Jan a Lute in Reprint

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The Journal of the American Nutraceutical Association www.ana-jana.org

Vol. 4, No. 2, Summer 2001 Reprint

A Peer-Reviewed Journal on Nutraceuticals and Nutrition

Mark Houston, MDEditor-in-Chief

ISSN-1521-4524

The Role of Lutein in Human Health

Andrew Shao, PhD

Technical Services Manager Vitamins and Dietary Supplements

Kemin Foods, L.C., Des Moines, Iowa


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Summer 20018 JANA Vol.4, No.2

R E V I E W A R T I C L E

The Role of Lutein in Human Health

Andrew Shao, PhD

Technical Services Manager Vitamins and Dietary Supplements

Kemin Foods, L.C., Des Moines, Iowa

* Correspondence:

Andrew Shao, PhD

Kemin Foods, LC

600 East Court Avenue, Suite A

Des Moines, IA 50309

Phone: 515-248-4000 Fax: 515-248-4051

Email: [email protected]

INTRODUCTION

Carotenoids are a class of compounds responsible for

the yellow and red pigments present in many commonly-

consumed fruits and vegetables with large amounts found

in green leafy vegetables such as spinach.1,2 Hundreds of

these compounds exist in nature, yet only a handful have

been detected in human serum (Table 1) and tissues.3,4

These select few may have some biologic function in

humans. Consequently, their consumption may play a role in

maintaining human health.(5,6) Many observational epidemio-

logic studies have shown an inverse relationship between

carotenoid intake and serum levels, and risk for diseases such

as cancer and cardiovascular diseases.5 While these studiessuggest that carotenoids may protect against chronic disease,

they have not firmly established a basis for the biologic plau-

sibility that they are involved in human health. For the major-

ity of the carotenoids present in the human body, little inves-

tigation has been done on specific function or tissue deposi-

tion. In addition, intervention studies have primarily focused

ABSTRACT

Lutein is a unique dihydroxy-carotenoid (or xantho-

phyll) present in many plants consumed in the human diet.

In humans, as in plants, lutein is believed to function in two

ways: first as a filter of high energy blue light, and second

as an antioxidant that quenches photo-induced free radicals

and reactive oxygen species (ROS). Epidemiologic evi-

dence suggests that lutein consumption is inversely related

to eye diseases such as age-related macular degeneration

(AMD) and cataracts. This is supported by the finding that

lutein (and a related compound, zeaxanthin) are specifical-

ly and selectively deposited in the macula lutea, an area of

the retina responsible for central and high acuity vision.Macular pigment, a yellow color in the center of the macu-

la, functions as a filter of the high energy blue light that

protects the sensitive rods and cones, and is comprised sole-

ly of lutein and zeaxanthin. Human intervention studies

show that lutein supplementation results in increased mac-

ular pigment. This suggests that lutein supplementation

may protect against AMD. There is also evidence suggest-

ing that lutein may have a protective effect against other

chronic diseases, such as certain cancers and cardiovascular

disease. However, further research is needed to determine

optimal lutein doses. The following paper represents a

comprehensive review of the available evidence supporting

a beneficial role for lutein in human health.

Table 1. Distribution of the major carotenoids in human serum

Carotenoid % Distribution in Serum

Lutein 20Lycopene 20

-carotene 10-carotene 10Phytofluene 8

-cryptoxanthin 8-carotene 6

-cryptoxanthin 4Phytoene 4

Anhydrolutein 3Zeaxanthin 3-carotene 2

Neurosporene 2


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Summer 2001 Vol. 4, No. 2 JANA 9

on the use of-carotene and its effect on various forms of can-

cer, and have been met with equivocal results.7-9

Lutein is a well-known carotenoid found readily in the

human diet, serum, and tissues (Table 1).10 Similar to other

carotenoids, epidemiologic data supports the hypothesis that

lutein intake is inversely associated with chronic diseases,

such as cancer of the breast11-13 and colon,14-16 and ocular dis-

eases such as cataracts17-20 and AMD.21-22 Lutein has also

been shown to be selectively and specifically deposited in

ocular tissues such as the macula, supporting the biologic

plausibility of lutein as a bioactive carotenoid.23 Furthermore,

macular pigment optical density (MPOD), which consists

entirely of the carotenoids lutein and zeaxanthin, may be a

potential biologic marker of both lutein status and macular

health.24 These findings and others have helped to establish

lutein as a unique carotenoid, and are reviewed extensively in

this article.

Lutein in nature

Carotenoids were originally thought to serve solely as

vitamin A precursors in the human body, but this has since

been shown to be limited primarily to the hydrocarbon

carotenoid, -carotene (Figure 1).25 Research over several

decades has revealed that carotenoids are capable of far

more than provitamin A activity. They are known to act nat-

urally in plants in two important ways: first in a photopro-

tective manner by absorbing damaging blue light from sun-

light; second as a quencher of photo-induced free radicals

and reactive oxygen species (ROS).26,27

Lutein, and a related compound zeaxanthin, are classi-

fied together in nature as dihydroxy xanthophylls, possess-

ing two hydroxyl groups. In contrast, hydrocarbon

carotenoids such as -carotene and lycopene possess no

oxygen atoms (Figure 2).28,29 The hydroxyl groups render

lutein and zeaxanthin more polar than the hydrocarbon

carotenoids, and may contribute to their unique role in ocu-

lar tissues. Lutein is found extensively in the human diet,primarily in dark, leafy green vegetables such as spinach

and kale.30 Although purified and crystallized lutein dis-

plays a distinct orange-yellow color (Figure 3), its color is

not evident in green leafy vegetables due to a masking

effect by chlorophyll. Lutein intake appears to be declining

in the US to between 1.5 and 2 mg/day, likely due to a

decrease in the consumption of dark greens.31

II. LUTEIN AND EYE HEALTH

Age-related macular degeneration

AMD, a degradation of the central portion of the reti-na (the macula lutea), is the principal cause of blindness

among people age 65 and older.32 The macula is located in

the posterior portion of the retina and possesses the highest

concentration of photoreceptors responsible for central

vision and high resolution visual acuity.33 It is a circular

area 5-6 mm in diameter with the fovea located at its cen-

ter (Figure 4). Age-related macular degeneration can be

classified into two categories: (1) early (or dry AMD) char-

acterized by accumulation of soft drusen (oxidatively dam-

aged cells and their components), and depigmentation of

Figure 1. Cleavage of -carotene to form retinal and

retinol (vitamin A).Note that certain xanthophylls such aslutein do not possess provitamin A activity.

