Available via license: CC BY 4.0
Content may be subject to copyright.
molecules
Review
The Pharmacological Effects of Lutein and Zeaxanthin
on Visual Disorders and Cognition Diseases
Yu-Ping Jia 1,† , Lei Sun 1, †, He-Shui Yu 1, Li-Peng Liang 1, Wei Li 1, Hui Ding 2, Xin-Bo Song 1,2
and Li-Juan Zhang 1, *
1College of Pharmaceutical Engineering of Traditional Chinese Medicine,
Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; 15692232675@163.com (Y.-P.J.);
sunleitj2013@163.com (L.S.); hs_yu08@163.com (H.-S.Y.); 15692232573@163.com (L.-P.L.);
cheercathy@163.com (W.L.); songxinbo@tjutcm.edu.cn (X.-B.S.)
2Tianjin Zhongyi Pharmaceutical Co., Ltd., Tianjin 300193, China; dinghui.hn@163.com
*Correspondence: zhanglijuan@tjutcm.edu.cn or lijuanzhang63@163.com; Tel.: +86-22-2749-4976
† These authors contribute equally to this work.
Academic Editor: Derek J. McPhee
Received: 21 February 2017; Accepted: 6 April 2017; Published: 20 April 2017
Abstract:
Lutein (L) and zeaxanthin (Z) are dietary carotenoids derived from dark green leafy
vegetables, orange and yellow fruits that form the macular pigment of the human eyes. It was
hypothesized that they protect against visual disorders and cognition diseases, such as age-related
macular degeneration (AMD), age-related cataract (ARC), cognition diseases, ischemic/hypoxia
induced retinopathy, light damage of the retina, retinitis pigmentosa, retinal detachment, uveitis and
diabetic retinopathy. The mechanism by which they are involved in the prevention of eye diseases
may be due their physical blue light filtration properties and local antioxidant activity. In addition to
their protective roles against light-induced oxidative damage, there are increasing evidences that L
and Z may also improve normal ocular function by enhancing contrast sensitivity and by reducing
glare disability. Surveys about L and Z supplementation have indicated that moderate intakes of L
and Z are associated with decreased AMD risk and less visual impairment. Furthermore, this review
discusses the appropriate consumption quantities, the consumption safety of L, side effects and future
research directions.
Keywords: lutein; zeaxanthin; carotenoids; AMD; ARC; cataract; cognition; ADI
1. Introduction
Carotenoids can be divided into two main classes: carotenes and xanthophylls. Carotenes are
non-polar molecules, which contain only carbon and hydrogen atoms, while xanthophylls are polar
carotenoids, which contain at least one oxygen atom [
1
]. In addition, xanthophylls can be subdivided
into hydroxycarotenoids containing one or two hydroxyl groups and ketocarotenoids containing
ketone groups. Over 600 types of carotenoids are found in Nature, of which 30–50 are part of the
normal human diet. However, only 10–15 are routinely detectable in the human serum, including lutein
(L), zeaxanthin (Z) and their metabolites [
2
–
5
]. L and Z are dietary carotenoids derived from dark
green leafy vegetables, oranges, yellow fruits and vegetables that form the macular pigment of human
eyes [
6
]. They cannot be synthesized in mammals and must be obtained from the diet for distribution to
various tissues, especially the retina [
7
]. Previous studies have shown that macular pigments (MPs) are
related to many static indicators of visual performance, such as visibility, disability glare and the critical
flicker fusion threshold (CFF) [
8
]. In addition, MPs may help to protect against age-related macular
degeneration (AMD) because of their effect on blue light filtration and local antioxidant activity [
9
].
MPs also have anti-inflammatory and light-screening properties [
7
,
9
]. As the important components of
Molecules 2017,22, 610; doi:10.3390/molecules22040610 www.mdpi.com/journal/molecules
Molecules 2017,22, 610 2 of 22
the MPs, L and Z are selectively concentrated in the foveal region [
10
,
11
] where they account for the
characteristic central yellow coloration known as the primate macula lutea. Their concentrations are
almost 1 mM in the Henle fiber layer which corresponds to the axons of the foveal photoreceptors.
Z dominates the center region, while L is dominant in the peripheral region of the retina [
12
].
The concentration of the macular pigment drops nearly 100 fold within just 1–2 mm from the foveal
center [
13
]. Another carotenoid, meso-zeaxathin (MZ), which is a stereoisomer of Z, is converted
from L within the retina [
1
]. The position of the double bond in one of the rings in L and Z molecules
creates differences in the distribution of these two macular pigments in the retina. In the inner macula,
the concentration of Z is about twice that of L. As eccentricity from the fovea increases, the ratio of
concentrations continuously changes, with L becoming the dominant component in the peripheral
retina. At distances exceeding 6 mm from the fovea, the L:Z ratio is between 2:1 and 3:1 [
14
,
15
].
Their antioxidant properties are due to their abilities to quench singlet oxygen, scavenge superoxide
and hydroxyl radicals, to protect membrane phospholipids against UV-induced peroxidation, and to
reduce lipofuscin formation. In addition, the maximum absorption of these MP is about 450 nm,
which is consistent with the action spectrum for light-induced damage [
16
]. Moreover, L and Z were
incorporated in higher amounts into cell membranes in a single orientation, making them behave like
optical filters to some extent. Therefore these MP could absorb and attenuate the photic damage in the
human lens [
17
]. In the inner retina they may serve as a filter for high energy and short wave-length
blue light [
18
,
19
], which may protect the outer retina from photochemical injury induced by these
high energy wavelengths [
20
]. Although blue light has a high energy, blue light filtration may be one
of the functions of MP [
21
]. L and Z are also found in the rod and presumably cone outer segments.
While in the outer retina, they may serve as antioxidants. Photoreceptor outer segments contain
chromophores that act as photosensitizers susceptible to oxidative damage. L and Z are capable of
quenching reactive oxygen species produced from chromophore irradiation, which may protect the
retina from the deleterious effects of lipid peroxidation [14].
It is generally assumed that the presence of L and Z is not incidental; rather, such high
accumulation in functional areas (like the fovea) implies that L and Z may have some functions [
22
].
There are three major hypotheses for function of L and Z are commonly proposed, i.e., the acuity,
visibility, and protective hypotheses [
16
,
23
]. These hypotheses are all based on just two fundamental
characteristics of the MP, i.e., their light filtration and antioxidant characteristics.
The eye is a major sensory organ that requires special care for a healthy and productive lifestyle.
Numerous studies have identified L and Z to be important components for eye health. Their role
in human health, in particular the health of eyes, is established from epidemiological, clinical and
interventional studies [
5
,
8
]. They constitute the main MPs found in the yellow spot of the human
retina which protect the macula from damage by blue light, improve visual acuity and scavenge
harmful reactive oxygen species. They have also been linked with reducing the risk of AMD and
ARC. They may also enhance visual performance by decreasing chromatic aberration and enhancing
contrast sensitivity [
24
]. Besides, research over the past decade mainly focused on the development of
carotenoid-rich foods to boost their intake especially for the elderly population [25–27].
In the human retina, the concentration of carotenoids reaches a level between 0.1 and 1 mM
in the central fovea [
28
], which is about 1000 times higher than in other tissues. Both xanthophylls
are accumulated in the region of photoreceptor axons [
29
] and within photoreceptor outer segments
(POSs) [
30
]. Although, macular xanthophylls in POS constitute about 10–25% of the amount in the
entire retina [
30
], the local concentration of macular xanthophylls in membranes of the rod outer
segment is about 70% higher than in residual retina membranes [
30
]. Moreover, Muller cells have also
been suggested as a place for xanthophyll accumulation [31].
Although L and Z differ only by the placement of a single double bond, this small change in
configuration has a great impact on the function of these two carotenoids [
32
]. Compared to L, Z is a
much more effective antioxidant [
33
]. MZ also has a greater capability of quenching oxygen radicals
than L [
13
]. The functional differences of these carotenoids correlate with the spatial distribution
Molecules 2017,22, 610 3 of 22
of L, MZ, and Z. The ratio of L to Z varies linearly with the ratio of rods to cones in the fovea.
MZ and Z predominate where cone density is highest and risk of oxidative damage is greatest [
33
].
The macular pigments also differ in other aspects. For example, L has a greater filtering efficiency,
and Z is superior in preventing lipid peroxidation induced by UV light [
34
]. These essential functions
of macular pigment may decrease oxidative stress in the retina and enhance vision in both normal
and diseased retinas. Although the structure and properties of L and Z to carotenoids are similar,
there are special properties for L and Z because of the oxygen in their structure. It is these special
properties that account for the biological functions of L and Z [
35
]. Nevertheless, there are negative
effects of L and Z. For example, increased risk of lung cancer in smokers after L and Z supplementation
and the development of crystalline maculopathy after supplementation of high dosages of L and
Z [
36
]. Besides, continuous intake of high doses of L may result in skin yellowing [
37
]. In this review,
the pharmacological effects and mechanisms of L and Z on visual disorders and cognition diseases are
summarized. Also, the safe dosages of L and Z as well as their structure-activity relationships are well
illustrated. In addition, areas requiring further research on L and Z are also introduced.
2. The Structure and Distribution of L and Z
L and Z are relatively polar carotenoids pigments found at high levels in parsley, spinach, kale,
egg yolk and lutein-fortified foods. Snodderly [
38
] demonstrated several beneficial health effects due
to their ability to act as scavengers for reactive oxygen species and to bind with physiological proteins
in humans. In general, carotenoids are tetraterpenoids with 40 carbon skeleton made up of eight
isoprene units and comprising two classes, namely the carotenes (purely unsaturated hydrocarbons)
and carotenoids with oxygen atoms, which are referred to as oxygenated carotenoids or xanthophyll
carotenoids. The macular carotenoids are dietary L and Z, and their conversion isomer MZ, which are
non-provitamin A carotenoids, (i.e., they cannot be converted into vitamin A). Important members
of the oxygenated carotenoids are L, Z,
β
-cryptoxanthin, capsanthin, astaxanthin, and fucoxanthin.
The percentages of main carotenoids in human serum are L (20%), lycopene (20%),
β
-carotene (10%);
β
-cryptoxanthin (8%),
α
-carotene (6%) and Z (3%) [
4
]. L and Z are the main dietary carotenoids found
in the human retina [
39
] and they probably protect the macula from being damaged by blue light,
improve visual acuity and scavenge harmful reactive oxygen species [
17
–
21
]. L and Z, along with
their common metabolite MZ, are commonly referred to as the macular pigments (MPs) [
14
]. The ratio
between L, Z and MZ changes as the eccentricity moves away from fovea [
12
,
40
]. Although L and Z
were also detected in prenatal eyes, they did not form visible yellow spots. No age-related (between
the ages of 3 and 95 years) differences were observed in the quantity of L and Z [
40
], but the ratio of
L to Z differed between infants and adults. In infants, L predominates over Z in the fovea, and the
opposite is true after 3 years of age [
40
,
41
]. Structurally the difference between L and Z is in the type of
ionone ring. L contains a
β
-ionone ring and an
ε
-ionone ring, whereas Z has two
β
-ionone rings. L and
Z are isomers, but not stereoisomers, which differ in the location of a double bond unsaturation in the
end ring. L can exist in eight possible stereoisomeric forms because of its three chiral centers, but in
Nature it exists mainly in the Z(cis)-form (R,R,R). Z, on the other hand, has two chiral centers but,
because of symmetry exists in only three stereoisomeric forms: (R,R), (S,S) and (R,S-meso). Although
plants and microorganisms can synthesize and interconvert carotenes and xanthophylls, mammals
cannot perform these biochemical reactions and need to obtain all of these carotenoids from the diet.
