Age-related macular degeneration: the protective effects of omega-3 fatty acids as anti-inflammatory agents

Inflammation is involved in the pathogenesis of age-related macular degeneration

Age-related macular degeneration (AMD) causes pathological abnormalities and atrophy of the photoreceptors and the retinal pigment epithelium (RPE) in the macula. There are two types of AMD: the exudative or ‘wet’ form with choroidal neovascularization, and the atrophic or ‘dry’ form with geographic atrophy of the photoreceptors and RPE. With the exception of choroidal neovascularization suppression treatment for the late-stage wet form, to date there is no definitive treatment for AMD. Care for dry AMD and earlier stage wet AMD is limited to risk factor management, such as smoking cessation and body mass reduction. Vitamins and other nutritional supplements have also been shown to slow disease progression [1].

Increased evidence has shown that an inappropriate inflammatory response is involved in AMD pathogenesis [2]. Genetic epidemiological studies have repeatedly reported the association of genes coding for immunological molecules, such as complement factor H (CFH), complement factor B, complement component 2 (C2), C3, C7, complement factor I and CX3CR1 with AMD pathogenesis [3,4]. These molecules have been identified in the ocular lesions of AMD patients [5,6]. Inflammatory cells – in particular, macrophages – have also been histologically identified near various AMD lesions [7,8]. Activated microglia are also present in the macular lesions of AMD retinas [9].

Manipulation of the murine immune system can generate AMD-like phenotypes. Mice immunized with a protein-conjugated fatty acid derivative developed localized retinal lesions resembling geographic atrophy [10]. Genetic or pharmacological targeting of CCR3 or eotaxins inhibited injury-induced choroid neovascularization in mice [11]. We reported that the Ccl2^-/-/Cx3cr1^-/- mouse develops a broad spectrum of AMD-like lesions with early onset and high penetrance. The over-expression of several immunological molecules has been detected in the retinas of Ccl2^-/-/Cx3cr1^-/- mice [12–14].

Protective effects of omega-3 polyunsaturated fatty acids are mediated by the anti-inflammatory actions of docosahexaenoic acid & eicosapentaenoic acid

Large-scale epidemiological studies have confirmed the protective effects of omega (n)-3 polyunsaturated fatty acids (PUFAs) against AMD onset and progression [15–22]. n-3 and n-6 PUFAs are two classes of PUFAs that are metabolically and functionally distinct and often have opposing physiological functions. Mammals depend on the dietary intake of n-3 fatty acids from sources such as fish oil, as mammalian cells lack the enzymes required to synthesize the 18-C precursor of n-3 fatty acids, and to convert n-6 to n-3 fatty acids [23]. It has been reported that n-3 fatty acids exert preventive and therapeutic effects for an array of diseases, including atherosclerosis, Alzheimer’s disease, arthritis, inflammatory bowel disease, asthma and sepsis, all of which have inflammation as a key component in their pathology [24]. PUFAs have also been recommended as a risk management option for AMD [1]. n-3 fatty acids are highly concentrated in the brain and retina [25]. Although n-3 PUFAs also display neuroprotective bioactivity, most reports have focused on the role of n-3 PUFAs in anti-inflammatory signaling [26]. The n-3 PUFAs can be incorporated into cell membranes and reduce the amount of arachidonic acid available for the synthesis of proinflammatory eicosanoids [24]. Supplementation with n-3 PUFA also appears to be able to reduce the production of proinflammatory cytokines, such as IL-1, IL-6, IL-8 and TNF-α, which are released from activated immune cells [27]. A microarray-based study investigating the gene-expression profiles of human peripheral blood mononuclear cells concluded that eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) intake resulted in altered gene expression, including decreased expression of the genes involved in inflammatory pathways, such as NF-κB signaling, eicosanoid synthesis, scavenger-receptor activity and hypoxia signaling [28].

We evaluated the effects of an n-3-rich diet on the retinal lesions of the Ccl2^-/-/Cx3cr1^-/- mouse, a model that develops AMD-like features, including focal deep retinal lesions, RPE abnormalities, photoreceptor degeneration and A2E lipofuscin accumulation. The Ccl2^-/-/Cx3cr1^-/- mice that ingested a high n-3 fatty acid diet demonstrated a slower progression of retinal lesions compared with a low n-3 fatty acid diet group. Some mice given the high n-3 fatty acid diet also showed lesion reversal. We found a shunted arachidonic acid metabolism pathway that resulted in decreases in proinflammatory derivatives (prostaglandin E₂ and leukotriene B₄) and increases in anti-inflammatory derivatives (prostaglandin D₂). We also measured lower ocular TNF-α and IL-6 transcript levels in mice fed with high levels of n-3 fatty acids. Our findings in mice are in line with human studies on risk reduction in AMD after treatment with long-chain n-3 fatty acids [29].

