The Three Macular Carotenoids: Complementary Functions of Lutein, Zeaxanthin and Meso-Zeaxanthin

JAMES STRINGHAM
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Figure 1. Chemical structures of the three macular carotenoids: Lutein, RR-zeaxanthin (“zeaxanthin”), and meso-zeaxanthin. From Nolan et al. (2013).

Lutein and the two zeaxanthin isomers, RR-zeaxanthin (3R,3’R-zeaxanthin) and meso-zeaxanthin (3R,3’S-RS-zeaxanthin) are the only three carotenoids found in the eye, specifically in the macula of the retina (Bone et al. 1997). RR-zeaxanthin and meso-zeaxanthin are both considered zeaxanthin; they differ only in the spatial orientation of the hydroxyl group on the C3’ chiral position (Nolan et al. 2013 – see Figure 1). 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 meso-zeaxanthin at the center of the macula (Bone et al. 1997).

Table 1. Concentrations and relative distribution in the macula for the three retinal carotenoids. From HKG Opththalmology, 2000; Vol. 1 #4.
Table 1. Concentrations and relative distribution in the macula for the three retinal carotenoids. From HKG Opththalmology, 2000; Vol. 1 #4.

Each of these carotenoids plays an important role in protecting the retina and enhancing visual performance (Bone et al. 2003; Thurnham & Howard, 2013; Stringham et al. 2011). 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. Meso-zeaxanthin has historically been incorrectly coupled with RR-zeaxanthin as an impurity or its isomer, and the measurement of meso-zeaxanthin in serum and foods had largely been ignored until awareness of its specific role in the eye emerged. One of the primary functions of the macular carotenoids is quenching potentially damaging free radical oxygen species (ROS). Each of the macular carotenoids is a potent antioxidant with specific targets. Meso-zeaxanthin is the most potent of the three, followed by RR-zeaxanthin, which is twice as potent as lutein in quenching reactive oxygen species (Bhosale & Bernstein, 2005). The protective role of lutein is more pronounced within the cellular membrane. Meso-zeaxanthin is located at the very center of the macula, the focal point of visual function. Its central location and stronger antioxidant potential make Meso-zeaxanthin critical in protecting the tissue at most risk – the center of the fovea has the highest packing density of photoreceptors, and maintains the highest metabolic rate, and light exposure – and therefore is under nearly constant assault (see Table 1 for specific locations of deposition for the three macular carotenoids). It is quite advantageous, therefore, that the tissue at most risk is protected by the strongest antioxidant of the three. meso-zeaxanthin also provides the best protection for the lipid membrane (Landrum et al. 1999; Subczynski et al. 2010). In terms of overall retinal protection, 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 (Li et al. 2010). Meso-zeaxanthin and RR-zeaxanthin are perpendicular to the cell membranes to better protect the lipid membrane from oxidation and absorb similar wavelengths of high energy light (Sujak et al. 1999). Lutein is both parallel and perpendicular to the cell membrane, and also oriented near the surface of the cell membrane; this makes it a better filter of blue light. Because lutein and the zeaxanthin isomers absorb different wavelengths of light, together, the three absorb a broader spectrum of high energy light, which offers greater protection of retinal tissue (see Figure 2 for a pictorial representation of this phenomenon). Structural differences, orientation to cell membranes, macular location and differing absorption spectra therefore help the three macular carotenoids work together to provide superior filtration of blue light as compared to each individually (Billsten et al. 2003; Li et al. 2010; Nolan et al. 2013).

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Figure 2. Anatomical location of the macular pigment, and spectral absorption of individual macular carotenoids that serve to make the overall macular pigment absorption spectrum (thick, dark orange line) relatively wide.

In addition, the three macular carotenoids work together for optimal eye health and visual function. Each individually and in combination with each other has been shown to increase macular pigment optical density. But the typical central peak of macular pigment optical density, found in the very center of the fovea, can be realized in subjects with atypical macular pigment spatial profiles at baseline only when supplemented with all three macular carotenoids (Nolan et al. 2012). 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. In terms of visual performance, increased density of the macular carotenoids is associated with faster visual processing (Hammond and Wooten, 2005), significantly improved visual performance in glare (Stringham et al. 2007; 2008; 2011; 2013) and reduced visual discomfort in bright light (Stringham et al. 2003; 2004; 2011; 2013).

