Volume 80, Issue 10 , Pages 592-598, October 2009
Macular pigment and healthy vision
Article Outline
- Lutein and zeaxanthin increase MPOD
- Lutein, zeaxanthin, and AMD risk
- AMD risk and MPOD
- Conclusions
- References
A growing body of evidence has established a link between lutein and zeaxanthin, higher levels of MPOD, increased visual performance, and decreased risk for AMD and other age-related eye diseases. A number of findings suggest that MPOD measurement may be a reliable tool to identify individuals at risk for or experiencing early-stage AMD. Devices are commercially available to measure MPOD and new objective technologies are emerging.
In addition to the macula, lutein and zeaxanthin are found in the lens. Oxidation of the lens proteins is a major cause of cataracts.3 As antioxidant nutrients neutralize free radicals associated with oxidative stress and retinal damage, lutein and zeaxanthin may reduce the risk of cataract. In fact, a recent study found that higher dietary intake of lutein, zeaxanthin, and vitamin E was associated with a significantly decreased risk of cataract formation.4
Lutein and zeaxanthin increase MPOD
Studies have found that high levels of lutein and zeaxanthin in the serum and diet are associated with a reduced risk for advanced age-related macular degeneration (AMD).5, 6, 7 There is also evidence that individuals with low levels of lutein and zeaxanthin in the serum and diet have lower macular pigment density.8, 9, 10 Therefore, it can be inferred that low levels of macular pigment may be a potential risk factor for AMD. In autopsy eyes, there was approximately 30% less macular pigment in eyes with AMD compared with control eyes.11
One of the largest clinical trials evaluating the impact of lutein upon MPOD was the Lutein Antioxidant Supplementation Trial (LAST).12 This trial supplemented 90 men who had atrophic AMD with 10 mg of lutein, 10 mg lutein plus antioxidants, or a placebo over the course of 1 year. Those receiving 10 mg of lutein experienced a 36% increase in MPOD, and a 43% increase was observed in those subjects who received 10 mg of lutein plus antioxidants. Additionally, visual acuity, visual function, photo-stress recovery time, and contrast sensitivity were also significantly improved in both groups receiving lutein.
Another trial determined that in healthy subjects after supplementation with 10 mg of lutein and 2 mg zeaxanthin, MPOD increased significantly over the course of 6 months.13 This increase in MPOD positively correlated with the subjects' ability to tolerate glaring light and recover from photo stress. These data suggest that high lutein concentrations in the macula can improve visual function in both healthy subjects and those with age-related eye disease.
The majority of published clinical studies show a positive effect on MPOD from either lutein/zeaxanthin supplementation or consumption in the form of dark green, leafy vegetables (see Table 1). Variations in results could be attributed to differences in study populations as well as the methods used to measure MPOD, type of diet consumed by the study subjects, and how closely subjects adhered to the supplementation/dietary regimens used. Regardless, the body of evidence suggests increased lutein intake, through lutein-rich food or dietary supplements, is likely to result in increased deposition of lutein and zeaxanthin into the macular area of the eye.
