The glucose and insulin responses after mango intake were also moderated, compared to ingesting of an isocaloric amount of white bread. While the effects of mango intake on microvascular function were not as significant as the response from other whole foods, other measures of cardiovascular health, as well as glucoregulatory benefits, warrant further study.Epidemiological studies suggest that diets rich in carotenoids can be beneficial for vision, heart, bone health, cognitive performance, and cancer prevention. The current review focuses on the potential role of the xanthophyll carotenoids lutein and zeaxanthin in eye health, specifically their potential role in reducing risk of age-related macular degeneration . We review the absorption, distribution, and metabolism of L and Z, and the current dietary recommendations for these carotenoids, then speculate about their putative role in maternal and infant health. Lastly, we discuss the potential value of goji berry within the diet as a food with the highest known amount of Z. Carotenoids contribute to the bright red, orange, and yellow color in plants. These fat-soluble phytochemicals are classified into two categories: carotenes, dutch buckets system which include only hydrocarbons, and xanthophylls that also contain oxygen. While some dietary carotenoids serve as vitamin A precursors most of the approximately 100 carotenoids found in plants do not. Among the carotenoids devoid of vitamin A activity are L and Z, along with meso-zeaxanthin , a stereoisomeric metabolite of L.
Absorption involves enterocyte uptake by CD36, scavenger receptor class B type I , and Niemann-Pick C1-like transporter 1 at the apical membrane. Xanthophylls are then secreted through the basolateral membrane of the enterocyte, mainly by ATP binding cassette A1 and carried by lipoproteins to target tissues. SR-B1, SR-B2, and CD36 transport L and Z into the tissues. Steroidogenic acute regulatory domain protein 3 has been identified as a binding protein for L in the retina, and glutathione S-transferase pi isoform for Z. Lutein, Z, and meso-Z impart a distinctive yellow color to the fovea of primates – the specialized central area of the macular region of the retina that is rich in cone photoreceptors and optimized for high-acuity central color vision. The compounds have a maximal absorbance at a wavelength near 460 nm and are most concentrated in the inner and outer plexiform layers, which consists primarily of axonal connections between the retinal layers. Their combined density is greatest in the center of the macula and decreases with increasing retinal eccentricity. In the central fovea, the concentration of Z and meso-Z is higher than L at a ratio of 2.4:1. Lutein is most abundant in the peripheral macula, with a Z + meso-Z to L ratio of 1:2 when measured by highperformance liquid charomatography. However, a newer technique, confocal resonance Raman microscopy suggests that the Z + meso-Z to L ratio is as high as 9:1 at the central fovea. Protection from blue light is critical for eye health. Compared to longer wavelengths of visible light, short blue wavelengths are higher in energy and generate reactive oxygen species .
Zeaxanthin can provide stronger oxidant defense than L during photooxidation, while lutein has a greater capacity to absorb short wavelength light irradiation in lipid membranes.20 Compared to other carotenoids , L and Z are more effective in scavenging ROS and can also reduce phospholipid peroxidation. The photoreceptor-retinal pigment epithelium complex in the outer retina is particularly susceptible to ROS damage due to its high polyunsaturated lipid content . Quenching of singlet oxygen appeared best when L, Z, and meso-Z were mixed in equal ratios rather than separately when assessed in an eye tissue model, suggesting some synergy between the these macular pigments in their antioxidant properties. The most common method to quantify xanthophylls in the retina is to assess macular pigment optical density . This parameter is measured through techniques such as heterochromatic flicker photometry , a non-invasive psychophysical technique, fundus reflectometry, resonance Raman spectroscopy, or autofluorescence imaging. The MPOD index is associated with plasma levels of L and Z, and has been used to assess the risk for AMD. However, some studies report no correlation between MPOD and risk of AMD, which suggests that other ocular measures may be useful to obtain a more complete profile of AMD risk. In human donor eyes, the amount of L and Z was inversely associated with AMD. Supplementation of L, Z, and meso-Z have been shown to significantly increase MPOD in both healthy individuals and patients diagnosed with AMD. However, studies using foods rich in L and Z have produced inconsistent results, which may be due to the relatively modest amounts of these carotenoids in foods compared to supplements. Importantly, the plasma concentration of L and Z has been more strongly associated with MPOD than the correlation between MPOD and dietary intake.
