinal photoreceptor cells, often leading to legal and eventually functional blindness.74 It is estimated that about 1.5 million people have RP worldwide. Most RP patients tend to share the experience of diminishing dark adaptation, night blindness and a progressive loss of peripheral vision at early disease stages. As visual loss in RP gradually progresses, they eventually lose central vision. Some patients become blind as early as age 30, and most are legally blind by age 60.75 Since no generally accepted medical treatment can stop the course of the disease, several researchers have undertaken studies with lutein and zeaxanthin supplements in hopes of improving patients functional vision, or at least slowing down the course of the disease.

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Table 3. Summary of epidemiological studies examining lutein and zeaxanthin and cataract Study and year BDES, Lyle et al., 1999 NHS, Chasan-Taber et al., 1999 HPFS, Brown et al., 1999 Gale et al., 2001 Reference 66 Study design, follow-up Cohort, 5 years Study population Men and women, US Women, US Sample size Exposure measure 1354 Lutein and zeaxanthin intake 77 466 Lutein and zeaxanthin intake 36 644 Lutein and zeaxanthin intake 372 Plasma lutein Plasma zeaxanthin 2322 Lutein and zeaxanthin intake 899 Plasma lutein Plasma zeaxanthin Plasma lutein and zeaxanthin 1802 Serum lutein and zeaxanthin Lutein and zeaxanthin intake 35 551 Lutein and zeaxanthin intake Comparison Quintile 5 vs 1 OR/RR (95% CI) 0.5 (0.30.8)

67

Cohort, 12 years

Quintile 5 vs 1

0.78 (0.630.95)

68

Cohort, 8 years

Men, US

Quintile 5 vs 1 >0.20 vs 0.14 mol L1 >0.05 vs 0.03 mol L1 Quintile 5 vs 1

0.81 (0.651.01)

69

Cross-sectional

Men and women, UK

0.5 (0.21.0) 0.7 (0.31.7) 0.64 (0.401.03)

MVIP, Vu et al., 2006 POLA, Delcourt et al., 2006

70

Cohort, 5 years

Men and women, Australia Men and women, France

52

Cross-sectional

Quintile 5 vs 1

0.82 (0.481.41) 0.57 (0.340.95) 0.65 (0.381.11)

CAREDS, Moeller et al., 2008

71

Cohort, 7 years

Women, US

Quintile 5 vs 1

0.68 (0.480.97) 0.77 (0.620.96)

Christen et al., 2008

Cohort, 10 years

Women, US

Quintile 5 vs 1

0.82 (0.710.95)

BDES, Beaver Dam Eye Study; CAREDS, Carotenoids in the Age-Related Eye Disease Study; CI, condence interval; HPFS, Health Professionals Follow-Up Study; MVIP, Melbourne Visual Impairment Project; NHS, Nurses Health Study; OR, odds ratio; POLA, Pathologies Oculaires Liees a lAge study; RR, relative risk.

In a small uncontrolled study, 16 RP patients received 40 mg lutein day1 for 9 weeks, and improvement in visual acuity and visual-eld area was found in one or both eyes.11 Subsequently, the study conducted by Aleman et al. demonstrated that supplementation with 20 mg lutein daily for 6 months could result in a signicant increase in MPOD in approximately half of the patients, while there was no detectable change in central visual function during the intervention.76 Likewise, a randomised controlled clinical trial demonstrated that lutein supplementation improved visual eld and also might improve visual acuity slightly in patients with RP.77 Adackapara et al. conducted a 48 week supplementation with lutein to evaluate the effect of lutein on retinal thickness of the patients with moderately advanced RP.78 Results showed that lutein did not exert a signicant effect on retinal thickness.

PROTECTIVE MECHANISMS OF LUTEIN AND ZEAXANTHIN IN EYE HEALTH

Antioxidant properties The human retina is particularly vulnerable to oxidative damage because of its high proportion of easily peroxidisable longchain polyunsaturated fatty acids (PUFA).79 High-energy shortwavelength visible light and high metabolic activity also promote the generation of reactive oxygen species (ROS) which are highly

