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The Three Macular Carotenoids

<p>The eye contains three carotenoids&#0151;lutein and two zeaxanthin isomers (mesozeaxanthin and RR-zeaxanthin)&#0151;each with a specific location and distinctive role in retinal protection and visual performance.</p>

Lutein and the two zeaxanthin isomers, RR-zeaxanthin (3R, 3’R-zeaxanthin) and RS-zeaxanthin (“mesozeaxanthin," 3R, 3R’S-mesozeaxanthin) are the only three carotenoids found in the eye, specifically in the macula of the retina.1 RR-zeaxanthin and mesozeaxanthin are both considered zeaxanthin. They are obtained via the diet, and concentrated in the central retina (termed the macula—the region of the retina responsible for highest visual performance). The location of their respective areas of deposition is highly specific: lutein is the dominant carotenoid in the peripheral macula, RR-zeaxanthin in the mid-peripheral macula and mesozeaxanthin at the center of the macula.

Each of these carotenoids plays an important role in protecting the retina and enhancing visual performance.2,3 The characterization and functions of lutein and RR-zeaxanthin are well known, and the science behind these two xanthophylls has grown at a steady rate.

Mesozeaxanthin historically had been incorrectly coupled with RR-zeaxanthin as an impurity or its isomer, and the measurement of mesozeaxanthin in serum and foods had largely been ignored until awareness of its specific role in the eye emerged. Each of the macular carotenoids is a powerful antioxidant with specific targets. Mesozeaxanthin is the most potent of the three, followed by RR-zeaxanthin, which is twice as potent as lutein in quenching free radicals.4 The protective role of lutein focuses on the cellular membrane. Mesozeaxanthin is located at the very center of the macula, the focal point of visual function. Its central location and stronger antioxidant potential make mesozeaxanthin critical in protecting the most at-risk tissue with the highest metabolic rate and light exposure, and it also provides the best protection for the lipid membrane.5,6

A mixture of the three macular carotenoids at a ratio of 1:1:1 has been shown to quench singlet oxygen more effectively than any of the three individually.7 Mesozeaxanthin and RR-zeaxanthin are perpendicular to the cell membranes to better protect the lipid membrane from oxidation, and also to absorb similar wavelengths of high-energy light.

Lutein is parallel, perpendicular to and oriented near the surface of the cell membrane, making it a better filter of blue light. However, because lutein and the zeaxanthin isomers absorb different wavelengths of light, together, the three absorb a broader spectrum of high energy light. Structural differences, orientation to cell membranes, macular location and differing absorption spectra help the three macular carotenoids work together to provide superior filtration of blue light as compared to each individually.8,9

In addition, the three macular carotenoids work together for optimal eye health and visual function. Each individually and in combination has been shown to increase macular pigment optical density. But the typical central peak of macular pigment can be realized in subjects with atypical macular pigment spatial profiles at baseline only when supplemented with all three macular carotenoids.10 This suggests that a combination of all three macular carotenoids is required to produce what appears to be a normal density distribution within the retina, and hence, most likely normal retinal health and function.

All three macular carotenoids have been studied in humans, but techniques for accurately measuring mesozeaxanthin have only recently been developed. In fact, mesozeaxanthin is often found in trace amounts within commercially available lutein and RR-zeaxanthin supplements (ranging from 0.02 to 0.07 percent if chiral analysis is performed). As such, whether as dietary intake or part of lutein and/or zeaxanthin isomer(s) supplementation, mesozeaxanthin has already been part of studies investigating the nutritional impact on visual performance and age-related macular degeneration (AMD) risk reduction.

There are more than 70 lutein studies at doses of 6 to 40 mg, more than 10 RR-zeaxanthin studies at doses of 1 to 20 mg, and several mesozeaxanthin studies at doses of 8 to 14.9 mg. Science continues to develop around the role of mesozeaxanthin in eye health, and it is already established as a critical macular carotenoid with a specific function in ocular health. Today, the significance of mesozeaxanthin in the retina is well-established. Mesozeaxanthin has proven bioavailability in humans,11 and has also been shown to be present in human serum pre-supplementation. Additionally, supplementation of mesozeaxanthin has resulted in both increased serum levels and macular pigment optical density,12 which, given its exceptional antioxidant properties, bodes well for human health.

