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 beneficial 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 specific 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
filtering activities and antioxidant properties. Although most studies point towards significant health benefits from lutein and
zeaxanthin, further large-scale randomised supplementation trials are needed to define 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 zeaxanthin could result in increasing their serum concentrations

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 identified 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 beneficial 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 α- and β-carotene, they do not have provitamin A
activity.4
Absorption of these two carotenoids is influenced 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
2
and macular pigment optical density, and these findings were
suggestive of a possible benefit 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 conflicting. Although the antioxidant
properties are thought to be primarily responsible for their
beneficial 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 defined 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 back-
ground 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 preven-
tion of AMD and other eye diseases.
References for this review were identified through a literature
search of the PubMed database and the Web of Science
database published up to April 2009. The literature search
was not confined to the English language, and relevant non-
English 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.
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 physicochem-
ical 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 efficiently 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 filters of blue light, and fluorescence emission studies
have confirmed 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
configuration 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 α- and β-carotene, lutein and
zeaxanthin can not be cleaved at the 15–15 bond by the specific
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 SOURCES OF LUTEIN
AND ZEAXANTHIN
Humans and primates do not have the capacity for de novo biosyn-
thesis of lutein and zeaxanthin, and therefore depend entirely on
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dietary sources of these compounds. Lutein is present in a wide va-
riety 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 lim-
ited to green, certain yellow–orange fruits and vegetables, most
abundantly in corn, nectarine, orange and papaya.3 Eggs, though
not the richest dietary source of lutein and zeaxanthin, are consid-
ered 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 difficult 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
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 day−1 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 day−1 .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 Mexican–Americans.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 influence
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
3
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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 β-
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-specific but
mutually beneficial. 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 post-
ingestion.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 reflects 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 L−1 within the Henle fibre
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 specific and efficient.24 Studies of tissue-specific
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-specific xanthophyll
binding proteins might mediate lutein and zeaxanthin capture.
Tubulin, present in abundance within the axonal layer of the
fovea, was initially identified 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-specific binding affinity. In a recent
report, a Pi isoform of glutathione S-transferase (GSTP1), as a
specific xanthophyll binding protein, was purified and isolated
from the Henle fibre region of the fovea, with high affinity and
specificity 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
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 in-
dustrialised countries.43 Two types of AMD exist: early (or dry)
4
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L Ma, X-M Lin
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 Bruch’s membrane, while late-stage manifestations encom-
pass choroidal neovascularisation (CNV), subretinal haemorrhage,
detachment of RPE, and retinal scarring.44,45 Although the patho-
physiology 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 pig-
ment, it comes as no surprise that lutein and zeaxanthin have the
beneficial effects on preventing the onset and progression of AMD.
Results from epidemiological studies that evaluated the rela-
tionship between dietary intake and/or blood levels of xanthophyll
carotenoids and AMD were not consistent; however, most indi-
cated a protective relationship (Table 1). Using the Eye Disease
Case–Control 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 sub-
jects 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 significant reduced risk for
AMD. The subsequent analysis of consumption of specific 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 findings.48
Nonetheless, it was noteworthy that this study found a clear in-
verse dose–response 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 co-
hort of 1787 participants, and found a significant 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 first 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 significantly 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 design, Study Exposure
Study and year Reference follow-up population Sample size measure Comparison OR/RR (95% CI)