Figure 2. Hydrocarbon carotenoids and xanthophylls.

Shown top to bottom are lycopene, -carotene, zeaxanthin,and lutein.


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Summer 200110 JANA Vol. 4, No.2

the retinal epithelium, and (2) late (or wet AMD) is charac-

terized by neovascularization of the macula and retina, and

accumulation of scar tissue.34 Advanced AMD often leads

to irreversible blindness, and there is currently no effective

treatment.35 Many factors contribute to an increased risk for

AMD, including age, cigarette smoking, female sex, light

iris color, family history, sunlight exposure, and poor nutri-

tional status (Table 2).36,37

Epidemiological evidence supporting a protective effect

of lutein against AMD

In 1988 Goldberg et al. analyzed a cross-sectional sam-

ple from the National Health and Nutritional Examination

Survey (NHANES), which used questionnaires to assess

nutrient intake in AMD cases and controls with healthy mac-

ulae. It was found that diets high in fruits and vegetables

were inversely associated with AMD risk.38 Such diets are

also high in many carotenoids, including lutein.30 In 1992

the Eye Disease Case-Control Study Group obtained per-

sonal, medical, physiological, biochemical, and ocular data

on 421 AMD patients and 615 controls.

Serum carotenoids (lutein, zeaxanthin, -carotene, a-

carotene, cryptoxanthin, and lycopene) were found to be

inversely related with AMD risk.21 Further analysis showed

that prevalence of AMD among those in this sample with

total serum carotenoid concentrations 2.39 mol/L was

66% lower than the prevalence among those with levels

1.02 mol/L.21 Although these studies provided a basis

for the hypothesis that dietary carotenoids in general may

have a protective effect against AMD, lutein and zeaxanthin

(and their metabolites) are the only carotenoids found in the

macula, and constitute the entire macular pigment.33 This

suggests that the observed protective effects of high fruit

and vegetable intake and high carotenoid consumption may

be due solely to lutein and zeaxanthin intake.

Figure 4. The human eye. Shown is the macula lutea,located in the mid portion of the retina.

Table 2. Risk factors for AMD

Parameter Hypothesis

Age Accumulation ofphoto-oxidative damage

Smoking Increase in amount of freeradicals; depletes body of antioxidants

Body fat Increased storage,less utilization of xanthophylls

Female sex Increased storage, lessutilization of xanthophylls

due to body fat

Light iris color Decreased capacity to filterdamaging blue light

Family history Genetic component to susceptibility

Sunlight exposure Increased amount ofdamaging blue light

Poor nutritional status Insufficient antioxidant supply

Fat intake Increased source of PUFAspromoting lipid peroxidation

Caucasians Lower melanin content,less protection against blue light

Figure 3. Purified crystalline lutein. Purified lutein crystals

isolated from marigold flower extract. Photo courtesy ofKemin Foods.


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The true ground-breaking epidemiological study show-

ing a direct relationship between lutein intake and AMD

risk was reported by Seddon et al. in 1994. Among the spe-

cific carotenoids, lutein and zeaxanthin were most strongly

associated with decreased AMD risk (57% lower risk for

highest quintile of lutein intake, 6mg/day, relative to the

lowest quintile, 0.5 mg/day).22 Consistent with this finding

was the inverse association between intake of spinach andcollard greens, two foods richest in lutein and zeaxanthin,

and AMD risk. This suggests that individuals deficient in

lutein intake are at higher risk for AMD. Subsequent epi-

demiological studies have not reported such striking rela-

tionships, with an inverse association between lutein intake

and serum levels and AMD risk being marginal at best.39,40

However, it should be acknowledged that many of these

study outcomes may be affected by unaccounted for physi-

ologic and nonphysiologic confounders. For example,

Mares-Perlman et al. reported finding no relationship

between lutein intake and AMD risk, but a weak association

between serum levels and AMD risk in a group ofNHANES III subjects.40 This inconsistency may be due to

effects of bioavailability, unreported carotenoid supplemen-

tation by subjects, and even inaccuracies in the nutrient

content of reported foods, all of which would contribute to

diluting relationships by increasing variability. Thus, while

future epidemiological studies (ideally prospective in

nature) should take these confounders into account, the

available evidence supports the hypothesis that lutein plays

a protective role against AMD.

Biologic plausibility and mechanism of action

Light-induced retinal damage depends largely onwavelength, exposure time, and power level, with blue light

(440 nm) requiring 100 times less energy to cause damage

than orange light (590 nm).41 Because of its molecular

structure, lutein does not absorb UV light (maximum

absorption at 446 nm, at the blue range of the electromag-

netic spectrum).

Rather, all UV light entering the eye is absorbed by the

lens. Elevation of blood oxygen levels in monkeys exposed

to blue light is associated with increased macular damage,

suggesting that the basic mechanism of photo-induced dam-

age involves free radicals produced by light and reactive

oxygen species.42

Characteristics of the macular pigmentmake it well suited to serve as a filter of incoming blue light,

such as its orientation (back of the retina), and its absorption

spectrum (420-460 nm). It is well accepted that the macular

pigments primary purpose is to function in a photoprotec-

tive manner by filtering out damaging blue light.24 Indeed,

Hammond et al. revealed that, in older subjects, the

strongest positive association between MPOD and visual

sensitivity was observed at 440 nm (vs. 550 nm) light.43 In

a recent report by Beatty et al., macular pigment was shown

to be significantly inversely related to age and predisposition

to AMD in a group of 46 subjects.44 These findings from

human studies suggest that the macular pigment serves to

protect the ocular cells of the macula, and that age-related

decreases in MPOD may increase susceptibility to macular

degeneration.

