Where Do Lutein and Zeaxanthin Fit?
A leading researcher discusses their roles in the AMD treatment and prevention equation.
AN INTERVIEW WITH PAUL BERNSTEIN MD, PHD

Nutritionist Penelope Edwards, MPH, CNS, interviewed Paul Bernstein, MD, PhD, for Retinal Physician recently about the evolving role of carotenoids, specifically lutein and zeaxanthin. Dr. Bernstein is an associate professor of Ophthalmology and Visual Sciences in the Retina Division at the Moran Eye Center, University of Utah School of Medicine.

Dr. Bernstein has conducted research on the topic of macular lutein and zeaxanthin concentrations and the relationship of these carotenoids to AMD. His findings have contributed significantly to the current understanding of the role lutein plays in ocular health.

Q. Dr. Bernstein, you pioneered the use of Raman spectroscopy to measure the levels of lutein, zeaxanthin, and their metabolites in the macula. Can you provide a short explanation of how this technology works?

While a number of important epidemiological studies have found that high dietary intakes of foods rich in lutein and zeaxanthin are associated with decreased risk of AMD, the critical information on how much of these protective nutrients actually make it to the macula is more challenging to obtain. We and other research groups have endeavored to develop methods to measure macular carotenoid pigments noninvasively in living human subjects.

At the Moran Eye Center, we have found that resonance Raman spectroscopy is a particularly useful method that is sensitive and specific for the macular carotenoids. In this technique, we flash a low-power blue laser spot on the macula of the human eye for less than a second, and we collect the light that is scattered back. A small amount of this returning light is shifted to longer wavelengths owing to molecular vibrations of the lutein and zeaxanthin in the macula.

It turns out that the concentration of the macular carotenoids is so high and their Raman vibrations are so strong that we can readily detect their signature Raman spectrum even in a complex biological system such as the eye. We can then calculate the levels of lutein and zeaxanthin from the strength of the collected Raman shifted light.

Q. What have you found out about lutein and macular health using the Raman method?

We have measured hundreds of subjects both with and without AMD. We have learned that macular carotenoid levels decline with age, reaching an especially low level after age 60, just when the risk of AMD rises dramatically. We have also found that macular pigment levels are significantly lower in AMD patients who were not taking lutein supplements, relative to age-matched controls. Interestingly, AMD patients who had been taking high dose lutein supplements for at least 3 months after their diagnosis of AMD had macular carotenoid levels that were nearly the same as the normal controls. These results are consistent with the hypothesis that AMD is in part a disorder related to low macular levels of lutein and zeaxanthin, and that supplementation can alter these levels in a potentially beneficial manner.

Q. Some research suggests that 6-10 mg of lutein/zeaxanthin represents a reasonable level for supporting macular health, while the average dietary intake is only 1-2 mg daily. Should people who are not consuming enough of these carotenoids consider supplementation?

Yes, I think that greater intake of lutein and/or zeaxanthin is probably beneficial for macular health, and 6 mg is a reasonable intake based on our Raman results and on various epidemiological studies.

Increasing dietary intake of lutein and zeaxanthin is clearly a healthy approach, but most Americans would have a hard time consuming that many fruits and vegetables daily, so supplements would certainly play an important role too. Ultimately, when noninvasive measurement of carotenoids is more widely available, individuals who have unusually low levels could be identified and targeted for aggressive nutritional intervention. For now, however, supplemental lutein doses considerable higher than 6-10 mg probably do not provide further enhancement because specific binding proteins in the macula become saturated.

Q. You and your colleagues discovered that the uptake of lutein and zeaxanthin into the retina from the circulation is carried out via xanthophyll binding proteins (XBP). Explain a little about lutein, zeaxanthin and meso-zeaxanthin: how they get into the macula; where they are located in the retina and macula; and the importance of XBP.

