Current evidence demonstrates that the carotenoids lutein, zeaxanthin and meso-zeaxanthin are readily bioavailable and if supplemented will effectively increase macular pigment levels. The distinction between each remains a focus of research in many labs. John T Landrum, PhD, and Richard A Bone, PhD, investigate

Nowhere in the human body is the nutritional significance of carot-enoids more evident than in the retina.1,2,3 Here, at the centre of the retina (the ?fovea?), dietary xanthophylls are accumulated, constituting the macular pigments or macula lutea.4,5

These yellow compounds are concentrated to the greatest extent within the inner retinal layers so that blue light, focused upon the fovea by the lens and cornea, is filtered and attenuated before reaching the critically functional photoreceptor and retinal pigment epithelium layers in the outer retina. 6

The concentration of these yellow carotenoids found in the macular region of the retina in the eye is about 10,000 times greater than that found in blood, attesting to a mechanism of active accumulation by this tissue.7

The carotenoids of the macular pigment are classified as xanthophylls and are structurally related to alpha- and beta-carotene; they differ from these carotenes only by the presence of hydroxyl groups. It is startling that the retina accumulates only the xanthophylls lutein and zeaxanthin, two of about a dozen abundant carotenoids found in the blood, while not even traces of the other carotenoids are found in this tissue.

Other tissues of the body, such as the liver, skin and fat, also have detectable levels of all serum carotenoids, but appear to have little or no specificity.8,9 One exception to this is the human lens. Here, like the retina, only lutein and zeaxanthin are present, though apparently at much lower concentrations than in the retina.10,11,12

Lutein and zeaxanthin each exist in a number of different isomeric forms in nature.13,14 This is because of the structural variability in the three-dimensional geometry of covalently bonded carbon atoms. In addition to the ?bent? or cis-carotenoids that result from the two possible arrangements of each double bond in the polyene chain, the presence of the oxygen atoms on the end groups in the molecules also confers the opportunity for stereoisomerism due to the handedness or chiral nature of the tetrahedral carbon.

Because of the specificity of the carotenoid biosynthetic pathways in higher plants, the diet of humans is almost devoid of all but two stereoisomers of lutein and zeaxanthin. Other isomers in most human food sources are present in very low quantities. The presence of the zeaxanthin isomer, meso-zeaxanthin, in a high percentage in the macular pigment, is an unexpected and interesting scientific mystery.15,16 (See sidebar, below.)

Functionality of xanthophylls in the eye
What might be the functions of the xanthophylls in the human eye? As early as 1933, Walls and Judd noted that colour matching in the central field of vision was influenced by a yellow pigment.17 One of the earliest suggestions on the function of macular pigment, its ability to absorb blue light, was put forward by George Wald, who won the Nobel Prize in 1967 for discoveries about the primary physiological and chemical visual processes in the eye.18

The imperfect refraction of the different wavelengths of light by a lens, called chromatic aberration, has been known for centuries to limit the quality of the image seen by an observer. Rudduck hypothesised that by reducing the transmittance of blue light through the retina, the macular pigments would improve visual acuity by diminishing the effects of any chromatic aberration due to the lens and cornea. 19 Walls, and later Reading and Weales, suggested that the macular pigment might reduce the amount of atmospherically scattered blue light reaching the photoreceptors, which results in a hazy appearance of distant objects. 20,21

Recently, it has been theorised that macular pigment is bound to visual function for individuals to improve contrast sensitivity, though this idea still is not universally accepted.22,23,24 A number of epidemiological studies (but by no means all)25 have implicated lutein and zeaxanthin in the reduction of risk for eye disease, specifically age-related macular degeneration (AMD) and cataracts.26,27,28,29

Both higher serum levels of lutein and zeaxanthin and increased levels of dietary intake were correlated with lower risk for advanced forms of AMD by the EDCC study.30,31 A similar finding has emerged from the ARED study.32 Notably, both of these are large studies including several thousand subjects. In other studies, risk of cataracts in both males and females was found to be lower by nearly 20 per cent for subjects who have a high dietary intake of lutein and zeaxanthin. Again, these studies included large numbers of subjects.26,27

Because these two eye diseases account for a majority of the reduced vision function (cataracts) and new cases of adult blindness (AMD) in Western populations, the possibility that dietary components may substantially lower the risk for their occurrence, or delay the most severe effects, poses some compelling questions. Among them, will dietary supplementation alter macular and lens xanthophyll levels? And if so, do these higher levels demonstrably reduce or delay incidences of AMD and cataracts?