Perhaps the most compelling piece of evidence sup-

porting a protective role for lutein in AMD is its selective

and specific deposition in the macula. Of all the carotenoids

found in human serum, only lutein and zeaxanthin (and their

metabolites) are located in the macula, with their concentra-

tion being greatest at the center of the fovea, diminishing

with increasing eccentricity (Figure 4).45 A number of stud-

ies have reported that lutein and zeaxanthin are solely

responsible for macular pigment.23,46,47 Not surprisingly,

these two xanthophylls absorb light of the characteristic

blue wavelength.48 Researchers have discovered what is

believed to be an intermediate metabolite in the conversion

of lutein to zeaxanthin, meso-zeaxanthin, in the macula.49

This suggests that in addition to having its own biologic

activity, lutein may act as a precursor of zeaxanthin.

As a highly vascularized tissue possessing a high con-

centration of polyunsaturated fatty acids (PUFAs), the mac-

ula is particularly susceptible to free radical oxidative dam-

age.33 The presence of oxidative metabolites in the macu-

la50 suggests that lutein may also offer protection to the

cells of the macula by acting as an antioxidant. Several

investigators have published reviews proposing that antiox-

idants, including lutein and zeaxanthin, help to inhibit

drusen formation and preserve macular health by acting as

free radical quenchers (Figure 5).28,34 Use of retinal pig-

ment epithelium (RPE) cells in culture as an in vitro model

has shown that treatment with antioxidants, including zeax-anthin, dramatically decreased oxidative stress-induced

lipid peroxidation and apoptosis (cell death).51 Thus, the

available evidence supports the notion that lutein and zeax-

anthin comprise the macular pigment, and provide photo-

chemical protection to the macula.

While it is clear that lutein and zeaxanthin comprise

the macular pigment, which in turn is proposed to protect

the cells of the macula from photo oxidative damage, little

has been done to investigate whether or not the concentra-

tions of lutein and zeaxanthin in the macula, per se, are

associated specifically with AMD risk in humans. A group

that includes two of the worlds leaders in ophthalmology

research, Dr. Richard Bone and Dr. John Landrum,

addressed this issue in a recent publication. Investigators

obtained donor eyes from AMD patients and control sub-

jects, and measured the concentrations of lutein and zeax-

anthin in the central regions of the retina (area including

and surrounding the macula). Within the inner region (area

most closely surrounding the macula), those subjects pos-

sessing the highest quartile of concentration were 99.9%

less likely to have AMD relative to those with the lowest

quartile (Figure 6).52 This study was the first to specifical-


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ly examine the relationship between lutein and zeaxanthin

concentration in the macular region and AMD risk in

humans. Such a relationship has not been reported for any

other carotenoid.

Although research at the cellular level directed at defin-

ing luteins mechanism of action in the macula is in its

infancy, initial studies offer encouraging insights. The

group headed by Dr. Paul Bernstein from the University of

Utah addressed this issue by isolating and purifying a puta-

tive xanthophyll-binding protein (XBP) from human retina

tissue. Using a combination of ion-exchange and gel-filtra-

tion chromatography, this group isolated two putative xan-

thophyll-binding proteins from human macular tissue of 25

and 55 kDa, respectively, with the former likely being a

truncated form of the latter.53 The XBP was shown to bind

selectively and specifically to the xanthophylls (lutein,

zeaxanthin, -cryptoxanthin) with the highest affinity being

for lutein (Figure 7). In contrast, other plasma-binding pro-

Figure 5. Proposed model for AMD protection by antioxidants. (From Winkler 1999.)

Oxidation

Photoxidation

Oxidants

Free Radicals

Reactive Oxygen

Species

Lipid Peroxides

Oxidized Proteins

DNA Breaks

Dark Sunglasses

Macular pigment

(Lutein/zeaxanthin)

Antioxidants/Enzymes

Carotenoids

Lutein

Glutathione

Vitamins C & E

Disease

Repair/Replace

ARMORY OF PROTECTANTS

Figure 6. Odds ratio (risk) for AMD as a function of luteinconcentration quartile in the inner region of the fovea inAMD cases vs. controls. Retinas were collected from donoreyes (AMD patient cases, n = 56; and controls, n = 56) andanalyzed for lutein and zeaxanthin concentration by HPLC.The above figure is representative of data collected fromconcentrations in the inner part of the fovea, where the rela-tionship was strongest. *95% CI; p = 0.0005 for trend.From Bone et al. 2001.

Figure 7. Binding of various carotenoids to XBP. Indicatedcarotenoids were added at 4 M concentrations to xantho-phyll-binding protein (XBP) preparations from humanperipheral retina. Shown is the mean SEM for the peakA260/A280 ratio (measurement of binding) determined bygel filtration chromatography; n = 3 5. From Yemelyanovet al. 2001.


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teins, such as albumin and low-density lipoprotein had little

or no affinity for any of the carotenoids. These data are the

first to demonstrate the presence of a specific lutein-binding

protein in ocular tissues. It is the first insight into estab-

lishing a potential transport pathway for lutein from the

serum and/or retina to the macula.

Nutritional importance of lutein in AMD

Although epidemiological studies offer strong support

for the notion that lutein consumption may be inversely

related to AMD risk, they are associative, and do not test

causality. Controlled intervention studies are needed to

determine whether lutein consumption per se results in a

direct health benefit. Due to the lengthy nature of AMD

development, it is very costly to test this using the disease

as the endpoint. Thus, for nutritional intervention studies,

scientists have turned to using macular pigment as a surro-

gate biomarker for lutein action. As previously dis-

cussed, MPOD, readily measured in animals and humans, is

well accepted as a marker of macular health.24 One of the

first lutein nutritional intervention studies was performed

on rhesus monkeys, a well-known human model, by

Malinow et al. in 1980.54 Monkeys maintained on a stan-

dard laboratory diet containing lutein possessed normal

MPOD levels, and drusen was nearly undetectable.

However, monkeys maintained on a xanthophyll-free diet

possessed no macular pigment, a high level of drusen in the

pigment epithelium, and serum xanthophylls were unde-

tectable. This study has been followed by a recent report by

Neuringer et al. showing once again that maintaining rhe-

sus monkeys on a xanthophyll-free diet results in zero mac-

ular pigment. They also showed that repleting the monkeys

with a diet supplemented with 6 mg/kg/day lutein and 2.2

mg/kg/day zeaxanthin, restored MPOD to near normal lev-

els in 6 to 12 months.55 These studies provide evidence

from a well-utilized human model that lutein and zeaxan-

thin are required for macular pigment, and that they must be

obtained from the diet.

Controlled intervention studies in humans have now

begun to appear in the literature (summarized in Table 3).

