Lutein and Zeaxanthin Supplementation Improves Dynamic Visual and Cognitive Performance in Children: A Randomized, Double-Blind, Parallel, Placebo-Controlled Study.

INTRODUCTION: Supplementation with dietary neuro-pigments lutein (L) and zeaxanthin (Z) has been shown to improve many aspects of visual and cognitive function in adults. In this study, we tested whether a similar intervention could improve such outcomes in preadolescent children. METHODS: Sixty children (age range 5-12 years) were randomized in a 2:1 ratio in this double-blind, placebo-controlled clinical trial. Subjects were supplemented with gummies containing either a combination of 10 mg lutein and 2 mg zeaxanthin (LZ) or placebo for 180 days. Macular pigment optical density (MPOD) was the primary endpoint. The secondary endpoints included serum levels of L and Z, and brain-derived neurotrophic factor (BDNF), critical flicker fusion (CFF), eye strain and fatigue using visual analogue scales (VAS), Children's Sleep Habits Questionnaire-Abbreviated (CSHQ-A), and Creyos Health cognitive domains like attention, focus/concentration, episodic memory and learning, visuospatial working memory, and visuospatial processing speed. Safety was assessed throughout the study on the basis of physical examination, vital signs, clinical laboratory tests, and monitoring of adverse events. RESULTS: The LZ group showed significant increases in MPOD at all visits post-supplementation, with significant increases as early as day 42 compared to placebo. The LZ group showed significant increases in serum lutein levels, reduced eye strain and fatigue, and improved cognitive performance (focus, episodic memory and learning, visuospatial working memory) at days 90 and 180 compared to placebo. Further, the LZ group showed significant increases in processing speed (CFF), attention, visuospatial processing, and serum Z and BDNF levels on day 180 compared to placebo. No safety concerns were observed. CONCLUSIONS: Supplementing LZ resulted in increased MPOD levels, along with increased serum levels of L, Z, and BDNF. These changes were associated with improved visual and cognitive performances and reduction in eye strain and eye fatigue in the children receiving LZ gummies. The investigational product was safe and well tolerated. TRIAL REGISTRATION: http://ctri.nic.in/ Identifier CTRI/2022/05/042364.

Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration.

BACKGROUND: Age-related macular degeneration (AMD) is a degenerative condition of the back of the eye that occurs in people over the age of 50 years. Antioxidants may prevent cellular damage in the retina by reacting with free radicals that are produced in the process of light absorption. Higher dietary levels of antioxidant vitamins and minerals may reduce the risk of progression of AMD. This is the third update of the review. OBJECTIVES: To assess the effects of antioxidant vitamin and mineral supplements on the progression of AMD in people with AMD. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, one other database, and three trials registers, most recently on 29 November 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared antioxidant vitamin or mineral supplementation to placebo or no intervention, in people with AMD. DATA COLLECTION AND ANALYSIS: We used standard methods expected by Cochrane. MAIN RESULTS: We included 26 studies conducted in the USA, Europe, China, and Australia. These studies enroled 11,952 people aged 65 to 75 years and included slightly more women (on average 56% women). We judged the studies that contributed data to the review to be at low or unclear risk of bias. Thirteen studies compared multivitamins with control in people with early and intermediate AMD. Most evidence came from the Age-Related Eye Disease Study (AREDS) in the USA. People taking antioxidant vitamins were less likely to progress to late AMD (odds ratio (OR) 0.72, 95% confidence interval (CI) 0.58 to 0.90; 3 studies, 2445 participants; moderate-certainty evidence). In people with early AMD, who are at low risk of progression, this means there would be approximately four fewer cases of progression to late AMD for every 1000 people taking vitamins (one fewer to six fewer cases). In people with intermediate AMD at higher risk of progression, this corresponds to approximately 78 fewer cases of progression for every 1000 people taking vitamins (26 fewer to 126 fewer). AREDS also provided evidence of a lower risk of progression for both neovascular AMD (OR 0.62, 95% CI 0.47 to 0.82; moderate-certainty evidence) and geographic atrophy (OR 0.75, 95% CI 0.51 to 1.10; moderate-certainty evidence), and a lower risk of losing 3 or more lines of visual acuity (OR 0.77, 95% CI 0.62 to 0.96; moderate-certainty evidence). Low-certainty evidence from one study of 110 people suggested higher quality of life scores (measured with the Visual Function Questionnaire) in treated compared with non-treated people after 24 months (mean difference (MD) 12.30, 95% CI 4.24 to 20.36). In exploratory subgroup analyses in the follow-on study to AREDS (AREDS2), replacing beta-carotene with lutein/zeaxanthin gave hazard ratios (HR) of 0.82 (95% CI 0.69 to 0.96), 0.78 (95% CI 0.64 to 0.94), 0.94 (95% CI 0.70 to 1.26), and 0.88 (95% CI 0.75 to 1.03) for progression to late AMD, neovascular AMD, geographic atrophy, and vision loss, respectively. Six studies compared lutein (with or without zeaxanthin) with placebo and one study compared a multivitamin including lutein/zeaxanthin with multivitamin alone. The duration of supplementation and follow-up ranged from six months to five years. Most evidence came from the AREDS2 study in the USA; almost all participants in AREDS2 also took the original AREDS supplementation formula. People taking lutein/zeaxanthin may have similar or slightly reduced risk of progression to late AMD (RR 0.94, 95% CI 0.87 to 1.01), neovascular AMD (RR 0.92, 95% CI 0.84 to 1.02), and geographic atrophy (RR 0.92, 95% CI 0.80 to 1.05) compared with control (1 study, 4176 participants, 6891 eyes; low-certainty evidence). A similar risk of progression to visual loss of 15 or more letters was seen in the lutein/zeaxanthin and control groups (RR 0.98, 95% CI 0.91 to 1.05; 6656 eyes; low-certainty evidence). Quality of life (Visual Function Questionnaire) was similar between groups (MD 1.21, 95% CI -2.59 to 5.01; 2 studies, 308 participants; moderate-certainty evidence). One study in Australia randomised 1204 people to vitamin E or placebo with four years of follow-up; 19% of participants had AMD. The number of late AMD events was low (N = 7) and the estimate of effect was uncertain (RR 1.36, 95% CI 0.31 to 6.05; very low-certainty evidence). There was no evidence of any effect of treatment on visual loss (RR 1.04, 95% CI 0.74 to 1.47; low-certainty evidence). There were no data on neovascular AMD, geographic atrophy, or quality of life. Five studies compared zinc with placebo. Evidence largely drawn from the largest study (AREDS) found a lower progression to late AMD over six years (OR 0.83, 95% CI 0.70 to 0.98; 3 studies, 3790 participants; moderate-certainty evidence), neovascular AMD (OR 0.76, 95% CI 0.62 to 0.93; moderate-certainty evidence), geographic atrophy (OR 0.84, 95% CI 0.64 to 1.10; moderate-certainty evidence), or visual loss (OR 0.87, 95% CI 0.75 to 1.00; 2 studies, 3791 participants; moderate-certainty evidence). There were no data on quality of life. Gastrointestinal symptoms were the main reported adverse effect. In AREDS, zinc was associated with a higher risk of genitourinary problems in men, but no difference was seen between high- and low-dose zinc groups in AREDS2. Most studies were too small to detect rare adverse effects. Data from larger studies (AREDS/AREDS2) suggested there may be little or no effect on mortality with multivitamin (HR 0.87, 95% CI 0.60 to 1.25; low-certainty evidence) or lutein/zeaxanthin supplementation (HR 1.06, 95% CI 0.87 to 1.31; very low-certainty evidence), but confirmed the increased risk of lung cancer with beta-carotene, mostly in former smokers. AUTHORS' CONCLUSIONS: Moderate-certainty evidence suggests that antioxidant vitamin and mineral supplementation (AREDS: vitamin C, E, beta-carotene, and zinc) probably slows down progression to late AMD. People with intermediate AMD have a higher chance of benefiting from antioxidant supplements because their risk of progression is higher than people with early AMD. Although low-certainty evidence suggested little effect with lutein/zeaxanthin alone compared with placebo, exploratory subgroup analyses from one large American study support the view that lutein/zeaxanthin may be a suitable replacement for the beta-carotene used in the original AREDS formula.