Table 1. Intervention studies examining the effect of lutein and zeaxanthin on MPOD
| Study | Cohort | Protocol | Effect on MPOD |
|---|---|---|---|
| Aleman et al.14 2001 | 47 retinitis pigmentosa and 11 Usher syndrome patients | 20 mg/d lutein for 6 months | Half the patients experienced an increase in MPOD |
| Berendschot et al.15 2000 | 8 healthy adult subjects | 10 mg/d lutein for 8 weeks | Significant increase in mean MPOD |
| Bernstein et al.16 2002 | 46 elderly subjects | High carotenoid diet or lutein supplement for 12 weeks | No change in mean MPOD |
| Bone et al.17 2003 | 3 healthy adult subjects | 2.4 to 30 mg/d lutein and 30 mg/d zeaxanthin for 20 weeks | Increase in mean MPOD |
| Bone et al.18 2007 | 10 healthy adult subjects | 5.5 mg/d lutein, 14.9 mg/d meso-zeaxanthin, 1.4 mg/d zeaxanthin for 4 months | Significant increase in MPOD |
| Cardinault et al.19 2003 | 12 healthy young and 17 healthy elderly subjects | 9 mg/d lutein for 5 weeks | No change in mean MPOD |
| Duncan et al.20 2002 | 7 choroideremia (form of retinal degeneration) patients | 20 mg/d lutein for 6 months | Significant increase in mean MPOD |
| Francoise et al.21 2006 | 46 healthy adults | 4-6 mg/d lutein for 12 weeks | No change in mean MPOD |
| Hammond et al.9 1997 | 13 healthy adult subjects | 10 mg/d lutein for 15 weeks | Significant increase in mean MPOD |
| Johnson et al.10 2000 | 7 healthy adult subjects | 10 mg/d lutein 15 for weeks | Significant increase in mean MPOD |
| Johnson et al.22 2008 | 49 healthy women | 12 mg/d lutein for 4 months | Significant increase in MPOD |
| Koh et al.23 2004 | 7 early ARM and 6 controls | 10 mg/d lutein for 20 weeks | Significant increase in MPOD in both groups |
| Kopsell et al.24 2006 | 20 healthy adults | 3 mg/d or 4.3 mg/d lutein for 12 weeks | Significant increase in MPOD in high lutein group |
| Kvansakul et al.25 2006 | 22 healthy males | 10 mg/d lutein and 10 mg/d zeaxanthin for 6 months | Significant increase in MPOD |
| Landrum et al.26 1997 | 2 healthy adult subjects | 30 mg/d lutein for 20 weeks | Significant increase in mean MPOD |
| Landrum et al.27 2000 | 24 healthy adult subjects | 2.4 mg/d lutein for 6 months | Significant increase in mean MPOD |
| Morganti et al.28 2004 | 50 healthy adults | 6 mg/d lutein for 2 months | Significant increase in MPOD |
| Richer et al.12 2004 | 90 AMD patients | 10 mg/d lutein for 12 months | Significant increase in mean MPOD |
| Richer et al.29 2007 | 59 AMD patients | 10 mg/d lutein for 12 months | Significant increase in MPOD with no plateau after 12 months' supplementation |
| Rodriguez-Carmona et al.30 2006 | 92 healthy adults | 10 mg/d lutein for 6 months | Significant increase in MPOD |
| Schalch et al.31 2007 | 92 healthy adults | 10 mg/d lutein for 6 months followed by 20 mg/d lutein for additional 6 months | Signfiicant increase in MPOD |
| Schweitzer et al.32 2002 | 10 health adults | 6 mg/d lutein for 40 days | Increase in MPOD |
| Stringham et al.13 2008 | 40 healthy young adults | 10 mg/d lutein and 2 mg/d zeaxanthin for 6 months | Significant increase in MPOD |
| Trieschman et al.33 2007 | 136 healthy adults | 12 mg/d lutein and 1 mg/d zeaxanthin | Significant increase in MPOD |
| Wenzel et al.34 2006 | 24 adult females | 6 eggs/week for 3 months | Significant increase in MPOD |
| Wenzel et al.35 2007 | 3 healthy adults | 30 mg/d lutein and 2.7 mg/d zeaxanthin for 4 months | Significant increase in MPOD |
| Yolton et al.36 2002 | 45 healthy young adults | 6 mg/d lutein for 7 months | No change in mean MPOD |
| Zeimer et al.37 2009 | 108 adults with and without AMD | 12 mg/d lutein and 1 mg/d zeaxanthin for 6 months | Significant increase in MPOD |
Lutein, zeaxanthin, and AMD risk
A link between lutein and zeaxanthin intake and AMD risk was first uncovered in an epidemiologic study published in 1994.6 This study compared the risk of developing AMD with nutrient intake and showed a significant 57% risk reduction for AMD as lutein and zeaxanthin intake reached 6 mg per day. Subsequent epidemiologic research suggests a positive association between lutein intake, serum levels of lutein, and AMD risk in humans (see Table 2). These studies provide insight from an observational perspective suggesting that dietary sources of lutein are associated with a reduced risk for AMD. However, controlled long-term intervention studies in humans are needed to establish causality.