The process of accumulation of L and Z in the eye is specific. Because of the different structures and
distribution of L and Z, they may play mutual effects on visual disorders and cognition diseases.
The structures of L, Z and their stereoisomers are shown in Figure 1.
Molecules 2017,22, 610 4 of 22
Molecules 2017, 22, 610 4 of 21
all-E-lutein [39]
(13Z)-lutein [42]
(13Z)-zeaxanthin [43]
(13′Z)-lutein [44]
Figure 1. Cont.
Figure 1. Cont.
Molecules 2017,22, 610 5 of 22
Molecules 2017, 22, 610 5 of 21
(9Z)-lutein [43]
(9Z)-zeaxanthin [43]
(9′Z)-lutein [45]
Figure 1. Cont.
Figure 1. Cont.
Molecules 2017,22, 610 6 of 22
Molecules 2017, 22, 610 6 of 21
(9Z,9′Z)-lutein [44]
meso-zeaxanthin [39]
Zeaxanthin [46]
Figure 1. The structures of L, Z and their stereoisomers.
3. The Effects on AMD
Age-related macular degeneration (AMD), the leading cause of blindness in the developed
world [35,40,47], accounts for more than 50% of all blindness in the US [48]. In the UK, almost
200,000 people aged 75 years or older were visually impaired due to AMD [49]. It represents a
progressive chronic disease of the central retina [50]. Owing to the sharp rise in the elderly population,
the disease has brought a huge burden for the health care system and had a profound impact on the
quality of life and independence of older individuals. It is estimated that by the year 2020 the number
of patients with late AMD will increase more than 50% to almost three million in the USA alone [51].
Although the pathogenesis of AMD is poorly understood, oxidative stress [52] has been implicated
as a major contributing factor. As L and Z are antioxidants selectively absorbed and maintained in
the retina, their role in AMD has been studied extensively. AMD is a progressively degenerative
disease at the central area of the retina, which results in severe visual impairment [53]. The cause of
AMD is complex, and many risk factors have been implicated including age, genetics, diet and other
environmental risk factors [35]. Epidemiological studies suggested that the appropriate consumption
of L and Z may be associated with lower risk of AMD [54,55].
The AMD risk factors discussed above are largely unmodifiable, so it has been important for
epidemiologists to focus on identifying readily modifiable risk factors that can be easily translated
into public health recommendations. First and foremost, smoking has been consistent due to its
oxidative burden on the body along with possible microvascular stresses. Besides, excessive light
exposure has been proven to be a more controversial risk factor for AMD due to the difficulty in
quantifying lifetime light exposure, so positive studies have largely concentrated on individuals with
extreme levels of daily sun exposure such as fishermen who have lower rates of AMD if they use sun
protection with hats and sunglasses relative to their compatriots who do not routinely employ such
Figure 1. The structures of L, Z and their stereoisomers.
3. The Effects on AMD
Age-related macular degeneration (AMD), the leading cause of blindness in the developed
world [
35
,
40
,
47
], accounts for more than 50% of all blindness in the US [
48
]. In the UK,
almost 200,000 people aged 75 years or older were visually impaired due to AMD [
49
]. It represents a
progressive chronic disease of the central retina [
50
]. Owing to the sharp rise in the elderly population,
the disease has brought a huge burden for the health care system and had a profound impact on the
quality of life and independence of older individuals. It is estimated that by the year 2020 the number
of patients with late AMD will increase more than 50% to almost three million in the USA alone [
51
].
Although the pathogenesis of AMD is poorly understood, oxidative stress [
52
] has been implicated
as a major contributing factor. As L and Z are antioxidants selectively absorbed and maintained in
the retina, their role in AMD has been studied extensively. AMD is a progressively degenerative
disease at the central area of the retina, which results in severe visual impairment [
53
]. The cause of
AMD is complex, and many risk factors have been implicated including age, genetics, diet and other
environmental risk factors [
35
]. Epidemiological studies suggested that the appropriate consumption
of L and Z may be associated with lower risk of AMD [54,55].
The AMD risk factors discussed above are largely unmodifiable, so it has been important for
epidemiologists to focus on identifying readily modifiable risk factors that can be easily translated into
public health recommendations. First and foremost, smoking has been consistent due to its oxidative
burden on the body along with possible microvascular stresses. Besides, excessive light exposure has
been proven to be a more controversial risk factor for AMD due to the difficulty in quantifying lifetime
light exposure, so positive studies have largely concentrated on individuals with extreme levels of
daily sun exposure such as fishermen who have lower rates of AMD if they use sun protection with
Molecules 2017,22, 610 7 of 22
hats and sunglasses relative to their compatriots who do not routinely employ such measures [
56
].
Also, animal models of AMD and cell culture studies
in vitro
have generally concluded that short
wavelength visible light is more damaging than longer visible wavelength, a phenomenon commonly
referred as the “blue light hazard” [18,57].
Increasing understanding of the pathogenesis of AMD revealed that cathepsin B and cystatin
C have important functions in the catabolism of outer membranous disc of visual cells. Cathepsin B
is a thiol-dependent lysosomal proteinase that can degrade collagens, connective tissue proteins,
and certain native enzymes [
58
]. Furthermore, the expression of cathepsin B and cystatin C was
significantly increased at both gene and protein levels in mice with an experimental model of AMD,
which further strengthened the association of these two enzymes with the development of AMD [
59
].
Visual cells also secrete cystatin C, resulting in protection of the surface proteins from degradation.
More recently, epidemiological evidence showed that cystatin C is associated with increased risk of
developing exudative AMD [
60
]. Furthermore, matrix metalloproteinases (MMPs) and tissue inhibitor
of metalloproteinases (TIMPs) produced by retinal pigment epithelium (RPE) cells are critically
involved in maintaining the homeostasis of matrix components in the eye tissues [
61
]. Currently,
attention has been increasingly paid to these molecular events previously not considered in the
context of RPE-driven mechanisms of AMD pathogenesis. Early AMD is characterized clinically by
yellowish deposits known as soft drusen accumulations and pigmentary abnormalities in the retinal
pigment epithelium (RPE) and Bruch’s membrane. Whereas most of the visual loss occurs in the late
stages of the disease due to one of two processes: neovascular AMD (wet AMD) and atrophic AMD
(dry AMD) [
47
,
62
,
63
]. The recent few decades have witnessed advances in the treatment of wet AMD.
Anti-angiogenic agents targeting choroidal neovascularization such as pegaptanib, bevacizumab, and
ranibizumab have shown a therapeutic promise for wet AMD [64,65].
The eye is an exceptional organ because of its continuous exposure to environmental chemicals,
radiation, and atmospheric oxygen. There is a general consensus that cumulative oxidative damage
is responsible for aging and may, therefore, play an important role in the pathogenesis of AMD [
66
].
Oxidative stress may cause injury to RPE [
67
], Bruch membrane [
68
], and choroid, which are layers
in the eye involved in the pathophysiology of AMD. Antioxidant strategy has been proposed and
tested in the treatment of dry AMD [
69
]. Apart from being related to aging, recent studies showed that
hydroquinone, a major prooxidant in cigarette smoke, atmospheric pollutants, sunlight exposure
and diet [
70
,
71
] induced actin reorganization and bleb formation involved in sub-RPE deposits
formation relevant to the pathogenesis of AMD [
72
]. Epidemiological evidence has shown that
high-fat diet, especially consumption of saturated fats, is associated with the incidence of AMD [
73
].
Recent animal studies demonstrated that genetic C57BL/6 mice with hyperlipemia did not show
significant RPE sediment, but the sediment was considerably increased when combined with blue
light exposure, suggesting that oxidative injury caused by light exposure was necessarily required for
massive formation of RPE sediment [74].
Under normal conditions, MMP-2 and TIMP-2 are expressed coordinately and maintained the
homeostasis of matrix components in eye tissues. In the pathogenesis of AMD, the equilibrium between
MMP-2 and TIMP-2 is disrupted, promoting the progression of the disease [
75
]. Present data [
59
]
showed that these two molecules were all upregulated in ARPE-19 cells under oxidative stress.
However, L/Z abolished the elevated expression of MMP-2 and TIMP-2 in H
2
O
2
-treated ARPE-19
cells, suggesting that L/Z could be beneficial for oxidative stress-involved AMD by regulating
matrix homeostasis.
Genome-wide association studies (GWAS) have decisively shown that more than half of AMD risk
is genetically determined by two major genetic loci, one on chromosome 1 encoding for complement
factor H and the other related complement genes and another one on chromosome 10 encoding for the
HTRA 1 and ARMS 2 genes, along with a large number of minor gene loci that can modestly enhance
protection against or risk of development of AMD [
76
]. Merle et al. suggested that LIPC and LPL
genes could both modify the risk for AMD and the metabolism of L and Z [77].
Molecules 2017,22, 610 8 of 22
Since late AMD not only jeopardizes a patient’s visual function and quality of life, but also
brings a tremendous socioeconomic burden, most treatment strategies are focused on addressing late
AMD [
78
]. However, the treatment of AMD at an earlier stage might slow the progression before
irreversible visual impairment occurs, which would be more effective in enhancing or maintaining
visual performances [
47
]. A meta-analysis showed that the dietary intake of L and Z could lead to
a 4% reduction in the risk of developing early AMD, as opposed to a 26% reduction for late AMD,
indicating that L/Z might be more effective in reducing the risk of progression from early AMD to late
AMD [79].
Current publications on the preventive and therapeutic effects of L and Z on AMD have reported
encouraging results [
80
]. Chew [
53
] et al. reported that a beneficial effect of L/Z was identified
when the entire study population was included, specifically, L/Z decreased the risk of progression
to advanced neovascular AMD by 10%; in the secondary analysis [
81
], patients who had the lowest
dietary intake of L/Z had a 26% decrease in the risk of disease progression. Subgroup analysis
showed additional benefits. The patients who took the AREDS formulation with L/Z and no
beta-carotene had 18% decrease in their risk of developing advanced AMD over the course of study
compared to those who took the AREDS formulation with beta-carotene and no L/Z, as well as
a 22% decrease in progression to neovascular AMD. The substitution of beta-carotene by L may
further improve the formulation [
82
]. Nevertheless, the recently concluded Age-Related Eye Disease
Study 2 (AREDS2) trial was unable to confidently demonstrate protective effects of L/Z [
81
,
83
],
and whether L/Z may protect against early AMD also remains unknown. In a National Eye Institute
press release [
84
], the primary outcome was clearly stated: “The plant-derived antioxidants L and Z
also had no overall effect on AMD when added to the combination; however, they may be safer than the
related antioxidant beta-carotene [
85
]”. Some AMD trials have found that, although macular pigment
optical density (MPOD) increased after L supplementation, visual function did not show significant
improvements
[83,86]
. This may because significant morphological changes do not adversely affect
retinal function at the earlier stage, leaving little room for measurable improvement [
87
]. This supports
the notion that early intervention might be more effective in enhancing or maintaining visual
function [88].
Various observational and interventional studies have suggested that the supplementation of L
and Z might reduce the risk of AMD [
18
,
55
,
57
,
79
,
83
,
89
–
103
]. Therefore, adding L and Z, along with
other minerals and antioxidants to the diet in subjects with low MPOD might result in an increase
in MPOD scores. Interestingly, in subjects that did not add supplementation to their diet the MPOD
scores were reduced. Although diet can play a major role in the increase or decrease of MPOD, the data
point to the possibility of enhancement of low MPOD through supplementation [94].