Lutein and zeaxanthin - radio- and chemoprotective properties. Mechanism and possible use.

Lutein and zeaxanthin are naturally occurring xanthophylls, mainly present in green, leafy vegetables and egg's yolk. Their presence is connected with blue spectrum light absorbance, including UV. This property, and fact, that these xanthophylls are accumulated by human eye's macula, leads to eye's protective functions of them including protection from age-related macular degeneration (AMD). Also, antioxidative features of lutein and zeaxanthin are boosting overall health of human body. Numerous studies proves anti-inflammatory and protective attributes of these compounds, based on many, different mechanisms. One of them is regulating redox potential in cells, and impact on expression of linked genes. In preventing of eye diseases, an important gene that is regulated by lutein and zeaxanthin is the Nrf2 gene, whose increased activity leads to optimizing the cellular response to reactive oxygen species (ROS) and preventing related diseases. Other research confirms antiproliferative properties of mentioned compounds in case of certain human cancer cell lines. There are e.g.: HepG2 (hepatitis cancer), MCF-7 (breast cancer), which treated in vitro with lutein solution showed reduction of cell growth. Lutein alone, during in vivo studies conducted on mice, exhibited also radioprotective properties, positively affecting the vitality of animals. Lutein provides also increasing of tolerance to UV radiation, reducing inflammatory processes in the skin and preventing oncogenesis. Low intake of lutein and zeaxanthin, associated with "western diet", rich in simple carbohydrates and processed food, common in developed countries, including Poland, is linked with diabetes and obesity incidence. Assuming, lutein and zeaxanthin significantly affect the well-being of the human body, and their appropriate amount in diet can help reduce risk of many diseases. For supplementation, the optimized dosage of these xanthophylls includes doses of 10 mg for lutein and 2 mg for zeaxanthin, and it is recommended to consume along with fats or meals rich in fats.

Review of Evidence for the Usage of Antioxidants for Eye Aging.

Oxidative stress is one of the common factors leading to age-related eye diseases in older adults. Factors such as high oxygen consumption, high concentration of polyunsaturated fatty acids, and cumulative exposure to high-energy visible light in the eyes, lead to excessive generation of reactive oxygen species, hence triggering apoptosis of ocular cells and giving rise to ophthalmic diseases. Dietary supplements such as carotenoids, anthocyanins, and vitamins have antioxidant properties which may be of benefit in retaining better vision or reversing vision impairment; thus, studies have been conducted to understand the role of dietary supplements in the treatment or prevention of ophthalmic diseases. While high concentration of carotenoids such as lutein and zeaxanthin decrease the risk of developing age-related macular disease, anthocyanins and vitamins play a role in the treatment and prevention of other ophthalmic diseases: saffron extract reduced intraocular pressure in glaucoma patients; bilberry extract prevented impairments in lenses and retina, as well as alleviate symptoms of dry eye disease; high concentration of beta-carotene may reduce the risk of developing cataract. Further studies with clinical measurements are required to investigate the effectiveness of antioxidants on visual function and ophthalmic diseases.

