Ocular nutrition: part 1: keeping your macula healthy: the role of Lutein, zeaxanthin, and meso-zeaxanthin.
Although yellow pigmentation of the macular region was first documented in 1782, it was attributed to the xanthophyll group of carotenoids much later in 1945 (1). It wasn't until 1985 that the retinal carotenoids were separated using high-performance liquid chromatography (2). Two slightly different chemical structures were found, and were termed lutein (L) and zeaxanthin (Z). The chemical structures of these retinal carotenoids are shown in figure 1.
[FIGURE 1 OMITTED]
Carotenoids are a family of pigments that are divided into two main groups: carotenes and xanthophylls. They are introduced to the human body through dietary means alone and although not considered to be essential micronutrients, they have antioxidant and photoprotective properties. These functions have prompted interest in their potential role in prevention of disease.
L and Z are two of around 600 plant pigments in the carotenoid group and are both xanthophylls. They have the structural formula [C.sub.40][H.sub.56][O.sub.2] are not made within the body, and so can only be obtained from the diet. Carotenoids are synthesised in plants, where they are essential for photosynthesis (3) and photoprotection. L and Z are found in most fruits and vegetables, although Z is found in much smaller quantities than L (4,5). The highest mole percentages of L and Z are found in egg yolk and maize (4), although good sources are also spinach (6), collard greens and kale (7). A full list of L and Z-containing foods can be found via the US Department of Agriculture website (www.nutrition.gov) by clicking on the 'What's in food' link.
Although humans consume a wide range of carotenoids, L, Z, lycopene, beta-carotene, alpha-carotene, and betacryptoxanthin account for 90% of circulating carotenoids (8). Carotenoids are water-insoluble molecules and are transported around the body by water-soluble lipo-proteins. Inside cells, they are solubilised in membranes or lipid vesicles, or bound to proteins. The transport and localisation of L and Z is thought to be mediated by carrier proteins (9-11). The human retina, and more specifically the macula, is the single richest site of carotenoid accumulation within the human body. Post-mortem retinal analysis has shown that the total L and Z concentration at the macula is 100 times more than at the peripheral retina. The assumption that L and Z within the retina is of dietary origin, is supported by fundus photographs of rhesus monkeys on carotenoid-depleted diets that demonstrate an absence of macular pigmentation (12).
Lutein and zeaxanthin--uptake and bioavailability
Although possible binding proteins have been identified, the mechanism for uptake of xanthophylls into the bloodstream is still not clear. The efficacy of absorption from the gut depends on its original source, for example, L from egg yolk (13) is more readily absorbed than that derived from green leafy vegetables (14). This relatively low absorption from green leafy vegetables may be caused by complexing with proteins in chloroplasts within cell structures (15). Xanthophylls that are associated with oil or fat, such as those found in egg yolk, may be more readily extracted during digestion (15).
Unesterified xanthophylls such as lutein in its pure form are absorbed by mucosal cells and subsequently appear unchanged in the circulation and peripheral tissue. Esterified xanthophylls must be de-esterified to their pure form before uptake (16,17). The xanthophylls are packaged as plasma lipoproteins by the liver, released into the systemic circulation, and absorbed by a range of tissues including liver, lung, adipose, skin, prostate, and macula (8,18). Their major storage site is adipose tissue (16,19), so much so that a negative correlation between adipose tissue L concentration and the amount of L and Z in the retina has been reported in women (20).
Although some tissues, such as the skin, are not particularly selective about carotenoid uptake and compositions (they are determined by serum levels), other tissues such as the macula are highly selective (2,21,22). It is likely that specific binding proteins are involved when tissues exhibit such highly selective uptake and deposition of biological molecules.
Primates fed carotenoid-free diets have no detectable yellow pigmentation of the macula (12) and studies have shown that macular pigment levels can be raised in humans using dietary supplementation (23-25). Serum concentrations of L and Z are also reported to be responsive to dietary modifications (20,24,25). A cross-sectional study reported that people with plasma concentrations of L in the lowest third of the distribution have a significant odds ratio for risk of age-related macular disease (ARMD) of 2.0 (95% CI: 1.0-4.1) compared with those in the highest third after adjustment for other risk factors (26). In other words, subjects in the study with low plasma L had a much greater chance of developing ARMD than those with high plasma L.