Due to mesozeaxanthin’s relatively recent empirical characterization, there have been concerns regarding its safety. Studies of mesozeaxanthin supplementation containing fairly high doses have produced no reports of adverse events. Mesozeaxanthin is considered safe for use in food and dietary supplements, and it meets the regulatory criteria per an FDA-acknowledged GRAS (generally accepted as safe) notification. In addition, a supplement containing mesozeaxanthin was proven safe in a toxicological study.13

Mesozeaxanthin is not only converted from lutein in the eye, as has been reported by some researchers,14,15 but is also found in the diet. Trace amounts of mesozeaxanthin are present in the diet in various parts of the world—it is found in 21 species of fish, shrimp and sea turtles, as well as some eggs.16 Additionally, mesozeaxanthin has been a component of a xanthophyll supplement added to chicken feed in Mexico in the last 10 years. Because of the lack of awareness of mesozeaxanthin and the previous difficulty in measuring this particular carotenoid, it had typically not been tested. It is possible, therefore, that its presence in the diet and serum has been potentially underreported, and it is most likely available in more foods than we are aware of.

In terms of supplementation, lutein was the first commercially available macular carotenoid. As the science progressed, the need for higher levels of RR-zeaxanthin was determined. It is now clear that RS-zeaxanthin (mesozeaxanthin) plays a critical role alongside lutein and RR-zeaxanthin in eye health. Given the specialized locations and functions of each macular carotenoid, it is reasonable to suggest that that the best way to support eye health and visual performance is to consume all three macular carotenoids, either from diet or from supplementation.

For a list of references, email

Hear Jim Stringham, Ph.D., research professor, University of Georgia, review each of the macular carotenoids (lutein, RR-zeaxanthin and meso-zeaxanthin) and their complementary functions to optimize visual function and support eye health in the SupplySide West education session, “The Three Macular Carotenoids: Complementary Functions of Lutein, RR-Zeaxanthin and Meso-Zeaxanthin" on Tues., Oct. 7 at 4 p.m. Stringham will present the latest cutting-edge research and review prenatal and neonatal research that indicates the important role of macular carotenoids in the very beginning of life.

Jim Stringham, Ph.D., is a research professor at the University of Georgia in Athens.


  1. Bone RA et al. “Distribution of lutein and zeaxanthin stereoisomers in the human retina.” Exp Eye Res. 1997; 64(2):211-8.
  2. Bone RA et al. “Lutein and zeaxanthin dietary supplements raise macular pigment density and serum concentrations of these carotenoids in humans.” J Nutr. 2003; 133(4):992-8.
  3. Thurnham DI, Howard AN. “Studies on mesozeaxanthin for potential toxicity and mutagenicity.” Food Chem Toxicol. 2013; 59:455-63.
  4. Bhosale P, Bernstein PS. “Synergistic effects of zeaxanthin and its binding protein in the prevention of lipid membrane oxidation.” Biochim Biophys Acta. 1740(2):116-21.
  5. Landrum JT et al. “Analysis of zeaxanthin distribution within individual human retinas.” Methods Enzymol. 1999; 299:457-67.
  6. Subczynski WK, Wisniewska A, Widomska J. “Location of macular xanthophylls in the most vulnerable regions of photoreceptor outer-segment membranes.” Arch Biochem Biophys. 2010; 504(1):61-6.
  7. Li B, Ahmed F, Bernstein PS. “Studies on the singlet oxygen scavenging mechanism of human macular pigment.” Arch Biochem Biophys. 2010; 504(1):56-60.
  8. Billsten HH et al. “Photophysical properties of xanthophylls in carotenoproteins from human retinas.” Photochem Photobiol. 2003; 78(2):138-45.
  9. Nolan JM et al. “What is mesozeaxanthin, and where does it come from?” Eye (Lond). 2013; 27(8):899-905.
  10. Nolan JM et al. “Macular carotenoid supplementation in subjects with atypical spatial profiles of macular pigment.” Exp Eye Res. 2012; 101:9-15.
  11. Thurnham DI, Trémel A, Howard AN. “A supplementation study in human subjects with a combination of mesozeaxanthin, (3R,3'R)-zeaxanthin and (3R,3'R,6'R)-lutein.” Br J Nutr. 2008; 100(6):1307-14.
  12. Connolly EE et al. “Augmentation of macular pigment following supplementation with all three macular carotenoids: an exploratory study.” Curr Eye Res. 2010; 35(4):335-51.
  13. Ravikrishnan R et al. “Safety assessment of lutein and zeaxanthin (Lutemax 2020): subchronic toxicity and mutagenicity studies.” Food Chem Toxicol. 2011; 49(11):2841-8.
  14. Johnson EJ. “The role of carotenoids in human health.” Nutr Clin Care. 2002 Mar-Apr;5(2):56-65.
  15. Bone RA et al. Macular pigment response to a supplement containing meso-zeaxanthin, lutein and zeaxanthin. Nutr Metab (Lond). 2007; 11;4:12.
  16. Maoka T et al. “The first isolation of enantiomeric and meso-zeaxanthin in nature.” Comp Biochem Physiol B. 1986; 83(1):121-4.
  17. Sujak A et al. “Lutein and zeaxanthin as protectors of lipid membranes against oxidative damage: the structural aspects.” Arch Biochem Biophys. 1999; 371(2):301-7.


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