Lutein, zeaxanthin, and
Macular pigments are xanthophyll carotenoids that provide the macula lutea with its yellow appearance. Lutein (L), zeaxanthin (Z), and
Macular pigments have a unique distribution within the retina. Concentrations of L, Z, and MZ are highest in the macula, especially in the center of the macula (the fovea). While zeaxanthin has a peak concentration in the central fovea, lutein predominates in the periphery [
Macular pigments are found in their highest concentration in the outer plexiform layer and inner plexiform layer [
Blue light filtration is one of the many functions of macular pigment [
Although L and Z differ only by the placement of a single double bond, this small alteration in configuration has a great impact on the function of these two carotenoids [
These essential functions of macular pigment decrease oxidative stress in the retina and enhance vision in both normal and diseased retinas.
Macular pigments enhance visual function in a variety of ways. The filtration of blue light reduces chromatic aberration which can enhance visual acuity and contrast sensitivity. L and Z also reduce discomfort associated with glare and improve visual acuity, photostress recovery time, macular function, and neural processing speed.
Discomfort glare is a term used to describe photophobia and discomfort experienced when intense light enters the eye. When testing photosensitivity, subjects are more sensitive to shorter wavelengths of light, which are capable of inducing retinal damage with less energy compared to other wavelengths. Despite increased sensitivity to shorter wavelengths, Stringham et al. found a minimum sensitivity was observed at macular pigment peak absorbance (460 nm). They proposed that photosensitivity serves as a protective function to prevent damage to the eye, and macular pigments could attenuate this visual discomfort by absorbing the high energy wavelengths before they reach the photoreceptor layer [
Disability glare is a term used to describe decreased visual acuity resulting from scattered light, another phenomenon that results from bright light settings. Stringham and Hammond Jr. demonstrated that subjects with higher macular pigment levels maintained acuity better than subjects with lower levels when exposed to both bright white light and short wavelength (blue) light [
Photostress recovery is another parameter of visual performance affected by macular pigments. Photostress recovery is a term used to describe the time necessary to recover vision following exposure to a bright light source. Physiologically, this describes the time necessary for photopigments bleached by a bright light source to regenerate. Stringham and Hammond Jr. demonstrated that subjects with higher macular pigment levels had shorter photostress recovery time when tested with intense short wavelength and bright white light sources [
Nolan et al. performed a randomized, placebo-controlled clinical trial supplementing young, healthy subjects with lutein for 12 months. Their goal was to identify if visual performance could be improved with supplementation in a population with relatively high macular pigment levels considered to be at peak visual performance. They were not able to show a significant change in visual performance in supplemented patients despite doubling serum L levels and significantly increasing central macular pigment levels. They did demonstrate, however, that there was a significant difference in visual performance in subjects in the lowest versus the highest tertile groups [
In addition to enhancing visual performance, macular pigments have also been implicated in benefiting neurophysiological health by affecting the complex relationships between optical, neurological, and physiological mechanisms underlying vision. Higher macular pigment levels are attributed to better critical flicker fusion frequency [
Macular pigments are present throughout the visual system, including the brain [
Age-related macular degeneration (AMD) is the most common cause of irreversible blindness in people over the age of 50 in the developed world [
Initial studies focused on the relationship between dietary intake of L and Z and the risk for AMD. While the results of these studies were variable, most suggested that high dietary intake of L and Z is associated with a decreased risk of AMD.
Ma et al. published a systematic review and meta-analysis on this subject [
In addition to the six papers analyzed by Ma et al., there were several other important observational studies published. The Eye Disease Case-Control Study reported that subjects with the highest quintile of carotenoid intake had a 43% reduced risk of AMD compared with subjects in the lowest quintile [
In the Age-Related Eye Disease Study (AREDS) Report 12, the relationship between dietary intake of L/Z and late AMD was studied in 4,519 AMD patients. Dietary L/Z intake was inversely associated with neovascular AMD (odds ratio (OR), 0.65; 95% CI: 0.45–0.93), geographic atrophy (OR, 0.45; 95% CI: 0.24–0.86), and large or extensive intermediate drusen (OR, 0.73; 95% CI, 0.56–0.96), comparing the highest versus lowest quintiles of intake, after adjustment for total energy intake and nonnutrient-based covariates. Other nutrients (
Furthermore, participants from the Rotterdam Study were enrolled into a case-control study investigating whether dietary nutrients could reduce the genetic risk of early AMD. A total of 2,167 participants from the population-based Rotterdam Study at risk of AMD were followed up for a mean of 8.6 years. They reported that high dietary intake of nutrients with antioxidant properties such as L and Z,
Several studies evaluated the serum levels of L/Z. The Beaver Dam Eye Study found that L/Z serum levels did not correlate with AMD [
A case-control study of human donor eyes by Bone et al. demonstrated that donors with AMD had significantly lower levels of macular pigment (MP) compared to eyes without; and donors with the highest quartile of L/Z had an 82% lower risk of having AMD compared to donors in the lowest quartile [
Subsequently concentrations of L and Z in the retina have been studied extensively. Macular pigment levels within the retina are easily measured
After the established correlation between the risk of AMD and low serum and retinal concentrations of L and Z, supplementation trials were initiated. These trials have shown extremely consistent results as compared to any other single nutrient supplementation trial.