Table 2. Observation studies showing an inverse association between lutein and AMD risk
| Study | Measured Outcome(s) | Result(s) |
|---|---|---|
| Bernstein et al.41 2002 | Lutein supplementation and MPOD in AMD patients | MPOD significantly higher in AMD patients using lutein supplementation versus subjects without supplementation |
| Cho et al.42 2004 | Fruit and vegetable intake and age-related maculopathy risk | Fruit intake was inversely associated with the risk of neovascular age-related maculopathy |
| Delcourt et al.43 2006 | Serum lutein and zeaxanthin levels and age-related maculopathy and cataract risk | Lutein and zeaxanthin were significantly inversely associated with the risk of age-related maculopathy |
| Eye Disease Case-Control Study5 1993 | Serum lutein levels and AMD risk | Significant inverse relationship between serum lutein concentration and AMD risk |
| Gale et al.44 2003 | Serum lutein and zeaxanthin levels and AMD risk | Inverse relationship between serum lutein and/or zeaxanthin concentration and AMD risk |
| Moeller et al.45 2006 | Serum lutein and zeaxanthin levels and AMD risk | Inverse relationship between serum lutein and/or zeaxanthin concentration and AMD risk |
| Seddon et al.6 1994 | Dietary intake of carotenoids and AMD risk | Significant inverse relationship between lutein intake and AMD risk |
| Snellen et al.7 2002 | Lutein intake and AMD risk | The prevalence rate of AMD in patients with low antioxidant intake and low lutein intake was twice as high as that in patients with high intake |
| Tan et al.46 2008 | Lutein and zeaxanthin intake and AMD risk | Significant inverse relationship between lutein and zeaxanthin intake and AMD risk |
| Vu et al.47 2006 | Lutein and zeaxanthin intake and AMD risk | Significant inverse relationship between lutein and zeaxanthin intake and AMD risk |
One such study, the Age-Related Eye Disease Study 2 (AREDS 2) conducted by the National Eye Institute, is currently under way. AREDS 2 will add the carotenoids lutein (10 mg/d) and zeaxanthin (2 mg/d), alone or in combination with the omega-3 fatty acids, docosahexaenoic acid (350 mg/d) and eicosapentaenoic acid (650 mg/d) to the original AREDS supplement formulation and assess the progression to AMD in individuals at high risk for the disease. An additional goal of the study is to assess whether forms of the AREDS supplement with reduced zinc and/or no beta-carotene work as well as the original supplement in reducing the risk of progression to advanced AMD.
In June 2008, 80 participating U.S. centers completed recruitment of 4,000 AMD patients for the study with each patient receiving treatment for 5 years. In addition to evaluating the rate of AMD progression, other outcomes will be simultaneously evaluated, including the effects of supplementation on the development of cataracts, cardiovascular disease, vision loss, visual function, and cognitive function, as well as genetic risk factors to AMD. One subset of participants in the AREDS 2 study will have their MPOD measured using autofluorescence spectroscopy (AF).
Since the original AREDS study was completed, additional evidence regarding nutrition and eye health has come to light. The decision to add lutein and zeaxanthin to the AREDS supplement formula was in part a result of analysis of the dietary intake of lutein and zeaxanthin in the AREDS participants that showed that those individuals with the highest intake had the lowest risk for AMD.38 In addition, a study comparing the amounts of lutein and zeaxanthin in donor eyes with and without AMD found that eyes with the highest quartile of lutein and zeaxanthin had an 82% lower risk for AMD compared with the lowest quartile.39 Another study currently in progress is the Carotenoids and Co-antioxidants in Age-Related Maculopathy (CARMA) study, which is investigating the potential benefits of supplementation with lutein and zeaxanthin and vitamin C, E, and zinc on the progression of age-related maculopathy.40
The body of evidence summarized in Table 2 must be evaluated collectively to determine the merits of supplementing the diet with a given nutrient. With this in mind, current research appears to support a beneficial role for lutein in eye health. Lutein intake may increase levels of this xanthophyll in the macula providing protection against damaging blue light and free radicals that contribute to AMD progression.