Association of Nutrients, Specific Dietary Patterns, and Probiotics with Age-related Macular Degeneration.

Age-related macular degeneration (AMD) is a complex disease that mainly affects people over 50 years of age. Even though management of the vascularisation associated with the "wet" form of AMD is effective using anti-VEGF drugs, there is currently no treatment for the "dry" form of AMD. Given this, it is imperative to develop methods for disease prevention and treatment. For this review, we searched scientific articles via PubMed and Google Scholar, and considered the impact of nutrients, specific dietary patterns, and probiotics on the incidence and progression of AMD. Many studies revealed that regular consumption of foods that contain ω-3 fatty acids is associated with a lower risk for late AMD. Particular dietary patterns, such as the Mediterranean diet that contains ω-3 FAs-rich foods (nuts, olive oil, and fish), seem to be protective against AMD progression compared to Western diets that are rich in fats and carbohydrates. Furthermore, randomized controlled trials that investigated the role of nutrient supplementation in AMD have shown that treatment with antioxidants, such as lutein/zeaxanthin, zinc, and carotenoids, may be effective against AMD progression. More recent studies have investigated the association of the antioxidant properties of gut bacteria, such as Bacteroides and Eysipelotrichi, with lower AMD risk in individuals whose microbiota is enriched with them. These are promising fields of research that may yield the capacity to improve the quality of life for millions of people, allowing them to live with a clear vision for longer and avoiding the high cost of vision-saving surgery.

Efficacy of different nutrients in age-related macular degeneration: A systematic review and network meta-analysis.

AIM: Age-related macular degeneration (AMD) has become a predominant global health concern. The visual function of individuals with AMD seems to improve with dietary antioxidants. We assessed the efficacy of different antioxidants (carotenoids, zinc, vitamin E, and multivitamin) on visual function and the incidence of developing late AMD. METHODS: We searched PubMed, EMBASE, and Cochrane Central Register of Controlled Trials for related published studies. We considered randomized controlled trials (RCTs) comparing different nutrients. The main outcomes measurements included changes in visual acuity (VA), and the rate of developing late AMD. The network meta-analysis was registered on PROSPERO (CRD42020171288). RESULTS: We identified 13 studies, including 85321 individuals randomly assigned to different nutrients or placebo groups. In the network meta-analysis, we found that there was more risk of progression to late AMD in the multivitamin group than carotenoids and vitamin E groups (RR 0.45, 95% CI 0.32 to 0.65; RR 0.56, 95% CI 0.40 to 0.79; RR 0.42, 95% CI 0.26 to 0.67). The nutrients of zinc and carotenoids (Lutein/Zeaxanthin) ranked first and second and showed better improvement in VA. The efficacy of carotenoids (ß-carotene) ranked first for delaying the progress of AMD among all of the four treatments. CONCLUSION: Taking multivitamin supplementation may not prevent the development of late AMD. The nutrient of zinc and carotenoids (lutein/zeaxanthin) supplementation were associated with better improvement in VA. Carotenoids (ß-carotene) were the most likely to prevent the progression of late AMD.

A Systematic Review of Carotenoids in the Management of Diabetic Retinopathy.

Diabetic retinopathy, which was primarily regarded as a microvascular disease, is the leading cause of irreversible blindness worldwide. With obesity at epidemic proportions, diabetes-related ocular problems are exponentially increasing in the developed world. Oxidative stress due to hyperglycemic states and its associated inflammation is one of the pathological mechanisms which leads to depletion of endogenous antioxidants in retina in a diabetic patient. This contributes to a cascade of events that finally leads to retinal neurodegeneration and irreversible vision loss. The xanthophylls lutein and zeaxanthin are known to promote retinal health, improve visual function in retinal diseases such as age-related macular degeneration that has oxidative damage central in its etiopathogenesis. Thus, it can be hypothesized that dietary supplements with xanthophylls that are potent antioxidants may regenerate the compromised antioxidant capacity as a consequence of the diabetic state, therefore ultimately promoting retinal health and visual improvement. We performed a comprehensive literature review of the National Library of Medicine and Web of Science databases, resulting in 341 publications meeting search criteria, of which, 18 were found eligible for inclusion in this review. Lutein and zeaxanthin demonstrated significant protection against capillary cell degeneration and hyperglycemia-induced changes in retinal vasculature. Observational studies indicate that depletion of xanthophyll carotenoids in the macula may represent a novel feature of DR, specifically in patients with type 2 or poorly managed type 1 diabetes. Meanwhile, early interventional trials with dietary carotenoid supplementation show promise in improving their levels in serum and macular pigments concomitant with benefits in visual performance. These findings provide a strong molecular basis and a line of evidence that suggests carotenoid vitamin therapy may offer enhanced neuroprotective effects with therapeutic potential to function as an adjunct nutraceutical strategy for management of diabetic retinopathy.

