Meso-Zeaxanthin: A summary of the research

THERE ARE NEW STUDIES SUPPORTING A TRIUMVERATE COCKTAIL

Written by Larry J Alexander OD FAAO Thursday, 15 November 2012

Meso-Zeaxanthin: A summary of the research

This update is in response to the continuing controversy regarding the importance of supplementation with carotenoids, specifically regarding the benefits of mesozeaxanthin, purportedly a semi-synthetic formulation. There have been additions to the research regarding this issue, but none-the-less the rhetoric has become quite contentious. 

In the European Food Safety Authority Journal 2010;8(2):1483 the Panel on Dietetic Products, Nutrition and Allergies was asked to provide a scientific opinion on a list of health claims pursuant to Article 13 of Regulation (EC) No 1924/2006. The panel concluded that a cause and effect relationship has not been established between the consumption of meso-zeaxanthin and maintenance of normal vision. This finding has been contorted by some to represent the fact that meso-zeaxanthin is of no benefit what-so-ever. The evidence regarding this issue has, however, changed since their 2010 report, but in the context of eyes with reduced retinal pigment levels as measured by MPOD Testing.

The controversy regarding the importance of behavioral modification and supplementation of nutrients for ocular disorders is becoming less contentious.  It is being reasonably well accepted that there is a relationship to macular pigment levels as related to the development and evolution of macular degeneration.1-4  Likewise, consumption of foods containing carotenoids or supplementation with carotenoids appears to be of benefit in improving the protective effects of macular pigment (Macular Protective Pigments or MPPs) even in active disease and reducing the risk of macular degenerative conditions. 5-11 

There is also more evidence surfacing relating macular degeneration to the inflammation cascading from photic stress. 12  It also appears that lutein and zeaxanthin actually reduce photo-oxidative damage by modulating the expression of inflammation related genes within the retinal pigment epithelial cells as well as elsewhere in the body. 13-15 

There is further research to validate that the co-consumption of lipids significantly affects the carotenoid availability. 16-17   It is also suggested that lutein protects the retina from ischemic/hypoxic damage by itsanti-oxidative, anti-apoptotic and anti-inflammatory properties. 18

Carotenoids are ubiquitous in nature presenting as colored pigments synthesized by flora and microbes.  These carotenoids perform critical functions in photo-protection within the retina. 19-20 Vertebrates and invertebrates cannot synthesize carotenoids but obtain them from diet.21-22

Of note, lutein and zeaxanthin are the most often studied of the supplemental carotenoids.  Lutein and zeaxanthin are structural isomers belonging to the carotenoid class and are found in the highest concentration in the human body in the macula. 23 The introduction of the topic of supplementation with meso-zeaxanthin has created contention surrounding the apparent lack of scientific support.  It is recognized that meso-zeaxanthin is present in the center of the macula in high concentration and is metabolized from lutein, but the controversy surrounds the ability to increase the concentration through supplementation.

This paper will address the proof of the potential benefit of using meso-zeaxanthin for supplementation in conditions such as age-related macular degeneration. It is estimated that the average daily intake of lutein + zeaxanthin in the U.S. is 2 – 3 mg, which is far below that shown to reduce the risk of age-related eye disease (Centers for DiseaseControl and Prevention). 24-35

Add to this the issue of malabsorption syndromes such as celiac and Crohn’s disease, which have been shown to demonstrate a significant reduction of absorption of macular carotenoids and one could propose that there exists a lutein/zeaxanthin dietary shortfall in the general population.26 

The macular pigment consensus panel concluded that it might be possible to identify individuals at reduced, medium and elevated risk for age-related eye disease based on high, medium, and low central macular pigment optical density (MPOD) levels.  This is qualified with the caveat that central MPOD is only weakly proportional to the total amount of xanthophyll pigments.  It is reported that the panel members agree that a central MPOD below 0.2 d.u is low, between 0.2 d.u. and 0.5 d.u is mid-range and above 0.5 d.u. is high.  The panel also recognized that there is no definitive clinically available “gold standard” at this point. 24

In summary carotenoids are important to macular pigment density.  Reduction in macular pigment levels apparently lend to the development of macular disease.  At this point there is no “gold standard” to measure the macular pigment density.  Humans cannot manufacture the carotenoids and have to consume them in their diets.  The exception to the rule is meso-zeaxanthin which is manufactured within the retinal tissue from existing lutein.

