Fatty Acids and Lipid Derivatives Protecting Photooxidative Attack in Age-related Macular Degeneration

gates of extracellular material ） and the growth of the choroidal vessels called choroidal neovascularization 5, 6 ） The appearance of drusen and neovascularization is the result of chronic changes of the macula and in particular of the retinal pigment epithelium （ RPE ） , of the choriocapillaris （ CC ） , as well as photoreceptors （ rods and cones ） and Bruch ’ s membrane （ BRM ） 7 − 10 ） . Two types of drusen are known, hard drusen and soft drusen. Hard drusen are typi-cally smaller than 63 μ m and have a flattened shape on ste-reoscopic photographs, while those larger than 125 μ m are often classified as soft drusen （ 125 μ m is the approximate diameter of the retinal veins at the edge of the optic disc ） 7 ） . Hard drusen are nodular accumulations of hyaline material on the outer part of the basement membrane of the retinal pigmented epithelium. Whereas soft drusen are considered groups of hard drusen, in addition, there are indistinct soft drusen which are localized detachments of the retinal epithelium and which can group together to form a retinal drusenoid detachment 11 ） . The molecular pathway that un-derlies geographic atrophy （ GA ） and vision loss. This pathway implies that RPE death consequently leads to photoreceptor loss, which progressively results in visual Abstract: The objective is the systematic review of studies published in Scielo, Redalyc, Dialnet, Web of Science, Scopus and Pubmed, related to the inclusion of fatty acids and lipid derivatives in the daily diet to prevent or delay the appearance or progression of Age-Related Macular Degeneration (AMD). The analysis of the research results consulted shows that AMD is one of the most frequent causes of blindness in subjects over 55 years of age. AMD is characterized by decreased vision, metamorphopsia, macropsies, micropsies, and central scotoma. Disease that must be diagnosed early as it can lead to irreversible blindness. Among the components of the diet that in numerous epidemiological studies have shown an association in the treatment of AMD and that are reviewed in this work are fatty acids, vitamins and carotenoids. There is ample evidence that fatty acids and lipid derivatives can be included in the diet plans of subjects with AMD.


Introduction
gates of extracellular material and the growth of the choroidal vessels called choroidal neovascularization 5,6 . The appearance of drusen and neovascularization is the result of chronic changes of the macula and in particular of the retinal pigment epithelium RPE , of the choriocapillaris CC , as well as photoreceptors rods and cones and Bruch s membrane BRM 7 10 . Two types of drusen are known, hard drusen and soft drusen. Hard drusen are typically smaller than 63 μm and have a flattened shape on stereoscopic photographs, while those larger than 125 μm are often classified as soft drusen 125 μm is the approximate diameter of the retinal veins at the edge of the optic disc 7 . Hard drusen are nodular accumulations of hyaline material on the outer part of the basement membrane of the retinal pigmented epithelium. Whereas soft drusen are considered groups of hard drusen, in addition, there are indistinct soft drusen which are localized detachments of the retinal epithelium and which can group together to form a retinal drusenoid detachment 11 . The molecular pathway that underlies geographic atrophy GA and vision loss. This pathway implies that RPE death consequently leads to photoreceptor loss, which progressively results in visual loss over time. Low levels of the ribonucleic acid RNA -cleaving enzyme, DICER1, in RPE cells were observed in patients with dry AMD. It was reported that decreased levels of DICER1 lead to a decreased rate in the breakdown of RNA-Alu molecules, which are noncoding sequences of RNA. The overabundance of cytoplasmic RNA-Alu activates inflammatory proteins such as NLRP3 in the inflammasome, which results in the activation of a cascade of molecular reactions that result in RPE cell loss. Furthermore, mitochondrial dysfunction has been associated with the development of dry AMD. The mitochondrial dysmorphology observed in the RPE in individuals with AMD was consistent with severe dysfunction 12 17 .
According to the fundoscopic abnormalities observed, two forms of AMD can be distinguished: the dry or non-exudative atrophic form and the neovascular or exudative form also called the wet form 18 . The dry or non-exudative atrophic form, known as geographic atrophy, it is characterized by the progressive accumulation of drusen between the RPE and the CC. Excessive drusen between the RPE and the CC hinder the transport of oxygen and nutrients, which degenerates the RPE system and photoreceptors, it can also progress to the wet form, which is the most aggressive form of AMD characterized by choroidal neovascularization. The angiogenesis process leads to the formation of very fragile blood vessels, which are responsible for bleeding and destruction of RPE cells see Fig. 1 19,20 .
AMD is considered a multifactorial disease that involves an interaction between genetic and environmental factors 21 , Environmental factors include: aging and smoking contribute significantly to the increased risk of AMD 22,23 . The disease increases with age and with it the loss of photoreceptors, mainly the rods, thus acting as a common cause of the development of AMD 24 . Cigarette smoke contains a high amount of toxic substances, which contribute to atherosclerosis, endothelial dysregulation, and angiogenesis. The presence of oxidative compounds in tobacco is associated with an increase in the formation of reactive oxygen species ROS and therefore with oxidative damage at the cellular level of RPE 25 29 , in addition, eating habits contribute significantly to the progressive development of the disease 30 .

