Carotenoids are composed of a 40-carbon polyene chain capped with cyclic end groups. Some are precursors for vitamin A synthesis. They are not made by the body and must be supplied from food or supplements. (1) Their concentration in blood is associated with a variety of positive health outcomes, yet over 95 percent of the US falls short on the carotenoid health index. (2)
Lutein and zeaxanthin are yellow-orange carotenoids—collectively called xanthophylls —that contain oxygen in both cyclic end groups, making them yellower, more water soluble, better blue light filters, and directs them to certain tissues, yet they do not have provitamin A activity. (3)
Dark green leafy vegetables are excellent sources. Other good sources include squash, peas, corn, pumpkin, peppers, kiwi, Brussels sprouts and broccoli. Eggs and oranges contain small but significant amounts of lutein and zeaxnathin. (4,5) Nutritional experts recommend up to nine servings of fruits and vegetables daily for optimal health, yet only a third of US adults meet this standard. (6) A recent decline in lutein intake in the US may have public health implications. (7) Most could benefit from lutein and zeaxanthin supplementation.
Plants synthesize one form of zeaxanthin, namely all-E, 3R,3’R-zeaxanthin (RR-zeaxanthin), which occurs with lutein in a 5:1 ratio (L:Z). (8,9,10,11) Another important stereoisomer found in the eye is all-E-3R,3’S-meso-zeaxanthin (meso-zeaxanthin), which is isolated from marine organisms. In the retina, meso-zeaxanthin is made from lutein. (12,13) Lutein is more prevalent in the diet and the body, but RR-zeaxanthin (3) and meso-zeaxanthin (14) contain extra conjugated double bonds, making them more potent antioxidants. (15,16) However, lutein filters blue light better than zeaxanthin, (17) though mezo-zeaxanthin has broader-range, blue light-filtering capacity. (14) This multi-functional trifecta works to protect both plants and animals from damaging sun exposure.
Some xanthophylls are found esterified with fatty acids (mostly in fruit), and some in free form (mostly in green vegetables). Both are well absorbed in the intestine, especially in conjunction with a fatty meal. (18) Xanthophylls are de-esterified after absorption and escorted largely via HDL-cholesterol in blood. (19) Esters function to protect carotenoids, which are inherently unstable. Fortunately, food technologists have devised ways to stabilize lutein and zeaxanthin and other reactive antioxidants. Dietary supplements contain both esterified and free forms of lutein and zeaxanthin.
The eyes have it
Lutein and zeaxanthin is present in the eye, skin, blood, brain and other human tissues. A wealth of clinical epidemiological, animal and in vitro studies supports the role of lutein and zeaxanthin in protecting organs exposed to excessive sunlight. (20) Their selective placement in ocular tissue (concentrated ~1000-fold over that in blood) forms the macular pigment in the retina. (21) The macular pigment protects against the photo-oxidative effects of ultraviolet (UV) radiation and high-energy blue light. (22,23) In the macula fovea, the ratio of lutein to RR-zeaxanthin to mesozeaxanthin is roughly 1:1:1, while lutein dominates in the peripheral retina. (24) Supplementation with lutein and zeaxanthin (25,26,27) or meso-zeaxanthin (13,28) enriches the macular pigment, which serve like internal sunglasses to preserve central vision.
Lutein and zeaxanthin are the only carotenoids in the retina and lens of the eye, where they help protect against oxidative stress and damage from solar radiation. (29,30,15) Supplementation with lutein and zeaxanthin reduced blue light reaching the retina by 30-40 percent and limited retinal damage. (31,32) Lutein and zeaxanthin function by blocking penetration of oxygen into membranes and preventing peroxidation of membrane fats. (33,34) Lutein and zeaxanthin can neutralize most free radical species, including singlet oxygen, superoxide, hydroxyl and peroxynitrite radicals and stimulate antioxidant enzymes (i.e., catalase, superoxide dismutase, and glutathione peroxidase. (35,36,15,16) They are more potent than alpha-tocopherol for protecting the lens against UVB insult. (37) Both zeaxanthins are bound to a pi isoform of glutathione-S-transferase in the macula (GSTP1), which protects against their degradation. (38)
Macular pigment helps prevent age-related macular degeneration (AMD), characterized by progressive loss of central vision, and the leading cause of blindness in western countries, affecting 25-30 million people worldwide. (39) With an estimated global total cost in 2010 of $907 billion, it is expected to triple in incidence by 2053. Nearly 30 percent of Americans over the age of 75 have some degree of AMD, and seven percent have late stage disease. (40) People with vision loss experience a reduced quality of life, greater difficulty with daily living and social dependence, higher rates of clinical depression, double the risk of premature death, increased risk of falls and related hip fractures, and premature admission to nursing homes. (41) Recent reviews concluded that supplementation could prevent vision loss in more than 300,000 people in the US at risk, saving $3.6 billion over five years by helping seniors avoid dependency. (42,39)
