Lutein and Zeaxanthin in the Eye

Carotenoids are a family of compounds abundantly found in fruits, vegetables and green plants. Of the more than 600 carotenoids found in nature, only about 20 are found in human plasma and tissues. Of these, only lutein and zeaxanthin are specifically located in the macula and lens of the eye. Lutein and zeaxanthin, until recently, had been reported together because of their similar chemical structures. They do, however, differ in the placement of one key double bond and in their stereochemistry, which give lutein and zeaxanthin distinct properties from one another.

The risk of chronic diseases, such as heart disease, cancer and age-related eye diseases, increases as the average person ages. The anticipated rise in the incidence of these chronic diseases as the population ages has led to increased research on preventive approaches, including nutrition. Recent studies have found that diets rich in lutein and zeaxanthin may play a role in reducing the risk of serious eye diseases such as age-related macular degeneration (AMD) and cataracts.

Lutein and zeaxanthin are the only carotenoids generally found in the eye despite the fact that higher concentrations of beta-carotene and lycopene are found in the blood. This phenomenon is especially striking for zeaxanthin considering its relatively minor presence in plasma. The biological function of lutein and zeaxanthin in the eye is not fully understood, although two functions have been proposed: their role as antioxidants and the absorption of damaging near-to-UV blue light, the most energetic portion of visible light.

An antioxidant is a molecule that protects against damaging reactive oxygen species (ROS). Singlet oxygen and peroxyl radicals are two ROS that arise from normal reactions in the body as well as from exposure to cigarette smoke, air pollutants, radiation, certain drugs and environmental toxins. ROS can react with DNA, protein, or lipids and impair their physiological function. It is believed that these reactions with ROS can initiate diseases such as cancer, cardiovascular disease and age-related macular degeneration. Carotenoids inactivate singlet oxygen by physical or chemical quenching. The efficiency of quenching depends upon molecular properties of the carotenoid, such as the number of double bonds, the type of end groups or other chemical properties.

Age-related macular degeneration (AMD) is the leading cause of legal blindness among the elderly in developed countries and a leading cause of vision impairment in general. Some surveys estimate that approximately 10 million Americans show early signs of this disease and 450,000 or more may already have significant vision loss from late-stage AMD. The risk of AMD increases with age and women may be at a higher risk than men. AMD is an incurable condition. Both the severity and irreversibility of AMD have prompted a search for ways to prevent or slow its progression.

The amount of lutein and zeaxanthin in the eye is referred to as macular pigment density. People with the highest risk of AMD, that is the elderly, women, smokers and people with light iris colors, also tend to have low macular pigment density. Macular pigment density can be increased by dietary means. Such evidence provides an indirect link between dietary intake of lutein and zeaxanthin, macular pigment density and AMD risk.

The association between dietary lutein and zeaxanthin and AMD risk has been explored in epidemiological studies. One study from Harvard found that the risk of severe AMD was significantly lower with increasing serum concentrations of lutein and zeaxanthin. This study also found that subjects in the highest quintile of lutein and zeaxanthin intake (5.8 mg/day) had a significantly lower AMD risk compared with those in the lowest quintile of intake. A plausible confirmation of this diet-AMD link is the finding that more frequent consumption of spinach or collard greens (rich sources of lutein and zeaxanthin) was also associated with lower AMD risk.

The correlation between dietary intake of lutein and zeaxanthin and risk of cataracts has also been explored in recent studies. Lutein and zeaxanthin are the only carotenoids found in the lens, but at much lower concentrations than in the macula. Cataracts are the leading cause of vision impairment in developed countries and a leading cause of blindness worldwide. Cataracts can only be treated by surgically replacing the lens, and cataract surgery is one of the most commonly performed procedures in the U.S. Three recent epidemiological studies have reported a correlation between higher dietary intake of lutein and zeaxanthin and a reduced risk of cataracts. One study found a statistically significant trend toward a reduced risk of cataract extraction surgery with increased intake of lutein and zeaxanthin. The reduction in risk reached significance only in the fourth quartile of intake with an average intake of 6.0 mg lutein and zeaxanthin per day.