The Anatomy and Physiology of Carotenoids in the Retina

From a structural standpoint, all carotenoids have a linear conjugated chain of double bounds.   Lutein is one of the more abundant carotenoids and can present in eight stereo-molecular forms.  Lutein is available from multiple food sources including green and yellow vegetables and fruits, milk, meat and egg yolks.27

It was suggested in the Wenzel study in 2006 that consumption of eggs increased serum lutein, zeaxanthin and MPOD compared to placebo controls without negatively affecting serum cholesterol.28 In the Goodow study the same year, serum lutein was shown to increase 26 % and serum zeaxanthin increase 38 % with the consumption of eggs without negatively affecting serum lipids.29 Furthermore it is reported that consumption of 2 to 4 egg yolks/day for 5 weeks benefited macular health in older adults with low macular pigment density. 

Serum HDL cholesterol increased in the group without a corresponding increase in LDL even in the presence of statin use.30 Furthermore, is reported that increasing the consumption of egg yolks does not decrease serum concentrations and lipoprotein distribution of other carotenoids, retinol and tocopherols, while increasing lutein and zeaxanthin. 31 Another study suggests that a high-protein energy-restricted diet high in cholesterol from eggs improved glycemic and lipid profiles, blood pressure and apo-B in individuals with type 2 diabetes. 32   Also it is noted that carbohydrate restriction favorably alters VLDL metabolism and apolipoprotein concentration.  Adding egg yolks to carbohydrate restriction diets favors the formation of larger LDL and HDL leading to an increase in plasma lutein and zeaxanthin. 33 Another study pointed to the fact that daily intake of eggs in a carbohydrate-restricted diet also decreased plasma C-reactive Protein levels implying a decrease in systemic inflammation.34 Consumption of omega-3 fatty acid enriched eggs and organic eggs may both significantly increase serum lutein in healthy lacto-ovo vegetarians consuming a predominately plant-based diet. 35   Dietary patterns do have a significant influence on protective levels of carotenoids.  Studies support consumption of eggs to both increase lutein and zeaxanthin levels while having no negative effect on serum lipid levels and suppressing inflammation.

Zeaxanthin has an identical chemical formula to lutein but the absorption spectrum is slightly shifted to the red.  Zeaxanthin has three stereoisomers (R,R), (S,S) and (R,S-meso) that all occur in nature.   Plants produce only the  (R,R) form.  The (R,S-meso) is formed from lutein.  Human macular pigment contains all three of the stereoisomers with meso-zeaxanthin comprising about 33%. 36-37

In nature, meso-zeaxanthin is reported to occur in the retinas of chickens, and turkeys.  It also is reported to be in the flesh of fish (salmon and trout) (especially if fed a diet of astaxanthin), shrimp and sea turtles. However, a recent report suggested that for all fish and seafoods tested, lutein, zeaxanthin and mesozeaxanthin were not detected.  But the report also cited that In eggs from the US, L + Z levels ranged from 1.0 to 1.6 mg/100 g yolk with L levels being 1.3-1.6 times higher than that of Z. One egg (California) contained a small amount of MZ (0.01 mg/100 g yolk). Carotenoid concentrations were significantly higher in Mexican eggs (p < 0.025, 3.44 mg/100 g yolk) with the ratio of L:Z:MZ being 1:1:1.3.  