AMD risk and MPOD
Although a direct link between AMD and MPOD requires further investigation, research suggests a strong indirect relationship when the body of evidence is considered (see Table 3). High concentrations of macular pigment, lutein and zeaxanthin, protect the macula from photo-oxidative damage caused by blue light.1, 2 This raises the question as to whether higher levels of MPOD or specific MPOD distributions help protect the eye against AMD. Associations have been made between risk factors for AMD and factors that influence MPOD levels such as sex, age, iris color, smoking, dietary intake, body mass index, and the presence of existing diseases.48, 49, 50 As the optical density and spatial distribution of macular pigment have been shown to differ among individuals, determination of the relationship between MPOD spatial profiles in normal and diseased human subjects may predicate MPOD levels and possible relationships between MPOD and pathophysiology of the human eye.51, 52
Table 3. Relationship between AMD risk and MPOD
| Study | Study Type | Findings |
|---|---|---|
| Age-Related Eye Disease Study Research Group 200738 | Epidemiologic | AREDS subjects reporting the highest dietary intake of lutein and zeaxanthin were statistically less likely to have advanced AMD (both neovascular AMD or geographic atrophy) or large or extensive intermediate drusen than those reporting lowest dietary lutein/zeaxanthin intake. |
| Beatty et al.57 2001 | Clinical study of 46 healthy white subjects | An age-related decline in the amounts of lutein and zeaxanthin in the retina (MPOD) was observed. Additionally, MPOD was significantly less in 9 healthy subjects known to be at high risk for AMD compared to 9 matched eyes at no such risk. |
| Bernstein et al.41 2002 | Clinical study | Average levels of lutein and zeaxanthin in eyes of subjects with AMD were 32% lower than levels in eyes of subjects without signs of AMD. |
| Bone et al.39 2001 | Research study on donor eyes at autopsy with and without AMD | Retinas of persons with AMD had significantly lower lutein and zeaxanthin in the macula than retinas of persons without signs of AMD |
| Ciulla and Hammond60 2004 | Clinical study with 390 subjects including subjects with cataracts (22) and AMD (59) | The amount of lutein and zeaxanthin in the macula (MPOD) did not change significantly with age even when elderly subjects with cataracts and AMD were considered. However, the low numbers of subjects with eye diseases might have limited the power of the study. |
| Eye Disease Case-Control Study 19935 | Epidemiologic | Data from this study indicated that persons with higher levels of circulating micronutrients having antioxidant capabilities, particularly carotenoids, have a reduced risk of neovascular AMD. |
| Koh et al.23 2004 | Clinical study with 13 subjects—7 with early ARM and 6 healthy eyes | Supplementation with lutein and zeaxanthin at 10 mg/day for 18 to 20 weeks resulted in increased MPOD in all subjects, even those with age-related maculopathy. The degree of MPOD increase in eyes with age-related maculopathy was statistically similar to those in healthy eyes. These data indicate that the potentially beneficial effects of lutein and zeaxanthin supplementation are not restricted to healthy eyes. |
| LaRowe et al.58 2008 | Cross-sectional study | After excluding women likely to have unstable diets and those having conditions related to AMD risk, a potentially protective trend (although not statistically significant) was observed between the amounts of lutein and zeaxanthin in the retina and AMD. Also, it was reported that higher levels of lutein and zeaxanthin in the retina may slow advancement of AMD. |
| Nolan et al.61 2007 | Epidemiologic | MPOD was significantly inversely associated with risk factors for age-related maculopathy including age, smoking, and family history of the disease. |
| Obana et al.59 2008 | Clinical study in Japanese subjects | MPOD levels declined with age in healthy Japanese subjects and were significantly lower in age-related maculopathy patients than in healthy subjects younger than 60. MPOD was also significantly lower in subjects with late AMD (late age-related maculopathy) than in subjects with early age-related maculopathy. |