Risks associated with AMD are divided into modifiable and fixed factors. (43) Besides age, fixed risk factors include being Caucasian, female, lighter eye color, and certain genetic polymorphisms (e.g., complement factors H and B). Higher prevalence in women may be related to having 38 percent less macular pigment than men. Once uncommon in Asia, the recent influx of western culture has increased AMD dramatically to levels approaching those in the West. (44) Modifiable factors include smoking, drugs, hypertension, obesity and diet. Clearly, lifestyle has a profound impact on visual health. In 2010, the World Health Organization reported that 80 percent of all visual impairment can be avoided or cured. (45)
High lutein and zeaxanthin levels in the retina were shown to protect photoreceptor cells against light-induced damage. (46) Conversely, low lutein and zeaxanthin in the macula is associated with higher AMD risk. (47) An epidemiological study in 1994 set the bar for lutein, showing that the relative risk for AMD is reduced significantly at roughly 6 mg intake. (48) The highest lutein and zeaxanthin intake was associated with a 65 percent less likelihood of neovascular AMD compared to the lowest intake. (49) A recent meta-analysis concluded that dietary lutein and zeaxanthin could be protective against late-onset AMD. (50) Intervention studies confirmed that lutein and zeaxanthin increased macular pigment and helped improve visual and macular function in AMD patients over a 6-12 month period. (51,52,26) Three controlled clinical trials employing various combinations of antioxidants and carotenoids also showed vision protection. (43) The National Eye Institute’s Age-Related Eye Disease Study (AREDS) is now focusing on lutein and zeaxanthin and omega-3 fatty acids in a multicenter trial. (53)
Cataract, or clouding of the lens, is another age-related eye disease that contributes significantly to vision loss. Cataracts cause nearly 50 percent (30-50 million cases) of all blindness worldwide, and affect over half of all Americans by age 80. (54) Good nutrition, including green leafy vegetables, fruit and antioxidants, help prevent cataracts. (7) Reduced risk was also linked to high intakes and serum levels of lutein and zeaxanthin, from studies involving over 100,000 subjects. (55,56,57,54,58,59,60,61) As little as 2.5 mg lutein daily lowers cataract risk. (62) The close relationship between lens clarity and macular pigment density implies a lutein and zeaxanthin connection. (63,64) Women with the highest (avg, 6.7 mg/day) lutein and zeaxanthin intake had significantly lower risk of cataract compared to women with the lowest (avg, 1.2 mg/day) intake. (65) Human clinical trials confirming the link between cataract and lutein and zeaxanthin are forthcoming in the AREDS2 trial. (53)
Can carotenoids actually help?
It’s one thing to prevent disease and another to improve vision. (66) Long-term lutein and zeaxanthin supplementation in humans showed improvements in eyesight, including visual performance and acuity (67,52), reduced glare sensitivity, (68) enhanced contrast sensitivity, (69) improved vision in dim light, (70) and reduced chromatic blur. (71) Sixty elderly veterans, who took zeaxanthin (8 mg/day) for 12 months, showed greater recognition of detail, improved 1.5 lines on the eye chart, experienced disappearance of blind spots, and improved ability to drive at night. (72) Optimal lutein and zeaxanthin dosing may actually help reverse the aging process.
Skin is also subject to sun damage. Solar radiation, paired with environmental pollutants, causes oxidative and genetic changes that can lead to photoaging and cancer. A lifetime of exposure causes wrinkles, dryness, sagging, discoloration and age spots. Antioxidants (i.e., ascorbic acid, tocopherol, alpha-lipoic acid, melatonin) are a promising therapeutic approach to counteract photoaging in humans. (20) Carotenoids are also deposited in the skin, where they protect against excessive sun exposure. A National Cancer Institute study showed that subjects in high versus low strata of vitamin D, lutein and total carotenoid intake had significantly reduced risk for melanoma. (73) In animals, higher lutein and zeaxanthin intakes for longer periods produced greater skin accumulation, which helped defend against sunburn. (74,75) Human subjects randomized to oral and/or topical lutein and zeaxanthin showed enhanced elasticity, skin hydration, and sunburn protection lutein and zeaxanthin work like sunscreen to protect against the elements. (76)
Dosing and safety
Lutein is found in supplements from 250 mcg to 20 mg per serving, and the recommended dose is 6-20 mg/day. While 6 mg reduced the risk of age-related disease, 20 mg may be optimal for visual health. However, numerous servings of fruits and vegetables daily are required to maintain a sufficient supply of lutein and zeaxanthin in the body. Long-term supplementation with xanthophylls can increase plasma concentrations significantly. (1) The elderly, and those prone to severe AMD, have less xanthophyll in their eyes, and may have trouble converting lutein to meso-zeaxanthin in the retina. (77,46) In these circumstances, meso-zeaxanthin could be considered conditionally essential. (78) Certainly, there is a substantial high-risk group that may benefit from meso-zeaxanthin supplementation. (28,79)