Nutrition and the aging retina: A comprehensive review of the relationship between nutrients and their role in age-related macular degeneration and retina disease prevention.

Age-related macular degeneration (AMD) is the leading cause of severe vision loss in developed countries and is highly common among aging individuals. Considering the rate at which the global population is aging, the increasing prevalence of AMD and age-related eye disease is cause for concern. AMD is associated with the degeneration of the macula, the most central region of the retina, leading to a loss of central vision. A wide array of research has focused on the ability of lipid soluble nutrients to prevent and mitigate the harmful effects of AMD. These nutrients in question tend to be highly saturated within retinal tissues including the carotenoids lutein and zeaxanthin and the polyunsaturated fatty acid docosahexaenoic acid (DHA). Additionally, the unique presence of very long chain polyunsaturated fatty acids (VLCPUFAs, C24-C36) in the retina may be essential to prevent retinal degeneration as demonstrated by abnormal retinal functioning in the absence of these novel fatty acids. Existing literature has suggested that lutein, zeaxanthin and DHA consumption tend to enhance the health of the retina, protecting against the development of AMD. However, little improvement to the previously deteriorated retina is demonstrated and more research is required to understand the role of these nutrients in the retina and for the prevention of AMD. Considering the global impact of AMD and age-related eye disease, utilizing nutrients to prevent the formation of these debilitating diseases is a highly affordable and promising strategy.

(3R, 3'R)-zeaxanthin protects the retina from photo-oxidative damage via modulating the inflammation and visual health molecular markers.

PURPOSE: Zeaxanthin protects the macula from ocular damage due to light or radiation by scavenging harmful reactive oxygen species. In the present study, zeaxanthin product (OmniXan®; OMX), derived from paprika pods (Capsicum annum; Family-Solanaceae), was tested for its efficacy in the rat retina against photooxidation. METHODS: Forty-two male 8-week-old Wistar rats exposed to 12L/12D, 16L/8D and 24L/0D hours of intense light conditions were orally administrated either 0 or 100 mg/kg BW of zeaxanthin concentration. Retinal morphology was analyzed by histopathology, and target gene expressions were detected with real-time polymerase chain reaction methods. RESULTS: OMX treatment significantly increased the serum zeaxanthin concentration (p < 0.001) and ameliorated oxidative damage by increasing the antioxidant enzyme activities in the retina induced by light (p < 0.001). OMX administration significantly upregulated the expression of genes, including Rhodopsin (Rho), Rod arrestin (SAG), Gα Transducin 1 (GNAT-1), neural cell adhesion molecule (NCAM), growth-associated protein 43 (GAP43), nuclear factor-(erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase (HO-1) and decreased the expression of nuclear factor-κB (NF- κB) and GFAP by OMX treatment rats. The histologic findings confirmed the antioxidant and gene expression data. CONCLUSIONS: This study suggests that OMX is a potent substance that can be used to protect photoreceptor cell degeneration in the retina exposed to intense light.

Redox-regulation of haemostasis in hypoxic exercising humans: a randomised double-blind placebo-controlled antioxidant study.

KEY POINTS: In vitro evidence has identified that coagulation is activated by increased oxidative stress, though the link and underlying mechanism in humans have yet to be established. We conducted the first randomised controlled trial in healthy participants to examine if oral antioxidant prophylaxis alters the haemostatic responses to hypoxia and exercise given their synergistic capacity to promote free radical formation. Systemic free radical formation was shown to increase during hypoxia and was further compounded by exercise, responses that were attenuated by antioxidant prophylaxis. In contrast, antioxidant prophylaxis increased thrombin generation at rest in normoxia, and this was normalised only in the face of prevailing oxidation. Collectively, these findings suggest that human free radical formation is an adaptive phenomenon that serves to maintain vascular haemostasis. ABSTRACT: In vitro evidence suggests that blood coagulation is activated by increased oxidative stress although the link and underlying mechanism in humans have yet to be established. We conducted the first randomised controlled trial to examine if oral antioxidant prophylaxis alters the haemostatic responses to hypoxia and exercise. Healthy males were randomly assigned double-blind to either an antioxidant (n = 20) or placebo group (n = 16). The antioxidant group ingested two capsules/day that each contained 500 mg of l-ascorbic acid and 450 international units (IU) of dl-α-tocopherol acetate for 8 weeks. The placebo group ingested capsules of identical external appearance, taste and smell (cellulose). Both groups were subsequently exposed to acute hypoxia and maximal physical exercise with venous blood sampled pre-supplementation (normoxia), post-supplementation at rest (normoxia and hypoxia) and following maximal exercise (hypoxia). Systemic free radical formation (electron paramagnetic resonance spectroscopic detection of the ascorbate radical (A•- )) increased during hypoxia (15,152 ± 1193 AU vs. 14,076 ± 810 AU at rest, P < 0.05) and was further compounded by exercise (16,569 ± 1616 AU vs. rest, P < 0.05), responses that were attenuated by antioxidant prophylaxis. In contrast, antioxidant prophylaxis increased thrombin generation as measured by thrombin-antithrombin complex, at rest in normoxia (28.7 ± 6.4 vs. 4.3 ± 0.2 µg mL-1 pre-intervention, P < 0.05) and was restored but only in the face of prevailing oxidation. Collectively, these findings are the first to suggest that human free radical formation likely reflects an adaptive response that serves to maintain vascular haemostasis.