Collectively, these studies have shown that providing lutein

to humans from foods,56,57 marigold flower extract (lutein

esters),58,59 or purified/crystalline lutein from marigold

flowers,60 results in significant increases in serum lutein

and MPOD in normal subjects. While serum lutein levels

typically increase within hours of ingestion, several or

more weeks are required before increases in MPOD are

detected. However, as shown by Johnson et al. (Figure 8)

the MPOD density and serum lutein do follow the same

pattern, suggesting that the increase in MPOD is supplied

by serum lutein obtained from supplementation.57 In con-

trast to lutein serum levels, the MPOD remains elevated forat least two months after supplementation. Doses as low as

2.4 mg lutein/day (purified form of lutein supplement) for

six months increased MPOD by 10% (Figure 9).60 As

expected, the bioavailability of lutein from vegetables, such

as spinach is lower than purified lutein (Johnson et al. 2000

vs. Landrum et al. 1997), but greater than lutein esters. The

largest response per mg in both serum lutein and MPOD

was observed with purified crystalline lutein (Table 3).

Human intervention studies examining visual function

as an endpoint to dietary supplementation are ongoing. The

largest of these prospective, randomized, placebo-con-

trolled studies, the Age-Related Eye Disease Study

Study n Supplement Dose Product/Form Supplementation Peak Response

(mg/day) Period (weeks) (% increase/mg lutein or lutein esters)

Serum Time to Peak MPOD Time to Peak

(weeks) (weeks)

Johnson

et al. 2000 7 10.2 Spinach/corn (lutein) 15 9.3% 4 2.6% 4

Landrumet al. 1997 2 60* Lutein esters 20 1.4% 17 0.4% 25

Berendschotet al. 2000 8 20* Lutein esters 12 4% 4 0.8% 16

Landrumet al. 2000 24 2.4 Purified lutein 24 43.3% 24+ 4.1% 24+

Table 3. Summary of human intervention studies investigating the effect of lutein on serum and MPOD responses.

*Based on 2:1 lutein ester to lutein equivalency ratio. Peak response refers to the highest levels attained in the study.+Peak response not assessed; increases based on pre- and post-supplementation values only.


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14 JANA Vol. 4, No. 2 Summer 2001

(AREDS), was initiated prior to luteins emerging role, and

thus does not contain lutein or zeaxanthin supplements.

Smaller trials, including case-studies that incorporated lutein

as a supplement are nearing completion, and some have been

published already. In 1999, Dr. Stuart Richer reported

improvements of up to 92% in 14 AMD patients assessed by

various visual acuity tests following diets containing five

ounces of spinach (equivalent to approximately 14 mg lutein)

and supplemented with purified lutein 4-7 times/week for up

to a year.61 However, this study was not placebo-controlled

and did not address changes in macular pathology. A recent

study from a group in Milan, Italy, showed that supplemen-tation of AMD patients with a daily vitamin/antioxidant

cocktail that included 15 mg of lutein for eighteen months

resulted in a 2-fold higher improvement in visual acuity rel-

ative to the placebo group.62 No changes were observed in

the number and size of drusen from either group.

Further human intervention studies are needed to better

define the protective effects of lutein supplementation on

AMD and visual acuity. Two expert researchers, Dr. Stuart

Richer and Dr. Max Snodderly, have ongoing double-blind,

placebo-controlled human intervention studies. Their

results will help determine the safety and efficacy of lutein

supplementation on visual acuity in patients with AMD.

Lutein and other eye diseases: cataracts and retinitis pig-

mentosa

Cataracts are prevalent in 40% of US adults over age

75.63 and their extraction is one of the most frequent and

costly surgeries performed on the elderly.64 Cataracts are

characterized by the presence of an ocular opacity, partial or

complete in one or both eyes, on or in the lens or capsule,

often impairing vision or causing blindness. The cause is

likely due to the oxidation of proteins, and subsequent pre-

cipitation of these damaged proteins in the lens of the eye.65

As is the case with AMD, a number of epidemiological

studies have reported that lutein intake and/or serum levels

are inversely associated with cataract risk.66,67 In 1992,

Hankinson et al. used a prospective cohort to show that

specifically spinach consumption (high in lutein), as

opposed to carrots (high in -carotene) was inversely relat-

ed to cataract extraction.17 Three recent prospective studies

all showed that of the carotenoids analyzed, only the intake

of lutein and zeaxanthin were inversely associated with

cataract extraction (20-50% risk reduction).18,20

In addi-tion, while total serum carotenoids were not related to

nuclear cataract, there was at least a marginal inverse asso-

ciation with serum lutein reported by Lyle et al.68 Results

of these studies are summarized in Table 4.

With respect to biologic plausibility, if lutein does con-

fer a protective effect against cataracts, one would expect it

deposited in the lens of the eye. In a manner parallel to that

with AMD, research has shown that of the handful of

carotenoids found in serum, once again it is the xantho-

phylls that are selectively deposited in the lens. A group

from the USDA Human Nutrition Research Center on

Aging at Tufts University reported that lutein and zeaxan-

thin were the only carotenoids detected in the lens of the

human eye.69 A group at the University of Utah headed by

Dr. Paul Bernstein showed recently that lutein is present in

other ocular tissues as well, including the retinal pigment

epithelium and ciliary body.70 While other carotenoids that

occur readily in the serum were detected, lutein was present

anywhere from 2- to 7-fold higher than -carotene or

lycopene.70 This once again reinforces the importance of

lutein relative to other carotenoids in eye health. Though a

strong case can be made for a protective effect of lutein

Figure 9. Effect of 2.4 mg/day supplemental lutein on serum lev-els and MPOD. Normal subjects were supplemented with 2.4 mgpurified lutein/day for six months. Serum lutein and MPOD weremeasured pre- and post-supplementation. Shown is mean SEMfor n = 24 subjects; * p < 0.05. From Landrum et al. 2000.

*

*

Figure 8. Effect of 10 mg lutein/day (from spinach and corn con-sumption) on serum lutein and MPOD. Normal subjects ingesteda diet supplemented with spinach (60g/day) and corn (150 g/day),equivalent to about 10 mg/day lutein, for 15 weeks. Serum luteinand MPOD were measured periodically. Shown is mean SEMfor n = 7 subjects; *p < 0.05 vs. wk 0 for serum; p < 0.05 vs. wk0 for MPOD. From Johnson et al. 2000.