Studies are searching for more potent derivatives of n-3 PUFAs

Although taking DHA, EPA and/or fish oil could provide protective effects against AMD onset or progression, the long-term intake of approximately DHA 2 g plus EPA daily, or consumption of enough fish to reach similar doses of DHA plus EPA, is not practical [28]. Great efforts have been made to find more potent derivatives of n-3 fatty acids. As one of the products of arachidonic acid metabolism, n-3 fatty acids play beneficial roles by serving as competitive inhibitors, decreasing the conversion of arachidonic acid to proinflammatory eicosanoids, such as prostaglandin and leukotriene, and serving as alternative substrates to produce E-series resolvins, such as resolvin E1, and D-series resolvins, such as resolvin D1 and protectin D1. The active derivatives also regulate the gene-expression profile to suppress proinflammatory genes [30,31]. It has been reported that EPA-derived resolvin E1 and DHA-derived resolvin D1/protectin D1 have much stronger anti-inflammatory activities in many models of diseases, such as colitis, periodontitis, acute kidney injury, peritonitis and exudative AMD [30,31]. Nanogram quantities of resolvin E1 and protectin D1 can promote phagocyte removal during acute inflammation by regulating leukocyte infiltration and increasing macrophage ingestion of apoptotic polymorphonuclear neutrophils in vivo and in vitro, while a microgram quantity of COX-2 inhibitor was required to achieve similar effects in the same testing system [32].

Nutrigenomics will become a new research avenue to determine which patients would benefit the most from n-3 fatty acid supplements to prevent AMD

While some nutritional supplements exert direct effects through intrinsic antioxidant properties or structural functions, many nutritional supplements undergo multiple metabolic alterations and, thus, have extensive interactions with genes. Understanding the interactions between nutrients and genes may help to target nutritional prevention strategies against disease towards the individuals who are most likely to respond. Nutrigenomics, or the study of interactions between genetic variability and nutritional factors, presents a new challenge to account for interindividual variations in disease susceptibility and individual responses to interventions [33]. This could have clinical relevance by predicting treatment outcomes and potentially preventing unwanted side effects in those individuals who may not benefit from treatment.

It has been reported that AMD-associated processes usually increase enzyme expression or activity of phospholipase A2, COX and 5-lipoxygenase, which are directly involved in arachidonic acid pathways [34]. The relationship between AMD and lipid-associated gene variants has been documented [35]. A pioneer study unveiled the possibility of predicting AMD nutrient-intervention outcomes using an individual’s profile of gene variations [36]. It is known that a combination of zinc and antioxidants (β-carotene, vitamin C and vitamin E) can produce a 25% overall reduction in the risk of developing advanced AMD over the next 5 years [37]. However, people carrying distinct AMD-susceptible single-nucleotide polymorphism profiles might differ in the levels of benefit from the intervention. In a study on the CFH Y402H/ARMS2 A69S variants and supplementation with antioxidants plus zinc, an interaction was observed between the Y402H variant and the intervention. For the individuals homozygous for the low-risk CFH variant (402YY), 34% in the placebo group progressed to advanced AMD, compared with 11% in the antioxidants-plus-zinc-treated group, resulting in a reduction of approximately 68%. For the individuals who are homozygous for the high-risk CFH variant (402HH), 44% in the placebo group progressed to advanced AMD, compared with 39% in the antioxidants-plus-zinc-treated group, resulting in a reduction of only 11%, indicating that the 402YY individuals benefited more from the treatment than the 402HH individuals. In addition, a similar interaction was observed in the groups taking zinc alone versus those taking no zinc [36].

In summary, the beneficial effects of nutritional supplements are supported by consistent data from human and animal studies. However, quantitative estimation of their benefit in combination with other impact factors is required to make sound dosage recommendations for genetically and environmentally high-risk populations. The role of n-3 fatty acids has been further examined in the Age-Related Eye Disease Study 2 (AREDS2), a randomized, controlled trial in individuals with an intermediate risk for AMD or with an advanced form of AMD in one eye. The AREDS2 study is led by Emily Chew of the National Eye Institute (MD, USA). Subjects are dosed with a supplement consisting of DHA 350 mg and EPA 650 mg, along with lutein/zeaxanthin, vitamins found in green, leafy vegetables. The results of this project could possibly provide more data for nutritional interventions for AMD.

Financial & competing interests disclosure

Jingsheng Tuo has received support from the National Eye Institute (MD, USA) NIH Intramural Research Program. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.