The first supplementation trial reported was the Veterans Lutein Antioxidant Supplementation Trial (LAST). This was a double-masked, placebo-controlled trial that investigated lutein supplementation alone compared to combined supplementation (lutein, other carotenoids, antioxidants, vitamins, and minerals) in 90 patients with dry AMD and geographic atrophy. Both groups demonstrated a significantly increased level of MP, improved visual acuity (VA) at near, and improved contrast sensitivity (CS). The disease progression was halted with supplementation over the course of the 12-month study. While the duration of the study was short and study group numbers were small, few studies have monitored the effects of MP supplementation alone compared to combined supplementation [
The Age-Related Eye Disease Study (AREDS) was one of the largest and earliest supplementation trials which demonstrated that subjects with extensive intermediate-sized drusen, at least one large druse, noncentral geographic atrophy, or advanced AMD in one eye had 25% reduced risk of severe vision loss at 5 years if supplemented with vitamin C (500 mg), vitamin E (400 IU), b-carotene (15 mg) with or without zinc (80 mg), and copper (2 mg cupric oxide) [
Weigert et al. evaluated the role of lutein supplementation in MPOD, visual acuity, and macular function (assessed with microperimetry) in intermediate to advanced AMD. A total of 126 patients were randomized to L (20 mg daily for 3 months and then 10 mg daily for 3 months) or placebo for a period of 6 months. Supplementation significantly increased MPOD. There was a trend toward increased macular function and visual acuity that was not statistically significant [
Ma et al. evaluated the role of macular pigment supplementation in early AMD over 48 weeks. A total of 107 subjects were randomized to a placebo, L (10 mg/day), L (20 mg/day), or L (10 mg/day) and Z (10 mg/day). They reported a significant increase in MPOD in all study groups with the exception of the 10 mg lutein group. There was no change in the placebo group. Subjects with the lowest baseline MPOD had the greatest increase in MPOD regardless of supplementation. Visual acuity (VA) improved in all treatment groups, but not significantly. Contrast sensitivity (CS) was significantly different at 48 weeks in all treatment groups. The authors noted that MPOD was significantly increased at 24 weeks, while VA and CS did not show improvement until 48 weeks, suggesting that visual function cannot be improved until MPOD levels reach and maintain high levels [
The CARMIS study reported a significant improvement in CS and NEI visual function questionnaire at 12 and 24 months in AMD patients supplemented with vitamin C (180 mg), vitamin E (30 mg), zinc (22.5 mg), copper (1 mg), L (10 mg), Z (1 mg), and astaxanthin (4 mg) compared to controls. VA was not significantly improved until 24 months [
The LUTEGA study evaluated the long term effects of L, Z, and omega-3 fatty acid supplementation on MPOD in 145 dry AMD patients randomized to placebo, daily or twice daily dosage of supplement. The supplement provided was L (10 mg), Z (1 mg), and omega-3 fatty acid (100 mg DHA, 30 mg EPA). After 12 months, MPOD increased significantly in supplementation groups and decreased significantly in controls. VA also improved compared to placebo. There was no significant difference in accumulation of MPOD between the two dosage groups. No progression was noted in any of the participants [
The CLEAR study evaluated the effects of L (10 mg) supplementation on early AMD subjects over a 12-month period. This group reported a significant increase in mean MPOD after 8 months of supplementation, with no change in the control group. VA improved in the study group and declined slightly in the placebo group. There was also an increase in serum L levels in the study group, increasing anywhere from 1.8 to 7.6 times the baseline values. Those with lower baseline serum levels tended to have greater improvements, but the response to supplementation varied markedly between individuals [
The CARMA study investigated the role of L and Z with other antioxidant vitamins and minerals in subjects determined to be at highest risk of progression to advanced AMD. A total of 433 subjects were randomized to the placebo or supplementation group. Patients were supplemented with Ocuvite twice daily (L 12 mg, Z 0.6 mg, vitamin E 15 mg, vitamin C 150 mg, zinc oxide 20 mg, and copper gluconate 0.4 mg). VA improved after 12 months of supplementation but was not significant until 24 months. CS was also improved, but not significantly. Fewer eyes in the active group progressed compared to controls (41.7% versus 47.4%, resp.). Macular pigment values in the study group demonstrated a small increase over time, while the placebo group steadily declined. Serum concentrations of all antioxidants were increased after six months of supplementation. The increases in these serum levels did not correlate with improvements in VA. However, an increase in serum L levels was associated with slower progression of AMD. A similar pattern was seen with serum Z levels but did not achieve statistical significance [