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against cataracts, whether lutein supplementation has a direct

effect on this disease remains to be established. More data

are required from prospective epidemiological studies and

from double-blind, placebo-controlled intervention studies

especially, to better define the role of lutein in cataracts.

Retinitis pigmentosa (RP), is a degenerative disease

characterized by atrophy of the retinal pigment, that leads to

damage of the photoreceptors and eventually blindness.71

There are few, if any, treatments available, although sup-

plementation with high doses of vitamin A has been shown

to slow the degenerative process.72

One internet study sug-gests that lutein supplementation improves visual acuity in

RP patients. Sixteen RP patients recruited and maintained

in the study via the internet were supplemented with 40 mg

lutein/day for 9 weeks. Using computer-simulation, patient

self-tested visual acuity improved significantly.73 While

these data are subjective, they suggest that lutein may have

a protective effect against RP. Double-blind, placebo-con-

trolled intervention studies are forthcoming.

Collectively, these data suggest that lutein may not

only be protective against AMD, but may play an important

role in eye health in general. This is particularly apparent

in light of the findings reported by Bernstein et al. showing

how lutein levels outnumber other well-known carotenoids

in several ocular tissues.70

III. LUTEIN AND CHRONIC DISEASE: CANCER,

HEART DISEASE, AND IMMUNE FUNCTION

In addition to their potential role against eye disease,

carotenoids have been hypothesized to have a role in the

prevention of cancer.5 At the cellular level, environmental

and metabolically-derived free radicals and reactive oxygen

species are believed to cause oxidative damage to DNA,

inducing mutations in key genes that control cell growth

(see Figure 5).74,75 As photoprotectors, carotenoids act as

absorbers of blue light and as barriers to photo-induced free

radical production.76 As antioxidants, they are believed to

protect cellular DNA by quenching free radicals and reac-

tive oxygen species, and by replenishing other antioxi-

dants.74,77 Finally, evidence suggests carotenoids exert

antiproliferative and differentiating effects that may pre-

vent transformed cells from becoming cancerous.78-80

As a relatively new member of the carotenoid family,the protective role of lutein against cancer has not been fully

established. Fruit and vegetable intake has been the focus of

most research testing this hypothesis, with -carotene being

the main carotenoid of interest. However, a growing body

of evidence suggests that lutein may have protective effects

against cancers of the breast, colon, lung, skin, cervix, and

ovaries.5 Table 5 summarizes the available evidence sup-

porting a protective role of lutein in various cancers.

Breast cancer

Breast cancer is the most common form of cancer in

women of developed countries, afflicting one in eight USwomen.81 The largest body of evidence linking lutein intake

and decreased cancer risk comes from studies on breast can-

cer. In 1996 Freudenheim et al. conducted the first case-

control study showing a 53% decreased risk for breast can-

cer for lutein and zeaxanthin intakes in the highest quartile

( 7.2 mg/day) vs. the lowest ( 3.6 mg/day).11 Consistent

with these results is another case-control study by

Longnecker et al. showing that consumption of spinach or

carrots more than twice weekly was associated with half the

Study Parameter Assessed Endpoint Assessed Comparison Outcome

Hankinson Spinach intake Incidence of Consumption 5et al. 1992 cataract extraction times/week risk 39%

vs. 1 time/month

Chasan-Tabar Carotenoid intake Incidence of cataract 13.7 vs. 1.1 mg/day lutein risk 22%et al. 1999 extraction

Brown Carotenoid intake Incidence of cataract 7.0 vs. 1.3 mg/day lutein risk 19%et al. 1999 extraction

Lyle Antioxidant intake Incidence of nuclear 1.3 vs. 0.3 mg/day lutein risk 50%et al. 1999 cataract

Lyle Serum carotenoids Incidence of nuclear 0.4 vs. 0.18 mol/L lutein risk 30%*et al. 1999 cataract

Table 4. Summary of epidemiological studies investigating lutein and cataract risk

*not statistically significant


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risk of developing breast cancer relative to those who did not

consume these vegetables.82 This is consistent with a subse-

quent prospective study by Zhang et al. showing that women

with intakes of lutein and zeaxanthin in the highest quintile

(9 mg/day) had a significant 21% decrease in breast cancer

risk relative to those in the lowest quintile (2mg/day).13 Two

studies have also reported an inverse association between

serum lutein and breast cancer risk.12,83

As is the case with other carotenoids, deposition of

lutein in tissues of interest helps to substantiate a hypothe-

sis of bioactivity. Lutein is readily present in both breast

tissue and breast milk.84,85 While intervention studies exam-

ining the effect of lutein supplementation on breast cancer

are absent, studies have shown that increasing carotenoid

intake increases serum lutein levels,86,87 which correlate

well with breast tissue levels.88 This suggests that increas-

ing lutein intake from foods or supplements increases the

amount deposited in breast tissue. Currently no human

intervention studies have examined the effect of lutein sup-

plementation on breast cancer incidence or progression.

However, a recent study by Brown et al. reported at the

Association for Research in Vision and Ophthalmology

2001 Annual Meeting showed that the inhibition of mam-

mary tumor development in mice on a high-lutein diet was

due to a decrease in tumor angiogenic (blood vessel growth)

activity.89

Reducing the blood supply to tumors is known toeffectively shrink their size. These data from mice indicate

that not only may lutein exert anticancer effects, but does so

when consumed in the diet.

Colon cancer

While it has decreased slightly in recent years, colon

cancer is a leading cause of death in the US.90 As with

breast cancer, a number of epidemiological studies have

revealed an inverse relationship between lutein intake and

colon cancer.16,91,92 In the most recent US-based study

(Slattery et al. in 2000), of all carotenoids analyzed, lutein

intake had the strongest inverse relationship with colon

cancer risk.16 Subjects consuming the highest quintile of

lutein (3 mg/day) had a 35% decreased risk for colon can-

cer relative to those in the lowest quintile (0.3 mg/day).

Lutein also accumulates in colonic epithelial cells in sub-

jects consuming a diet rich in vegetables.93 This helps to

establish a basis for the biologic plausibility for lutein and

colon cancer prevention or protection.