Lutein and zeaxanthin are found in many colorful fruits and vegetables, such as greens (e.g., collard, mustard, kale, etc.), corn, peppers and oranges. Determining daily dietary intake of lutein and zeaxanthin is challenging because the most commonly used analytical techniques have not distinguished between their chemical structures; therefore, intake studies have generally reported them together. Also, the database on the lutein and zeaxanthin content of different foods is very limited and at times inconsistent. The available food composition data estimate an approximate 5:1 ratio of lutein to zeaxanthin intake in the U.S., mainly because lutein is typically found in much higher amounts than zeaxanthin in many fruits and vegetables.

The Nurses Health Study, Health Professional’s Follow-Up Study and Eye Disease Case-Control Study all reported an association between dietary intakes of lutein and zeaxanthin around 6 mg per day and a decreased risk of AMD and cataracts. However, data from both the National Cancer Institute (NCI) 5-A-Day for Better Health Program and the Centers for Disease Control and Prevention (CDC) Behavioral Risk Factor Surveillance System indicate that only about 23% of people are meeting the goal of 5 servings of fruits and vegetables a day. Comparing typical intakes reported by food surveys to the findings of epidemiological studies, there appears to be a dietary gap of at least 2 to 4 mg/day. Whether lutein or zeaxanthin is more important for eye health is unclear at this time; however, in vitro evidence suggests that zeaxanthin may be a better antioxidant than lutein. Until additional studies are available, it seems prudent to recommend consuming a diet rich in both lutein and zeaxanthin to promote eye health.

Carotenoids are a family of compounds abundantly found in fruits, vegetables and green plants. They provide the bright yellow, orange and red colors to many of the fruits and vegetables that we eat. The vibrant colors in green leafy plants are masked by chlorophyll, but when the chlorophyll is bleached in the autumn, these carotenoids reveal themselves as the beautiful colors of fall foliage.

Of the more than 600 known carotenoids in nature, only about 20 are found in human plasma and tissues. The principal carotenoids found in humans include alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein, lycopene and zeaxanthin. Carotenoids have been of interest to the nutrition community because several of them (e.g., alpha-carotene, beta-carotene and beta-cryptoxanthin but not lutein, lycopene or zeaxanthin) can be converted to vitamin A by the body. Carotenoids also function as antioxidants that can protect cells from oxidative damage. Over the years, scientists have studied the link between oxidative damage to the body and the development of a number of chronic diseases.

People are living longer primarily due to improvements in public health, healthcare and food quality. Maintaining health and quality of life is a challenge for the aging population. Primary prevention efforts, including dietary modification, may help avoid the healthcare costs that are likely to be incurred from treating the increased incidence of chronic diseases. There is growing scientific evidence that lutein and zeaxanthin may benefit eye health. Recent epidemiological studies have associated higher intakes of these carotenoids with a reduced risk of age-related macular degeneration (AMD) and cataracts.

Lutein and zeaxanthin are found abundantly in dark green leafy vegetables and in lesser amounts among other colorful fruits and vegetables, such as corn, Brussels sprouts and peppers. While many sources of these carotenoids contain much more lutein than zeaxanthin, some commonly consumed foods such as orange juice, oranges and corn actually contain more zeaxanthin than lutein and may contribute significantly to overall zeaxanthin intake.(1,2)

Figure 1: Foods Known to be High in Lutein and Zeaxanthin(1) (>1 mg/100 g serving)

Image needs to be replaced when correct one is available!