The L and Z in the retina is also known as the macular pigment (MP), and the density of the MP is greatest within the central 7[mm.sup.2] of the human retina.
Lutein and Z are produced as a single stereoisomer by plants (27). However, the central retina also contains a high concentration (between 25%28 and 30% (29)) of meso-zeaxanthin (MZ). Mesozeaxanthin has been found in the human macula, retina and retinal pigment epithelium (RPE), but has not been detected in the plasma or liver (21). Within the central macula, L, Z, and MZ are found in equal quantities, but the ratio of MZ to Z decreases with increasing eccentricity (28). This forms the basis for the assumption that MZ is formed via isomerization of L28, and it is thought that the conversion mechanism is concentrated at the macula. The xanthophyll binding protein may also act as an enzyme for the conversion of L to MZ. Supplementation with 16mg MZ and 4 mg L is reported to increase macular pigment optical density (MPOD) levels by 18% in 120 days (30). This percentage increase is similar to that found when supplementing with only 20 mg L daily. This further supports the L to MZ conversion theory.
Spatial profile and distribution of xanthophylls and macular pigment
Macular pigment has been located in the inner axons of the photoreceptors and the rod outer segments. Within the central fovea, the carotenoids are most concentrated within the photoreceptor axons of the Henle nerve fibre layer (31). It may be that L and Z are be transported here from the choroid, passing across the RPE and the photoreceptor outer segments.
In the perifoveal region, L and Z are present in the outer segments of rod photoreceptors (32,33), where there is a high concentration of polyunsaturated fatty acids. These are particularly prone to oxidative attack. Within the rod outer segments, the concentration of L and Z is highest in the perifoveal region, where it is approximately 2.5 times higher than in the peripheral retina (33).
The ratio of L to Z and MZ within 0.25mm of the fovea is approximately 1:2.4 (34), but the situation reverses at the retinal periphery, where the ratio is 2:1 (see figure 2) (34).
[FIGURE 2 OMITTED]
There is a one hundred-fold drop in the concentration of MP in the peripheral retina compared with the fovea, although levels vary considerably between donors (2,35). The ratio of L to Z and MZ varies linearly with the ratio of rods to cones with increasing eccentricity up to approximately 6 degrees from the fovea (34).
The hypothesis that Z is only found in the rods is refuted by the fact that the fovea contains predominately cones, as well as by the fact that squirrel monkey and macaque retinae have their highest concentration of L and Z in the central fovea (36).
Functions of macular pigment
It has been suggested that xanthophylls play a similar role in humans as in plants, as antioxidants and screeners of high-energy blue light (37). MP may prevent light-initiated oxidative damage to the retina and therefore protect against subsequent age-related deterioration (38).
Oxidative damage may be an important factor in the development of age-related diseases (39,40). Chemically, oxidation refers to the removal of electrons and, when it occurs within the body, it can result in the formation of cytotoxic chain reactions. Reactive oxygen species (ROS) is a term used to describe some types of free radicals, hydrogen peroxide and singlet oxygen, which are all capable of damaging membrane lipids, proteins, nucleic acids, and carbohydrates via oxidation (41).
The eye is particularly prone to ROS damage. The transparency of the cornea, aqueous humor, lens and retina allow continuous exposure to light, which along with ageing, inflammation, air pollutants, and cigarette smoke, has been shown to increase production of ROS (42,43). Polyunsaturated fatty acids are abundant in the retina, predominantly found in photoreceptor outer membranes, and are readily oxidised (42,44,45). Phagocytosis, a process that produces ROS, occurs within the RPE.
Carotenoids are also able to quench singlet oxygen (a potent oxidant) (51), scavenge reactive oxygen species (52), limit peroxidation of membrane phospholipids (53), and reduce lipofuscin formation (54). The presence of MP in the rod outer segments and RPE (32,33) is suggestive of a ROS-quenching function. The fact that L and Z have been found in higher concentration in the rod outer segments of the perifoveal retina than the peripheral retina, lends support to their proposed protective role in age-related macular disease (32).
The absorbance spectrum of MP peaks at 460nm and it is purported to act as a broadband filter, reducing the sensitivity of the macular region to short wavelength light which is most damaging in the 440 to 460nm range (46,47) (see figure 3). The presence of MP in the inner retinal layers (48) supports a photoprotective role.