Liu et al. performed a meta-analysis which compared the results of the above-mentioned seven randomized, double-blind, placebo-controlled trials, including the LAST, Weigert et al., Ma et al., CARMIS, LUTEGA, CLEAR, and CARMA studies [
After the release of several smaller supplementation trials mentioned above, the Age-Related Eye Disease 2 Study (AREDS2) was published. AREDS2 was a multicenter, randomized, double-masked, placebo-controlled clinical trial following 4,203 participants with intermediate AMD or large drusen in 1 eye and advanced AMD in the fellow eye for approximately 5 years. Participants were assigned to one of four groups: placebo, L (10 mg) and Z (2 mg), omega-3 fatty acids (DHA 350 mg and EPA 650 mg), or a combination of L, Z, and omega-3 fatty acids. In addition they were given either the original AREDS formulation or some modification of the original formulation (eliminating
These studies established that structural changes in the retina can be achieved with supplementation, and over time supplementation appears to affect visual acuity. More recent studies have evaluated functional changes in carotenoid supplementation with the multifocal electroretinogram (MfERG). As a secondary analysis to their initial study, Ma et al. compared 107 subjects with early AMD randomly assigned to one of four treatment groups (placebo, L 10 mg/day, L 20 mg/day, or L 10 mg/day and Z 10 mg/day) comparing MfERG responses at baseline, 24, and 48 weeks. They demonstrated that early functional abnormalities in the central retina of subjects with early AMD at baseline could be improved with supplementation of L and Z. They attributed these improvements to the significant increase in MPOD seen at both 24 and 48 weeks [
These trials suggest that with long term supplementation of antioxidants in patients with AMD increase in macular pigment in the retina allows for improved macular function, visual acuity, and contrast sensitivity. Evidence suggests with supplementation serum levels increase quickly, macular pigment increases over a period of several months, and a minimum of one to two years is necessary before improvements in visual function reach statistical significance. Recent studies show that macular pigment levels continue to increase with long term supplementation [
Previous studies mainly investigated the preventive and therapeutic effects of L and Z; very little was known on the effects of MZ on the AMD. Recent reports investigating the ratio of L, Z, and MZ supplementation suggest supplementing with a higher proportion of MZ leads to higher MPOD values and an improvement in CS [
While the last two decades of research have provided many insights into the role of macular pigments and other antioxidants in AMD, future research studies investigating the optimal antioxidant supplement, the role of early supplementation, the relationship of MPOD as a risk factor for disease onset and progression, and the impact of genetic risk factors are necessary to better understand the disease process and provide more therapeutic options to patients with AMD.
The role of carotenoids in age-related macular degeneration has been studied extensively. The encouraging results have led to subsequent investigations into the role of antioxidants in other diseases, including diabetic retinopathy and retinopathy of prematurity. The retinal ischemia in these conditions can lead to neovascularization, hemorrhage, and blindness. Oxidative stress plays a role in the pathogenesis of both conditions, and early evidence suggests antioxidant supplementation may prevent disease progression [
In retinopathy of prematurity, premature infants are exposed to higher oxygen tensions compared to conditions
During fetal development L is the dominant retinal carotenoid [
Two multicenter placebo-controlled randomized clinical trials studying ROP prevention supplemented preterm infants (<33 weeks of gestational age) with 0.5 mL daily dosage of 0.14 mg L and 0.0006 mg Z via oral feeds of maternal milk, donor human milk, or preterm formula [
A third clinical trial investigated the effect of weight-based dosages, as AMD trials have suggested better outcomes with higher carotenoid doses. This trial did not show a difference in ROP incidence with weight-based doses, but the study was limited by small sample size [
The fourth multicenter randomized controlled trial compared carotenoid levels in preterm infants fed formula with and without L, lycopene, and
To date no clinical trials have specifically tested the hypothesis that L affects ROP outcomes. While future supplementation trials monitoring long term outcomes in ROP would be beneficial, current evidence suggests a role for carotenoid supplementation in the prevention of ROP and normal photoreceptor development in preterm infants.