Partial answers to these questions have emerged from numerous studies on the effects of supplementation. Dietary supplements containing lutein, zeaxanthin and, very recently, meso-zeaxanthin, have become available commercially in the US. The biological availability of a supplement—the extent to which it is absorbed from the diet as measured by its presence in the blood—is a key factor essential for its transport to functionally significant sites. Serum studies show that the responses of individuals to dietary supplementation with lutein/zeaxanthin and/or meso-zeaxanthin vary over a wide range and that a daily dose of as little as 2.4mg/day of lutein can result in an average serum increase of 120 per cent.33,34

Factors that have emerged as significantly affecting the response of individuals to carotenoid intake are the extent of dissolution and the presence of other carotenoids.35 Tanumihardjo recently showed that dramatically increased serum levels result for xanthophylls that are fully dissolved in oil as compared to those in suspensions.36 In another recent study, a combined supplement composed of 10mg/day of lutein and 10mg/day of zeaxanthin resulted in steady-state serum levels for each carotenoid that was approximately half that observed in a dose of 10mg of only lutein or only zeaxanthin.37,38 At high levels of intake, a saturation limit for the absorption of carotenoids is apparently reached and the two compete to some extent.

The ability of supplementation to alter macular pigment levels has been demonstrated in several different laboratories since our original report in 1997.38,39,40,41,42 Measurement of macular carotenoids in vivo is an exciting area of investigation, and many contending methodologies have been developed. (See sidebar, below.) Unfortunately, there is no methodology currently available for the in vivo measurement of lens xanthophylls.

Another approach is the in vitro study of tissue cultures. Cell lines derived from enterocytes (CaCo-2),43,44,45 retinal pigment epithelium cells (ARPE-19)46,47,48,49 and human lens epithelial cells50 are all being investigated as in vitro models for carotenoid metabolism. Researchers using each of these cell lines have confirmed that xanthophylls accumulate within the cells. A wide range of studies using these cell lines is under way to help establish the functions of xanthophylls. Especially interesting and relevant are studies of the ability of xanthophylls to protect retinal pigment epithelium and human lens epithelium cells from light-induced damage.

Therapeutic effects
Because the retina contains a mixture of carotenoids, product developers are left with a choice of which carotenoids and of how much of each would be an ideal supplement. Researchers have seen that during supplementation with lutein, zeaxanthin and meso-zeaxanthin, individuals may respond over a wide range of latitudes; inter-subject variability can be dramatic.51 While small daily doses of lutein, for example 2.4mg/day, are adequate to produce changes in the macular pigment optical density of some subjects, others apparently do not respond at doses that are as great as 20mg/day.51 Clearly, it is not yet possible to predict a best dose for any given individual.

Part of the cause for the low response in some subjects may lie with the methodology. When heterochromatic flicker photometry is utilised to measure macular pigment optical density, a reference point is chosen in the peripheral retina and all changes are measured relative to this point. In at least one study, evidence indicates that increases in pigmentation at the reference point may have contributed to an apparent low response in the subjects.38

It has been recently demonstrated that the meso-zeaxanthin present in the eye is a metabolic product that originates from lutein.52 Monkeys that were completely deficient in macular pigmentation regained these carotenoids when supplemented over a period of many weeks. Those given pure zeaxanthin were found to have only that carotenoid present in the retina, whereas those fed lutein were found to have both lutein and meso-zeaxanthin, supporting our hypothesis that meso-zeaxanthin is derived from lutein.15 As yet researchers lack a complete understanding of the pathway by which the conversion occurs.3