[FIGURE 3 OMITTED]
Blue light is the highest energy form of visible light and is known to induce photo-oxidative damage by generation of ROS. Lutein is reported to be a superior filter (49) due to the fact that it is orientated both parallel and perpendicular to the plane of the membrane (50). Zeaxanthin is orientated perpendicular to the membrane plane only and so may not be able to absorb the excitation beam from all directions. Zeaxanthin, however, is reported to be a superior photoprotector during prolonged light exposure; the shorter time-scale of protective efficacy of L has been attributed to oxidative damage of the carotenoid itself (50).
As well as reducing the potential for photo-oxidation, the blue-light filtering by MP may also reduce glare, increase contrast, reduce chromatic aberration, and improve visual acuity.
Effect of nutritional supplementation or dietary modification on MPOD
Although the L and Z content of human diets is related to retinal L and Z levels, there is some variability in retinal response between subjects (20,24,51). Short-term feeding studies have reported increases in retinal L and Z levels following a diet of L- and Z-rich foods (20,24) and supplements (23,51-53) for at least three months. The variability in retinal response may be related to differences in the bioavailability of carotenoids from different foods (54). Cooking, chopping, or ingesting carotenoid-containing foods with dietary fat can all increase bioavailability of L and Z (55). In other words, eating chopped spinach leaves with a little olive oil would make it easier for L and Z to be extracted during digestion than eating whole spinach leaves without oil. Also, choosing a nutritional supplement that contains L and Z bound in oil may also be more beneficial than choosing a dry powder formulation.
It has also been suggested that retinal levels of L and Z may be more easily affected by dietary modification and nutritional supplementation in men than women. Higher MPOD levels in men has been reported in some studies (56-58) but not others (59-60). MPOD levels are also reported to be lower in those people with higher levels of body fat (56,61,62); this may be explained by the fact that adipose tissue is a preferred storage site for L and Z, and so the retina has to compete for the xanthophylls. MP is known to be lower in those with lighter iris colour (61) and in those who smoke (57,60,62,63). Cultural differences in L and Z intake have been reported; for example, Hispanic and White Americans consume around half as much L as African Americans (64).
There have been no large-scale studies looking at the effect of L and Z supplementation in MPOD. The results of several small studies suggest that MPOD can be modified by nutritional supplementation and dietary modification but only for some people. For example, MPOD increased by 4% to 5% in eight males supplementing with 10mg L daily (52). Additionally, an average increase in MPOD of 19% was found in people supplementing with spinach (providing 10.8mg L and 0.3 mg Z) or sweet corn (providing 0.4mg of L and 0.3mg Z) for up to 15 weeks, although three out of 13 participants were non-responders (24). The fact that some people do not appear to have a retinal response to L and Z supplementation may be related to the xanthophyll-binding protein (10). It could be that some people are genetically predisposed not to have the binding protein, which would mean that they are unlikely to respond to any amount of supplementation or dietary modification.
The RPE and age-related macular disease
The RPE consists of a single layer of cells and is positioned between the photoreceptors and Bruch's membrane (see figures 4 and 5). The RPE cells perform several functions, including absorption of light, enabling the turnover of photoreceptor outer segments, formation of visual pigments by storing and releasing vitamin A. The RPE cells also absorb light and prevent incident light being reflected back to the neural retina, which result in loss of image sharpness. The number of RPE cells per eye can range from 4.2 to 6.1 million, and in younger eyes these form a highly organised hexagonal pattern (see figure 5). In older eyes, the regular pattern is lost as a result of the low regenerative ability of these cells. Cell loss prompts hyperplasia (abnormal multiplication) of adjacent cells. Interestingly, monkeys that were fed diets free of L and Z had a significantly lower RPE cell density, than those fed normal diets (65).
[FIGURES 4-5 OMITTED]
The RPE cells are joined by tight junctions forming a barrier that limits the flow of ions and prevents diffusion of large toxic molecules from the choriocapillaris to the photoreceptors. Each RPE cell supports around 50 photoreceptors. A breach in the connection between photoreceptors and RPE cells, as well as damage to RPE cells, will result in visual loss.
The basal end of each RPE cell rests on a basement membrane that forms part of Bruch's membrane, and the apical end have multiple microvilli measuring 5-7[micro]m that project between the outer segments of the rods and cones. The apical microvilli continuously erode the outer segments of the rods. Lysosymes within the microvilla contain hydrolytic enzymes that break down the photoreceptor outer segments. In this way, the RPE cell phagocytoses the discs of broken down visual pigment within the outer segments. Lipofuscin granules are the final products of this process. As we age, lipofuscin collects within the RPE cells (66), and this continual increase in the lipofuscin content of RPE cells between the age of 20 and 70 years has been described as 'physiological' (67).