reactive and readily react with lipid, protein and nucleic acids in the macula, thereby resulting in irreversible damage to various cell structures. It is generally believed that cumulative oxidative damage is in part responsible for the pathogenesis of AMD.80 Similarly, when the underlying epithelial cells in the lens are exposed to the action of exogenous and endogenous reactive oxygen species, the crystalline proteins cross-link and aggregate, and cataract is produced.81 The antioxidant properties of carotenoids have been proven mainly based on their abilities to quench singlet oxygen, scavenge free radicals, inhibit peroxidation of membrane phospholipids and reduce lipofuscin formation. Since lutein and zeaxanthin are the main carotenoids accumulating in the macula and lens, they are thought to play a unique role in the protection against light-initiated oxidative damage. Khachik et al. demonstrated the appearance of direct oxidative metabolites of lutein and zeaxanthin within the retina which are not of dietary origin, thereby conrming the antioxidant activity of these carotenoids in the eye.7,14 Meanwhile, these carotenoids were found in signicant quantities within the rod outer segment membranes of retina and epithelium/outer cortex of the lens, the parts which were most susceptible to oxidative damage, supporting the hypothesis that lutein and zeaxanthin protect these tissues against oxidative stress.81,82 Of note, biophysical and biochemical properties of xanthophyll carotenoids may affect photoreceptor

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Lutein and zeaxanthin and eye health membrane function by altering permeability, uidity, lipid phase properties, and the activation of membrane-bound proteins. Both of them can reside perpendicular to the plane of the membrane with the hydroxyl groups protruding from the lipid cell membrane into the intra- and extra-cellular plasma, and thus can interact with the ROS outside the membrane. This property makes them more effective antioxidants, in contrast with nonpolar carotenoids such as lycopene and -carotene.20,83 In addition, xanthophyll carotenoids, which effectively preserve membrane structure and decrease the oxygen diffusionconcentration products, control the rate of chemical reactions with oxygen and help to prevent the fatty acids from lipid peroxidation.22,84 Oxidised molecules and shed outer segment membrane of the photoreceptors are phagocytosed by the RPE. With age, the RPE gradually accumulate as lipofuscin, which is a potent photoinducible generator of ROS with production peaking in response to the blue light region of the visible spectrum.85 Lipofuscin reacts with neighbouring integral cellular molecules; impairs the activities of catalase, superoxide dismutase, and cathepsin D; and thereafter results in lipid peroxidation as well as RPE cellular dysfunction, leading to the damaging buildup of drusen which characterises AMD.86 N-retinylideneN-retinylethanolamine (A2E), a major uorophore of the RPE lipofuscin, is formed in rod outer segments by a sequence of reactions. The accumulation of A2E in RPE cells compromise both lysosomal function and structural integrity.87,88 Moreover, it may actually induce apoptosis of cultured RPE cells when exposed to blue light. The presence of lutein and zeaxanthin has been shown to reduce formation of lipofuscin in cultured RPE cells exposed to normobaric hyperoxia.85 In human retina, lipofuscin concentration in the RPE dips to a local minimum in the fovea, where highest levels of macular xanthophylls may help to retard photo-oxidative processes contributing to lipofuscin formation.89 Therefore, lutein and zeaxanthin appear to have benecial effects on decreasing the amount of lipofuscin and A2E formed and attenuating photooxidative damage of RPE cells induced by lipofuscin. Filters of blue light Excessive light exposure leads to retinal damage and increases the rate of photoreceptor apoptosis, and there is an exponential rise in the retinal injury with decreasing wavelength.90 Ham and colleagues analysed light induced retinal damage as a function of wavelength by exposing rhesus monkey retinas, and noted that the high-energy blue wavelengths of visible light were 100 times more effective at inducing retinal photochemical retinal injury than the low-energy red wavelengths of visible light.91 The spectrum of lutein and zeaxanthin includes a broad absorption band, with a peak at 450 nm roughly, and therefore these carotenoids can absorb and attenuate the damaging blue light before it reaches the photoreceptors.92 It has been estimated that macular carotenoids reduce the amount of blue light reaching the macula by as much as 40%.93 In human retina, lutein and zeaxanthin reach their highest concentrations in the photoreceptor axon layer and the inner plexiform layer of the fovea, which is also consistent with their roles as optical lters.38,94 The cumulative light damage of the retina is reected in the morphological and functional changes of the macula with aging, including reductions in cone density and retinal sensitivity of the short wavelength cone (S-cone). Reduced Scone sensitivity is found in the elderly and very early in the