Figure 3: Foods Known to be High in Zeaxanthin(1,2) (>100 mcg/100 g serving)

Fruits and vegetables are the primary sources of dietary carotenoids in the U.S. diet. Data from NCI’s 5-A-Day for Better Health Program indicate that in 1995 only 23% of U.S. adults were consuming the recommended minimum of 5 servings of fruits and vegetables per day.(3) The CDC’s Behavioral Risk Factor Surveillance System confirmed this finding and noted that while fruit and vegetable consumption increased by almost four percent between 1990 to1994, there was little change between 1994 and 1996, suggesting a plateau in fruit and vegetable intake levels after 1994.(4) The NCI survey found the median consumption of fruits and vegetables in 1996 was 3.5 servings per day for most adults and both surveys showed that certain segments of the adult population (e.g., current smokers, obese, inactive people, those with less education or those with lower incomes) are consuming fewer than the recommended number of servings per day.(3,4)

Determining the daily intake of lutein versus zeaxanthin is problematic. Until recently, the two carotenoids had been reported together because their chemical structures are similar. In addition, food composition databases contain limited data on lutein and zeaxanthin and these data are, at times, inconsistent.(5,6) Based on the ENVIRON recipe database, the 1994-1996 USDA Continuing Survey of Food Intake by Individuals (CSFII) and the 1998 USDA-NCI Carotenoid Database, the U.S. aggregate dietary intake shows an approximate 5:1 ratio of lutein to zeaxanthin with an average adult intake of lutein and zeaxanthin of approximately 943 and 176 mcg/day, respectively.(7) Other studies using food frequency questionnaires report average intakes of 2 to 4 mg/day total of lutein and zeaxanthin in various smaller populations.(5,6,8)

The risk of AMD increases with age and is higher among whites and women in the U.S.(9,10) It is interesting to note that a Roche-sponsored analysis of the CSFII database found that non-Hispanic whites tend to consume much less lutein and zeaxanthin than do non-Hispanic blacks, and women consistently consume less than men. The differences in intake due to age, race and sex are consistent with those reported by another study using the 1992 National Health Interview Survey (NHIS) data.(8)

Lutein and Zeaxanthin Intake by Age, CSFII 1994 - 1996 (7)

Two Assessments of Lutein and Zeaxanthin Intake by Gender and Race (mcg/day)(8,11)

The unique chemical structures of carotenoids determine their color as well as other physical and chemical properties. Carotenoids are long chain molecules (40 carbon atoms) with a series of centrally-located, conjugated double bonds. These conjugated double bonds contribute to the carotenoids’ vibrant colors and their ability to quench free radicals. Lutein and zeaxanthin, which are deep yellow in hue, have very similar chemical structures making it difficult to distinguish them analytically. For this reason, many studies have reported lutein and zeaxanthin as aggregate rather than individual values.(12,13) Lutein and zeaxanthin have the same number of double bonds; however, there’s a difference in the position of one of the double bonds. In lutein, the position of this double bond forms a more chemically reactive allylic hydroxyl end group versus an extra conjugated double bond in zeaxanthin. Conjugated double bonds are especially effective in quenching singlet oxygen. For this reason, zeaxanthin may be a better antioxidant than lutein and in vitro evidence supports this point.(14)

Xanthophylls contain carbon, hydrogen and oxygen, including the oxygen-containing hydroxyl groups that make them more polar in nature. Lutein and zeaxanthin are thought to orient themselves so that they span cell membranes with their lipophilic hydrocarbon chain inside the lipid bilayer and their hydrophilic hydroxyl groups emerging on either side.(15) In contrast, lycopene and beta-carotene tend to be situated on the periphery of the membrane. This orientation maximizes lutein and zeaxanthin’s contact with the highly oxidizable cell membrane lipids while also increasing membrane stability.

An antioxidant is a molecule that protects against damaging reactive oxygen species (ROS). Singlet oxygen and peroxyl radicals are two ROS that arise from normal reactions in the body or exposure to cigarette smoke, air pollutants, radiation, certain drugs and environmental toxins. Either species may react with DNA, protein or lipids and impair their physiological function.(16) It is believed that these reactions with ROS can be the initial events in the pathogenesis of diseases such as cancer, cardiovascular disease and age-related macular degeneration.(17) Carotenoids deactivate singlet oxygen by physical or chemical quenching. The efficiency of quenching depends upon such molecular properties of the molecule as the number of double bonds, the type of end groups or other chemical groups found in carotenoids.(18)