The accumulation of lipofuscin in the liposomes of the RPE can adversely affect RPE function, and may be involved in the development of ARMD. If the RPE is not able to phagocytose the photoreceptor outer segments completely, then remnants of the outer segments accumulate on the inner collagenous layer of Bruch's membrane (68). These remnants have been morphologically described as basal linear deposit (69) and are clinically recognised as large drusen (67). ARMD may also be related to the effects of A2-E, which is a lipofuscin-associated chromophore. Chromophore is the name given to a molecule that can exhibit colour within a compound. The A2-E chromophore requires light for its formation, is found within lipofuscin, and is derived from photoreceptor outer segments (70). A2-E is likely to interfere with mitochondrial respiration within RPE cells (71), which is likely to compromise cellular survival. Apoptosis (self-destruction of damaged cells) is four times higher in the centre of the macula than in the periphery (72), which supports a role for this mechanism in the development of age-related macular disease. Interestingly, it has been reported that quail that were exposed to bright light and supplemented with Z demonstrated significantly less photoreceptor apoptosis than quail that were exposed to light and fed diets low in carotenoids (73,74).
Drusen represent the first clinical appearance of ARMD. They result from the accumulation of insoluble, lipophilic material between Bruch's membrane and the RPE. The RPE deforms and thins as it stretches to cover the bulge formed by druse. The thinning of the light-absorbing layer of cells results in more light being reflected back from the retina in these areas, and permits the physical examination of drusen (75,76). The deformation of the RPE layer compromises the contact between the microvilli of RPE cells and the photoreceptors. Photoreceptor death follows the complete separation of photoreceptors and the RPE. The timescale for this process can vary from individual to individual (75).
Wet or neovascular ARMD results when the separation of the RPE and Bruch's membrane is associated with growth of new blood vessels into the subretinal space. These new blood choriocapillaris, which is responsible for the nutrition and oxygenation of the outer retina.
Relating the function of L Z and MZ to retinal structure and disease pathogenesis
The MP is thought to reduce the amount of light reaching the RPE by 40-90% and in turn this should reduce the rate of formation of A2-E and ROS. L and Z have been shown to reduce lipofuscin formation in cultured RPE cells. A2E is toxic, appears to reduce mitochondrial integrity, and also exhibits phototoxic behaviour when exposed to blue wavelengths of light. The phototoxicity of A2-E is reduced by L, which suggests that some of the protective effect of carotenoids may occur at the level of the RPE.
It is thought that the carotenoids are transported from the choroid, across the RPE and the photoreceptor outer segments and that L and Z molecules are preferentially orientated to absorb plane polarised light incident perpendicular to the nerve axons.
UV light is a source of potential damage for the cornea and the lens but very little reaches the retina. However, the retina is prone to photochemical damage from visible light between the wavelengths of 400 and 500nm. The retina is most at risk from blue light between the wavelengths of 430 and 470nm (77).
Meso-zeaxanthin is a xanthophyll that is not found within the human diet but is found to reach a maximum level in the central macular, where L levels reach a minimum (78). This suggests that it may have some specific function at the macula. There may be a functional relationship between L and MZ within the central macula, as there is an inverse relationship between the two xanthophylls in terms of concentration at that location. Meso-zeaxanthin may be more effective than L at some essential role within the central macula, and may not be needed in the peripheral retina. This suggests some kind of protective function in ARMD. It may also be that L is oxidised within the central retina and then reduction results in its conversion to MZ (78). The evidence suggests that there are specific mechanisms or biological pathways in place for the conversion of L to MZ within the central macula.
In summary, the fact that L and Z are selectively absorbed at the macula, and the fact that L is likely to be converted to MZ at the fovea suggests some specific role and has prompted interest in the possible functions of these carotenoids at that location. These functions may include screening of photo-oxidation inducing blue wavelengths of light, scavenging of free radicals, and also protection of RPE cells.
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(71.) Schutt F, Davies S, Kopitz J, Holz F, Boulton M. Photodamage to human RPE cells by A2-E, a retinoid component of lipofuscin. Investigative Ophthalmology & Visual Science 2000;41:2303-2308.