Association of Mortality with Ocular Diseases and Visual Impairment in the Age-Related Eye Disease Study 2: Age-Related Eye Disease Study 2 Report Number 13.

PURPOSE: To evaluate the association of mortality with visual acuity (VA) impairment, age-related macular degeneration (AMD), and cataract surgery. DESIGN: Cohort study. PARTICIPANTS: Participants with at least intermediate AMD enrolled in a randomized controlled clinical trial of lutein/zeaxanthin and/or omega-3 fatty acids, the Age-Related Eye Disease Study 2 (AREDS2), for treatment of AMD and cataract. METHODS: Baseline and annual eye examinations included best-corrected visual acuity (BCVA) assessments, slit-lamp examinations, and stereoscopic fundus photographs that were centrally graded for development of late AMD (central geographic atrophy or neovascular AMD) or pseudophakia. Cause-specific mortality was determined on the basis of the International Classification of Diseases 9th or 10th Revision codes. Risk of all-cause and cause-specific mortality was assessed with Cox proportional hazards models adjusted for age, sex, AMD severity, VA, history of cataract surgery, and assigned AREDS2 study treatment. Analyses included baseline covariates: race, education, smoking status, diabetes, and cardiovascular disease. RESULTS: During follow-up (median 5 years), 368 (9%) of the 4203 AREDS2 participants died. Participants with neovascular AMD in 1 eye at baseline had a statistically significant increased risk for mortality compared with participants with no or few drusen (hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.21-2.01; P < 0.001). Poorer survival was associated with bilateral cataract surgery before enrollment compared with baseline bilateral phakia (HR, 1.63; 95% CI, 1.29-2.07; P < 0.001) and with BCVA of less than 20/40 compared with participants with 20/40 or better (HR, 1.56; 95% CI, 1.06-2.30; P = 0.024), adjusted for age, sex, and statistically significant covariates. Participants who received antivascular endothelial growth factor therapies for neovascular AMD had decreased mortality compared with those who did not (HR, 0.71; 95% CI, 0.57-0.88; P = 0.002). The association between all-cause mortality and AREDS2 treatment whether assessing the main or individual treatment effect was not significantly different (omega-3 fatty acids main effect HR, 1.18; 95% CI, 0.96-1.45; P = 0.12; lutein/zeaxanthin main effect HR, 1.04; 95% CI, 0.85-1.28; P = 0.71). CONCLUSIONS: In AREDS2, the presence of late AMD, bilateral cataract surgery, and VA less than 20/40 was associated with decreased survival. However, oral supplementation with omega-3 fatty acids, lutein plus zeaxanthin, zinc, or beta-carotene had no statistically significant impact on mortality.

A Deep Phenotype Association Study Reveals Specific Phenotype Associations with Genetic Variants in Age-related Macular Degeneration: Age-Related Eye Disease Study 2 (AREDS2) Report No. 14.

PURPOSE: Age-related macular degeneration (AMD), a multifactorial disease with variable phenotypic presentation, was associated with 52 single nucleotide polymorphisms (SNPs) at 34 loci in a genome-wide association study (GWAS). These genetic variants could modulate different biological pathways involved in AMD, contributing to phenotypic variability. To better understand the effects of these SNPs, we performed a deep phenotype association study (DeePAS) in the Age-Related Eye Disease Study 2 (AREDS2), followed by replication using AREDS participants, to identify genotype associations with AMD and non-AMD ocular and systemic phenotypes. DESIGN: Cohort study. PARTICIPANTS: AREDS and AREDS2 participants. METHODS: AREDS2 participants (discovery cohort) had detailed phenotyping for AMD; other eye conditions; cardiovascular, neurologic, gastrointestinal, and endocrine disease; cognitive function; serum nutrient levels; and others (total of 139 AMD and non-AMD phenotypes). Genotypes of the 52 GWAS SNPs were obtained. The DeePAS was performed by correlating the 52 SNPs to all phenotypes using logistic and linear regression models. Associations that reached Bonferroni-corrected statistical significance were replicated in AREDS. MAIN OUTCOME MEASURES: Genotype-phenotype associations. RESULTS: A total of 1776 AREDS2 participants had 5 years follow-up; 1435 AREDS participants had 10 years. The DeePAS revealed a significant association of the rs3750846 SNP at the ARMS2/HTRA1 locus with subretinal/sub-retinal pigment epithelial (RPE) hemorrhage related to neovascular AMD (odds ratio 1.55 [95% confidence interval 1.31-1.84], P = 2.67 × 10-7). This novel association remained significant after conditioning on participants with neovascular AMD (P = 2.42 × 10-4). Carriers of rs3750846 had poorer visual acuity during follow-up (P = 6.82 × 10-7) and were more likely to have a first-degree relative with AMD (P = 5.38 × 10-6). Two SNPs at the CFH locus, rs10922109 and rs570618, were associated with the drusen area in the Early Treatment Diabetic Retinopathy Study Report (ETDRS) grid (P = 2.29 × 10-11 and P = 3.20 × 10-9, respectively) and the center subfield (P = 1.24 × 10-9 and P = 6.68 × 10-8, respectively). SNP rs570618 was additionally associated with the presence of calcified drusen (P = 5.38 × 10-6). Except for positive family history of AMD with rs3750846, all genotype-phenotype associations were significantly replicated in AREDS. No pleiotropic associations were identified. CONCLUSIONS: The association of the SNP at the ARMS2/HTRA1 locus with subretinal/sub-RPE hemorrhage and poorer visual acuity and of SNPs at the CFH locus with drusen area may provide new insights in pathophysiological pathways underlying different stages of AMD.