4. The Effects on ARC
Cataract is a clouding or opacification of the lens inside the eye that obstructs the passage of
light [
95
]. Age-related cataract (ARC) is the leading causes of blindness and vision impairment
worldwide [
96
,
104
]. It was estimated that 20 million people older than 40 years old were visually
impaired due to ARC in the United States [
97
]. In developing countries, cataracts are the principal cause
of blindness among people over 40 years of age due to improper nutrition and infectious diseases [
35
].
Although new therapeutic methods emerged in recent years and most ARC cases could be cured,
the high treatment costs and increasing demands for therapy will challenge the long-term economic
stability of health care systems [
98
,
100
]. With the rapidly aging population, ARC has brought a massive
burden on health care and become an important public health issue. Thus, identifying modifiable
factors available to prevent or delay the development of ARC is a crucial strategy.
The cumulative oxidation of proteins or lipids within the lens has been found to be involved in
the pathogenesis of cataract, and nutritional antioxidants might protect the lens against formation of
cataract [
100
–
102
]. Light-initiated oxidative damages are hypothesized to be the mechanism involved
in ARC [
103
] and antioxidants might prevent or minimize oxidative damage to the lens [
101
,
105
].
Molecules 2017,22, 610 9 of 22
As the only carotenoids present in the lens, L and its isomer Z are capable of filtering out ultraviolet
light and blue light, scavenging free radicals, and thereby possibly decreasing light-induced oxidative
damage to the lens, which indicates that they may play a protective role in the prevention of
cataract [18,57].
Risk factors for cataract development include increasing age, diabetes [
106
], smoking [
107
],
alcohol use, trauma, and prolonged exposure to UV light [
108
]. A longitudinal study has shown
that plasma Z reduces the risk of cataract [
109
]. Xanthophylls, in particular Z, could attenuate
photochemical damage by filtering high-energy short-wavelength light [
110
]. In addition, they serve to
protect the lens from oxidative damage by scavenging reactive oxygen species (ROS), indicating
that these carotenoids may play a potentially important role in the prevention of ARC [
111
].
However, others failed to find such association or the results regarding certain subtypes of ARC
were inconsistent [
25
,
112
]. Besides, a meta-analysis reported that no significant protective effects were
found for each of these carotenoids against either cortical cataract or posterior subcapsular cataract,
except a borderline significant association between blood L and subcapsular cataract [
113
]. Chew et al.
failed to prove a protective effect for
β
-carotene or for L and Z with respect to cataracts or cognitive
function [83,107].
The difference in associations between cataract subtypes and serum L and Z was probably due
to the distinct pathogenesis for each type of ARC [
114
]. With increasing age, a lower percentage
of reduced glutathione can reach the lens nucleus, which makes the nucleus become less able to
repair oxidative damage [
115
]. In contrast, glutathione levels in the outer cortex of the lens remain
at high levels, even in nuclear cataracts [
116
]. Therefore, nuclear cataract may be more prone to a
significant association with serum L and Z. In addition, Gale [
117
] et al. have found that risk of posterior
subcapsular cataract was lowest in those with higher concentration of L.; however, subcapsular cataract
is least common among these three main types of ARC and further studies are needed to confirm such
finding [
118
]. Besides, Liu [
113
] et al. demonstrated that increased blood concentrations of L and Z
might be associated with a reduced risk of nuclear cataract. However, there is insufficient evidence to
support a significantly inverse relationship between blood L or Z level and risk of other subtypes of
ARC [113].
Evidence has emerged suggesting that healthy lifestyle and proper nutrition may have a
beneficial effect on the onset of cataracts [
119
]. Numerous epidemiological studies have investigated
the relationship between dietary intake and blood levels of L and Z and the risk of ARC [
120
].
Because the accuracy of dietary intake measurements is greatly influenced by the different dietary
assessment methods across the studies and the individual differences in utilization and absorption,
blood concentrations appears to be a stronger predictor of nutritional status [121].
Therefore, dietary L and Z intake might be associated with a reduced risk of ARC,
especially nuclear cataract in a dose-response manner, indicating a beneficial effect of L and Z in
ARC prevention [122].
5. The Effects on Cognitive Function
The relationship between L, a dietary xanthophyll carotenoid, and visual and cognitive health
is particularly compelling because L is taken up selectively into eye and brain tissue [
10
,
123
,
124
].
In part, the beneficial effects of L are thought to be attributable to its antioxidant and anti-inflammatory
properties. Given that the eye is an extension of the neural system, L is increasingly recognized as
having a role in cognitive function [
26
]. In pediatric brains, the relative contribution of L to the total
carotenoids is twice that found in adults, accounting for more than half the concentration of total
carotenoids. The greater proportion of L in the pediatric brain suggests a need for L during neural
development as well [
125
]. Apart from cognitive function relationships with macular pigment there
is less evidence for a relationship between Z and cognition. A number of recent studies evinced a
possible role for L and Z in cognitive function [
123
,
126
,
127
]. For instance, one of the investigations
conducted as part of the Irish Longitudinal Study on Aging determined that older adults with higher
Molecules 2017,22, 610 10 of 22
macular pigment optical density (MPOD) had better results in various indices of cognitive function
compared to those with lower MPOD [
126
]. Furthermore, several studies have shown cognitive
impairment to be related to age-related eye diseases (AREDs) [
128
,
129
], suggesting that similar factors
may be involved. These observations are in line with the view that vision and cognition are not
easily separable. The rationale supporting a role for L in cognitive function is based on the following
observations: (1) L is the predominant carotenoid in human brain tissue in early as well as late
life [
123
,
124
]; (2) primate retinal L concentrations, i.e., macular pigment density, are related to brain L
concentrations [
130
]; (3) macular pigment density is related to cognitive function in adults [
126
,
127
];
and (4) L supplementation in adults improves cognitive function [131].
5.1. The Effects on Infancy Cognition Function
Environmental enrichment, as would occur with visual cues, has long been investigated
as an influence on brain structure and function. Morphological and functional effects elicited
by environmental enrichment at the neuronal level have been reported to be accompanied by
improvements in cognitive performance [132].
The retina and brain are especially in need of antioxidants because of their high metabolic rates,
and the human newborn brain has a relative deficiency of endogenous antioxidant enzymes [
133
].
Nevertheless, the relative contribution of L to total carotenoids was approximately twice that found in
adults (59% vs. 31%, respectively) [
123
,
124
], indicating a possible additional role of L in early neural
development. Optimal visual performance in early life could influence brain development, which is
rapid in the first year [
134
]. Besides, analyses of the various cognitive scores revealed no significant
relationship between MPOD levels and cognition. Zimmerman et al. suggested that MPOD can be
used as a biomarker in order to determine the amount of L and Z that people have in their brain tissue
in its infancy [
135
]. Vishwanathan et al. further identified that biochemically measured concentrations
of L and possibly Z in the macula are a biomarker of brain L and Z status in primates. Therefore,
an integrated measure of total MPOD may be a useful tool in evaluating the role of xanthophylls in
cognitive function [130].
5.2. The Effects on Adult Cognition Function
Among the carotenoids, L and Z are the only two that cross the blood-retina barrier to
form macular pigment in the eye [
38
], and L is the dominant carotenoid in human brain
tissue
[123,124,130,136–138]
. And only L was consistently associated with a wide range of cognitive
measures that included executive function, language, learning, and memory, which are all associated
with specific brain regions [
123
]. Besides, in a double-blinded, placebo-controlled trial of women
who received L supplementation (12 mg/d), docosahexaenoic acid supplementation (800 mg/d), or a
combination of the two for 4 months, verbal fluency scores improved significantly in all three treatment
groups. Memory scores and rates of learning improved significantly in the combined treatment
group, who also displayed a trend toward more efficient learning [
131
]. Terry et al. suggested that
individuals with less L may have compensatory neural mechanisms to help them to engage in learning
and recalling processes [
139
]. Taken together, these observations suggested that L could influence
cognitive function. Hoffmann [
140
] et al. found that supplementation of Z promoted a better long
term delayed memory.
How (and really if) they influence brain function, however, is less clear. One possibility is simply
protection from the accumulated effects of oxidative and inflammatory stress [
141
]. Data linking
reduced MPOD to dementia [
142
] and cognitive impairment [
143
] is consistent with that possibility.
Another possibility, more relevant to younger individuals and palliative approaches, is a direct
improvement by some type of local interaction with neural cells (the so-called neural efficiency
hypothesis) [
144
]. Besides, it has also been suggested that the carotenoids may play a beneficial role by
enhancing gap junctional communication in the brain [
125
]. Furthermore, the visual benefits of MP
are not restricted to the effects of its optical properties, reflected in a growing body of evidence that
Molecules 2017,22, 610 11 of 22
the macular carotenoids may have a favorable effect on neuronal processing [
145
]. These carotenoids
have been shown to improve communication through cell-to-cell channels, modulate the dynamic
instability of microtubules (structural units of neurons), and prevent degradation of synaptic vesicle
proteins [146,147].
5.3. The Effects on Alzheimer’s Disease (AD)
Alzheimer’s disease (AD) is an age-related neurodegenerative disease characterized by the
accumulation of amyloid plaques and neurofibrillary tangles in the brain [
148
]. It is the most
common form of dementia. Although the cause of AD remains unclear, genetic predisposition and
environmental factors are thought to initiate a pathophysiologic cascade, leading to AD pathology
and dementia. Accumulating evidence suggests that oxidative stress plays an important role in
disease pathogenesis [
149
]. Free radical species produced during oxidative stress are suspected
to mediate protein oxidation, lipid peroxidation, and DNA and RNA oxidation in multiple brain
regions [
150
]. Devore [
136
] et al. have shown that antioxidant-rich food reduces the risk of AD
by inhibiting oxidative stress. Besides, Lindbergh et al. demonstrated that L and Z may benefit
cognitive function in older adults by increasing neurobiological efficiency in brain regions at risk
for age-related deterioration [
137
]. Recent preliminary data have shown that L may influence the
differentiation of pluripotent neural stem cells [
138
]. However, opinions vary. Among older persons
with AMD, oral supplementation with LCPUFAs or L/Z had no statistically significant effect on
cognitive function [
107
]. Cognitive dysfunction is a complex process. More research to be conducted is
still needed to verify the reliability of the results.
6. The Consumption and Edible Safety of Lutein
L is present in natural foods and does not need to be added in a balanced diet. L is beneficial
to human health and is closely related to the occurrence of some diseases, such as AMD, ARC etc.
When dietary intake is insufficient, the appropriate dosage of L may have a positive effect on preventing
the occurrence of related diseases. For people aged, 18–79 year in many countries, the lowest dietary
intake of L is 0.67 mg/d [151], the highest is 6.88 mg/d [152], and the normal intake level always lies
in 1.10–4.25 mg/d [
120
,
153
–
160
]. According to the limited dietary survey data in China, in people
above 30 years of age, the minimum dietary intake of L is between 1.48, 10.20 mg/d [
160
,
161
] and the
maximum is between 2.94 [162] and 7.77 mg/d [163].
6.1. The Intervention of Lutein in AMD Study
L intervention study showed that L supplementation can improve the L level in patients with
AMD, and to a certain extent, can improve a visual function index. The improvement of visual
function generally in L intervention for a long time is effective. For example, the focus of its multifocal
electroretinogram response amplitude increased significantly after taking L 10 mg/d per day for the
early and middle stage AMD patients [
164
]. The MPOD of male patients with AMD was increased
by 36% after one year of taking L 10 mg/d. And visual acuity, contrast sensitivity and glare recovery
time were improved significantly [
165
]. The TOZAL [
166
] study also found that visual function was
improved when daily use of L 8 mg for more than 6 months for patients with dry AMD. In general,
in the intervention study of L in the AMD population, the significant dose range of L intervention
was 2.5 [
167
]–20 mg [
168
], and the lowest effective dose was 2.5 mg/d. In addition, the duration of
intervention was closely related to the intervention dose.