Lung cancer

More Americans die from lung cancer than any othercancer.94 Data from epidemiologic studies support a protec-

tive effect of fruit and vegetable consumption on lung can-

cer risk.95 However, researchers have proceeded cautiously

when examining whether or not lutein has a beneficial

effect on lung cancer in light of intervention studies that

showed that -carotene supplementation increased cancer

incidence in smokers.8,96 Inverse associations have been

reported between lutein intake and serum levels and lung

cancer risk in both retrospective case-control studies and

prospective cohorts.97-102 The strongest association for

lutein was reported by De Stefani et al. who showed that

subjects consuming lutein in the highest quartile ( 3.2 mg

lutein/day) had nearly half the risk of lung cancer relative

to those in the lowest quartile (< 1 mg/day).100

Oxidative stress from smoke may play an important

role in lung carcinogenesis.103-105 The protective effect of

carotenoids and other antioxidants may be related to their

ability to scavenge free radicals contained in smoke.106

Concurrently, smoking depletes the body of these important

antioxidants107 as smokers tend to have lower plasma levels

of antioxidants relative to nonsmokers.108 Even exposure

to passive smoke is associated with lower serum carotenoid

Cancer Tissue Deposition Epidemiology Intervention StudiesShowing Inverse association

Breast Yes Intake & serum Inhibition of mammarytumor development*

Colon Yes Intake Inhibition of coloncarcinoma propagation*

Lung Yes Intake & serum NA

Skin Yes NA Inhibition of UV-induced erythema and dermatitis

Cervix Yes Intake & serum NA

Ovarian Yes Intake NA

Table 5. Summary of lutein effects on cancer

NA = research not available; *based on animal and/or cell culture studies


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levels.109 This effect not only predisposes smokers to lung

cancer, but decreases macular pigment110 and increases the

risk for AMD.111 Increasing intake of green leafy vegeta-

bles can increase serum lutein in smokers to levels compa-

rable to those in nonsmokers.112 Thus, smokers especially

may require supplementation of their diet with antioxidants

to offset the depleting effects of smoking.

Skin cancerSkin cancer is a growing concern in the US. With one

million cases diagnosed each year, skin cancer is contribut-

ing more and more to overall mortality.113 Increased sun

exposure (UV light) is thought to be largely responsible. Of

all the organ systems in which lutein may have a protective

role, none may be more relevant than skin. Carotenoids

function in plants as blue light filters and free-radical-scav-

enging compounds.26 In skin, lutein and other carotenoids

may function in a similar manner, either by topical applica-

tion114 or by ingestion.115 Despite this apparently obvious

relationship, very little data are available in the literature.

Epidemiologic studies examining relationships betweenlutein intake or serum levels, sun exposure, and skin cancer

risk are unavailable. However, there is some evidence

showing that lutein along with other carotenoids may have

a protective effect. The presence of lutein in the skin sug-

gests that it may have a biologic function there.116 In a

recent study by Stahl et al., subjects who ingested a

carotenoid supplement daily for 12 weeks that included 0.12

mg lutein developed significantly less erythema (skin red-

ness) in response to UV irradiation at week 12 relative to

week 0 (Figure 10).117 This study does not establish a direct

link between lutein supplementation and protection of the

skin, but it does suggest that lutein may be involved. Higher

levels of lutein are present in skin amyloid from subjects

suffering from systemic amyloidosis (deposition of glyco-

proteins in various tissues and organs), relative to normal

skin.118 Given that accumulation of these glycoproteins can

lead to oxidative damage, accumulation of lutein suggests

the presence of a natural defense mechanism that relies on

the free-radical-scavenging ability of lutein.

The remainder of the evidence comes from cell culture

and animal models. Taylor et al. showed that addition of 5

mg lutein to the skin of mice inhibited ultraviolet B radiation

(UVB)-induced epidermal cell proliferation and erythema by

50%.119 This is direct evidence that topically-applied lutein

exerts photoprotective effects. The recent observation that

mice fed a diet supplemented with purified lutein (0.04 or

0.4%, respectively) had significantly decreased UVB

induced skin inflammation (Figure 11) is the first of its kind

to demonstrate the direct effect of dietary lutein on UVB

induced skin damage.120 These findings suggest that specifi-

cally dietary sources of lutein may offer a protective effect

against oxidative damage induced by UVB light.Furthermore, in a different study the same researchers also

showed a decreased UVB induced immunosuppressive

response in mice fed purified lutein, suggesting again a pro-

tective role of lutein against UVB damage.

These findings support the hypothesis that either topical

application or ingestion of lutein protects the skin from

UVB-induced damage. This in turn suggests that lutein may

play a protective role against skin cancer, primarily as a fil-

ter of blue light, but also as a free-radical scavenger. Further

Figure 10. Effect of carotenoid supplementation on UV-inducedskin redness (erythema). Subjects were given a carotenoid sup-plement that included 0.12 mg lutein daily for 12 weeks. Dorsalskin was then exposed to UV light, and erythema was measured24-hours later. Each subject served as their own control. Shownis the mean SD for n = 20 subjects; *p < 0.05 vs. control. FromStahl et al. 2000.

Figure 11. Effect of lutein supplementation on UV-induced

inflammation in mice. Mice were fed a standard laboratory diet

containing no lutein, 0.04% lutein, or 0.4% lutein, respectively.

24 hours after exposure to UVB irradiation (ears), ear swelling

was assessed. Shown is the mean SEM from n = 10 mice pergroup; *p = 0.025 vs. control diet. From Faulhaber et al. 2001.

ControlCarotenoid

SupplementControl CarotenoidSu lement

*


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intervention studies are required to confirm these effects in

humans, and determine safe and efficacious doses.