Age-related macular degeneration is the third leading cause of blindness worldwide after uncorrected refractive errors and cataracts. An estimated 288 million people worldwide are projected to suffer from AMD by 2040. In the United States, the prevalence of early-stage AMD was 9.1 million in 2010, and this number is projected to increase to 17.8 million by 2050. AMD is characterized by a gradual loss of eyesight from the central visual field.40 Although the exact etiology of AMD is not clear, common pathologic progress includes oxidative stress, lipofuscin toxicity, lipid accumulation, immune dysregulation, and choroidal hyperperfusion. Age-related processes such as a decrease in retinal neuronal elements, alterations in the size and shape of RPE cells, and thickening of Bruch’s membrane alsoparticipate in the pathology of AMD. Damage to mitochondria in RPE cells has also been suggested to play a role. Dry AMD, also termed non-exudative AMD, involves the formation of drusen, which are mainly lipid and protein deposits that accumulate between the RPE and Bruch’s membrane in the macula. In contrast, wet AMD, also termed exudative or neovascular AMD, is a consequence of abnormal blood vessel formation arising from the choroid, known as choroidal neovascularization . Clinically, AMD is classified as early or intermediate stage based on the size and number of drusen, as well as presence of pigmentary changes.46 The AMD is considered late or advanced stage in the presence of CNV, where fluid accumulation may result in damage to the neurosensory retina and fibrous scarring, or geographic atrophy , where loss of the RPE result in damage to overlying photoreceptors and underlying choriocapillaris causing irreversible vision loss. The main risk factors for AMD are aging and smoking, although some studies have shown no difference in MPOD between healthy older individuals and healthy young. Other risk factors may include race, obesity, previous cataract surgery, presence of cardiovascular disease, and hypertension. According to the U.S. National Institutes of Health, the prevalence of AMD is highest among Caucasians as compared to other races, and higher in females than in males. Genetic factors are also associated with AMD, with several high-risk single-nucleotide polymorphisms identified from genome wide association studies. The strongest risk variants include the Y402H variant of complement factor H gene as well as those in the age-related maculopathy susceptibility 2 locus. Whether the color of the iris or sunlight exposure are related to the risk of AMD is still being explored. Dietary interventions using L- and Z-rich foods have generated inconsistent results regarding the risk of AMD. In a cohort study that assessed dietary carotenoid consumption among individuals without AMD at baseline over more than 20 years, increased predicted plasma carotenoid score of L, Z, β-carotene, α-carotene and β-cryptoxanthin were associated with a lower risk of advanced, but not early or intermediate AMD. Similarly, dutch buckets a meta-analysis of six longitudinal cohort studies found that the dietary intake of L and Z significantly reduced the risk of GA by 26% and CNV by 32%, with no apparent impact on early stages. Another metaanalysis concluded that supplementation with L, Z, and meso-Z significantly increased MPOD levels in both AMD patients and healthy individuals in a dose-response manner.70 However, whether the improvement in MPOD could be sustained after L and Z supplementation is discontinued remains unclear. The Age-Related Eye Disease Study was a multi-center study that assessed the efficacy of a dietary anti-oxidant supplements on subjects who are 50 to 80 years old, with and without AMD or cataracts, for more than seven years. The initial study used a formula containing 15 mg of β-carotene, 500 mg of vitamin C, 400 IU of vitamin E, with or without 80 mg of zinc and 2 mg of copper.
Lutein and Z were not included because the scientific evidence to include these two carotenoids was not yet clear. Compared to the placebo group, participants consuming the antioxidants plus zinc and copper showed a 28% reduction in progression to advanced AMD after five years. Subsequently, the AREDS2 was conducted with a newer formulation that included vitamins C and E, either 10 mg of L plus 2 mg of Z, and either 350 mg of docosahexaenoic acid plus 650 mg of eicosapentaenoic acid , or both. Patients were also given either 25 or 80 mg of zinc, each with 2 mg of copper. Beta-carotene was eliminated from the supplement due to a potential increased risk of lung cancer among smokers, who were already at high risk for AMD. Primary analyses of the AREDS2 formula found no additional benefit in reducing progression to advanced AMD, in comparison to the original AREDS formula. However, in a secondary analysis of combined data from AREDS and AREDS2, the progression risk in those receiving L and Z was significantly lower than in other groups. Neither formulation reduced the progression from early to intermediate AMD. These clinical trials did not monitor the MPOD status over time, thus limiting our understanding of the link between L and Z intake, retinal accumulation, and AMD development or progression. To date, the AREDS2 formula remains the standard of care for management of patients with intermediate AMD.The accumulation of L and Z in the macula starts in utero in primates and plays a critical role in visual development and maturation later in life. Lutein and Z were detected as early as 20 weeks of gestation in macular tissue from human fetuses inspected at autopsy.15 Unlike fully matured human eyes, L is the dominant macular pigment in infants under the age of two regardless of eccentricities. The retina is less mature at birth compared to other eye structures, with complete differentiation requiring four to five years. The maturation of the macula is associated with a change in the L:Z ratio over the first four years of life, which correlates with the development of cone photoreceptors. Studies in premature infants illustrate the importance of these L and Z in visual development. In preterm human neonates, extremely low levels of serum L and Z are associated with an undetectable MPOD.79 When a carotenoid-fortified formula containing 211 µg/L of combined L and Z was given to preterm infants, plasma carotenoid levels became comparable to breastfed preterm infants, and were significantly higher than those fed formulas without L or Z fortification. In a small study that monitored the concentration of L and Z in various infant formulas and breast milk from different mothers, Z was not detected in any formula but was present in all breast milk samples, while L was consistently higher in breast milk. Serum L was also noted to be six-fold higher in breastfed infants compared to those fed with a formula devoid of L. Further studies are warranted to assess the prospective effects of L- and Z-fortified formula on MPOD and visual development in infants as they enter adulthood. Lutein and Z may also protect against oxidative damage in premature infants, especially those with retinopathy of prematurity . Premature infants with ROP usually have poor visual acuity, even after laser treatment or intravitreal injection of anti-vascular endothelial growth factor agents. In a model of oxygen-induced retinopathy, mouse pups given L showed less vessel leakage and lower avascular area compared to those given a L-free control. The authors suggested that the anti-oxidant properties of L may have contributed to these results, although ROS levels were not measured. Studies that investigate L and Z supplementation in ROP babies have produced inconsistent results.