| Richer et al.12 2004 | Clinical study with 90 AMD patients (half receiving lutein/zeaxanthin and half placebo) | Supplementation with 10 mg/day for 12 months resulted in a 36% increase in MPOD in these AMD patients as well as improvements in visual functionality (visual acuity, contrast sensitivity, and glare recovery) |
| Seddon et al.6 1994 | Epidemiologic | Persons with a diet rich in lutein/zeaxanthin (6 mg/day) had significantly less (57%) risk to have AMD than persons with a diet low (1 mg/day) in these xanthophylls |
There are a few devices commercially available to measure MPOD. These devices utilize one of the following methods: heterochromatic flicker photometry (HFP), resonance Raman spectroscopy, and autofluorescence imaging (AFI). HFP is a subjective test that involves color intensity matching of flickering blue and green light.53, 54 The subject varies the intensities of the 2 lights until the perception of flicker is minimized or eliminated. MPOD is calculated from the level of maximum radiance of blue light needed to match the reference light and cause a “null-flicker.” Resonance Raman spectroscopy utilizes a low-intensity argon laser to illuminate a subject's retina, which resonantly excites the macular carotenoids. The wavelength-shifted light is analyzed and used to calculate MPOD.55 AFI is a relatively new technology that utilizes the fluorescence of lipofuscin in the retinal pigment epithelium (RPE). To measure macular pigment with this technique, the fluorescence of lipofuscin is excited at a wavelength also blocked by macular pigment. Thus, the fluorescence of lipofuscin is attenuated in direct relationship to the amount of macular pigment present. AFI, now being utilized in AREDS 2, has advantages over other methods in that it can obtain an objective, rapid measurement that not only quantifies macular pigment levels but also is capable of mapping spatial variations in macular pigment distribution.56
Evaluating the relationship between AMD and MPOD is challenging because of the special equipment required to measure MPOD, difficulties in accurately measuring MPOD in elderly patients, particularly those with eye diseases, and the normal variability in MPOD among individuals. However, a number of findings suggest that MPOD measurement may be a reliable marker to identify individuals at risk or experiencing early-stage AMD.39, 41, 57, 58, 59 Low levels of MPOD may indicate a decrease in the light-filtering capacity of the macula, thereby increasing one's risk for AMD. Conversely, high levels of MPOD may be a protective factor against photo-oxidative damage by blue light and reduce an individual's risk for AMD as well as potentially other age-related eye diseases.
Conclusions
A proper diet, including a variety of fruits and vegetables, has been shown clinically to help protect against development or progression of AMD. Over the last 2 decades, an understanding of the macular pigment and its role in eye protection has prompted researchers to investigate the impact of lutein and zeaxanthin consumption on MPOD and age-related eye disease. A growing body of evidence has established a positive correlation among increased lutein consumption, higher levels of MPOD, and decreased risk for AMD. Therefore, the components of macular pigment, lutein and zeaxanthin, are likely able to protect against chronic and cumulative eye damage through their capacity to filter the most energetic and potentially damaging wavelengths of visible light and neutralize free radicals caused by oxidative stress. Although more research is needed to definitively identify low levels of MPOD as a causative factor of AMD, it is biologically plausible that MPOD may decrease the progression of age-related maculopathy and AMD, and adequate supplementation with lutein and zeaxanthin may help decrease the rate if not the progression of these ocular diseases.
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PII: S1529-1839(09)00426-6
doi:10.1016/j.optm.2009.08.002
Volume 80, Issue 10 , Pages 592-598, October 2009