Vision is the process of converting light into image signals that the brain can understand. The macula, a tiny area at the center of the retina, is a collection of photoreceptor cells, mostly cone cells, responsible for turning light into color images with fine detail in the brain. The macula very selectively concentrates lutein and zeaxanthin into a layer of retinal tissue that overlies this area of the eye. Lutein and zeaxanthin are specifically distributed within the macula, showing remarkably high concentrations of meso-zeaxanthin and zeaxanthin relative to lutein in the inner retina.(19-22) Early anatomists referred to this area as the macula lutea or “yellow spot” because of the deep yellow hue of lutein and zeaxanthin. Among people in the U.S., alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein and lycopene are the primary carotenoids found in plasma with zeaxanthin present at lower levels.(23,24) By comparison, the unique concentration of lutein and zeaxanthin in the eye is remarkable. It is hypothesized that this could be a function of the more polar properties of xanthophylls.

The selectivity of lutein and zeaxanthin in the eye and their lack of pro-vitamin A activity suggest they could play a novel role in eye health. However, their biologic function in the eye is not fully understood. Two functions have been proposed: their role as antioxidants and the absorption of near-to-UV blue light.

The yellow carotenoids lutein and zeaxanthin specifically absorb near-to-UV blue light (blue being the complementary color to yellow). Blue light, especially visible blue light wavelengths just above the UV spectrum, is the highest energy and potentially most damaging wavelength of light that reaches the retina.(25) The way the retina is organized, light must first pass through the highest concentrations of lutein and zeaxanthin (in Henle’s fiber layer)(26) before reaching the sensitive rod and cone cells.

As antioxidants, lutein and zeaxanthin can also inhibit the formation of damaging free radicals by quenching singlet oxygen. Two circumstances that can produce free radicals in a tissue — high metabolic activity and the interaction of energy with tissue — both exist in the macula. The metabolic processes that convert light energy into brain signals are very active in the macula, while at the same time, the lens is tightly focusing light on this small area of tissue. The parts of the retina most susceptible to oxidative damage are the outer segments of the rod cells. This area is rich in polyunsaturated fatty acids that are readily oxidized. Recent studies indicate that lutein and zeaxanthin are found in significant quantities within these outer segments.(27,28) In addition, in vitro evidence suggests that zeaxanthin’s extra conjugated double bond may make it a better antioxidant than lutein.(14)

The relative importance of the light absorption versus the antioxidant properties of lutein and zeaxanthin may be age dependent. For example, lutein and zeaxanthin’s near-to-UV blue light filtering properties may be more important in the younger years when the lens is clear and damaging light can more easily reach the eye. As we grow older, the lens naturally becomes more yellow (brunescence)(29) and allows less near-to-UV blue light to reach the retina. Likewise, the antioxidant properties of lutein and zeaxanthin may be relatively more important later in life when the body produces far more ROS.

Age-related macular degeneration (AMD) is the leading cause of legal blindness among elderly in the U.S. and other developed countries and a leading cause of vision impairment in general.(30,31) Based on data from the Third National Health and Nutrition Examination Survey (NHANES III), 9.2% of people in the U.S. over age 40 show some early form of AMD while 0.4% have evidence of late AMD.(10) For the U.S. population in 1999, this would include more than 10 million people with early-stage AMD and 450,000 with late-stage AMD.(32) Estimates of prevalence in the U.S. range from 2% to 10% among people 43 to 54 years of age to 15% to 30% among people over the age of 75, depending on the diagnostic criteria used.(10,33,34) In 1990-1991, one half of the new cases of legal blindness reported in England and Wales were attributed to AMD.(35)

The risk of AMD increases with age and some data suggest that women have a slightly higher risk than men.(9) Other inherent risk factors include lighter iris color and race (i.e., Caucasians over 60 years old have a higher AMD risk than do African-Americans of the same age).(10) Behaviors such as smoking and the amount of sunlight exposure to the eyes may also increase AMD risk.(36,37)

The two common types of AMD are dry and wet.(38) The “dry” form accounts for 90% of all cases of AMD and is characterized by age-associated thinning of the tissues of the macula. Vision loss from “dry” macular degeneration is irreversible and currently untreatable.(30) The exact cause of the breakdown of cells in this region is not yet known.