6.2. Intervention Doses in Lutein and ARC Studies
The results of L intake showed that L intake of 6–10 mg/d can reduce the possibility of cataract
surgery 20–50% [
169
]. When L/Z intake was 2.4 mg/d, the risk of core lens opacity was reduced
significantly. In a limited study on the intervention of L in ARC, by double-blind of intervention
study of ARC patients, Olmedilla [
170
] et al. found that the level of serum L, visual acuity and glare
Molecules 2017,22, 610 12 of 22
sensitivity improved significantly. In this study, the intervention dose of L was 6.42 mg/d. These results
indicated that L has a positive effect on the prevention of cataract [
171
]. In the ARC study, the effective
dose of L was 2.4–6.42 mg/d [
93
,
170
,
172
]. Nevertheless, the intervention of L on cognitive function
has not been reported.
6.3. Safe Consumption of Lutein
According to the toxicological evaluation of L food safety, the ADI value of EFSA is
1 mg/(kg
·
d) [
173
], JECFA 2 mg/(kg
·
d) [
174
]. The former is much safer. That is to say, it is safe
for 60 kg adults taking in L at 60 mg/d. EFSA panel [
175
] pointed out that the content of L in infant
formula milk power and food is not more than 250
µ
g/L. The results showed that the serum L level of
smokers was significantly lower than that of non-smokers [
176
]. Smokers are at a state of oxidative
stress for a long time and they have a higher risk of disease. L can prevent the occurrence of related
diseases by anti-oxidation [
177
]. Nevertheless, the study [
176
] found that smokers who take high
doses of L supplement have an increased risk of lung cancer. Therefore, caution should be given to
smokers with higher doses of L (>10 mg/d) supplements. Excessive intake of L can cause yellowing of
the skin. As in the continuous taking higher doses of L (
≥
15 mg/d) after 2–5 months, skin stained
yellow. But this change is reversible and it will not damage the organs. Yellow skin will die away
after stopping taking L for a period of time [
37
,
178
]. Because L is a fat soluble compounds and it can
accumulate in the body. The excessive consumption of L can increase its concentration in plasma and
skin, leading to yellow skin [
179
]. All in all, L is a component of human food. Its safety has been
proved by the toxicological evaluation of food safety, authoritative institutions at home and abroad,
the results of the study of population and clinical intervention. It is safe to human body in a certain
range of use (≤60 mg/d).
7. Conclusions and Future Directions
L and Z are selectively concentrated in the different zone of eyes. Because of their physical
and chemical properties, the direct biological effects of L are mainly manifested in antioxidation,
filtering blue light and the formation of retinal MPs. Thus, it reduces damage to the retina. In addition,
L and Z distributed in the macular area may play a protective role in retinal cells, such as preventing
the occurrence of AMD, ARC and cognitive function etc. The AREDS 2 project completed in the
United States in 2013 for 4203 AMD patients with a combination of L for 5 years was negative [
180
].
The study should focus on the prevention of high risk groups to avoid the occurrence of AMD or
ARC, rather treatment. At the same time, the negative results of the AREDS 2 study could not be
understood as the negative result of the biological function of L in the prevention of disease. Besides,
the biological effect of L is not proportional to the food consumption. Long term intake of high doses
of L by smokers are associated with increased risk of lung cancer [
176
]. The best biological effects can
be achieved only at the appropriate dose. As mentioned above, L supplements, especially for smokers,
are not consumed more than 6 mg/d. Based on the analysis of the present research data, it is suggested
that L can play a role in the regulation of cell signal transduction pathway through its antioxidant,
anti-inflammatory effects as well as the conduction velocity of nerve cells. And the intervention dose
of L on cognitive function remains to be further studied.
How to set the amount of L supplements and the use of methods, in order to achieve the purpose
of avoiding the occurrence of yellow skin? Studies have shown that in the human body, it takes
14–16 h for plasma concentration of L to reach its peak following intake [
181
,
182
]. About the half-life
in blood and cleared time difference between the results of study, some studies suggest that plasma L
has a half-life of about 76 days [
183
]; studies also have shown that L is cleared in only 528 h (that is
22 days) [
184
]. If the L in plasma reached the effective concentration, using the method of intermittent
treatment L supplements to maintain its lowest effective dose range, it would be more beneficial
than continuous supplement once a day. However, it is necessary to determine the kinetics of blood
metabolism and the relationship between time and dose effect for a brief time and dose.
Molecules 2017,22, 610 13 of 22
In summary, the aim of study is to explore the edible quantity and edible method which can
achieve the best biological effect and can be used for a long time without adverse effect, such as for
skin yellowing and smokers. Based on the results of the present study, the recommended dietary
intake of L supplements does not exceed 6 mg/d, methods for the consumption of L supplements can
be tried in a discontinuous manner. Further research is needed to provide sufficient evidence.
Acknowledgments:
This work was financially supported by the Science and Technology Program of Tianjin
(14TXZYJC00440, 15PTCYSY00030).
Conflicts of Interest: The authors report no conflict of interest.
Abbreviations
The following abbreviations are used in this manuscript:
L lutein
Z zeaxanthin
MZ meso-zeaxanthin
MP macular pigment
AMD age-related Macular degeneration
ARC age-related Cataract
AD Alzheimer’s disease
MPOD macular pigment optical density
ADI acceptable daily intake
mg/d mg/day
kg·d kg·day
References
1.
Bone, R.A.; Landrum, J.T.; Hime, G.W.; Cains, A.; Zamor, J. Stereochemistry of the human macular
carotenoids. Investig. Ophthalmol. Vis. Sci. 1993,34, 2033–2040.
2.
Carotenoids. Handbook; Britton, G.; Liaaen-Jensen, S.; Pfander, H. (Eds.) Birkhäuser Basel: Basel,
Switzerland, 2004.
3.
Khachik, F.; Beecher, G.R.; Goli, M.B.; Lusby, W.R. Separation, identification, and quantification of carotenoids
in fruits, vegetables, and human plasma by high performance liquid chromatography. Pure Appl. Chem.
1991
,
63, 71–80. [CrossRef]
4.
Khachik, F.; Spangler, C.J.; Smith, J.C.; Canfield, L.M.; Steck, A.; Pfander, H. Identification, quantification,
and relative concentrations of carotenoids and their metabolites in human milk and serum. Anal. Chem.
1997,69, 1873–1881. [CrossRef] [PubMed]
5.
Bernstein, P.S. The role of lutein and zeaxanthin in protection against age-related macular degeneration.
Acta Hortic. 2015,1106, 153–160. [CrossRef]
6.
Van-De-Kraats, J.; Kanis, M.S.; Van-Norren, D. Lutein and zeaxanthin measured separately in the living
human retina with fundus reflectometry. Investig. Ophthalmol. Vis. Sci.
2008
,49, 5568–5573. [CrossRef]
[PubMed]
7.
Gong, X.; Rubin, L.P. Role of macular xanthophylls in prevention of common neovascular retinopathies:
Retinopathy of prematurity and diabetic retinopathy. Arch. Biochem. Biophys.
2015
,572, 40–48. [CrossRef]
[PubMed]
8.
Renzi, L.M.; Hammond, B.R. The relation between the macular carotenoids, lutein and zeaxanthin,
and temporal vision. Ophthalmic Physiol. Opt. 2010,30, 351–357. [CrossRef] [PubMed]
9.
Kijlstra, A.; Tian, Y.; Kelly, E.R.; Berendschot, T.T. Lutein: More than just a filter for blue light. Prog. Retin.
Eye Res. 2012,31, 303–315. [CrossRef] [PubMed]
10.
Bone, R.A.; Landrum, J.T.; Tarsis, S.L. Preliminary identification of the human macular pigment. Vis. Res.
1985,25, 1531–1535. [CrossRef]
11.
Arnold, C.; Winter, L.; Fröhlich, K.; Jentsch, S.; Dawczynski, J.; Jahreis, G.; Böhm, V. Macular xanthophylls
and
ω
-3 long-chain polyunsaturated fatty acids in age-related macular degeneration: A randomized trial.
JAMA Ophthalmol. 2013,131, 564–572. [CrossRef] [PubMed]
Molecules 2017,22, 610 14 of 22
12.
Bone, R.A.; Landrum, J.T.; Friedes, L.M.; Gomez, C.M.; Kilburn, M.D.; Menendez, E.; Vidal, I.; Wang, W.
Distribution of lutein and zeaxanthin stereoisomers in the human retina. Exp. Eye Res.
1997
,64, 211–218.
[CrossRef] [PubMed]
13.
Landrum, J.T.; Bone, R.A. Lutein, zeaxanthin, and the macular pigment. Arch. Biochem. Biophys.
2001
,385,
28–40. [CrossRef] [PubMed]
14.
Bone, R.A.; Landrum, J.T.; Fernandez, L.; Tarsis, S.L. Analysis of the macular pigment by HPLC: Retinal
distribution and age study. Investig. Ophthalmol. Vis. Sci. 1988,29, 843–849.
15.
Handelman, G. J.; Dratz, E.A.; Reay, C.C.; van Kuijk, F.J.G.M. Carotenoids in the human macula and whole
retina. Investig. Ophthalmol. Vis. Sci. 1988,29, 850–855.
16.
Wooten, B.R.; Hammond, B.R. Macular pigment: Influence on visual acuity and visibility. Prog. Retin.
Eye Res. 2002,21, 225–240. [CrossRef]
17.
Subczynski, W.K.; Wisniewska, A.; Widomska, J. Location of macular xanthophylls in the most vulnerable
regions of photoreceptor outer-segment membranes. Arch. Biochem. Biophys.
2010
,504, 61–66. [CrossRef]
[PubMed]
18.
Nd, B.F.; Snodderly, D.M.; Johnson, E.J.; Schalch, W.; Koepcke, W.; Gerss, J.; Neuringer, M. Nutritional
manipulation of primate retinas, V: Effects of lutein, zeaxanthin, and n-3 fatty acids on retinal sensitivity to
blue-light-induced damage. Investig. Ophthalmol. Vis. Sci. 2011,52, 3934–3942.
19.
Berrow, E.J.; Bartlett, H.E.; Eperjesi, F.; Gibson, J.M. The effects of a lutein-based supplement on objective and
subjective measures of retinal and visual function in eyes with age-related maculopathy—A randomised
controlled trial. Br. J. Nutr. 2013,109, 1–7. [CrossRef] [PubMed]
20.
Ham, W.T.; Mueller, H.A.; Sliney, D.H. Retinal sensitivity to damage from short wavelength light. Nature
1976,260, 153–155. [CrossRef] [PubMed]
21.
Bernstein, P.S.; Khachik, F.; Carvalho, L.S.; Carvalho, L.S.; Muir, G.J.; Zhao, D.Y.; Katz, N.B. Identification
and quantitation of carotenoids and their metabolites in the tissues of the human eye. Exp. Eye Res.
2001
,72,
215–223. [CrossRef] [PubMed]
22.
Granado, F.; Olmedilla, B.; Blanco, I. Nutritional and clinical relevance of lutein in human health. Br. J. Nutr.
2003,90, 487–502. [CrossRef] [PubMed]
23.
Reading, V.M.; Weale, R.A. Macular pigment and chromatic aberration. J. Opt. Soc. Am.
1974
,64, 231–234.
[CrossRef] [PubMed]
24.
Renzi, L.M.; Hammond, B.R. The effect of macular pigment on heterochromatic luminance contrast. Exp. Eye
Res. 2010,91, 896–900. [CrossRef] [PubMed]
25.