Supplementation
The possibility of raising the density of macular pigment in the eye through dietary modification was first put to the test in 1997.40 In our lab, we showed that consumption of 30mg/day lutein for 140 days resulted in 20-40 per cent increases in macular pigment density. In the same year, another group demonstrated that increased consumption of lutein- and zeaxanthin-containing foods (spinach and corn) caused a corresponding increase in macular pigment in most of their subjects.39

Since then, many supplementation trials using lutein have been conducted, including some in which the effects of these carotenoids on visual function have been studied.24,53,54,55 The results of these latter studies are mixed. In some studies, small improvements in vision were noted; in others, no significant changes were reported.

The third component of the macular pigment, meso-zeaxanthin, in combination with smaller amounts of lutein and zeaxanthin, has also been successfully assessed in our lab for its potential to raise macular pigment density.56,57

Typical supplementation studies include monitoring the macular pigment density by one of the methods described in the sidebar below and by tracking the serum concentration of the carotenoid by high-performance liquid chromatography. The characteristic time course of the serum concentration of the carotenoid is based upon measurements that we made with a daily dose of 30mg lutein.

Coincident with the commencement of supplementation, the serum concentration begins to rise, eventually levelling at a plateau that represents a roughly 10-fold increase over baseline. Upon cessation of supplementation, the concentration falls in an exponential fashion back to baseline. There is often a lag of a couple of weeks after supplementation begins before the macular pigment shows signs of responding. Thereafter, a slow, roughly linear increase is observed that continues a few weeks beyond the supplementation period until the serum concentration of carotenoid has returned to baseline.

The observed slow increase is consistent with a process involving transport of the relatively large, lipophilic carotenoid molecule from the vascular choroid to the avascular central region of the retina. Surprisingly, the elevated level of macular pigment shows no tendency to fall appreciably during the months following the trial.40

In our lab, we have studied lutein supplementation with doses ranging from 2.4mg to 30mg per day. 57 Although the individual responses have been quite variable, there is a general tendency for the increase in macular pigment density to increase with dose.

Meso-zeaxanthin supplementation appears to produce similar increases in macular pigment to those obtained with an equal dose of lutein.56 Zeaxanthin at 30mg/day produced about one-third the response of lutein at the same dose; however, this may have been due to the very different formulations of the two products.

Generally, comparing results of different studies is complicated by a number of variables, in addition to formulation, such as carotenoid source (food or commercial supplement), dosage, period of supplementation, and method used to measure the macular pigment. While nearly all subjects show a clear serum response to supplementation, a response in the macular pigment is not always apparent, especially in short-term studies.

Current evidence supports the hypothesis that the carotenoids lutein, zeaxanthin and meso-zeaxanthin are readily bioavailable and will effectively increase macular pigment levels. The exact functional distinction between each remains a topic of research in many labs. Consensus seems to be developing that the xanthophylls should be a component of a healthy diet. Individuals at risk of macular degeneration or cataracts may now ensure a reasonable level of intake by supplementation.

John T Landrum, PhD, is a professor in the department of chemistry and biochemistry and Richard A Bone, PhD, is a professor in the department of physics, both at Florida International University in Miami. They hold patents on an eye-care supplement containing lutein, zeaxanthin and meso-zeaxanthin, and for an instrument useful in measuring macular pigment in vivo.
Respond: editor@ffnmag.com.
All correspondence will be forwarded to the authors.