In the US the presence of MZ in the macula is reported not likely due to dietary sources, although this a possibility when consuming eggs of chickens fed MZ. 38 Manufactured meso-zeaxanthin mixtures are used in chicken feed, most specifically in Mexico, to improve the color and lutein concentration of egg yolks.39-44  It is reported that the chemical transformation of lutein into meso-zeaxanthin is accomplished commercially by catalytic treatment of lutein with a base at elevated temperature.  This process creates a mixture of lutein with 80 % meso-zeaxanthin. 45

General belief is that the macular pigments (xanthophylls) have a protective role in the maintenance of macular health by way of the antioxidant activity, by working to reduce lipofuscin formation, as well as by providing photoprotective effects.  Lutein and zeaxanthin along with meso-zeaxanthin make up the macula lutea.  46-55 The three pigments are located in the Henle fibers and outer segments of the photoreceptors. 56-58  

There appear to be no apparent safety issues associated with the consumption of lutein and zeaxanthin, but meso-zeaxanthin has not been studied excessively.  A toxicity trial in a small animal model demonstrated the “No-Observed-Adverse-Effect-Level” for meso-zeaxanthin exceeding 200 mg/kg/day. 59  Another study confirmed absence of mutagenicity.60  Yet another report revealed that renal and liver function, lipid profiles, hematological factors and markers of inflammatory process were unaffected by meso-zeaxanthin supplementation.61

From an anatomical standpoint the central 3 mm of the macula the carotenoids have approximately equal distribution but the three change toward the retinal periphery.  The following figure demonstrates the propensity for lutein to increase toward the periphery and the meso-zeaxanthin to increase toward the fovea.

Distribution of Macular Carotenoids (Adapted) 62-63

 meso-xeanthin

The meso-zeaxanthin appears to be present in the macula as the result of conversion from lutein or zeaxanthin. 64-65 Studies regarding the presence of mesozeaxanthin in the blood serum are controversial as they are a very low levels and difficult to measure. 66-67

Within the framework of the development of macular degeneration, oxidative stress plays an important role.  Polyunsaturated fatty acids that are oxidized are typically eliminated through choroidal circulation accumulating under the photoreceptors.  Short wavelength blue light then acts on photosensitizers that then form the inflammatory agent reactive oxygen species (ROS) in the retina. 68-70

Mechanism of Action of the Carotenoids

The macular carotenoids purportedly act as antioxidants and a blue-light filter to offset the ill effects of photosenitization and oxidation associated with macular degeneration.71-74   It is reported that zeaxanthin is more potent as an antioxidant than lutein and this can be manipulated by dietary intake. 75-77 It is also reported that zeaxanthin may protect against age-related macular degeneration and that age + a dietary lack of zeaxanthin is the most important risk factor for development. 78-79

A recent animal study also suggested that zeaxanthin + antioxidants may delay or reverse alterations in the retinal pigment epithelium and deposits on the basement membrane while reducing vascular endothelial growth factor expression (VEGF). 80   

There is one study that concludes that zeaxanthin alone does not have a positive effect on MPOD, but this is then contradicted by other reports. 81-82 It is also suggested that meso-zeaxanthin is slightly more protective than zeaxanthin.83   In an in-vitro study, the symbiotic effect of a mixture of lutein, zeaxanthin and meso-zeaxanthin produces a profound effect on singlet oxygen deactivating ability (anti-oxidant capacity).  The mixture is 37 % more effective than meso-zeaxanthin alone, 91 % more effective than zeaxanthin alone, and 140 % more effective than lutein alone.84

One study is in conflict with these findings reporting that meso-zeaxanthin supplementation may actually reduce lutein and zeaxanthin absorption in-vivo. 85  Another study with the in vivo and in vitro structure found that meso-zeaxanthin was found to scavenge superoxide radicals, hydroxyl radicals and inhibited in vitro lipid peroxidation.  The report substantiated meso-zeaxanthin as having significant in vitro and in vivo antioxidant activity. 86