Cervical and ovarian cancers

In addition to the more common cancers, it appears that

lutein intake may be inversely associated with risk of cervi-

cal and ovarian cancers. While the research is much lessextensive relative to other carotenoids, there are sufficient

data to support a role for lutein. Lutein is readily found in

both cervical and ovarian tissues,121 and the serum level of

lutein from patients with cancerous or precancerous cervi-

cal tissue was shown to be lower than that of noncancer

subjects.122 This suggests lutein may play a protective role

against cervical cancer. However, the majority of the avail-

able epidemiologic data do not show such a relationship

with cervical cancer as the endpoint. It is possible that

lutein may exert its effects earlier in the process of cervical

cancer development. Infection by the human papilloma

virus (HPV) is believed to be a significant contributor to

cervical carcinogenesis.123 In 1997 Giuliano et al. reported

that women who screened negative for HPV had, on aver-

age, nearly a 30% higher serum level of lutein than those

who had screened positive.124 A similar relationship was

found for other carotenoids as well. These data suggest that

women with a lower intake of some carotenoids, including

lutein, may be more susceptible to HPV infection and sub-

sequent development of cervical cancer. It has been pro-

posed that this effect may be related to the ability of potent

antioxidants, such as carotenoids and tocopherols, to main-

tain a normal immune response, which in turn helps to

negate viral infection.124

While studies investigating effects of lutein on ovariancancer are scarce, there is enough evidence to suggest that it

may be protective. In addition to the presence of lutein in

ovarian tissue,121 the results from a case-control study

released earlier this year by Berton et al. indicate that lutein

intake may be inversely associated with ovarian cancer

risk.125 Investigators found that lutein consumption of 24

mg/week was associated with a 40% decreased risk for ovar-

ian cancer relative to an intake of less than 4 mg/week. No

associations were observed for - and -carotene. When

analyzed by food, the data showed a similar relationship

between spinach (high in lutein) intake and decreased risk.125

In summary, lutein appears to exert effects at all threestages of cancer progression: acting as a filter of blue light, as

a free-radical scavenger to inhibit initiation of DNA damage

and subsequent transformation of cells, and as an antiprolifer-

ative agent, inhibiting the propagation of cancer cells.

However, limitations inherent in epidemiologic studies (i.e.,

lack of proper controls, recall bias, confounding effects of

other nutrients) prevent us from drawing clear conclusions

from them regarding independent effects of lutein. The

effects observed in these studies are likely due to the com-

bined influence of many carotenoids and other antioxidants.

In contrast to AMD, a specific role for lutein in cancer

has not been as well defined, and human intervention stud-

ies are unavailable. However, currently available evidence

in the literature suggests that a diet low in lutein may be

associated with an increased risk for certain cancers. The

notion that lutein may play a protective role against the

development of various forms of cancer enforces the need

for its increased consumption in the form of foods and/orsupplements. Further research is needed to better define this

effect of lutein, and better establish safe and effective doses.

Heart disease

Cardiovascular disease is the leading cause of death in

the US: more people die from this disease than from any other

single cause.126 A plethora of epidemiologic studies and

research reviews have tested and implicated the intake of

antioxidants, such as carotenoids and vitamins C and E, as

having an inverse association with and protective effect

against heart disease.5,6.127-129 As is the case with cancer, the

majority of studies have focused on -carotene, with clinical

intervention studies displaying equivocal results.127 Emerging

evidence suggests that intake of the hydroxycarotenoids (xan-

thophylls: lutein, zeaxanthin, and -cryptoxanthin) may be

associated with a decreased risk for cardiovascular disease

and events associated with it, such as stroke.

The two prospective epidemiologic studies examining

stroke incidence that have specifically included lutein in the

analysis (Hirvonen et al. and Ascherio et al.) reported that

lutein intake is inversely related to stroke risk.130-131 Of all

the carotenoids analyzed by Ascherio et al., only lutein

intake was shown to be even marginally inversely related to

ischemic stroke risk (37% decreased risk for highest quin-

tile, 6.8 mg/day vs. lowest quintile, 1.3 mg/day;p = 0.1 for

trend).130 Hirvonen et al. reported that lutein intake was

inversely associated (less than half the risk) with hemor-

rhagic stroke.131 Until recently, epidemiologic data show-

ing a relationship between serum lutein levels and heart

disease were not available. Dwyer et al. reported this year

that serum lutein levels were inversely related to arterial

wall thickness in a group of subjects from the Los Angeles

area over an 18-month follow up period.132 This is consis-

tent with results reported in the same paper indicating that

mice supplemented with lutein had significantly less ather-

osclerotic lesions than control mice.132

One model to explain heart disease maintains that free

radicals and ROS oxidize low density lipoproteins (LDL),

which damages the endothelial cells lining the arterial

walls. Studies have shown that carotenoids, and specifical-

ly lutein, inhibit LDL oxidation in vitro.133,134 There are

other studies that show marginal effects ex vivo (i.e., sup-

plementation with carotenoids, and analysis of serum sam-

ples for LDL oxidation).135,136 Some research also suggests

that carotenoids exert their antiatherogenic effect by


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inhibiting the signaling from damaged endothelial cells that

attracts monocytes. Once damaged, the endothelial cells

express adhesion molecules on their cell surface that are

recognized by monocytes, which engulf the damaged cells

in an attempt to destroy them. This step initiates the athero-

genic pathway, and development of cardiovascular dis-

ease.137,138 Indeed, it has been shown that lutein, -carotene,

and lycopene all decrease the expression of adhesion mole-cules on the surface of interleukin-stimulated human aortic

endothelial cells in culture. This results in a decrease in

adhesion to subsequently added monocytes.132,139

Immune function

Evidence has existed for more than 10 years showing

that supplementation with carotenoids, such as -carotene

may boost immune function in humans.140,141 While this is

a relatively new area of research with respect to lutein, there

are compelling data from recent dog and cat model studies.

Kim et al. reported that lutein provided in the diet of cats

and dogs increased the humoral immunity of both

species142,143 In both studies, investigators observed that

lutein-supplemented animals significantly increased lym-

phocyte and antibody production in response to a vaccina-

tion relative to animals on a control diet.142,143 This sug-

gests that lutein boosted the immune function of these ani-

mals. More studies are needed to determine if the same

effects can be elicited in humans.

IV. SUPPLEMENTS AS A SOURCE OF LUTEIN

Safety and bioavailability

To validate epidemiologic studies linking lutein intaketo human health, researchers have begun to perform con-

trolled supplementation studies focusing on bioavailability,

tissue deposition, and biomarkers of disease outcome or

disease itself. Questions have subsequently arisen concern-

ing the bioavailability of lutein from foods and supplements

alike. How bioavailable is lutein from supplements? What

factor(s) influence this? Can supplemental lutein affect the

bioavailability of other carotenoids?