Fatty Acids and Lipid Derivatives in Age-Related Macular Degeneration
Age-related macular degeneration and maculopathies are the result of a photooxidative attack, supplementation of the diet with vitamins C, E, lutein, zeaxanthin, carotenoids and fatty acids have been shown to slow the progression of atrophic macular degeneration, avoiding progress towards its most severe form and / or neovascular forms 31 37 . They have been proposed to limit damage to photoreceptors at the macular level, by protecting against the cumulative effects of oxidative stress, which would be a mechanism of cellular injury that is caused by reactive oxygen intermediaries 31 . The retina is considered susceptible to oxidative stress due to its high oxygen consumption and the high natural exposure of irradiation that accumulates 38 41 . In the case of omega-3 and omega-6 fatty acids, eicosapentaenoic acid EPA and arachidonic acid AA were used respectively for their effects against oxidative stress and inflammatory processes. AA acts as a precursor for pro-inflammatory processes known as series 2 prostanoids, while EPA provides precursors for the production of anti-inflammatory mediators of series 3 prostanoids. Inflammation is a process in the innate immune system, the excessive production of pro-inflammatory products during chronic inflammation can have detrimental effects, increasing susceptibility to disease, due to the increase in reactive oxygen species, the induction of a state of cellular stress, Fig. 1 Types of age-related macular degeneration. a Wet AMD b Dry AMD.

Fatty Acids and Lipid Derivatives in Age-related Macular Degeneration
the alteration in inactive molecules such as: growth factors, remodeling of matrix proteins and tissue structure 42 .
PUFAs are important components of the outer segments of retina photoreceptors and have been shown to interact with rhodopsin, suggesting their role in phototransduction. DHA is the major polyunsaturated fatty acid in the retina and brain. Its presence in the disk membrane of retinal photoreceptor outer segment is indispensable for retinal function and protects against damage from bright light and oxidative stress. DHA accounts for 20-30 of the fatty acids in phosphatidylcholine PC or phosphatidylethanolamine PE of outer segment disk membranes. It has been also suggested that particularly VLC-PUFAs C26 are suited to build highly curved membranes in photoreceptor outer segment disks. During the process of daily renewal, photoreceptors are constantly shedding their outer segment membranes, which are phagocytosed by the RPE where PUFAs are recycled and further processed. The membrane-bound n-3 and n-6 PUFAs are cleaved by phospholipases A1 and A2, leading to metabolism by three major pathways, the cyclooxygenases COX , lipoxygenases LOX , and cytochrome P450 oxidases, resulting in metabolites with diverse functions, n-3 metabolites such as prostaglandins are anti-inflammatory and n-6 metabolites such as PGE2 and TXA2 are inflammatory. DHA serves as a precursor to neuroprotective docosanoids, while the release of longer PUFAs C30 can lead to the formation of elovanoids, two more classes of pro-homeostatic lipid mediators 43 50 .
Vitamin C, vitamin E, lutein and zeaxanthin act in the central area of the macula, the macular pigment can protect the underlying photoreceptor cell layer from light damage by filtering blue light 51 , the Blue Mountain Eye study reported that the increase in lutein and zeaxanthin in the diet, showed a reduction in the risk of early incidence and neovascularization of AMD with a period of between 5 and 10 years 52 . The Age-Related Eye Disease Study AREDS 42 and the Age-Related Eye Disease Study 2 AREDS2 51 53 have improved the scientific understanding of the effect of nutritional supplementation mainly based on antioxidants in reducing the development of AMD. In the AREDS2 study, supplementation with lutein, minerals, omega-3 polyunsaturated fatty acids and fatty acid derivatives were used Table 1 48 50, 54 .

Conclusions
The high consumption of saturated fatty acids, snuff, alcohol, sedentary lifestyle has led to an increase in diseases that are now considered public health problems, development of AMD is multifactorial, however, nutritional support is a challenge partly because to the regulatory environment and difficulties in designing clinical trials to answer these questions, environmental factors such as the quitting smoking and eating a healthy diet serve to prevent or slow the progression of AMD. In subjects who already present some degree of the pathology, they are recommended to take AREDS-type supplements, based on available scientific evidence. These findings enhance the understandings of dietary impacts on neovascular AMD and provide a context for future nutritional intervention studies.

Authors' Contributions
IAGM, DMP participated in the study concept, design, writing and critical review of the manuscript. Table 1 Participation of lipid derivatives and fatty acids in Age-Related Macular Degeneration.

Nutritional component
Relationship with AMD

LUTEIN AND ZEAXANTINE
Natural yellow pigments serve as antioxidants, in AMD it acts as filters to blue light, also reduces the oxidative effect, this because in the macula it is susceptible to oxidative damage, which would cause a progressive deterioration of the pigment epithelium, which can be counteracted by the various existing defense mechanisms, an example of which is enzymes with antioxidant activity. In the specific case of zeaxanthin, it participates in the inhibition of cell neoplastic transformation.

VITAMIN E
The specific mechanism of its antioxidant action is not fully elucidated. The most probable hypothesis is based on the fact that tocopherol reacts with peroxyl radicals (ROO-), interrupting the oxidation chain reaction, most likely in this way it acts to protect the macula from oxidative stress.

OMEGA-3
Omega-3 involved in the formation of EPA and DHA acids, which in turn participate in brain development and retina, omega-3 are related to the prevention of cardiovascular diseases, dermal processes and inflammatory processes, which is an important part of AMD.