Research Frontiers: How Bone and Landrum discovered meso-zeaxanthin
How is it that we came to study meso-zeaxanthin, a subtle structural feature of the xanthophylls that occurs in the human macular pigment? In the late 1980s, we thought it would be a worthwhile endeavour to establish conclusively which stereoisomers of the xanthophylls compose the macular pigment. We had become aware of several publications, especially those of Takao Matsuno in Japan, Synnove Liaan-Jensen in Norway, Katerina Scheidt in Switzerland and others, that demonstrated analytical methodologies to accomplish this.1,2,3 There were also reports of the presence of a variety of different isomers in the tissues of marine fish, though these were not in mammals. It was our expectation that the human macular pigment would contain only the most abundant isomers of lutein and zeaxanthin found in the diet. Our discovery that meso-zeaxanthin comprises about 25 per cent of the total carotenoid content of the central region in the macula demonstrates that serendipity, as much as careful planning, still accounts for many illuminating scientific discoveries.4

—JL, RB

References
1. Matsuno T, et al. Isolation of three new carotenoids and proposed metabolic pathways of carotenoids in hen?s egg yolk. Comp Biochem Physiol 1986; 84B:477-81.
2. Buchecker R, et al. Helv Chim Acta 1973; 56:2899-901.
3. Schiedt K. New aspects of carotenoid metabolism in animals. Carotenoids: Chem Biol 1990; NA:247-68.
4. Bone RA, Landrum JT, et al. Stereochemistry of the human macular carotenoids. Invest Ophthalmol Vis Sci 1993; 34:2033-40.


Toolbox: Quantifying the macular pigment
Over the years, several noninvasive methods have been developed for determining the level of macular pigment in a person?s eyes.1

Heterochromatic flicker photometry (HFP) is a testing procedure in which the subject views a small patch of light that alternates rapidly between blue (460nm) and green (540nm), resulting in a flickering, turquoise appearance.2 The brightness of the blue portion of this stimulus is adjusted until the flickering stops and the stimulus appears steady. This occurs when the brightness is the same for the blue and green portions of the stimulus.

A person with a dense macular pigment will require more blue light to achieve the no-flicker condition compared with a person having little macular pigment. This is because the macular pigment absorbs the blue light but is completely transparent to the green light.

An additional measurement is made while looking to one side of the stimulus so that it is imaged on the retina away from the macular pigment. This measurement provides a reference relative to which the previous measurement is gauged. HFP, while being the most common, involves active participation by the person being tested, unlike the following procedures in which participation is completely passive.

Reflectometry is a procedure often based on retinal photography.3,4,5,6 In order to capture an image of the retina, a retinal camera delivers a flash through the eye?s pupil and captures the returning light either as a digital image or on photographic film. In reflectometry, the flash is modified to deliver specific wavelengths to the retina. When blue light is used, the macular pigment stands out as a darker patch, but under green or red light, the retina appears more uniform. The green (or red) image is then digitally divided, pixel by pixel, by the blue image. From the resulting image, it is easy to generate a map showing how the density of the macular pigment varies across the retina.

Reflectometry is complicated by other light-absorbing pigments in the retina, including melanin, haemoglobin and the photo pigments found in the rods and cones. Fortunately, photo pigments can be temporarily ?bleached? prior to capturing images by exposing the retina to a fairly bright light. A superior type of retinal camera, called a scanning laser ophthalmoscope, has also been used to measure macular pigment.7

Auto fluorescence spectrometry relies on the presence of a fluorescent material, lipofuscin, in the retinal pigment epithelium found behind the neural retina.8,9,10 In this method, lipofuscin is excited first by blue light and then by green light, and the resulting fluorescence in each case is detected and quantified.

Because blue light is attenuated by the macular pigment in the central part of the retina, it produces less fluorescence than green light. By comparing the amounts of fluorescence produced by each colour, the level of macular pigmentation can be determined.

Raman spectroscopy is a general technique that has been applied to the measurement of macular pigment. The macula is illuminated with light of a specific wavelength that excites the macular pigment molecules. As they relax, the molecules radiate light with a slightly lower energy characteristic of the absorbing carotenoids. The intensity of this Raman signal, which is measured with a photo-detector, depends on the number of radiating molecules, meaning the amount of macular pigment present.11,12

—JL, RB

References
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12. Bernstein P, et al. Resonance Raman measurement of macular carotenoids in normal subjects and in age-related macular degeneration patients. Ophthalmology 2002;109:1780-7.


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