In diabetic retinopathy, prolonged hyperglycemia causes oxidative stress via several different pathways [
While a number of studies have examined the role of carotenoids in the development of diabetes mellitus (DM), there are a limited number of studies examining their role in the development of diabetic retinopathy. A serum analysis of patients with Type II DM demonstrated that patients with a higher concentration of serum L, Z, and lycopene compared to serum alpha-carotene,
Evidence supporting the role of macular pigments in the prevention and treatment of retinopathies is currently limited, but animal models and early human supplementation trials suggest there is a role for lutein and zeaxanthin in reducing oxidative damage and possibly preventing disease progression.
Age-related cataracts are another leading cause of blindness in the United States and worldwide. Treatments that can delay the progression of lens opacities have been studied extensively as this would reduce the burden of disease and reduce healthcare costs. Numerous studies have investigated the role of dietary nutrients in the development of cataracts or need for cataract surgery [
The first trial to suggest a relationship between vitamins and minerals and cataractogenesis was a trial in Linxian, China, aimed at reducing the risk of esophageal and gastric cancer in a nutritionally deprived population. The initial trial compared multivitamin/mineral supplement and placebo, and the second trial compared 4 different supplements (retinol/zinc, riboflavin/niacin, ascorbic acid/molybdenum, and selenium/vitamin e/
While the trials mentioned above were underway, Hammond et al. demonstrated that higher levels of MPOD correlated with a more transparent lens. They hypothesized that higher concentrations of xanthophylls in the retina correlate with higher concentrations in the lens, impacting the rate of cataract progression [
A retrospective study by Gale et al. demonstrated a 50% reduced rate of posterior subcapsular cataract in subjects with higher plasma L concentrations. High plasma vitamin C, vitamin E, and Z were not associated with a decreased risk [
Another population-based study (Pathologies Oculaires Liees a l’Age (POLA) study) investigating plasma L and Z levels of 899 subjects found those with the highest quintile of plasma Z had a significantly reduced risk of AMD, nuclear cataract, or any cataract [
In a ten-year prospective study examining serum carotenoid levels in 35,551 female subjects, Christen et al. demonstrated that women in the highest quintile of L and Z intake had an 18% lower risk of developing cataract compared to those in the lowest quintile [
Subsequently a few prospective supplementation trials have investigated the role of carotenoids in the prevention of cataract formation. Omedilla et al. studied the visual effects of L supplementation on subjects with cataracts in a double-blind placebo-controlled study. Visual acuity and glare sensitivity were improved after 2 years of supplementation with L 15 mg. However, sample sizes of the treatment and study groups were small (
Three xanthophylls (L, Z, and MZ) are found selectively within retina, concentrated in the macula, and have been appropriately referred to as macular pigments. Epidemiological studies have revealed that low macular pigment levels are associated with higher risk of AMD. Several large observational studies demonstrated that high dietary intake and higher serum levels of L and Z are associated with a lower risk of AMD, especially late AMD. Randomized controlled clinical trials have revealed that supplementation of L and Z increases macular pigment density, improves visual function, and decreases the risk of progression of intermediate AMD to late AMD, especially neovascular AMD. Future studies may include additional assessments of the relationship between macular pigment and different genotypic and phenotypic forms of AMD, the optimum dosages of L, MZ, and Z, and the possible synergistic effects associated with supplementing with other nutrients. Current studies on preventive and therapeutic effects of L and Z on ROP, DR, and cataract have yielded varied results. Further investigations are necessary to fully understand the role of macular pigment in the prevention and treatment of eye diseases such as AMD, ROP, DR, and cataract.
None of the authors have a proprietary interest in the information presented, but a full list of disclosures is included. Nicole K. Scripsema and Dan-Ning Hu have no financial disclosures. Richard B. Rosen is a consultant to Ocata Medical (formerly Advance Cellular Technologies), Allergan, Clarity, Nano Retina, Regeneron, and Optovue and has a personal financial interest in Opticology.
The authors declare that there is no conflict of interests regarding the publication of this paper.
Funding for the submission of this paper was generously donated by the Dennis Gierhart Charitable Fund.