The Impact of Supplemental Antioxidants on Visual Function in Nonadvanced Age-Related Macular Degeneration: A Head-to-Head Randomized Clinical Trial.

Purpose: The purpose of this study was to evaluate the impact of supplemental macular carotenoids (including versus not including meso-zeaxanthin) in combination with coantioxidants on visual function in patients with nonadvanced age-related macular degeneration. Methods: In this study, 121 participants were randomly assigned to group 1 (Age-Related Eye Disease Study 2 formulation with a low dose [25 mg] of zinc and an addition of 10 mg meso-zeaxanthin; n = 60) or group 2 (Age-Related Eye Disease Study 2 formulation with a low dose [25 mg] of zinc; n = 61). Visual function was assessed using best-corrected visual acuity, contrast sensitivity (CS), glare disability, retinal straylight, photostress recovery time, reading performance, and the National Eye Institute Visual Function Questionnaire-25. Macular pigment was measured using customized heterochromatic flicker photometry. Results: There was a statistically significant improvement in the primary outcome measure (letter CS at 6 cycles per degree [6 cpd]) over time (P = 0.013), and this observed improvement was statistically comparable between interventions (P = 0.881). Statistically significant improvements in several secondary outcome visual function measures (letter CS at 1.2 and 2.4 cpd; mesopic and photopic CS at all spatial frequencies; mesopic glare disability at 1.5, 3, and 6 cpd; photopic glare disability at 1.5, 3, 6, and 12 cpd; photostress recovery time; retinal straylight; mean and maximum reading speed) were also observed over time (P < 0.05, for all), and were statistically comparable between interventions (P > 0.05, for all). Statistically significant increases in macular pigment at all eccentricities were observed over time (P < 0.0005, for all), and the degree of augmentation was statistically comparable between interventions (P > 0.05). Conclusions: Antioxidant supplementation in patients with nonadvanced age-related macular degeneration results in significant increases in macular pigment and improvements in CS and other measures of visual function. (Clinical trial, http://www.isrctn.com/ISRCTN13894787).

[Behind blue eyes ­ the evidence for ocular nutritional supplements on the Swedish market]. / Bakom blå ögon svagt evidensläge för kosttillskott för ögonhälsa.

Behind blue eyes - the evidence for ocular nutritional supplements on the Swedish market Health claims for food are harmonized in the European Union by the European Food Safety Authority (EFSA). Nutritional supplements containing vitamin A or B, docosahexaenoic acid or zinc are allowed to state in their marketing that they preserve vision. This decision is based only on studies of cell metabolism and deficiency diseases and not on clinical interventions. A preventive effect on progression of age-related macular degeneration has however been proven with the AREDS-formula, with an absolute risk reduction for severe visual loss of 6% in certain groups. This treatment may however be associated with considerable side effects. Only 2 of the 25 nutritional supplements for preserved vision available on the Swedish market today follows the AREDS-formula. The present marking of ocular nutritional supplements might therefore be misleading for the customer.

Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration.