Dry AMD can develop into a more severe form if blood vessels from the retina begin to grow into the macula. This form, called “wet” AMD, can rapidly cause blindness due to the leakage of blood into the vitreous humor, the normally clear fluid between the lens and the retina. New laser treatments only temporarily retard or halt the damage.(38) Both the severity and irreversibility of AMD have prompted research on how to slow or prevent its progression.

There is indirect evidence of an association between low amounts of lutein and zeaxanthin in the eye (macular pigment density) and the risk of AMD. One autopsy study found that the eyes of people with AMD contained significantly less lutein and zeaxanthin than the eyes of those without AMD.(39) There are also parallels in several of the key risk factors for both AMD and low macular pigment density, including advanced age(40), female gender(41), smoking(42) and lighter iris color.(43)

Macular pigment density is ultimately dependent on dietary intake of lutein and zeaxanthin. Studies indicate that most people show an increase in macular pigment density when they consume large quantities of lutein or zeaxanthin from food. Further research is needed to understand why some of the subjects did not respond to the increased dietary intake. In addition, the limited data available on supplementation with purified lutein indicate that macular pigment density can likewise be increased by these means. Studies using diet or supplements to increase macular pigment density have used:

• Spinach as a lutein-rich food (60 g/day)(44)
• Spinach (60 g/day) as a lutein-rich food plus corn (150 g/day)
• as a zeaxanthin-rich food(44)
• High-dose purified lutein dietary supplement (30 or 10 mg/day)(45-47)
• Low-dose lutein supplement as bilberry extract (2.4 mg/day)(48)

One high-dose purified lutein dietary supplement study showed that after supplementation was discontinued, macular pigment density remained elevated for months after plasma concentrations returned to their original levels.(45) Thus, it is clear that the eye can accumulate and retain lutein and zeaxanthin from food or dietary supplement sources.

Two major epidemiological studies have examined the correlation of lutein and zeaxanthin intake with AMD risk. The Eye Disease Case-Control Study (EDCC) examined 391 patients with wet AMD and 578 controls. The first report from this study found that AMD risk was significantly lower with increasing serum concentrations of lutein and zeaxanthin.(49) In the second report, subjects in the highest quintile of lutein and zeaxanthin intake (5757 mcg/day) had a significantly lower AMD risk compared to those with the lowest quintile of intake (1211 mcg/day).(50) As confirmation of the dietary findings, more frequent consumption of spinach or collard greens (among the richest sources of lutein and zeaxanthin in the diet) was also associated with lower AMD risk.(50) The correlation between lutein and zeaxanthin and AMD is remarkably consistent in the EDCC Study across serum levels, total intakes and consumption of specific rich food sources. In contrast, the Beaver Dam Eye Study examined 1,968 subjects, including 314 individuals with early-stage AMD and 30 with late-stage AMD and found no significant difference in AMD risk between the highest and lowest quintiles of lutein and zeaxanthin intake (864 vs. 155 mcg/1000 kcal/day).(51)

The different results reported between the Beaver Dam Eye Study and Eye Disease Case Control Study are not necessarily inconsistent. One possible explanation may be the different intakes of lutein and zeaxanthin reported within the two populations. The highest quintile of lutein and zeaxanthin intake in the Beaver Dam Eye Study was close to the median intake in the EDCC Study (an estimated 1728 mcg/day (based on a 2000 kcal/d diet) vs. 5757 mcg/day). Only the highest quintile of intake in the EDCC Study had a statistically significant correlation with AMD; therefore, the Beaver Dam population may not have consumed enough lutein and zeaxanthin to significantly reduce their risk. Also, the EDCC Study was comprised solely of people with the severe form of wet AMD while the cases in the Beaver Dam Eye Study were mostly in the early stages of the disease.

Less attention has been focused on the potential role of lutein and zeaxanthin in cataract risk. In fact, lutein and zeaxanthin are the only carotenoids generally detectable in the human lens(52), although at levels considerably lower than in the macula.