All carotenoids are best consumed with a meal (fats) to encourage more effective absorption but it must be realized that the presence of adipose tissue (obesity) binds the carotenoids and decreases bioavailability. 87-91

It is important to also recognize the fact that inflammation is a significant part of the genesis of age-related macular degeneration.  A prospective study confirmed that regular consumption of docosahexaenoic acid (DHA) and eicosapentaaenoic acid (EPA) was associated with a significant decrease in the risk of AMD.92 As with everything in life, there must be balance.  A diet too high in omega 6 and omega 3 saturated fats and total fats are associated with an increase in the risk of macular degeneration as carotenoids bind to fat and become unavailable. 93 Also if one combines a poor diet and decreased macular pigmentation with increased exposure to blue light the risk of ARM increases significantly. 94

Effects of  Dietary Supplementation with Lutein, Zeaxanthin and Meso-Zeaxanthin

If the consumption of foods to provide the necessary carotenoids were appropriate, supplementation would be unnecessary.  In reality, it is estimated that the average daily intake of lutein + zeaxanthin in the U.S. is 2 – 3 mg, which is far below that shown to reduce the risk of age-related eye disease (Centers for Disease Control and Prevention). 24-25   A recent study reports that intakes of lutein were greater than zeaxanthin and intakes of zeaxanthin to lutein decreased with age (lower for females). 95   The aged female population, which is most at risk for age-related macular degeneration, are actually consuming fewer carotenoids. 

The primary issue of dispute within the industry appears to be the contention that there is a lack of proof that supplementation with meso-zeaxanthin actually raises the levels in the blood and within the retina.  In one study published in 2003 it was shown that supplementation with 16 mg of meso-zeaxanthin and 4 mg of lutein increased macular pigment optical density levels by 18 % in 120 days.  This finding was similar to the increase found when supplementing with only 20 mg of lutein.96

In a controlled study published in 2007, a supplement containing 21.8 mg of a mixture of meso-zeaxanthin:lutein:zeaxanthin in a ratio of 11:4:1 was taken over a 120 day period.  It was shown that the meso-zeaxanthin was effectively absorbed into the serum and macular pigment density increased. There were, however, potential limitations to this study based on research protocol. 97 Another study published in 2008 evaluated 19 persons taking a supplement of meso-zeaxanthin:lutein:zeaxanthin in a ratio of 7:9:1 demonstrated that serum levels of meso-zeaxanthin reached 0.24 micrormol/L with levels in women 3 X higher than men.  This study also suggested that meso-zeaxanthin supplementation may actually reduce leutein and zeaxanthin absorption. 85 Bone’s 2007 study also suggested that the meso-zeaxanthin actually reduced efficacy of lutein and zeaxanthin as well as beta carotene. 97

The results of the Meso-zeaxanthin Ocular Supplementation Trial (MOST) were published in 2010.  This study evaluated the macular pigment response and serum carotenoid response in persons with and without early age-related macular degeneration following consumption of meso-zeaxanthin : lutein : zeaxanthin in a ratio of 7.3:3.7:0.8.  The supplement was not suspended in oil.  The study showed statistically significant increases in serum concentration of lutein and meso-zeaxanthin and macular pigment optical density after only two weeks of supplementation. 

The MPOD showed the most response near the fovea but there was a generalized spatial improvement across the measured area over an eight-week timeframe.  This overall improvement was interpreted as the ability to rebuild central MPOD in subjects with atypical profiles at baseline. The MOST report also suggested that some patients may lack the ability to convert Lutein to Meso-Zeaxanthin. This has been suggested as a potential variable response to the ingestion of carotenoids based on genetic influences. 