BACKGROUND: It has been proposed that antioxidants may prevent cellular damage in the retina by reacting with free radicals that are produced in the process of light absorption. Higher dietary levels of antioxidant vitamins and minerals may reduce the risk of progression of age-related macular degeneration (AMD). OBJECTIVES: The objective of this review was to assess the effects of antioxidant vitamin or mineral supplementation on the progression of AMD in people with AMD. SEARCH METHODS: We searched CENTRAL (2017, Issue 2), MEDLINE Ovid (1946 to March 2017), Embase Ovid (1947 to March 2017), AMED (1985 to March 2017), OpenGrey (System for Information on Grey Literature in Europe, the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 29 March 2017. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared antioxidant vitamin or mineral supplementation (alone or in combination) to placebo or no intervention, in people with AMD. DATA COLLECTION AND ANALYSIS: Both review authors independently assessed risk of bias in the included studies and extracted data. One author entered data into RevMan 5; the other author checked the data entry. We graded the certainty of the evidence using GRADE. MAIN RESULTS: We included 19 studies conducted in USA, Europe, China, and Australia. We judged the trials that contributed data to the review to be at low or unclear risk of bias.Nine studies compared multivitamins with placebo (7 studies) or no treatment (2 studies) in people with early and moderate AMD. The duration of supplementation and follow-up ranged from nine months to six years; one trial followed up beyond two years. Most evidence came from the Age-Related Eye Disease Study (AREDS) in the USA. People taking antioxidant vitamins were less likely to progress to late AMD (odds ratio (OR) 0.72, 95% confidence interval (CI) 0.58 to 0.90; 2445 participants; 3 RCTs; moderate-certainty evidence). In people with very early signs of AMD, who are at low risk of progression, this would mean that there would be approximately 4 fewer cases of progression to late AMD for every 1000 people taking vitamins (1 fewer to 6 fewer cases). In people at high risk of progression (i.e. people with moderate AMD) this would correspond to approximately 8 fewer cases of progression for every 100 people taking vitamins (3 fewer to 13 fewer). In one study of 1206 people, there was a lower risk of progression for both neovascular AMD (OR 0.62, 95% CI 0.47 to 0.82; moderate-certainty evidence) and geographic atrophy (OR 0.75, 95% CI 0.51 to 1.10; moderate-certainty evidence) and a lower risk of losing 3 or more lines of visual acuity (OR 0.77, 95% CI 0.62 to 0.96; 1791 participants; moderate-certainty evidence). Low-certainty evidence from one study of 110 people suggested higher quality of life scores (National Eye Institute Visual Function Questionnaire) in treated compared with the non-treated people after 24 months (mean difference (MD) 12.30, 95% CI 4.24 to 20.36). Six studies compared lutein (with or without zeaxanthin) with placebo. The duration of supplementation and follow-up ranged from six months to five years. Most evidence came from the AREDS2 study in the USA. People taking lutein or zeaxanthin may have similar or slightly reduced risk of progression to late AMD (RR 0.94, 95% CI 0.87 to 1.01; 6891 eyes; low-certainty evidence), neovascular AMD (RR 0.92, 95% CI 0.84 to 1.02; 6891 eyes; low-certainty evidence), and geographic atrophy (RR 0.92, 95% CI 0.80 to 1.05; 6891 eyes; low-certainty evidence). A similar risk of progression to visual loss of 15 or more letters was seen in the lutein and control groups (RR 0.98, 95% CI 0.91 to 1.05; 6656 eyes; low-certainty evidence). Quality of life (measured with Visual Function Questionnaire) was similar between groups in one study of 108 participants (MD 1.48, 95% -5.53 to 8.49, moderate-certainty evidence). One study, conducted in Australia, compared vitamin E with placebo. This study randomised 1204 people to vitamin E or placebo, and followed up for four years. Participants were enrolled from the general population; 19% had AMD. The number of late AMD events was low (N = 7) and the estimate of effect was uncertain (RR 1.36, 95% CI 0.31 to 6.05, very low-certainty evidence). There were no data on neovascular AMD or geographic atrophy.There was no evidence of any effect of treatment on visual loss (RR 1.04, 95% CI 0.74 to 1.47, low-certainty evidence). There were no data on quality of life. Five studies compared zinc with placebo. The duration of supplementation and follow-up ranged from six months to seven years. People taking zinc supplements may be less likely to progress to late AMD (OR 0.83, 95% CI 0.70 to 0.98; 3790 participants; 3 RCTs; low-certainty evidence), neovascular AMD (OR 0.76, 95% CI 0.62 to 0.93; 2442 participants; 1 RCT; moderate-certainty evidence), geographic atrophy (OR 0.84, 95% CI 0.64 to 1.10; 2442 participants; 1 RCT; moderate-certainty evidence), or visual loss (OR 0.87, 95% CI 0.75 to 1.00; 3791 participants; 2 RCTs; moderate-certainty evidence). There were no data reported on quality of life.Very low-certainty evidence was available on adverse effects because the included studies were underpowered and adverse effects inconsistently reported. AUTHORS' CONCLUSIONS: People with AMD may experience some delay in progression of the disease with multivitamin antioxidant vitamin and mineral supplementation. This finding was largely drawn from one large trial, conducted in a relatively well-nourished American population. We do not know the generalisability of these findings to other populations. Although generally regarded as safe, vitamin supplements may have harmful effects. A systematic review of the evidence on harms of vitamin supplements is needed. Supplements containing lutein and zeaxanthin are heavily marketed for people with age-related macular degeneration but our review shows they may have little or no effect on the progression of AMD.

Phospholipid oxidation and carotenoid supplementation in Alzheimer's disease patients.

Alzheimer's disease (AD) is a progressive, neurodegenerative disease, characterised by decline of memory, cognitive function and changes in behaviour. Generic markers of lipid peroxidation are increased in AD and reactive oxygen species have been suggested to be involved in the aetiology of cognitive decline. Carotenoids are depleted in AD serum, therefore we have compared serum lipid oxidation between AD and age-matched control subjects before and after carotenoid supplementation. The novel oxidised phospholipid biomarker 1-palmitoyl-2-(5'-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC) was analysed using electrospray ionisation tandem mass spectrometry (MS) with multiple reaction monitoring (MRM), 8-isoprostane (IsoP) was measured by ELISA and ferric reducing antioxidant potential (FRAP) was measured by a colorimetric assay. AD patients (n=21) and healthy age-matched control subjects (n=16) were supplemented with either Macushield™ (10mg meso-zeaxanthin, 10mg lutein, 2mg zeaxanthin) or placebo (sunflower oil) for six months. The MRM-MS method determined serum POVPC sensitively (from 10µl serum) and reproducibly (CV=7.9%). At baseline, AD subjects had higher serum POVPC compared to age-matched controls, (p=0.017) and cognitive function was correlated inversely with POVPC (r=-0.37; p=0.04). After six months of carotenoid intervention, serum POVPC was not different in AD patients compared to healthy controls. However, POVPC was significantly higher in control subjects after six months of carotenoid intervention compared to their baseline (p=0.03). Serum IsoP concentration was unrelated to disease or supplementation. Serum FRAP was significantly lower in AD than healthy controls but was unchanged by carotenoid intervention (p=0.003). In conclusion, serum POVPC is higher in AD patients compared to control subjects, is not reduced by carotenoid supplementation and correlates with cognitive function.

Effects of Mixed Carotenoids on Adipokines and Abdominal Adiposity in Children: A Pilot Study.