Karppi, J.; Laukkanen, J.A.; Kurl, S. Plasma lutein and zeaxanthin and the risk of age-related nuclear cataract
among the elderly Finnish population. Br. J. Nutr. 2012,108, 148–154. [CrossRef] [PubMed]
26.
Johnson, E.J. A possible role for lutein and zeaxanthin in cognitive function in the elderly. Am. J. Clin. Nutr.
2012,96, 1161S–1165S. [CrossRef] [PubMed]
27.
Alassane, S.; Binquet, C.; Cottet, V.; Fleck, O.; Acar, N.; Daniel, S.; Delcourt, C.; Bretillon, L.; Bron, A.M.;
Creuzot, G.C. Relationships of macular pigment optical density with plasma lutein, zeaxanthin, and diet
in an elderly population: The montrachet study. Investig. Ophthalmol. V. Sci.
2016
,57, 1160. [CrossRef]
[PubMed]
28.
Landrum, J.T.; Bone, R.A.; Moore, L.L.; Gomez, C.M. Analysis of zeaxanthin distribution within individual
human retinas. Methods Enzymol. 1999,299, 457–467. [PubMed]
29.
Snodderly, D.M.; Auran, J.D.; Delori, F.C. The macular pigment. II. Spatial distribution in primate retinas.
Investig. Ophthalmol. V. Sci. 1984,25, 674–685.
30.
Sommerburg, O.; Siems, W.G.; Hurst, J.S.; Lewis, J.W.; Kliger, D.S.; van Kuijk, F.J. Lutein and zeaxanthin are
associated with photoreceptors in the human retina. Curr. Eye Res. 1999,19, 491–495. [CrossRef] [PubMed]
31.
Gass, J.D.M. Müller cell cone, an overlooked part of the anatomy of the fovea centralis: Hypotheses
concerning its role in the pathogenesis of macular hole and foveomacualr retinoschisis. Arch. Ophthalmol.
1999,117, 821–823. [CrossRef] [PubMed]
32. Johnson, E.J. The role of carotenoids in human health. Nutr. Clin. Care 2002,5, 56–65. [CrossRef] [PubMed]
33.
Kim, S.R.; Nakanishi, K.; Itagaki, Y.; Sparrow, J.R. Photooxidation of A2-PE, a photoreceptor outer segment
fluorophore, and protection by lutein and zeaxanthin. Exp. Eye Res.
2006
,82, 828–839. [CrossRef] [PubMed]
34.
Junghans, A.; Sies, H.; Stahl, W. Macular pigments lutein and zeaxanthin as blue light filters studied in
liposomes. Arch. Biochem. Biophys. 2001,391, 160–164. [CrossRef] [PubMed]
Molecules 2017,22, 610 15 of 22
35.
Elsm, A.A.; Akhtar, H.; Zaheer, K.; Ali, R. Dietary sources of lutein and zeaxanthin carotenoids and their role
in eye health. Nutrients 2013,5, 1169–1185.
36.
Choi, R.Y.; Chortkoff, S.C.; Gorusupudi, A.; Bernstein, P.S. Crystalline maculopathy associated with high-dose
lutein supplementation. Jama Ophthalmol. 2016,134, 1445–1448. [CrossRef] [PubMed]
37.
Harikumar, K.B.; Nimita, C.V.; Preethi, K.C.; Kuttan, R.; Deshpande, J. Toxicity profile of lutein and lutein
ester isolated from marigold flowers (Tagetes erecta). Int. J. Toxicol. 2008,27, 1–9. [CrossRef] [PubMed]
38.
Snodderly, D.M. Evidence for protection against age-related macular degeneration by carotenoids and
antioxidant vitamins. Am. J. Clin. Nutr. 1995,62, 1448S–1461S. [PubMed]
39.
Krinsky, N.I.; Landrum, J.T.; Bone, R.A. Biologic mechanisms of the protective role of lutein and zeaxanthin
in the eye. Annu. Rev. Nutr. 2003,23, 171–201. [CrossRef] [PubMed]
40.
Miller, J.W. Age-related macular degeneration revisited—Piecing the puzzle: The LXIX Edward Jackson
memorial lecture. Am. J. Ophthalmol. 2013,155, 1–35. [CrossRef] [PubMed]
41.
Moukarzel, A.A.; Bejjani, R.A.; Fares, F.N. Xanthophylls and eye health of infants and adults. Leban. Med. J.
2009,57, 261–267.
42.
El-Sm, A.A.; Young, J.C.; Akhtar, H.; Rabalski, I. Stability of lutein in wholegrain bakery products naturally
high in lutein or fortified with free lutein. J. Agric. Food Chem. 2010,58, 10109–10117.
43.
Dachtler, M.; Glaser, T.; Kohler, K.; Albert, K. Combined HPLC-MS and HPLC-NMR on-line coupling for the
separation and determination of lutein and zeaxanthin stereoisomers in spinach and in retina. Anal. Chem.
2001,73, 667–674. [CrossRef] [PubMed]
44.
Kull, D.R.; Pfander, H. Isolation and structure elucidation of two (Z)-isomers of lutein from the petals of
rape (Brassica napus). J. Agric. Food Chem. 1997,45, 4201–4203. [CrossRef]
45.
Calvo, M.M. Lutein: A valuable ingredient of fruit and vegetables. Crit. Rev. Food Sci. Nutr.
2005
,45, 671–696.
[CrossRef] [PubMed]
46.
Khachik, F.; de Moura, F.F.; Zhao, D.Y.; Aebischer, C.P.; Bernstein, P.S. Transformations of selected carotenoids
in plasma, liver, and ocular tissues of humans and in nonprimate animal models. Investig. Ophthalmol. V. Sci.
2002,43, 3383–3392.
47.
Lim, L.S.; Mitchell, P.; Seddon, J.M.; Holz, F.G.; Wong, T.Y. Age-related macular degeneration. Insight J. Am.
Soc. Ophthalmic Regist. Nurses 2012,379, 1728–1738. [CrossRef]
48.
Sparrow, J.R.; Ueda, K.; Zhou, J. Complement dysregulation in AMD: RPE-Bruch’s membrane-choroid.
Mol. Asp. Med. 2012,33, 436–445. [CrossRef] [PubMed]
49.
Evans, J.R.; Fletcher, A.E.; Wormald, R.P. Age-related macular degeneration causing visual impairment in
people 75 years or older in Britain: An add-on study to the Medical Research Council Trial of Assessment and
Management of Older People in the Community. Ophthalmology 2004,111, 513–517. [CrossRef] [PubMed]
50. Jager, R.D. Age-related macular degeneration. N. Engl. J. Med. 2008,358, 2606–2617. [CrossRef] [PubMed]
51.
Friedman, D.S.; O’Colmain, B.J.; Muñoz, B.; Tomany, S.C.; McCarty, C.; de Jong, P.T.; Nemesure, B.;
Mitchell, P.; Kempen, J. Prevalence of age-related macular degeneration in the United States. Arch. Ophthalmol.
2004,122, 564–572. [PubMed]
52.
Fernández-Robredo, P.; Sádaba, L.M.; Salinas-Alamán, A.; Recalde, S.; Rodríguez, J.A.; García-Layana, A.
Effect of lutein and antioxidant supplementation on VEGF expression, MMP-2 activity, and ultrastructural
alterations in apolipoprotein E-deficient mouse. Oxid. Med. Cell. Longev.
2013
,2013, 433–454. [CrossRef]
[PubMed]
53.
Chew, E.Y.; Clemons, T.E.; Agrón, E.; Sangiovanni, J.P.; Davis, M.D.; Ferris, F.L. Ten-year follow-up
of age-related macular degeneration in the age-related eye disease study: AREDS report no. 36.
JAMA Ophthalmol. 2014,132, 272–277. [CrossRef] [PubMed]
54.
Richer, S.P.; Stiles, W.; Grahamhoffman, K.; Levin, M.; Ruskin, D.; Wrobel, J.; Park, D.W.; Thomas, C.
Randomized, double-blind, placebo-controlled study of zeaxanthin and visual function in patients with
atrophic age-related macular degeneration: The Zeaxanthin and Visual Function Study (ZVF) FDA IND #78,
973. Optom. J. Am. Optom. Assoc. 2011,82, 667–680.
55.
Ma, L.; Yan, S.F.; Huang, Y.M.; Lu, X.R.; Qian, F.; Pang, H.L.; Xu, X.R.; Zou, Z.Y.; Dong, P.C.; Xiao, X.; et al.
Effect of lutein and zeaxanthin on macular pigment and visual function in patients with early age-related
macular degeneration. Ophthalmology 2012,119, 2290–2297. [CrossRef] [PubMed]
56.
Khan, M.A.; Gurunadh, V.S. Is sunlight exposure a risk factor for age-related macular degeneration?
A systematic review and meta-analysis. Br. J. Ophthalmol. 2013,97, 389–394. [CrossRef]
Molecules 2017,22, 610 16 of 22
57.
Bian, Q.; Gao, S.; Zhou, J.; Qin, J.; Taylor, A.; Johnson, E.J.; Tang, G.; Sparrow, J.R.; Gierhart, D.; Shang, F.
Lutein and zeaxanthin supplementation reduces photooxidative damage and modulates the expression of
inflammation-related genes in retinal pigment epithelial cells. Free Radic. Biol. Med.
2012
,53, 1298–1307.
[CrossRef] [PubMed]
58.
Obermajer, N.; Jevnikar, Z.; Doljak, B.; Kos, J. Role of cysteine cathepsins in matrix degradation and cell
signalling. Connect. Tissue Res. 2008,49, 193–196. [CrossRef] [PubMed]
59.
Xu, X.; Hang, L.; Huang, B.; Wei, Y.; Zheng, S.; Li, W. Efficacy of ethanol extract of Fructus lycii and its
constituents lutein/zeaxanthin in protecting retinal pigment epithelium cells against oxidative stress:
In vivo
and
in vitro
models of age-related macular degeneration. J. Ophthalmol.
2013
,2013, 862806. [CrossRef]
[PubMed]
60.
Paraoan, L.; Hiscott, P.; Gosden, C.; Grierson, I. Cystatin C in macular and neuronal degenerations:
Implications for mechanism(s) of age-related macular degeneration. Vis. Res.
2010
,50, 737–742. [CrossRef]
[PubMed]
61.
Treumer, F.; Klettner, A.; Baltz, J.; Hussain, A.A.; Miura, Y.; Brinkmann, R.; Roider, J.; Hillenkamp, J. Vectorial
release of matrix metalloproteinases (MMPs) from porcine RPE-choroid explants following selective retina
therapy (SRT): Towards slowing the macular ageing process. Exp. Eye Res.
2012
,97, 63–72. [CrossRef]
[PubMed]
62.
Muni, R.H.; Altaweel, M.; Tennant, M.; Weaver, B.; Kertes, P.J. Agreement among Canadian retina specialists
in the determination of treatment eligibility for photodynamic therapy in age-related macular degeneration.
Retina 2008,28, 1421–1426. [CrossRef] [PubMed]
63.
Veritti, D.; Sarao, V.; Lanzetta, P. Neovascular age-related macular degeneration. Ophthalmologica
2012
,227,
11–20. [CrossRef] [PubMed]
64.
Dhoot, D.S.; Kaiser, P.K. Ranibizumab for age-related macular degeneration. Expert Opin. Biol. Ther.
2012
,12,
371–381. [CrossRef] [PubMed]
65.
Chakravarthy, U. Bevacizumab for the treatment of neovascular age-related macular degeneration.
Ann. Pharmacother. 2012,46, 290–296. [CrossRef] [PubMed]
66.
Jarrett, S.G.; Boulton, M.E. Consequences of oxidative stress in age-related macular degeneration.