Cataracts are opaque or translucent areas in the lens that can cause blurry vision and are formed from the breakdown of proteins. Cataracts are the leading cause of vision impairment in the U.S. and other developed countries(30) and the leading cause of blindness in other parts of the world.(53) Blindness from cataracts is more prevalent in countries where people do not have ready access to cataract extractions and other expensive surgical procedures. In 1994, 2 million cataract extraction surgeries were performed in the U.S. making it the most common surgical procedure performed.(54) There were 1.6 million cataract patients in Japan in 1996.(55)

The prevalence of cataracts in the U.S. increases significantly with age, from only 5% to 10% of people under the age of 65 to 30% to 40% of people 75 to 85 years old.(33,56) Women may also have a slightly higher risk of cataracts than do men.(33,56) Other risk factors for cataracts include: smoking(36), amount of sunlight exposure to the eye(37), diabetes(57) and inflammation.(58) Cataracts can be treated only by surgically replacing the natural lens.

Three recent epidemiological trials have examined the correlation between dietary lutein and zeaxanthin and the risk of cataracts or cataract surgery.(59-61) One study analyzed prospective follow-up data from the Nurse’s Health Study and found a statistically significant trend toward reduced risk of cataract extraction surgery with increasing intakes of lutein and zeaxanthin. The reduction in risk reached significance only in the fourth quintile of intake (with an average intake of 6.0 mg lutein and zeaxanthin per day).(59)

Global Distribution of Blindness and Blindness Related to Cataract, by Region(53)

Another epidemiological study conducted a similar analysis of data from the Health Professional’s Follow-up Study and also found a statistically significant trend toward lower risk of cataract extraction with higher lutein and zeaxanthin intake, though individual quintiles did not reach statistical significance. The average intake in the highest quintile was 6.9 mg lutein and zeaxanthin per day.(60) The 5-year longitudinal follow-up of the Beaver Dam Eye Study also found that subjects in the highest quintile of lutein and zeaxanthin intake had a significantly lower risk of cataracts compared to those with the lowest intakes.(61) These studies are notable because some previous studies that have looked at this question have not consistently found statistically significant results.

The mechanism of this effect is unclear, but one observational study found that lower macular pigment density is correlated with higher lens optical density among older adults (48 to 72 years old).(62) Higher lens optical density is thought to be a good predictor of cataract risk.

Different epidemiological studies have consistently reported an association between intakes of lutein and zeaxanthin around 6 mg per day and a decreased risk of AMD and cataracts. Comparing the typical intakes reported by food surveys to the findings of epidemiological studies, there appears to be a dietary gap of at least 2 to 4 mg/day. Whether lutein or zeaxanthin is more important for eye health is unclear at this time; however, in vitro evidence suggests that zeaxanthin may be a better antioxidant than lutein. In the mean time, it seems prudent to recommend consuming a diet rich in both lutein and zeaxanthin to promote eye health.

Odds Ratio of AMD Risk Across Quintiles of Lutein and Zeaxanthin Intake

Age-related diseases are a growing public health concern because a significant portion of our population is living longer than ever before. As a result, the number of new cases of certain chronic diseases, including AMD and cataracts, is increasing. Preventing or inhibiting their progression is important because of the debilitating nature of vision loss and high healthcare costs associated with AMD and cataracts. The scientific data describing the beneficial role of nutrients in age-related eye disease are rapidly evolving. Several observational epidemiological studies have shown a correlation between dietary lutein and zeaxanthin intake and a reduced risk of AMD or cataracts. Lutein and zeaxanthin, selectively concentrated in the macula and to a lesser extent in the lens, possess physical and chemical properties that are biologically well suited to protect these regions in the eye. Based on typical intake in the general population and reported intakes of lutein and zeaxanthin associated with reduced risk, people may need to increase consumption of these carotenoids to cover a potential dietary gap of at least 2 to 4 mg/day. In addition to good nutrition and regular eye examinations, other lifestyle factors, such as smoking cessation and avoidance of excessive sunlight exposure, are important to help reduce the risk of AMD and cataracts.

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Association for Macular Diseases
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