Context: Carotenoids have been implicated in the regulation of adipocyte metabolism. Objective: To compare the effects of mixed-carotenoid supplementation (MCS) versus placebo on adipokines and the accrual of abdominal adiposity in children with obesity. Design and Setting: Randomized (1:1), double-blind, placebo-controlled intervention trial to evaluate the effects of MCS over 6 months in a subspecialty clinic. Participants: Twenty (6 male and 14 female) children with simple obesity [body mass index (BMI) > 90%], a mean age (± standard deviation) of 10.5 ± 0.4 years, and Tanner stage I to V were enrolled; 17 participants completed the trial. Intervention: MCS (which contains ß-carotene, α-carotene, lutein, zeaxanthin, lycopene, astaxanthin, and γ-tocopherol) or placebo was administered daily. Main Outcome Measures: Primary outcomes were change in ß-carotene, abdominal fat accrual (according to magnetic resonance imaging), and BMI z-score; secondary outcomes were adipokines and markers of insulin resistance. Results: Cross-sectional analysis of ß-carotene showed inverse correlation with BMI z-score, waist-to-height ratio, visceral adipose tissue, and subcutaneous adipose tissue (SAT) at baseline. MCS increased ß-carotene, total adiponectin, and high-molecular-weight adiponectin compared with placebo. MCS led to a greater reduction in BMI z-score, waist-to-height ratio, and SAT compared with placebo. The percentage change in ß-carotene directly correlated with the percentage change in SAT. Conclusions: The decrease in BMI z-score, waist-to-height ratio, and SAT and the concomitant increase in the concentration of ß-carotene and high-molecular-weight adiponectin by MCS suggest the putative beneficial role of MCS in children with obesity.

Putative protective role of lutein and zeaxanthin in diabetic retinopathy.

Diabetic retinopathy (DR) is one of the most important microvascular complications of diabetes and remains the leading cause of blindness in the working-age individuals. The exact aetiopathogenesis of DR remains elusive despite major advances in basic science and clinical research. Oxidative damage as one of the underlying causes for DR is increasingly being recognised. In humans, three hydroxycarotenoids, lutein (L), zeaxanthin (Z) and meso-zeaxanthin (MZ), accumulate at the central retina (to the exclusion of all other dietary carotenoids), where they are collectively known as macular pigment. These hydroxycarotenoids by nature of their biochemical structure and function help neutralise reactive oxygen species, and thereby, prevent oxidative damage to the retina (biological antioxidants). Apart from their key antioxidant function, evidence is emerging that these carotenoids may also exhibit neuroprotective and anti-inflammatory function in the retina. Since the preliminary identification of hydroxycarotenoid in the human macula by Wald in the 1940s, there has been astounding progress in our knowledge of the role of these carotenoids in promoting ocular health. While the Age-Related Eye Disease Study 2 has established a clinical benefit for L and Z supplements in patients with age-related macular degeneration, the role of these carotenoids in other retinal diseases potentially linked to oxidative damage remains unclear. In this article, we comprehensively review the literature germane to the putative protective role of two hydroxycarotenoids, L and Z, in the pathogenesis of DR.

Lutein and Zeaxanthin Isomers in Eye Health and Disease.

Current evidence suggests lutein and its isomers play important roles in ocular development in utero and throughout the life span, in vision performance in young and later adulthood, and in lowering risk for the development of common age-related eye diseases in older age. These xanthophyll (oxygen-containing) carotenoids are found in a wide variety of vegetables and fruits, and they are present in especially high concentrations in leafy green vegetables. Additionally, egg yolks and human milk appear to be bioavailable sources. The prevalence of lutein, zeaxanthin, and meso-zeaxanthin in supplements is increasing. Setting optimal and safe ranges of intake requires additional research, particularly in pregnant and lactating women. Accumulating evidence about variable interindividual response to dietary intake of these carotenoids, based on genetic or metabolic influences, suggests that there may be subgroups that benefit from higher levels of intake and/or alternate strategies to improve lutein and zeaxanthin status.

Lutein, Zeaxanthin and Meso-zeaxanthin Supplementation Associated with Macular Pigment Optical Density.

The purpose of this study was to evaluate the effects of lutein, zeaxanthin and meso-zeaxanthin on macular pigment optical density (MPOD) in randomized controlled trials (RCTs) among patients with age-related macular degeneration (AMD) and healthy subjects. Medline, Embase, Web of Science and Cochrane Library databases was searched through May 2016. Meta-analysis was conducted to obtain adjusted weighted mean differences (WMD) for intervention-versus-placebo group about the change of MPOD between baseline and terminal point. Pearson correlation analysis was used to determine the relationship between the changes in MPOD and blood xanthophyll carotenoids or baseline MPOD levels. Twenty RCTs involving 938 AMD patients and 826 healthy subjects were identified. Xanthophyll carotenoids supplementation was associated with significant increase in MPOD in AMD patients (WMD, 0.07; 95% CI, 0.03 to 0.11) and healthy subjects (WMD, 0.09; 95% CI, 0.05 to 0.14). Stratified analysis showed a greater increase in MPOD among trials supplemented and combined with meso-zeaxanthin. Additionally, the changes in MPOD were related with baseline MPOD levels (rAMD = -0.43, p = 0.06; rhealthy subjects = -0.71, p < 0.001) and blood xanthophyll carotenoids concentration (rAMD = 0.40, p = 0.07; rhealthy subjects = 0.33, p = 0.05). This meta-analysis revealed that lutein, zeaxanthin and meso-zeaxanthin supplementation improved MPOD both in AMD patients and healthy subjects with a dose-response relationship.