Mol. Asp. Med. 2012,33, 399–417. [CrossRef] [PubMed]
67.
Sugino, I.K.; Wang, H.; Zarbin, M.A. Age-related macular degeneration and retinal pigment epithelium
wound healing. Mol. Neurobiol. 2003,28, 177–194. [CrossRef]
68.
Mettu, P.S.; Wielgus, A.R.; Ong, S.S.; Cousins, S.W. Retinal pigment epithelium response to oxidant injury in
the pathogenesis of early age-related macular degeneration. Mol. Asp. Med.
2012
,33, 376–398. [CrossRef]
[PubMed]
69.
Zuhal, Y.; Irem, U.N.; Filiz, Y. The role of oxidative stress and antioxidants in the pathogenesis of age-related
macular degeneration. Clinics 2011,66, 743–746.
70.
Thornton, J.; Edwards, R.; Mitchell, P.; Harrison, R.A.; Buchan, I.; Kelly, S.P. Smoking and age-related macular
degeneration: A review of Association. Eye 2005,19, 935–944. [CrossRef] [PubMed]
71.
Kowluru, R.A.; Menon, B.; Gierhart, D.L. Beneficial effect of zeaxanthin on retinal metabolic abnormalities in
diabetic rats. Investig. Ophthalmol. Vis. Sci. 2008,49, 1645–1651. [CrossRef] [PubMed]
72.
Pons, M.; Cousins, S.W.; Csaky, K.G.; Striker, G.; Marin-Castaño, M.E. Cigarette smoke-related hydroquinone
induces ilamentous actin reorganization and heat shock protein 27 phosphorylation through p38 and
extracellular signal-regulated kinase 1/2 in retinal pigment epithelium: implications for age-related macular
degeneration. Am. J. Pathol. 2010,177, 1198–1213. [PubMed]
73.
Klein, R.; Peto, T.; Bird, A.; Vannewkirk, M.R. The epidemiology of age-related macular degeneration.
Am. J. Ophthalmol. 2004,137, 486–495. [CrossRef] [PubMed]
74.
Espinosa-Heidmann, D.G.; Sall, J.; Hernandez, E.P.; Cousins, S.W. Basal laminar deposit formation in APO
B100 transgenic mice: complex interactions between dietary fat, blue light, and vitamin E. Investig. Ophthalmol.
V. Sci. 2004,45, 260–266. [CrossRef]
75.
Catanuto, P.; Espinosaheidmann, D.; Pereirasimon, S.; Espinosa-Heidmann, D.; Pereira-Simon, S.; Sanchez, P.;
Salas, P.; Hernandez, E.; Cousins, S.W.; Elliot, S.J. Mouse retinal pigmented epithelial cell lines retain their
phenotypic characteristics after transfection with human papilloma virus: A new tool to further the study of
RPE biology. Exp. Eye Res. 2009,88, 99–105. [CrossRef] [PubMed]
Molecules 2017,22, 610 17 of 22
76.
Seddon, J.M. Genetic and environmental underpinnings to age-related ocular diseases. Investig. Ophthalmol.
Vis. Sci. 2013,54, ORSF28–ORSF30. [CrossRef] [PubMed]
77.
Merle, B.M.; Maubaret, C.; Korobelnik, J.F.; Delyfer, M.N.; Rougier, M.B.; Lambert, J.C.; Amouyel, P.; Malet, F.;
Le Goff, M.; Dartigues, J.F.; et al. Association of HDL-related loci with age-related macular degeneration and
plasma lutein and zeaxanthin: The Alienor study. PLoS ONE 2013,8, e79848. [CrossRef] [PubMed]
78.
Jeganathan, V.S.; Verma, N. Safety and efficacy of intravitreal anti-VEGF injections for age-related macular
degeneration. Curr. Opin. Ophthalmol. 2009,20, 223–225. [CrossRef] [PubMed]
79.
Ma, L.; Dou, H.L.; Wu, Y.Q.; Huang, Y.B.; Xu, X.R.; Zou, Z.Y.; Lin, X.M. Lutein and zeaxanthin intake and
the risk of age-related macular degeneration: A systematic review and meta-analysis. Br. J. Nutr. 2012,107,
350–359. [CrossRef] [PubMed]
80.
Scripsema, N.K.; Hu, D.N.; Rosen, R.B. Lutein, zeaxanthin, and meso-zeaxanthin in the clinical management
of eye disease. J. Ophthalmol. 2015,2015, 1–13. [CrossRef] [PubMed]
81.
Chew, E.Y.; Clemons, T.E.; Sangiovanni, J.P.; Danis, R.P.; Ferris, F.L.; Elman, M.J.; Antoszyk, A.N.; Ruby, A.J.;
Orth, D.; Bressler, S.B.; et al. Secondary analyses of the effects of lutein/zeaxanthin on age-related macular
degeneration progression: AREDS2 report No. 3. JAMA Ophthalmol.
2014
,132, 142–149. [CrossRef] [PubMed]
82.
Charters, L. AREDS gets another look: Removing beta-carotene, adding lutein/zeaxanthin shows clear
benefits. Formulary 2013,48, 229–229.
83.
Chew, E.Y.; Clemons, T.E.; SanGiovanni, J.P.; Danis, R.; Ferris, F.L.; Elman, M.; Antoszyk, A.; Ruby, A.;
Orth, D.; Bressler, S.; et al. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration:
The Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. J. Am. Med. Assoc.
2013
,309,
2005–2015.
84.
NIH Study Provides Clarity on Supplements for Protection against Blinding Eye Disease; National Eye Institute:
Washington, DC, USA, 2013.
85.
Musch, D.C. Evidence for including lutein and zeaxanthin in oral supplements for age-related macular
degeneration. JAMA Ophthalmol. 2014,132, 139–141. [CrossRef] [PubMed]
86.
Murray, I.J.; Makridaki, M.; Rl, V.D.V.; Carden, D.; Parry, N.R.; Berendschot, T.T. Lutein supplementation
over a one-year period in early AMD might have a mild beneficial effect on visual acuity: The CLEAR study.
Investig. Ophthalmol. V. Sci. 2013,54, 1781–1788. [CrossRef] [PubMed]
87.
Ma, L.; Dou, H.L.; Huang, Y.M.; Huang, Y.M.; Lu, X.R.; Xu, X.R.; Qian, F.; Zou, Z.Y.; Pang, L.H.; Dong, P.C.;
et al. Improvement of retinal function in early age-related macular degeneration after lutein and zeaxanthin
supplementation: A randomized, double-masked, placebo-controlled trial. Am. J. Ophthalmol.
2012
,154,
625–634. [CrossRef] [PubMed]
88. Woo, J.H.; Sanjay, S.; Eong, K.A. Benefits of early awareness in age-related macular degeneration. Eye 2009,
23, 2271–2271. [CrossRef] [PubMed]
89.
Pinazodurán, M.D.; Gómezulla, F.; Arias, L.; Araiz, J.; Casaroli-Marano, R.; Gallego-Pinazo, R.;
García-Medina, J.J.; López-Gálvez, M.I.; Manzanas, L.; Salas, A.; et al. Do nutritional supplements have a
role in age macular degeneration prevention? J. Ophthalmol. 2014,2014, 901686–901686.
90.
Chew, E.Y. Nutrition effects on ocular diseases in the aging eye. Investig. Ophthalmol. Vis. Sci.
2013
,54, 42–47.
[CrossRef] [PubMed]
91.
Beatty, S.; Chakravarthy, U.; Nolan, J.M.; Muldrew, K.A.; Woodside, J.V.; Denny, F.; Stevenson, M.R. Secondary
outcomes in a clinical trial of carotenoids with coantioxidants versus placebo in early age-related macular
degeneration. Ophthalmology 2013,120, 600–606. [CrossRef] [PubMed]
92.
Ho, L.; Van Leeuwen, R.; Witteman, J.C.M.; van Duijn, C.M.; Uitterlinden, A.G.; Hofman, A.; de Jong, P.T.V.M.;
Vingerling, J.R.; Klaver, C.C. Reducing the genetic risk of age-related macular degeneration with dietary
antioxidants, zinc, and omega-3 fatty acids. Arch. Ophthalmol. 2011,129, 758–766. [CrossRef] [PubMed]
93.
Barker, F.M. Dietary supplementation: Effects on visual performance and occurrence of AMD and cataracts.
Curr. Med. Res. Opin. 2010,26, 2011–2023. [CrossRef] [PubMed]
94.
Davis, R.L. Preliminary results in macular pigment optical density associated with and without zeaxanthin
and lutein supplementation. Adv. Ophthalmol. Vis. Syst. 2015,2, 0066. [CrossRef]
95.
Cabot, F.; Saad, A.; Mcalinden, C.; Haddad, N.M.; Grise-Dulac, A.; Gatinel, D. Objective assessment
of crystalline lens opacity level by measuring ocular light scattering with a double-pass system.
Am. J. Ophthalmol. 2013,155, 629–635. [CrossRef] [PubMed]
Molecules 2017,22, 610 18 of 22
96.
Stevens, G.A.; White, R.A.; Flaxman, S.R.; Price, H.; Jonas, J.B.; Keeffe, J.; Leasher, J.; Naidoo, K.; Pesudovs, K.;
Resnikoff, S.; et al. Global prevalence of vision impairment and blindness: Magnitude and temporal trends,
1990–2010. Ophthalmology 2013,120, 2377–2384. [CrossRef] [PubMed]
97.
Ferrandez, A.M.; Blin, O. Causes and prevalence of visual impairment among adults the United States.
Arch. Ophthalmol. 2004,122, 477–485.
98.
Rao, G.N.; Khanna, R.; Payal, A. The global burden of cataract. Curr. Opin. Ophthalmol.
2011
,22, 4–9.
[CrossRef] [PubMed]
99.
Fernandez, M.M.; Afshari, N.A. Cataracts: We have perfected the surgery, but is it time for prevention?
Curr. Opin. Ophthalmol. 2011,22, 2–3. [CrossRef] [PubMed]
100.
Fan, X.; Zhang, J.; Zhang, J.; Theves, M.; Strauch, C.; Nemet, I.; Liu, X.; Qian, J.; Giblin, F.J.; Monnier, V.M.
Mechanism of lysine oxidation in human lens crystallins during aging and in diabetes. J. Biol. Chem.
2009
,
284, 34618–34627. [CrossRef] [PubMed]
101.
Zhang, J.; Yan, H.; Löfgren, S.; Tian, X.; Lou, M.F. Ultraviolet radiation-induced cataract in mice: The effect of
age and the potential biochemical mechanism. Investig. Ophthalmol. Vis. Sci.
2012
,53, 7276–7285. [CrossRef]
[PubMed]
102.
Tan, A.G.; Mitchell, P.; Flood, V.M.; Burlutsky, G.; Rochtchina, E.; Cumming, R.G.; Wang, J.J. Antioxidant
nutrient intake and the long-term incidence of age-related cataract: The Blue Mountains Eye Study. Am. J.
Clin. Nutr. 2008,87, 1899–1905. [PubMed]
103.
Andley, U.P. Effects of alpha-crystallin on lens cell function and cataract pathology. Curr. Mol. Med.
2009
,9,
887–892. [CrossRef] [PubMed]
104.
Neroev, V.V.; Katargina, L.A.; Kogoleva, L.V. The prevention of blindness and visual impairment in children
with retinopathy of prematurity. Curr. pediatrics 2015,14, 265–270. [CrossRef]
105.
Selin, J.Z.; Rautiainen, S.; Lindblad, B.E.; Morgenstern, R.; Wolk, A. High-dose supplements of vitamins C
and E, low-dose multivitamins, and the risk of age-related cataract: A population-based prospective cohort
study of men. Am. J. Epidemiol. 2013,177, 548–555. [CrossRef] [PubMed]
106.