Meso-zeaxanthin is the most recently characterized of the three retinal carotenoids, and is often found in trace amounts within commercially available lutein and RR-zeaxanthin supplements (ranging from 0.02-0.07% if chiral analysis is performed [Nolan et al. 2013]). As such, whether as dietary intake or part of lutein and/or zeaxanthin isomer(s) supplementation, Meso-zeaxanthin has already been part of studies investigating the nutritional impact on visual performance and AMD risk reduction. There are over 70 lutein studies at doses of 6-40mg, over 10 RR-zeaxanthin studies at doses of 1-20mg and several meso-zeaxanthin studies at doses of 8-14.9mg. Science continues to develop around the role of meso-zeaxanthin in eye health, and it is already established as a critical macular carotenoid with a specific function in ocular health. Today the significance of meso-zeaxanthin in the retina is well-established (e.g., Thurnam et al. 2008). Meso-zeaxanthin has proven bioavailability in humans (Thurnham et al. 2008), and has also been shown to be present in human serum pre-supplementation. Additionally, supplementation of meso-zeaxanthin has resulted in both increased serum levels and macular pigment optical density (Connolly et al. 2010), which, given its exceptional antioxidant properties, bodes well for human health.

Traces of meso-zeaxanthin are present in the diet and can be found in 21 species of fish, shrimp and turtles.
Traces of meso-zeaxanthin are present in the diet and can be found in 21 species of fish, shrimp and turtles.

Due to meso-zeaxanthin’s relatively recent empirical characterization, there have been some concerns with regard to its safety. Studies of meso-zeaxanthin supplementation containing fairly high doses (e.g. Connolly et al. 2010), have produced no reports of adverse events. In addition, meso-zeaxanthin is considered safe for use in food and dietary supplements and it meets the regulatory criteria per an FDA-acknowledged GRAS notification (http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-foods-gen/documents/document/ucm275974.pdf). In addition, a supplement containing meso-zeaxanthin was proven to be unequivocally safe in a GLP toxicological study (Ravikrishnan et al. 2011). Meso-zeaxanthin is not only converted from lutein in the eye (Neuringer et al. 2004) but is also found in the diet. Trace amounts of meso-zeaxanthin 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 eggs in California and Mexico (Maoka et al. 1986). Additionally, meso-zeaxanthin has been a component of a xanthophyll supplement added to chicken feed in Mexico over the last 10 – 15 years (Nolan et al. 2013). Because of the lack of awareness of meso-zeaxanthin 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.

The eye contains three carotenoids – lutein and two zeaxanthin isomers (meso-zeaxanthin and RR-zeaxanthin) – each with a specific location and distinctive role in retinal protection and visual performance. In terms of supplementation, lutein was the first commercially available macular carotenoid. As the state of the science has progressed, the need for higher levels of RR-zeaxanthin was determined. It is now clear that meso-zeaxanthin 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, via diet or supplementation.

 

JAMES STRINGHAMArticle by: James Stringham, Ph.D.

About the author: Dr. Stringham earned his doctoral degree in experimental psychology from the University of New Hampshire in 2003. During postdoctoral appointments at the Schepens Eye Research Institute at Harvard Medical School and the Medical College of Georgia, he conducted research on ocular lutein, age‐related macular degeneration, the effects of intense light on visual performance, and plasticity of the visual system. Dr. Stringham then took a position as a visiting assistant professor at the University of Georgia, where he continued and extended a research program involving lutein and many facets of visual performance. In 2007, he became a senior vision scientist in the Air Force Research Laboratory (AFRL), where he was involved in extensive testing of the effects of lutein and zeaxanthin on human visual performance. Currently he is a research scientist at the University of Georgia, where his research includes studying the effects of lutein, zeaxanthin, and mesozeaxanthin on a variety of human physiological, health, and performance parameters.


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