The limitations of this study were the lack of controls and a small sample size. When carefully evaluated, this study also raises the question regarding the issue of meso-zeaxanthin dampening the effect of lutein and zeaxanthin. 67   In a relatively new report assessing the spatial profile of macular pigment with the typical peak at the fovea, The subjects were supplemented with a carotenoid recipe.  All subjects were selected having atypical spatial profiled. The subjects were classified as : Group 1: (n = 10), 20 mg/day lutein (L), 2 mg/day zeaxanthin (Z); Group 2: (n = 10), 10 mg/day meso-zeaxanthin (MZ), 10 mg/day L, 2 mg/day Z; Group 3: (n = 10), 17 mg/day MZ, 3 mg/day L, 2 mg/day Z. Subjects took one capsule/day over an eight week period. Macular Pigment was measured at 0.25°, 0.5°, 1°, 1.75°and 3° using customized-heterochromatic flicker photometry at baseline, four weeks and 8 weeks.

The report concluded that the typical central peak of MP can be realized in subjects with atypical spatial profiles, following supplementation with a preparation containing all three macular carotenoids, but not with a supplement lacking MZ.  98  In another recent study the same plan was followed measuring both macular pigment optical density and visual performance (visual acuity and contrast sensitivity. The groups were supplemented with a carotenoid recipe. The subjects were classified as: Group 1: 20 mg lutein (L) and 2 mg zeaxanthin (Z); Group 2: 10 mg L, 2 mg Z and 10 mg meso-zeaxanthin (MZ); Group 3: placebo. Outcomes measures included visual performance and MPOD response, and data were collected at baseline, at three months and at six months. 

The results showed a significant increase in MPOD at all eccentricities only in Group 2.  Likewise, only Group 2 demonstrated improvements in visual performance.  The results suggest that supplementation with all three macular carotenoids may offer advantages over preparations lacking MZ, both in terms of MPOD response and in terms of visual performance enhancement 99  In yet another recent publication it was shown that a mixture of meso-zeaxanthin, zeaxanthin, and lutein in a ratio of 1:1:1 can quench more singlet oxygen than the individual carotenoids alone at the same total concentration. 100

Conclusion

It is unarguable that the dietary consumption of and/or supplemenation with xanthophyll carotenoids are of benefit in the management of age-related macular degeneration.  While the best option is to lead the ideal life and consume only the best of foods, that is not the social norm so supplementation has become the compromise.   Likewise, it is unarguable that meso-zeaxanthin peaks at the fovea an is a critical protective pigment  (along with lutein and zeaxanthin) in the macular area and that it is created from lutein.  The is the contention is that persons with macular degeneration may have difficulty converting lutein to meso-zeaxanthin and that supplementation with meso-zeaxanthin may be of benefit.  This discussion addresses the issue of advisability of supplementation with meso-zeaxanthin based on in-vivo and in-vitro scientific evidence and represents an update on applicable science.   That being said,recent work appears to create an argument for the benefits of an admixture of the three carotenoids lutein, zeaxanthin and meso-zeaxanthin.

Clinicians must rely on some sort of scientific corroboration to initiate what we would consider effective threatment.  Ethics and economics must be considered when intervening with therapy.  So we must look to the scientific evidence with as little bias as possible.  The studies cited in the original report corroborated the use of xanthophyll consumption or supplementation for minimizing the risk of age-related macular degeneration.   The updates cited herein actually bring a little more clarity to the meso-zeaxanthin issue. Issues in regard to the original contention regarding the advisability of meso-zeaxantin supplementation, as well as any supplement intervention, continue to be a problem.  Those issues include:

  • What about the universality of the ingredients used in all of these studies. Which variety of lutein was used in each study?  Esterized and non-esterized lutein have variable bioavailability. 101
  • What variation of zeaxanthin was used in each study? 
  • Meso-zeaxanthin was never studied using just the stand-alone product but was always mixed with lutein and zeaxanthin.  According to the newest research, perhaps that is not an issue.  Perhaps the triumvirate cocktail of lutein, zeaxanthin and meso-zeaxanthin is the best answer.
  • Apparently no study actively controlled diet or other behavioral issues.  Issues such as consumption of fat have a tremendous influence on macular and serum carotenoids.
  • Why not consider the fact that all of these supplements should be consumed with eggs or other healthy fats to further potentiate the effect. 
  • It is also recognized that meso-zeaxanthin has not been definitively proven to exist in a natural food source.  Meso-zeaxanthin is manufactured commercially by conversion of lutein in a superheated chemical process. 102