(72.) Del Priore L, Newark N, Tezel T, Kuo Y-H, Kaplan H. The retinal pigment epithelium undergoes age-related apoptosis in human eyes. The Retina Society, USA, 33rd Annual Meeting. Coral Gables, Florida, 2000.
(73.) Thomson LR, Toyoda Y, Delori FC, et al. Long-term dietary supplementation with zeaxanthin reduces photoreceptor death in light-damaged Japanese quail. Experimental Eye Research2002;75:529-542.
(74.) Thomson LR, Toyoda Y, Langner A, et al. Elevated retinal zeaxanthin and prevention of light-induced photoreceptor cell death in quail. Investigative Ophthalmology & Visual Science 2002;43:3538-3549.
(75.) Sarks J, Sarks S, Killingsworth M. Evolution of soft drusen in age-related macular degeneration. Eye 1994;8:269-283.
(76.) Sarks S. Ageing and degeneration in the macular region: a clinico-pathological study. British Journal of Ophthalmology 1976;60:324-341.
(77.) Ham W, Mueller H, Ruffolo J. Basic mechanisms underlying the production of photochemical lesions in the mammalian retina. Current Eye Research1984;3:165-174.
(78.) Landrum JT, Bone RA. Lutein, zeaxanthin, and the macular pigment. Archives of Biochemistry and Biophysics2001;385:28-40.
Course code: c-6940
Please note, there is only one correct answer. Enter online or by form provided
An answer return form is included in this issue. It should be completed and returned to CET initiatives (c-6940) OT, Ten Alps plc, 9 Savoy Street, London WC2E 7HR by August 15 2007.
1. What is the concentration of meso-zeaxanthin in the central retina?
a) 10 - 20 %
b) 90 - 100 %
c) 25 - 30 %
d) 30 - 40 %
2. Meso-zeaxanthin has been detected in the:
a) Macula and liver
b) Retina and plasma
c) Plasma but no the liver
d) Macula but not the plasma or liver
3. The absorption spectrum of the macular pigment peaks at:
a) 400 - 420 nm
b) 420 - 440 nm
c) 440 - 460 nm
d) 460 - 480 nm
4. Which of the following is not a function of carotenoids within the retina?
a) Production of singlet oxygen
b) Scavenging of ROS
c) Limiting lipid peroxidation
d) Quenching singlet oxygen
5. Which of the following does not increase the bioavailability of carotenoids from food?
b) Eating the food source with water
c) Eating the food source with oil
6. Which statement is true?
a) MPOD is higher in those with higher body fat
b) MPOD is higher in those with light iris colour
c) MPOD is higher in those who smoke
d) MPOD is higher in those with dark iris colour
7. The RPE is positioned:
a) Between the sclera and the choroid
b) Between the neural retina and the vitreous
c) Between the Bruch's membrane and the photoreceptors
d) Between Bruch's membrane and the choroid
8. Which of the following functions does the RPE not perform?
a) Absorption of light
b) Storage of vitamin E
c) Turnover of photoreceptor outer segments
d) Facilitation of the formation of visual pigment
9. The function of the microvilli on the apical end of the RPE cells is:
a) Erosion of the photoreceptor outer segments
b) Facilitation of oxygen transfer
c) Facilitation of replication of visual pigment sacks
d) Facilitaion of transfer of vitamin E
10. What is basal laminar deposit?
a) Remnants of RPE cells
b) Remnants of bipolar cells
c) Waste material transported from the choroid
d) Remnants of photoreceptor outer segments
11. Clinical examination of drusen with an ophthalmoscope is possible because:
a) Drusen fluoresce
b) There is reduced blood flow around the drusen
c) The RPE deforms and stretches to cover the bulge caused by the drusen
d) The RPE cells migrate away from the drusen
12. Which of the following is false?
a) Lutein and zeaxanthin act as blue light filters
b) Lutein and zeaxanthin quench ROS
c) Lutein and zeaxanthin reduce lipofuscin formation in RPE cells
d) Lutein and zeaxanthin increase blood flow to the macula
Dr Hannah Bartlett & Dr Frank Eperjesi
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|Title Annotation:||CET: CONTINUING EDUCATION & TRAINING|
|Author:||Bartlett, Hannah; Eperjesi, Frank|
|Date:||Jul 13, 2007|
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