Preface

This volume of *Nutrients* includes eleven independent contributions that focus on the mechanisms and use of nutrition and supplementation in the prevention and slowing of congenital and acquired eye disease. This topic is becoming increasingly important because of the aging population in developed countries and because, for the most common blinding eye disease, dry age-related macular degeneration, prevention is important as there is no cure.

This volume is divided into three sections: 1. some mechanisms underlying effects of nutrition on eye function and disease, three papers; 2. lutein, zeaxanthin and macular pigment, four papers; 3. ocular nutritional supplementation, four papers.

In Section 1, Demmig-Adams and Adams have reviewed carotenoid-based visual cues and roles of carotenoids in human vision, with an emphasis on protection by lutein and zeaxanthin against vision loss. The authors have summarised dietary sources of lutein and zeaxanthin and given attention to synergistic interactions of lutein and zeaxanthin with other dietary factors affecting human vision (such as antioxidant vitamins, phenolics, and poly-unsaturated fatty acids) and the emerging mechanisms of these interactions. They have emphasised lipid oxidation products serving as messengers with functions in gene regulation and complete their review with a comparison between photo-physics of light collection and photo-protection in photosynthesis and vision, which are identified as targets for future research.

Perusek and Maeda continue Section 1 with a review of the impact of supplementation with preformed cis-retinoid derivatives. Leber's congenital amaurosis (LCA) is a degenerative retinal disease that is usually confirmed early in life, and results in complete blindness in the third or fourth decade. People with this condition lack the functional enzymatic reactions to regenerate the vitamin A derivative 11- cis retinal, which is required to maintain vision. In animal models, supplementation with preformed cis-retinoid derivatives bypasses defective steps in the visual cycle so that these pigments can be regenerated. However, toxic effects are seen with prolonged supplementation with vitamin A derivatives. The review highlights novel methods for employing artificial visual chromophore 9-*cis*-retinoids used in clinical trials involving people with LCA.

The third paper in Section 1 is a review by Zhong *et al*. in which the authors discuss vitamin A functions and transport in the context of the natural history of vitamin A-based light sensors. They propose that the expanding functions of vitamin A and the choice of monostable pigments are the likely evolutionary driving forces for precise, efficient, and sustained vitamin A transport. The authors describe how determining the mechanism by which vitamin A is transported into the right cell type in the appropriate amount will help to devise treatment strategies for conditions resulting from insufficient or excessive tissue retinoid levels.

In Section 2, the first paper is by Koushan *et al*. who reviewed the role of lutein and zeaxanthin as blue-light blockers and quenchers of oxygen free radicals. As well as providing an overview of the role of lutein and zeaxanthin in age-related macular disease, the authors highlight potential therapeutic roles in treating non-proliferative diabetic retinopathy, prevention of apoptosis in the cells of the outer nuclear layer of the retina, the reduction of oxidative stress in human lens cells and risk reduction for cataract.

In the second paper of Section 2, Abdel-Aal *et al*. in their review discuss the potential development of high-lutein functional foods. Wheat species such as einkorn and durum wheat have a relatively high lutein content compared with other wheat species such as spelt, soft and hard wheat. Functional foods such as flat bread, cookies and muffins have been developed and found to have about 1 mg lutein per serving. Corn products are also rich in lutein and zeaxanthin and have been used to produce high-carotenoid tortilla and chips containing 73 and 61 g/g of lutein respectively.

In the third paper of Section 2, Bovier *et al*. report a moderate, but significant inverse relationship between macular pigment, measured using heterochromatic flicker photometry, and body fat, measured using dual energy x-ray absorptiometry. The authors suggest that a stronger inverse relationship may have been shown in an older group (mean age in this cohort was 22.5 years). Obesity has been linked with increased risk of age-related macular degeneration (AMD). Bovier *et al*. suggest that this link may be explained by a reduction in optimal nutrition status within the retina, as well as by direct stress effects.

It is well documented that macular pigment can protect the retina via blue-light screening and its antioxidant properties. In the fourth paper of Section 2, Loskutova *et al*. provide an overview of the ways in which macular pigment can improve visual performance through the reduction of both glare disability light scatter and chromatic aberration. As well as having optical properties, macular pigment may have a favourable impact on neuronal processing.

In Section 3, the first paper is a review by Schleicher *et al*. in which they highlight the link between consumption of high glycaemic index foods and AMD. They discuss the complex nature of the relationship between essential fatty acids and AMD; several large scale epidemiological studies suggest that AMD risk is reduced with consumption of higher levels of omega-3 essential fatty acid consumption. However, no such relationship was reported in the AREDS study. Consumption of four portions of fish per week has also been associated with a reduced risk for AMD, although the authors suggest that as the relationship between fish consumption and AMD risk is not as strong as that between omega-3 essential fatty acids and AMD, as other components of the fish may attenuate the actions of omega-3 EFA. Lutein and zeaxanthin are singled out as the most beneficial carotenoids for retinal health, with 10 mg lutein per day conferring maximum benefit. The data for other nutrients are conflicting.

In the second paper of Section 3, Richer *et al*. describe three patients with treatment-resistant AMD (progress with AREDS and AREDS 2, refuse intra-vitreal anti-VEGF injections or fail to respond to Lucentis®, Avastin® or Eylea®) who took an oral resveratrol based nutritional supplement called Longevinex® (Resveratrol Partners, LLC, Las Vegas, NV, USA). This product provides 100 mg of *trans*-resveratrol as well as a blend of other red wine polyphenols, 1200 g vitamin D3, and a copper/iron/calcium binding molecule called IP6. In all three cases, supplementation resulted in a quick anatomical and bilateral visual benefit. For example, one patient reported better vision after just five days of supplementation, and spectral domain OCT showed improvements similar to that seen with anti-VEGF therapy. Future randomised placebo controlled studies are needed to confirm these exciting reports.

The third paper of Section 3, is a brief report by Garcia-Layana *et al*. who found that daily supplementation by 23 participants with 12 mg lutein, 0.6 mg zeaxanthin, and 280 mg DHA for one year significantly increased macular pigment optical density (MPOD) compared with a placebo group of 21 participants (p<0.05). The mean increase in MPOD for the intervention group was 0.162 as measured by heterochromatic flicker photometry.

In the fourth paper of Section 3, Richer and colleagues evaluated retinal thinning (RT) and present a new spectral domain OCT clinical metric called '% extra-foveal RT', which correlates well with functional visual loss in people with AMD but with minimal visible retinal changes. They suggest that this new metric can be used to monitor the effect of nutritional supplementation in this type of patient.

We hope that this selection of papers will provide readers with useful updates on this range of research of the relationship between what people eat and their long term eye health. We would like to thank the authors of these papers for their contributions and appreciate their time and effort, as well as that of the reviewers prior to initial publication in the journal *Nutrients,* and finally the editorial staff at MDPI for all the background work that made this volume possible.

Frank Eperjesi and Hannah Bartlett *Guest Editors* 