All lutein and zeaxanthin in the body must come from dietary sources, usually fruits and vegetables or from supplements. The macula of the human eye contains by far the highest concentrations of these carotenoids anywhere in the human body. In the macula, there are approximately equal amounts of three xanthophyll carotenoids: lutein, zeaxanthin and meso-zeaxanthin. Lutein's dietary source is primarily dark green leafy vegetables. Zeaxanthin is less common in the human diet — coming from certain orange and yellow fruits and vegetables. Meso-zeaxanthin is not found in the normal human diet, and is thought to originate from lutein. The high concentrations and specific uptake of the macular carotenoids is mediated by specific binding proteins that draw them into the tissue and stabilize them. My laboratory has recently identified the first XBP in any vertebrate system. This XBP binds zeaxanthin and meso-zeaxanthin and seems to enhance their antioxidant functions.

Q. You recently published a paper describing an XBP that appears to be specific for zeaxanthin. Since most food sources like spinach contain far more lutein than zeaxanthin, is the body able to convert sufficient amounts of lutein to zeaxanthin or meso-zeaxanthin?

The macula seems to want unusually high levels of zeaxanthin, yet we get very little in the normal human diet. Lutein is much more common in our diet, and it appears that some of our dietary lutein is converted to meso-zeaxanthin in the macula, although the enzymes responsible for this conversion have not yet been identified.

Q. Just what is our state of knowledge about the relative importance of these two carotenoids? Do we need to be supplementing higher levels of zeaxanthin as well as lutein?

The jury is still out on this question. There is much more experience with lutein supplements, and there is some evidence that lutein can be a precursor for macular meso-zeaxanthin, but it is also true that there is an exceptionally large amount of zeaxanthin in the macula. Eventually, there will have to be head-to-head studies of these 2 compounds to determine if one is better than the other.

Q. Some research papers have hinted at gender differences in handling lutein. In one study, lutein supplements raised plasma levels of this carotenoid equally well in both sexes, yet some women did not increase their macular pigment density as well as the men. It has been suggested that some lutein may get diverted away from the eye and stored in fat tissue instead — more so in women than in men. What are your thoughts?

I am not convinced there is a major difference between women and men in this regard. At least in our Utah Raman studies, we do not see a major difference between women and men.

Q. The antioxidant treatment arm of the age-related eye disease study (AREDS) included beta-carotene, not lutein. The findings showed that zinc and the antioxidant combination given in this trial was best at slowing AMD progression and vision loss. Do you think that beta-carotene plays a role in protecting retinal tissues, and if so, how?

In the AREDS study, it is impossible to sort out the effect of beta-carotene independently from the effects of vitamin E and vitamin C. Very little beta-carotene is actually present in the retina, so if it is having any effect, it probably is due to its vitamin A precursor role. Because high doses of beta-carotene are associated with increased risk of lung cancer in smokers, many people would like to use lower doses and add lutein and/or zeaxanthin to the AREDS formula.

Q. The National Eye Institute (NEI) is planning a large-scale trial examining the effects of lutein in AMD patients. Will they be utilizing the Raman technology to measure carotenoid levels in the macula? Will you be involved in this study?

As of December 2005, the NEI is evaluating applications for up to 60 sites for the AREDS II study which is expected to begin in 2006. A combination of 10 mg of lutein and 2 mg of zeaxanthin will be tested against placebo. There will also be an omega-3 fatty acid arm of the study. If we are selected as a site, we would be interested in monitoring patient response to supplementation with our ocular resonance Raman instruments.

Q. What do you see as the most important gaps in our knowledge when it comes to the role of lutein and zeaxanthin in the macula?

Although there is good epidemiologic and anecdotal evidence, we still don't have good prospective results that lutein and zeaxanthin can decrease risk of developing AMD; hopefully, AREDS II will give us some answers. From a basic science standpoint, there are still many gaps in our knowledge of the uptake, metabolism, and function of lutein and zeaxanthin that my laboratory hopes to solve.

Q. If you won some sort of research grant lottery and had unlimited funding, what study would you conduct?

On the clinical side, I would like to see a large-scale multiyear placebo-controlled head-to-head study of lutein and zeaxanthin supplementation in high-risk patients for AMD using multiple methods to assess macular response. On the basic science side, I would like to bring the state of knowledge of carotenoid metabolism in humans to a level comparable to the intricate knowledge we have of their roles in photosynthesis and photoprotection in plants.

Penelope Edwards is a science advisor to ScienceBased Health. Dr. Bernstein is a member of the ScienceBased Health Scientific Advisory Board. He can be e-mailed at paul.bernstein@hsc.utah.edu.