Hennis, A.; Wu, S.Y.; Nemesure, B.; Leske, M.C. Risk factors for incident cortical and posterior subcapsular
lens opacities in the Barbados Eye Studies. Arch. Ophthalmol. 2004,122, 525–530. [CrossRef] [PubMed]
107.
Chew, E.Y.; Clemons, T.E.; Agrón, E.; Launer, L.J.; Grodstein, F.; Bernstein, P.S. Effect of omega-3 fatty acids,
lutein/zeaxanthin, or other nutrient supplementation on cognitive function: The AREDS2 randomized
clinical trial. Jama J. Am. Med. Assoc. 2015,314, 791–801. [CrossRef] [PubMed]
108.
Cruickshanks, K.J. Sunlight exposure and risk of lens opacities in a population-based study. Arch. Ophthalmol.
1998,116, 714. [CrossRef]
109.
Delcourt, C.; Carriere, I.M.; Barberger, G.P.; Schalch, W. Plasma lutein and zeaxanthin and other carotenoids
as modifiable risk factors for age-related maculopathy and cataract: the POLA Study. Investig. Ophthalmol.
V. Sci. 2006,47, 2329–2335. [CrossRef] [PubMed]
110. Le, M.; Lin, X.M. Effects of lutein and zeaxanthin on aspects of eye health. J. Sci. Food Agric. 2010,90, 2–12.
111.
Lakshminarayana, R.; Aruna, G.; Sathisha, U.V.; Dharmesh, S.M.; Baskaran, V. Structural elucidation
of possible lutein oxidation products mediated through peroxyl radical inducer 2,2’-Azobis
(2-methylpropionamidine) dihydrochloride: Antioxidant and cytotoxic influence of oxidized lutein in
HeLa cells. Chemico-Biol. Interact. 2013,203, 448–455. [CrossRef] [PubMed]
112.
Ravindran, R.D.; Vashist, P.; Gupta, S.K.; Young, I.S.; Maraini, G.; Camparini, M.; Jayanthi, R.; John, N.;
Fitzpatrick, K.E.; Chakravarthy, U.; et al. Inverse association of vitamin C with cataract in older people in
India. Ophthalmology 2011,118, 1958–1965. [CrossRef] [PubMed]
113.
Liu, X.H.; Yu, R.B.; Liu, R.; Hao, Z.X.; Han, C.C.; Zhu, Z.H.; Ma, L. Association between lutein and zeaxanthin
status and the risk of cataract: A Meta-Analysis. Nutrients 2014,6, 452–465. [CrossRef] [PubMed]
114.
Ghaem, M.H.; Tai, B.C.; Wong, T.Y.; Tai, E.S.; Li, J.; Wang, J.J.; Mitchell, P. Metabolic syndrome and risk
of age-related cataract over time: An analysis of interval-censored data using a random-effects model.
Investig. Ophthalmol. V. Sci. 2012,54, 641–646. [CrossRef] [PubMed]
115.
Beebe, D.C.; Holekamp, N.M.; Shui, Y.B. Oxidative damage and the prevention of age-related cataracts.
Ophthalmic Res. 2010,44, 155–165. [CrossRef] [PubMed]
116.
Kui-Yi, X.; Lou, M.F. Effect of age on the thioltransferase (glutaredoxin) and thioredoxin systems in the
human lens. Investig. Ophthalmol. Vis. Sci. 2010,51, 6598–6604.
Molecules 2017,22, 610 19 of 22
117.
Gale, C.R.; Hall, N.F.; Phillips, D.I.; Martyn, C.N. Plasma antioxidant vitamins and carotenoids and
age-related cataract. Ophthalmology 2001,108, 1992–1998. [CrossRef]
118.
Koo, E.; Chang, J.R.; Agrón, E.; Clemons, T.E.; Sperduto, R.D.; Ferris III, F.L.; Chew, E.Y. Ten-year
incidence rates of age-related cataract in the Age-Related Eye Disease Study (AREDS): AREDS report
no. 33. Ophthalmic Epidemiol. 2013,20, 71–81. [CrossRef] [PubMed]
119.
Mares, J.A.; Voland, R.; Adler, R.; Tinker, L.; Millen, A.E.; Moeller, S.M.; Blodi, B.; Gehrs, K.M.;
Wallace, R.B.; Chappell, R.J.; et al. Healthy diets and the subsequent prevalence of nuclear cataract in
women. Arch. Ophthalmol. 2010,128, 738–749. [CrossRef] [PubMed]
120.
Christen, W.G.; Liu, S.; Glynn, R.J.; Gaziano, J.M.; Buring, J.E. Dietary carotenoids, vitamins C and E, and
risk of cataract in women: A prospective study. Arch. Ophthalmol.
2008
,126, 102–109. [CrossRef] [PubMed]
121. Von, L.J. Metabolism of carotenoids and retinoids related to vision. J. Biol. Chem. 2012,287, 1627–1634.
122.
Ma, L.; Hao, Z.X.; Liu, R.R.; Yu, R.B.; Shi, Q.; Pan, J.P. A dose-response meta-analysis of dietary lutein and
zeaxanthin intake in relation to risk of age-related cataract. Graefe’s Arch. Clin. Exp. Ophthalmol.
2014
,252,
63–70. [CrossRef] [PubMed]
123.
Johnson, E.J.; Vishwanathan, R. Relationship between serum and brain carotenoids,
α
-tocopherol, and retinol
concentrations and cognitive performance in the oldest old from the Georgia Centenarian Study.
J. Aging Res.
2012,2013, 214–219. [CrossRef] [PubMed]
124.
Vishwanathan, R.; Kuchan, M.J.; Sen, S.; Johnson, E.J. Lutein is the predominant carotenoid in infant brain:
Preterm infants have decreased concentrations of brain carotenoids. J. Pediatr. Gastroenterol. Nutr.
2014
,59,
659–665. [CrossRef] [PubMed]
125.
Johnson, E.J. Role of lutein and zeaxanthin in visual and cognitive function throughout the lifespan. Nutr. Rev.
2014,72, 605–612. [CrossRef] [PubMed]
126.
Feeney, J.; Finucane, C.; Savva, G.M.; Cronin, H.; Beatty, S.; Nolan, J.M.; Kenny, R.A. Low macular pigment
optical density is associated with lower cognitive performance in a large, population-based sample of older
adults. Neurobiol. Aging 2013,34, 2449–2456. [CrossRef] [PubMed]
127.
Vishwanathan, R.; Iannaccone, A.; Scott, T.M.; Kritchevsky, S.B.; Jennings, B.J.; Carboni, G.; Forma, G.;
Satterfield, S.; Harris, T.; Johnson, K.C.; et al. Macular pigment optical density is related to cognitive function
in older people. Age Ageing 2014,43, 271–275. [CrossRef] [PubMed]
128.
Ong, S.Y.; Cheung, C.Y.; Li, X.; Lamoureux, E.L.; Ikram, M.K.; Ding, J.; Cheng, C.Y.; Haaland, B.A.;
Saw, S.M.; Venketasubramanian, N.; et al. Visual impairment, age-related eye diseases, and cognitive
function: The Singapore Malay Eye study. Arch. Ophthalmol. 2012,130, 895–900. [CrossRef] [PubMed]
129.
Rogers, M.A.M.; Langa, K.M. Untreated poor vision: A contributing factor to late-life dementia.
Am. J. Epidemiol. 2010,171, 728–735. [CrossRef] [PubMed]
130.
Vishwanathan, R.; Neuringer, M.; Snodderly, D.M.; Schalch, W.; Johnson, E.J. Macular lutein and zeaxanthin
are related to brain lutein and zeaxanthin in primates. Nutr. Neurosci.
2013
,16, 21–29. [CrossRef] [PubMed]
131.
Johnson, E.J.; McDonald, K.; Caldarella, S.M.; Chung, H.Y.; Troen, A.M.; Snodderly, D.M. Cognitive findings
of an exploratory trial of docosahexaenoic acid and lutein supplementation in older women. Nutr. Neurosci.
2015,11, 75–83. [CrossRef] [PubMed]
132.
Sale, A.; Berardi, N.; Maffei, L. Enrich the environment to empower the brain. Trends Neurosci.
2009
,32,
233–239. [CrossRef] [PubMed]
133.
Buonocore, G.; Perrone, S.; Bracci, R. Free radicals and brain damage in the newborn. Biol. Neonate
2001
,79,
455–458.
134.
Knickmeyer, R.C.; Gouttard, S.; Kang, C.; Evans, D.; Wilber, K.; Smith, K.; Hamer, R.M.; Lin, W.; Gerig, G.;
Gilmore, J.H. A structural MRI study of human brain development from birth to 2 years. J. Neurosci.
2008
,
28, 12176–12182. [CrossRef] [PubMed]
135.
Zimmerman, D. Macular pigment optical density as a possible biomarker for predicting the effects of lutein
and zeaxanthin on cognition among young healthy adults. Diss. Theses Gradworks 2014,52, 2014–2027.
136.
Devore, E.E.; Grodstein, F.; van Rooij, F.J.; Hofman, A.; Stampfer, M.J.; Witteman, J.C.; Breteler, M.M. Dietary
antioxidants and long-term risk of dementia. Arch. Neurol. 2010,67, 819–825. [CrossRef] [PubMed]
137.
Lindbergh, C.; Terry, D.; Mewborn, C.; Renzi-Hammond, L.; Hammond, B.; Miller, S. Aging and
dementia-1lutein and zeaxanthin supplementation improves neurocognitive function in older
adults as measured using functional magnetic resonance imaging: A randomized controlled trial.
Natl. Acad. Neuropsychol. 2016,31, 574. [CrossRef]
Molecules 2017,22, 610 20 of 22
138.
Kuchan, M.; Wang, F.; Geng, Y.; Feng, B.; Lai, C. Lutein stimulates the differentiation of human stem
cells to neural progenitor cells
in vitro
. In Presented at Advances and Controversies in Clinical Nutrition,
Washington, DC, USA, 5–7 December 2013.
139.
Terry, D.; Duda, B.; Mewborn, C.; Lindbergh, C.; Bovier, E.; Shon, D.; Puente, A.; Chu, K.; Washington, T.;
Stapley, L.; et al. Brain activity associated with verbal learning and recall in older adults and its relationship
to lutein and zeaxanthin concentrations. Arch. Clin. Neuropsychol. 2014,29, 506. [CrossRef]
140.
Hoffmann, K.; Richer, S.; Wrobel, J.; Chen, E.; Podella, C. A prospective study of neuro-cognitive enhancement
with carotenoids in elderly adult males with early age related macular degeneration. Ophthalmol. Res. Int. J.
2015,4, 1–8. [CrossRef] [PubMed]
141.
Fatani, A.J.; Parmar, M.Y.; Abuohashish, H.M.; Ahmed, M.M.; Al-Rejaie, S.S. Protective effect
of lutein supplementation on oxidative stress and inflammatory progression in cerebral cortex of
streptozotocin-induced diabetes in rats. Neurochem. J. 2016,10, 69–76. [CrossRef]
142.
Nolan, J.M.; Loskutova, E.; Howard, A.N.; Moran, R.; Mulcahy, R.; Stack, J.; Bolger, M.; Dennison, J.;
Akuffo, K.O.; Owens, N. Macular pigment, visual function, and macular disease among subjects with
Alzheimer’s disease: An exploratory study. J. Alzheimer’s Dis. 2014,42, 1191–2002.
143.