Bioavailability is defined as both the intestinal absorp-

tion and usage of a given nutrient by the body.25 Studies have

shown that lutein from supplements appears readily in the

plasma (absorption), is deposited in tissues such as the eye,and even results in positive effects on potential disease bio-

markers i.e., macular pigment, skin erythema (utilization).

Doses as low as 2.4 mg/day have been shown to increase

serum lutein levels and increase macular pigment.60 Doses

up to 40 mg/day have been shown to improve visual acuity

in patients suffering from certain ocular diseases62,73 with no

negative side effects or toxic effects reported. Furthermore,

a purified lutein product extracted from marigold flowers

(Kemin Foods, L.C., Des Moines, IA) has just been deter-

mined GRAS (generally recognized as safe for use in certain

foods and beverages) by a panel of experts. Thus, it is clear

that supplements are a readily bioavailable and safe source

of lutein that can be used to increase dietary intake of this

nutrient. This is especially important in light of the findings

that consumption of lutein from green leafy vegetables has

declined in the US31 and that smokers and patients suffering

from chronic diseases often present with low serum antiox-idant levels.83,108,144

Several factors can affect carotenoid bioavailability,

the majority of which appear to influence carotenoids from

foods.145-147 In contrast to foods, the absorption of supple-

mental forms of carotenoids are not influenced by food

matrices, cooking, etc.148 However, two important factors

affect absorption of supplemental carotenoids, such as

lutein. (1) Because lutein is a fat-soluble compound,

absorption across the brush-border membrane is dependent

on the presence of a small amount of fat (approximately

5g/meal).147 Fat triggers the release of bile acids from the

gall bladder which help to disperse the fat (and fat-solublenutrients and vitamins) into small droplets (micelles) which

are readily absorbed by the intestinal cells. Without this

small amount of fat (for example, if a carotenoid supple-

ment were taken alone, on an empty stomach), fat-soluble

compounds will pass through the gastrointestinal tract

unabsorbed.147 (2) As is the case with similarly charged

minerals, carotenoids with similar structure can compete

for absorption.146,147 This issue has specific relevance to

supplements. Often supplemental forms of nutrients are

ingested in doses more concentrated than those found in

foods, and which are free from the constraining matrix of

food (i.e.,water, fiber,). It has been proposed that supple-

ment use of carotenoids could disrupt the balance of

absorption resulting in decreased bioavailability of certain

nutrients,29 as has been shown to occur between lutein and

-carotene. However, the effects observed have been

inconsistent, with lutein shown to inhibit -carotene

absorption and vice-versa.149,150 Moreover, this interaction

is so inconsistent to the extent that it varies markedly from

individual to individual.151 Hence, inter-carotenoid interac-

tions that exist in the gut may be more pronounced with

supplementation. What effect these interactions have on the

bodys nutrient status or susceptibility to disease is

unknown and warrants further research.

Thus, the available evidence supports a clear role for

sources of lutein in human health. The studies cited in

this review suggest that consumption of lutein from foods

or from dietary supplements will result in a health benefit

to the public.

V. FOCUS FOR FUTURE RESEARCH

Establishing lutein as a vitamin

By definition, a vitamin is an essential nutrient


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required by the body that must be obtained from the diet.152

Research supporting a protective role for lutein in human

health has increased dramatically in the last six years in epi-

demiologic studies, animal and human intervention trials,

and in in vitro cell culture studies. However, as a variety of

phytonutrients contained in fruits and vegetables, including

carotenoids, and others yet to be identified, are all needed

for optimal health and protection from chronic disease, spe-cific carotenoids have not been identified as required and

essential nutrients. With the exception of lutein and AMD,

there is no disease state that can be linked specifically to a

deficiency in any one carotenoid. With the exception of

MPOD, there are no accepted methods for carotenoid status

assessment to even begin to determine what a deficiency

is. No epidemiologic or intervention study shows a consis-

tent inverse relationship with one particular carotenoid and

any chronic disease risk or outcome. However, the argu-

ment can be made that lutein may be required in the diet to

protect from macular degeneration. Humans cannot syn-

thesize lutein, therefore it must be obtained in the diet.26

The fact that lutein and zeaxanthin are the only carotenoids

found in the macula suggests that these compounds have a

specific function in this tissue.45 The macular pigment is

known to be a vital protector of the cells and tissue of the

macula from blue light.24 Lutein and zeaxanthin are known

to comprise the macular pigment,47 and research showing

that lutein is converted to zeaxanthin in the macula suggests

that lutein is the required starting material.49 Providing

lutein in the diet (either as foods or supplements) increases

macular pigment (Table 3), and may increase visual acuity

in patients with AMD.61,62 These findings also suggest that

MPOD can not only be used as a biomarker of macular

health, but may also be a marker of lutein status. For many

nutrients, serum levels are not an accurate reflection of

nutritional status. Tissue levels verify absorption and are a

far better reflection of the bodys overall status. However,

measurement of tissue levels can be an invasive and

impractical method of assessment. MPOD accurately

reflects the amount of lutein in the macula, and its mea-

surement involves a noninvasive procedure.

The gold standard for vitamin classification is the deple-

tion-repletion study.153 Such studies have been performed

with lutein using the rhesus monkey model. Feeding mon-

keys a lutein-free diet (depletion), causes eventual loss of all

macular pigment.54,55 Repleting monkeys with lutein andzeaxanthin results in restoration of macular pigment.55 These

studies were unable to assess visual acuity nor examine ocu-

lar pathology. However, they indicate that lutein is required

in the diet for macular pigment, and that a diet low in lutein

can result in deficiency (as assessed by macular pigment).

Because macular pigment is known to be a marker for mac-

ular health, this suggests lutein is required in the diet for

macular health. No evidence exists to support any such

claim for other carotenoids.153

Despite the strides made in lutein research, further stud-

ies are still needed in several areas. First, using the rhesus

monkey model it may be possible to determine if lutein

depletion results in AMD and if the macular pathology can

be reversed with lutein repletion. Second, epidemiologic and

intervention studies have cited a wide range of lutein doses,

with no one amount or range clearly defined. Using MPOD

as a lutein status assessment tool, we must better define dailydoses of lutein that can be recommended in the human diet.

Finally, we must continue to execute human intervention

studies to better define efficacy of lutein supplements.

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