www.soci.org development of retinal disease.95 It has been observed that there was a signicantly increased loss of S-cone sensitivity across the retina in the older group compared to the younger group; moreover, the S-cone sensitivity in central fovea, where macular xanthophyll levels are highest, suffers less sensitivity loss than elsewhere, indicating that macular xanthophylls may help retard age-related visual loss by preventing light-induced photoreceptor damage.96 Studies in quail exposed to bright light indicated that the number of apoptotic photoreceptors in light-damaged eyes was inversely correlated with the level of zeaxanthin in the retina. No such relationship was found between serum zeaxanthin and the number of apoptotic photoreceptors.15,97 Further studies reported that zeaxanthin supplementation in Japanese quail for 6 months markedly decreased levels of photoreceptor apoptosis in response to light damage.97 This evidence directly conrms the hypothesis that macular xanthophylls prevent or retard some of the destructive processes that ultimately lead to photoreceptor death. The ltering efcacy of lutein and zeaxanthin are superior to those of lycopene and -carotene in model membrane systems.98 The xanthophylls were incorporated in higher amounts into cell membranes in an orderly orientation, making them ideal optical lters.99 Furthermore, lutein has been reported to act quite differently in model membranes from zeaxanthin because of the subtle modication at one of its terminal rings (-ring).19 Zeaxanthin tends to span the bilipid layer occupying a site that lies perpendicular to the membrane surface with the hydroxyl groups in the water phase. Lutein, on the other hand, appears to have a different preferred orientation in which the hydroxyl group on the -ring is either vertical or horizontal to the membrane plane. The two orthogonal orientations of the lutein molecule allow absorption of light from all possible directions, thus making lutein have a greater ltering efcacy than zeaxanthin.22,100

CONCLUSIONS AND FUTURE CONSIDERATIONS

The xanthophylls, lutein and zeaxanthin, have specic distribution patterns in human tissue especially in the macula and lens. The presence of these xanthophylls is thought to provide a unique function in these two vital ocular tissues. Currently, an increasing number of epidemiological studies and clinical trials, but not all, have shown that higher levels of lutein and zeaxanthin in diet and serum are associated with a lower risk of eye diseases. Laboratory data also suggest an important role for these two carotenoids in protecting the neural retina from photo-oxidative damage and the development of common visually disabling disorders, by absorbing blue light and quenching ROS via the powerful antioxidant activity. The combination of evidence suggests that lutein and zeaxanthin may help to delay the series of events in the retina and the lens that lead up to age-related eye diseases and pigmentary abnormalities. However, it should be noted that the roles of lutein and zeaxanthin in the human eye are not completely understood, and the results from such studies have not been entirely consistent. Xanthophyll-binding proteins are likely to be involved in accumulation and stabilisation of these xanthophylls in the retina and the lens, but until recently little has been known about their specic capture and stabilisation mechanism, and the identity of possible lutein-binding protein has proven to be more elusive. Further evidence must be gathered to clarify the mechanism for high-afnity selective uptake of these carotenoids

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www.soci.org and to demonstrate the presence and the localisation of these carotenoids in the microstructure of retinal cells. Similarly, the current research on xanthophyll metabolism is limited and inconsistent. Bioavailabilities of xanthophyll carotenoids are likely affected by several factors at the various stages of digestion, absorption and transport process, possibly leading to more studies to elucidate the catabolism and physiological activity of these carotenoids. Although the most recent evidence available to support the possibility that lutein and zeaxanthin have an important role in reducing risk of eye diseases is somewhat consistent, the statistical power is limited by the relatively small sample size. Additional research is needed to establish the efcacy of the preventive and therapeutic aspects of these carotenoids in certain ocular abnormalities. Large-scale long-term prospective interventional trials need to be conducted to better understand the essentiality of lutein and zeaxanthin supplementation for reducing ocular disease risk and improving the clinical features of eye disorders in humans, and later to identify the effective daily dosages of lutein and zeaxanthin. Meanwhile, it is worth noting that incorporating ve portions of fruits and vegetables per day in the diet may be considered a healthy dietary choice, in addition to avoidance of certain unhealthy lifestyle factors, for preserving eye health.

L Ma, X-M Lin

ACKNOWLEDGEMENTS
The authors acknowledge support received from the National Natural Science Foundation of China (NSFC-30671758) and the Chinese Nutrition Society (No. 06 094). The authors declare no conicts of interests.

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