High-dose meso-zeaxanthin has been shown to elevate serum levels and support vision health. (28,80) At the molecular level, meso-zeaxanthin is more intimately associated with photoreceptors than the other xanthophylls, and may be the ultimate deterrent to free radical damage. (46) Typical diets do not contain meso-zeaxanthin, which must be either supplemented, or converted from lutein in the macula. (5)
Meso-zeaxanthin may also protect other organs, when taken in sufficient quantities. It is protective against drug-induced nephrotoxicity and hepatotoxicity in rodents. (81,82) Rats fed meso-zeaxanthin and treated with a carcinogen (NDEA) showed reduced tumor incidence. (83) Meso-zeaxanthin is obviously part of the body’s defense against disease. (26)
The three xanthophylls found in the eye differ slightly in structure, but are not redundant with regard to function. They appear to possess different anti-oxidative and photoprotective properties. Their high levels in the macula reflect their differential protective effects on vision. Zeaxanthin has a stabilizing effect on cell membranes, and is more protective during prolonged UV exposure. (34) Meso-zeaxanthin may be an even better antioxidant than RR-zeaxanthin in preventing oxidation of membrane lipids.(38) Long-term supplementation with all three xanthophylls (10.6 mg mesozeaxanthin, 5.9 mg lutein, 1.2 mg zeaxanthin) increased macular pigment and serum concentrations significantly in humans, with no adverse effects. (28) The triple antioxidant combination of xanthophylls contributes to healthy vision, but also to skin, heart and brain health, to provide broad-spectrum anti-oxidative protection for an aging population. (84,11)
A life without vision is frankly unimaginable. Nevertheless, vision problems like AMD and cataracts are accepted as a consequence of old age. Scientists have repeatedly demonstrated the protective effects of xanthophylls on the eyes, but most people do not share this knowledge. Though diets rich in fruits, vegetables and eggs increase tissue levels of lutein and zeaxanthin, it may be difficult to achieve optimal amounts through dietary sources alone. Supplementing with lutein and zeaxanthin may be the best way to ensure protective levels of these critical nutrients.
Carotenoids for more than vision
Cardiovascular disease is the leading killer in the western world, and another process fueled by oxidative stress and inflammation. Oxidation of LDL-cholesterol (oxLDL) is involved in the initiation and progression of atherosclerosis, and is a key biomarker and validated therapeutic target for atherosclerosis. (1,2,3) OxLDL triggers the pro-inflammatory response in arterial walls. (4) By neutralizing peroxynitrite free radicals and retarding oxLDL in vivo, xanthophylls and other carotenoids may protect arteries. (5,6) In mice on high-fat diets, lutein and zeaxanthin lowered oxLDL by 78 percent, and reduced lesion size by 44 percent. (7) In humans, zeaxanthin correlates negatively with carotid artery stiffness, which was 80 percent greater in people at the lowest vs. highest end of serum lutein and zeaxanthin levels. (8) The data suggest that lutein and zeaxanthin could play a key role in reducing heart disease and its enormous burden on health care.
Cognitive health can be supported with antioxidants. While only one-sixth of the carotenoids content in the diet, and one-third of that found in serum, lutein and zeaxanthin comprise nearly 75 percent of carotenoids found in brain tissue. Lutein and zeaxanthin is concentrated in regions of the brain involving learning, memory, cognition, vision, hearing, and speech. (9) Macular pigment density is a surrogate marker for lutein and zeaxanthin levels in the brain. (10) Just as vegetables can slow cognitive decline, (11,12) higher brain lutein levels are linked to better cognition. (13) Cognitive impairment in the elderly is also linked to low blood zeaxanthin. (14) A controlled clinical trial in elderly women employing lutein and zeaxanthin and omega-3 (DHA) showed improved verbal fluency with either nutrient, and improved memory with the combination. (15) Lutein and zeaxanthin inhibits peroxidation of DHA, which makes up a major part of brain matter. (16,17) Lutein and omega-3 may also be complementary in prevention of AMD, and are recent additions to infant formula for brain and eye health. (18,13)
Cancer?Natural carotenoids are also anti-carcinogenic, again by virtue of their antioxidant capacity. (19) Low blood levels of carotenoids are associated with breast and colon cancer. (20,21) Conversely, lutein and zeaxanthin may help reduce the risk of cancer. (22,19) Inhabitants of the island of Fiji have some of the lowest cancer rates in the world, and their lutein intake is unusually high (18-23 mg/day), with no apparent side effects. (23) Xanthophylls have demonstrated to be remarkably safe for long-term consumption at very high doses. (24,24,26,27,28,29) Both free lutein and lutein esters are GRAS-affirmed, and have been available in Europe and the US for many years.
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