EDCCS, 1993 50 Case–control Men and 421 cases, 615 Serum lutein ≥0.668 vs 0.3 (0.2–0.6)
women, US controls and ≤0.247 µmol
zeaxanthin L−1
EDCCS, Seddon 47 Case–control Men and 356 cases, 520 Lutein and Quintile 5 vs 1 0.43 (0.2–0.7)
et al., 1994 women, US controls zeaxanthin
intake
BDES, 54 Nested Men and 167 cases, 167 Serum lutein Quintile 5 vs 1 1.4 (0.7–2.5)
Mares-Perlman case–control women, US controls and
et al., 1995 zeaxanthin
Bone et al., 1997 53 Case–control Men and 56 cases, 56 Retinal lutein Quartile 4 vs 1 0.18 (0.05–0.64)
women, US controls and
zeaxanthin
Snellen et al., 48 Case–control Men and 72 cases, 66 Lutein and Quartile 4 vs 1 0.4 (0.2–0.9)
2002 women, controls zeaxanthin
Netherlands intake
Gale et al., 2003 51 Cross-sectional Men and 380 Plasma lutein Tertile 3 vs 1 0.59 (0.30–1.11)
women, UK
Plasma 0.50 (0.24–1.00)
zeaxanthin
Plasma lutein 0.53 (0.29–1.11)
and
zeaxanthin
CAREDS, Moeller 49 Cohort, 7 years Women, US 1787 Lutein and Quintile 5 vs 1 0.57 (0.34–0.95)
et al., 2006 zeaxanthin
intake
POLA, Delcourt 52 Cross-sectional Men and 899 Plasma lutein Quintile 5 vs 1 0.31 (0.09–1.07)
et al., 2006 women,
France
Plasma 0.07 (0.01–0.58)
zeaxanthin
Plasma lutein 0.21 (0.05–0.79)
and
zeaxanthin
AREDS, 2007 8 Case–control Men and 1568 casesa , Lutein and Quintile 5 vs 1 0.73 (0.56–0.96)
women, US 1115 controls zeaxanthin
intake
118 casesb , 0.45 (0.24–0.86)
1115 controls
658 casesc , 0.65 (0.45–0.93)
1115 controls
Robman et al., 56 Cohort, 7 years Men and 254 Lutein and Quintile 5 vs 1 2.65 (1.13–6.22)
2007 women, zeaxanthin
Australia intake
Cho et al., 2008 55 Cohort, Men and 113 058 Lutein and Quintile 5 vs 1 1.18 (0.64–2.17)
18 years women, US zeaxanthin
intake
BMES, Tan et al., 26 Cohort, Men and 3654 Lutein and Tertile 3 vs 1 0.35 (0.13–0.92)
2008 10 years women, zeaxanthin
Australia intake

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, confidence interval; EDCCS, Eye Disease Case Control Study Group; OR, odds ratio;
POLA, Pathologies Oculaires Lie’es a’ l’Age 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 significantly
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 confirms the above
correlation.53 In this case–control 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 significantly lower in eyes with
5

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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 first of its kind to specifically 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 confirmed by
other investigators.54,55 For example, Mares-Perlman et al. failed
to confirm 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 reflect differences in the study
design and methods used to define 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 day−1 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 two-
fold, 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 significantly 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 supplemen-
tation 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 perfor-
mance 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 sig-
nificant improvements in visual acuity, contrast sensitivity and
glare recovery. Likewise, Parisi et al. evaluated the influence of
supplementation on retinal function in non-advanced AMD pa-
tients and in healthy control subjects by recording multifocal
electroretinograms.60 A significant increase in response ampli-
tude 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 opacification 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 β-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 significantly
associated with intake of lutein plus zeaxanthin. The published
data from the POLA study showed only plasma zeaxanthin, but
not lutein, was significantly 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
Reference Sample
Study and year number Follow-up Study population size Supplement dose Results

Landrum et al., 1997 28 140 days Men, US 2 30 mg lutein Significant

increase in
serum lutein
level and
MPOD
Rosenthal et al., 2006 57 6 months Men and women, US 45 2.5 mg lutein; Significant
5 mg lutein; increase in
10 mg lutein serum lutein
level and no
effect on visual
acuity
Huang et al., 2008 58 6 months Men and women, US 40 10 mg lutein and Significant
2 mg increase in
zeaxanthin serum levels of
lutein and
zeaxanthin,
and MPOD
LUNA, Trieschmann 59 6 months Men and women, 136 12 mg lutein and Significant
et al., 2007 Germany 1 mg increase in
zeaxanthin serum level
lutein and
MPOD
LAST, Richer et al., 10 12 months Men and women, US 90 10 mg lutein; Significant
2004 10 mg lutein improvements
plus in MPOD, visual
antioxidants; acuity, contrast
placebo sensitivity, and
glare recovery
TOZAL, Cangemi 61 6 months Men and women, US 37 8 mg lutein, Significant
et al., 2007 0.4 mg improvement
zeaxanthin in visual acuity
plus
antioxidants
Parisi et al., 2008 60 12 months Men and women, 27 10 mg lutein, Significant
Italy 1 mg increases in
zeaxanthin multifocal elec-
plus troretinogram
antioxidants; N1–P1
placebo response
amplitude
densities of R1
and R2