Review of the literature does not unequivocolly support supplementation with meso-zeaxanthin or deny its benefits, but definitely begs the issue for further clinical reasearch. The research should, however, consider some or all of the following:

  • You must control for diet.
  • You must consume the supplement with a fat transport mechanism.
  • You must control for genetic markers-DNA testing.
  • You must control for smoking and ideal weight.
  • You must control for malabsorption syndromes.
  • You should address co-existent inflammatory disease...CRP levels.
  • Someone should use meso-zeaxanthin as a stand-alone supplement...again perhaps not necessary.
  • You must address quality control of all products to improve bioavailability.

Even more importantly, one pill, one supplement is not the total answer to the issue of minimizing the risk for the development of Age-Related Macular Degeneration.  In actual fact it is not the solution for diabetes, heart disease or any other human afflictions.  While controversy exists regarding the issue of the importance of meso-zeaxanthin as a supplement to assist in the prevention of age-related macular degeneration, it is critical to look at the gestalt of the disease.  It is important to recognize that the risks of ARM are complicated.  There are genetic factors, environmental factors and ocular structure factors. There is the original-sin risk of genetic tendencies which have become fairly specific for smoking, inflammation and oxidation.  Add the complexities of the behavior of the patient including issues such as obesity and smoking.  Fold in the ocular predispositions such as significant retinal pigmentary disorders that are not really related to the issues of intraretinal (Henle layer) pigment. 

The issue is best summarized from a direct quote from a recent abstract....” The findings (of our study) show an association of consuming a diet rich in DHA with a lower progression of early AMD. In addition to the AREDS supplement, a lower dietary glycemic index (dGI) with higher intakes of DHA and EPA was associated with a reduced progression to advanced AMD.” 103

While the issue of the benefits of supplementation with meso-zeaxanthin is still a bit contentious from a scientific standpoint, it appears that the science is progressing regarding substantiation of the benefits.  It appears that the TRIUMVERATE COCKTAIL OF LUTEIN, ZEAXANTHIN AND MESO-ZEAXANTHIN may create a more protective effect by enhancing the density of the retinal pigment epithelium.  However, the elephant in the room is the caveat that unless the following issues are addressed, supplementation alone is a crutch made of balsa wood. 

As clinicians we must also address and attempt to modify:

  • SMOKING
  • OBESITY
  • DIET
  • GLYCEMIC INDEX
  • OVERALL INFLAMMATORY DISEASE-CRP
  • EXPOSURE TO SHORT WAVELENGTH LIGHT
  • COLLATERAL SYSTEMIC DISEASE
  • HOMOCYSTEINE LEVELS
  • HORMONE LEVELS

Perhaps the answer is as simple as feeding chickens meso-zeaxanthin and eating their eggs to maximize macular pigment density.  You get DHA, EPA, lutein, meso-zeaxanthin and zeaxanthin.  The TRIUMVERATE COCKTAIL with the obligatory Omega 3 transport mechanism all for the cost of $0.25 per egg.

 

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About the Author(s)

Larry J Alexander OD FAAO

Larry J Alexander OD FAAO

Dr. Alexander (1948-2016) was a 1971 graduate of Indiana University School of Optometry. He served in the US Navy then served as a Professor at the University of Alabama Birmingham School of Optometry. Larry contributed to a number of chapters in textbooks and has published three editions of Primary Care of the Posterior Segment, as well as contributed to the professional literature. He also lectured extensively in the area of ocular and systemic disease. His areas of special interest included dysfunctional tear syndrome, glaucoma and macular degeneration.  His lessons are the basis for this site and he will be dearly missed. 

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