Renzi, L.M.; Dengler, M.J.; Puente, A.; Miller, L.S.; Hammond, B.R. Relationships between macular
pigment optical density and cognitive function in unimpaired and mildly cognitively impaired older
adults. Neurobiol. Aging 2014,35, 1695–1699. [CrossRef] [PubMed]
144.
Zimmer, J.P.; Hammond, B.R., Jr. Possible influences of lutein and zeaxanthin on the developing retina.
Clin. Ophthalmol. 2007,1, 25–35. [PubMed]
145.
Renzi, L.M.; Bovier, E.R.; Hammond, B.R., Jr. A role for the macular carotenoids in visual motor response.
Nutr. Neurosci. 2013,16, 262–268. [CrossRef] [PubMed]
146.
Crabtree, D.V.; Ojima, I.; Geng, X.; Adler, A.J. Tubulins in the primate retina: evidence that xanthophylls may
be endogenous ligands for the paclitaxel-binding site. Bioorg. Med. Chem. 2001,9, 1967–1976. [CrossRef]
147.
Ozawa, Y.; Sasaki, M.; Takahashi, N.; Kamoshita, M.; Miyake, S.; Tsubota, K. Neuroprotective effects of lutein
in the retina. Curr. Pharm. Des. 2012,18, 51–56. [CrossRef] [PubMed]
148.
Mauer, K.; Mauer, U. Alzheimer. The life of a physician and the career of a disease. Bull. Hist. Med.
2003
,78,
728–730.
149.
Markesbery, W.R. The role of oxidative stress in Alzheimer disease. Arch. Neurol.
1999
,56, 1449–1452.
[CrossRef] [PubMed]
150.
Markesbery, W.R.; Lovell, M.A. Damage to lipids, proteins, DNA, and RNA in mild cognitive impairment.
JAMA Neurol. 2007,64, 954–956. [CrossRef] [PubMed]
151.
Johnson, E.J.; Maras, J.E.; Rasmussen, H.M.; Tucker, K.L. Intake of lutein and zeaxanthin differ with age, sex,
and ethnicity. J. Am. Dietetic Assoc. 2010,110, 1357–1362. [CrossRef] [PubMed]
152.
Cho, E.; Hankinson, S.E.; Rosner, B.; Willett, W.C.; Colditz, G.A. Prospective study of lutein/zeaxanthin
intake and risk of age-related macular degeneration. Am. J. Clin. Nutr. 2008,87, 1837–1843. [PubMed]
153.
O’Neill, M.E.; Carroll, Y.; Corridan, B.; Olmedilla, B.; Granado, F.; Blanco, I.; Vanden Berg, H.; Hininger, I.;
Rousell, A.M.; Chopra, M.; et al. A European carotenoid database to assess carotenoid intakes and its use in
a five-country comparative study. Br. J. Nutr. 2001,85, 499–507. [CrossRef] [PubMed]
154.
Nebeling, L.C.; Forman, M.R.; Graubard, B.I.; Snyder, R.A. Changes in carotenoid intake in the United States:
The 1987 and 1992 National Health Interview Surveys. J. Am. Dietetic Assoc. 1997,97, 991–996. [CrossRef]
155.
Seddon, J.M.; Reynolds, R.; Rosner, B. Associations of smoking, body mass index, dietary lutein, and the LIPC
gene variant rs10468017 with advanced age-related macular degeneration. Mol. Vis.
2010
,16, 2412–2424.
[PubMed]
156.
Wenzela, A.J.; Sheehanb, J.P.; Burkeb, J.D.; Lefsrudc, M.G.; Curran-Celentanob, J. Dietary intake and serum
concentrations of lutein and zeaxanthin, but not macular pigment optical density, are related in spouses.
Nutr. Res. 2007,27, 462–469. [CrossRef]
157.
Granadolorencio, F.; Olmedillaalonso, B.; Blanconavarro, I.; Botellaromero, F.; Simal-Anton, A. Assessment
of carotenoid status and the relation to glycaemic control in type I diabetics: A follow-up study. Eur. J.
Clin. Nutr. 2006,60, 1000–1008. [CrossRef] [PubMed]
158.
Ciulla, T.A.; Curran-Celantano, J.; Cooper, D.A.; Hammond, B.R.; Danis, R.P.; Pratt, L.M.; Riccardi, K.A.;
Filloon, T.G. Macular pigment optical density in a midwestern sample. Ophthalmology
2001
,108, 730–737.
[CrossRef]
Molecules 2017,22, 610 21 of 22
159.
Lyle, B.J.; Mares-Perlman, J.A.; Klein, B.E.; Klein, R.; Greger, J.L. Antioxidant intake and risk of incident
age-related nuclear cataracts in the Beaver Dam Eye Study. Am. J. Epidemiol.
1999
,149, 801–809. [CrossRef]
[PubMed]
160.
Wang, Z.X.; Liu, M.; Zhang, H.Z.; Gu, Y.G.; Xing, Q.Y.; Lai, J.Q. Dietary carotenoid intake in four seasons in
urban and rural communities in Jining. J. Nutr. 2009,31, 6–10.
161.
Wang, Z.; Lin, X. Analysis of dietary lutein and zeaxanthin intake in summer and autumn in Beijing
community. Food Nutr. China 2010,2010, 77–80.
162. Song, X.; Wang, Z. Analysis of carotenoid intake in adult diet. Chin. Public Health 2007,23, 1378–1380.
163.
Zhang, F.; Zhu, Y.; Cai, M. Correlation analysis between dietary intake and serum levels of level in a
community of Shanghai. Environ. Occup. Med. 2012,29, 563–565.
164.
Parisi, V.; Tedeschi, M.; Gallinaro, G.; Varano, M.; Saviano, S.; Piermarocchi, S. Carotenoids and
antioxidants in age-related maculopathy Italian study: Multifocal electroretinogram modifications after 1
year. Ophthalmology 2008,115, 324–333. [CrossRef] [PubMed]
165.
Richer, S.; Stiles, W.; Statkute, L.; Pulido, J.; Frankowski, J.; Rudy, D.; Pei, K.; Tsipursky, M.; Nyland, J.
Double-masked, placebo-controlled, randomized trial of lutein and antioxidant supplementation in the
intervention of atrophic age-related macular degeneration: The Veterans LAST study (Lutein Antioxidant
Supplementation Trial). Optometry 2004,75, 216–230. [CrossRef]
166.
Cangemi, F.E. TOZAL Study: An open case control study of an oral antioxidant and omega-3 supplement
for dry AMD. BMC Ophthalmol. 2007,7, 1–10. [CrossRef] [PubMed]
167.
Rosenthal, J.M.; Kim, J.; de Monastario, F.; Thompson, D.J.; Bone, R.A.; Landrum, J.T.; de Moura, F.F.;
Khachik, F.; Chen, H.; Schleicher, R.L.; et al. Dose-ranging study of lutein supplementation in persons aged
60 years or older. Investig. Ophthalmol. Vis. Sci. 2006,47, 5227–5233. [CrossRef] [PubMed]
168.
Weigert, G.; Kaya, S.; Pemp, B.; Sacu, S.; Lasta, M.; Werkmeister, R.M.; Dragostinoff, N.; Simader, C.;
Garhöfer, G.; Schmidt-Erfurth, U.; et al. Effects of lutein supplementation on macular pigment optical density
and visual acuity in patients with age-related macular degeneration. Investig. Ophthalmol. Vis. Sci.
2011
,52,
8174–8178. [CrossRef] [PubMed]
169. Alves, R.A.; Shao, A. The science behind lutein. Toxicol. Lett. 2004,150, 57–83. [CrossRef] [PubMed]
170.
Olmedilla, B.; Granado, F.; Blanco, I.; Vaquero, M. Lutein, but not alpha-tocopherol, supplementation
improves visual function in patients with age-related cataracts: A 2-y double-blind, placebo-controlled pilot
study. Nutrition 2003,19, 21–24. [CrossRef]
171.
Ribayamercado, J.D.; Blumberg, J.B. Lutein and zeaxanthin and their potential roles in disease prevention.
Int. Symp. Eggs Hum. Health 2004,23, 567S–587S.
172.
Olmedilla, B.; Granado, F.; Blanco, I.; Vaquero, M.; Cajigal, C. Lutein in patients with cataracts and age-related
macular degeneration: A long-term supplementation study. J. Sci. Food Agric.
2001
,81, 904–909. [CrossRef]
173.
European Food Safety Authority. Scientific opinion on the re-evaluation of lutein (e 161b) as a food additive.
EFSA J. 2010,8, 1678. [CrossRef]
174.
Joint, F.A.O. Evaluation of Certain Food Additives: Sixty-Third Report of the Joint FAO/WHO Expert Committee on
Food Additives; World Health Organization: Geneva, Switzerland, 2005; pp. 23–26.
175.
European Food Safety Authority. Safety, bioavailability and suitability of lutein for the particular nutritional
use by infants and young children-Scientific Opinion of the Panel on Dietetic Products, Nutrition and
Allergies. EFSA J. 2008,6, 1–24.
176.
Satia, J.A.; Littman, A.; Slatore, C.G.; Galanko, J.A.; White, E. Long-term use of beta-carotene, retinol,
lycopene, and lutein supplements and lung cancer risk: Results from the Vitamins and Lifestyle (VITAL)
study. Am. J. Epidemiol. 2009,170, 401–402.
177.
Institute of Medicine (US) Panel on Dietary Antioxidants and Related Compounds. Dietary Reference Intakes
for Vitamin C, Vitamin E, Selenium, and Carotenoids; National Academies Press: Washington, DC, USA, 2000.
178.
Olmedilla, B.; Granado, F.; Southon, S.; Wright, A.J.; Blanco, I.; Gil-Martinez, E.; van den BERG, H.;
Thurnham, D.; Corridan, B.; Chopra, M.; et al. A European multicentre, placebo-controlled supplementation
study with alpha-tocopherol, carotene-rich palm oil, lutein or lycopene: Analysis of serum responses.
Clin. Sci. 2002,102, 447–456. [CrossRef] [PubMed]
179.
Maharshak, N.; Shapiro, J.; Trau, H. Carotenoderma—A review of the current literature. Int. J. Dermatol.
2003,42, 178–181. [CrossRef] [PubMed]
Molecules 2017,22, 610 22 of 22
180.
Alholou, S.; Tucker, W.R.; Agron, E.; Clemons, T.E.; Chew, E.Y. The association of statin use with
cataract progression using propensity matching in the Age-Related Eye Disease Study 2 (AREDS2).
Investig. Ophthalmol. Vis. Sci. 2014,55, 1675.
181.
Kelm, M.A.; Flanagan, V.P.; Pawlosky, R.J.; Novotny, J.A.; Clevidence, B.A.; Britz, S.J. Quantitative
determination of
13
C-labeled and endogenous beta-carotene, lutein, and vitamin A in human plasma.
Lipids 2001,36, 1277–1282. [CrossRef] [PubMed]
182.
Lienau, A.; Glaser, T.; Tang, G.; Dolnikowski, G.G.; Grusak, M.A.; Albert, K. Bioavailability of lutein in
humans from intrinsically labeled vegetables determined by LC-APCI-MS. J. Nutr. Biochem.
2003
,14, 663–670.
183.
Burri, B.J.; Park, J.Y.K. Compartmental models of vitamin a and
β
-carotene metabolism in women. Adv. Exp.
Med. Biol. 1998,445, 225–237. [PubMed]
184.
Yao, L.H.; Liang, Y.X.; Trahanovsky, W.S.; Serfass, R.E.; White, W.S. Use of a
13
C tracer to quantify the plasma
appearance of a physiological dose of lutein in humans. Lipids 2000,35, 339–348. [CrossRef] [PubMed]
Sample Availability: Samples of the compounds lutein and zeaxanthin are available from the authors.
©
2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).