LAST, Lutein Antioxidant Supplementation Trial; LUNA, LUtein Nutrition effects measured by Autofluorescence 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 significant 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 significantly, 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, α-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
α-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.
7

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 www.soci.org L Ma, X-M Lin

Table 3. Summary of epidemiological studies examining lutein and zeaxanthin and cataract
Study design, Sample
Study and year Reference follow-up Study population size Exposure measure Comparison OR/RR (95% CI)

BDES, Lyle et al., 66 Cohort, 5 years Men and women, 1354 Lutein and Quintile 5 vs 1 0.5 (0.3–0.8)
1999 US zeaxanthin
intake
NHS, 67 Cohort, 12 years Women, US 77 466 Lutein and Quintile 5 vs 1 0.78 (0.63–0.95)
Chasan-Taber zeaxanthin
et al., 1999 intake
HPFS, Brown 68 Cohort, 8 years Men, US 36 644 Lutein and Quintile 5 vs 1 0.81 (0.65–1.01)
et al., 1999 zeaxanthin
intake
Gale et al., 2001 69 Cross-sectional Men and women, 372 Plasma lutein >0.20 vs ≤0.14 µmol L−1 0.5 (0.2–1.0)
UK
Plasma >0.05 vs ≤0.03 µmol L−1 0.7 (0.3–1.7)
zeaxanthin
MVIP, Vu et al., 70 Cohort, 5 years Men and women, 2322 Lutein and Quintile 5 vs 1 0.64 (0.40–1.03)
2006 Australia zeaxanthin
intake
POLA, Delcourt 52 Cross-sectional Men and women, 899 Plasma lutein Quintile 5 vs 1 0.82 (0.48–1.41)
et al., 2006 France
Plasma 0.57 (0.34–0.95)
zeaxanthin
Plasma lutein and 0.65 (0.38–1.11)
zeaxanthin
CAREDS, Moeller 71 Cohort, 7 years Women, US 1802 Serum lutein and Quintile 5 vs 1 0.68 (0.48–0.97)
et al., 2008 zeaxanthin
Lutein and 0.77 (0.62–0.96)
zeaxanthin
intake
Christen et al., 9 Cohort, 10 years Women, US 35 551 Lutein and Quintile 5 vs 1 0.82 (0.71–0.95)
2008 zeaxanthin
intake

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

In a small uncontrolled study, 16 RP patients received
40 mg lutein day−1 for 9 weeks, and improvement in visual
acuity and visual-field 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 significant 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 field 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 significant 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 long-
chain polyunsaturated fatty acids (PUFA).79 High-energy short-
wavelength visible light and high metabolic activity also promote
the generation of reactive oxygen species (ROS) which are highly
8
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 confirming the antioxidant activity of these carotenoids
in the eye.7,14 Meanwhile, these carotenoids were found in
significant 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, fluidity, 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
β-carotene.20,83 In addition, xanthophyll carotenoids, which
effectively preserve membrane structure and decrease the oxygen
diffusion–concentration 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-retinylidene-
N-retinylethanolamine (A2E), a major fluorophore 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 beneficial 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
filters.38,94 The cumulative light damage of the retina is reflected
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 S-
cone sensitivity is found in the elderly and very early in the
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development of retinal disease.95 It has been observed that there
was a significantly 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 confirms the
hypothesis that macular xanthophylls prevent or retard some of
the destructive processes that ultimately lead to photoreceptor
death.
The filtering efficacy of lutein and zeaxanthin are superior to
those of lycopene and β-carotene in model membrane systems.98
The xanthophylls were incorporated in higher amounts into
cell membranes in an orderly orientation, making them ideal
optical filters.99 Furthermore, lutein has been reported to act
quite differently in model membranes from zeaxanthin because
of the subtle modification at one of its terminal rings (ε-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 ε-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 filtering efficacy than zeaxanthin.22,100
CONCLUSIONS AND FUTURE
CONSIDERATIONS
The xanthophylls, lutein and zeaxanthin, have specific 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 specific 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-affinity selective uptake of these carotenoids
9
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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 efficacy 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
five 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.
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
conflicts of interests.
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