Fish/Fish Oil: Eye Disease Benefits

Omega-3 fights age-related macular degeneration 

Age-related macular degeneration (AMD), which is characterized by choroidal neovascularization (CNV), or blood vessel growth, is the primary cause of blindness in elderly individuals of industrialized countries. The prevalence of the disease is projected to increase 50% by the year 2020. There is an urgent need for new pharmacological interventions for the treatment and prevention of AMD.

Researchers from Massachusetts Eye and Ear/Schepens Eye Research Institute, Harvard Medical School and other institutions have demonstrated for the first time that the omega (ω)-3 long-chain polyunsaturated fatty acids (LCPUFAs), DHA and EPA, and their specific bioactive products derived from the cytochrome P450 (CYP) pathway, can influence choroidal neovascularization (CNV) and vascular leakage by modulating micro-environmental immune cell recruitment to the site of these lesions. Their findings were

"These are the first results showing that omega (ω)-3 LCPUFAs and their CYP derived metabolites can regulate choroidal angiogenesis in vivo. The fact that this can be accomplished with physiologically relevant naturally occurring lipid metabolites is of significant clinical interest as these molecules are readily available and considered to be safe. Our findings not only show promising therapeutic potential for resolution of neovascular AMD, but also for other conditions or diseases that involve pathologic angiogenesis and inflammation,” said Kip Connor, Ph.D., Assistant Professor in Ophthalmology at Harvard Medical School and senior author of the paper.

The omega (ω)-3 and ω-6 long-chain polyunsaturated fatty acids (LCPUFAs) are two classes of dietary lipids that are essential fatty acids and have opposing physiological effects. To evaluate the effect of LCPUFAs on CNV development, researchers fed mice one of three experimental diets beginning two weeks before CNV induction by laser photocoagulation. The experimental diets were enriched with either ω-3 or ω-6 LCPUFAs, or in the case of the control diet, devoid of the primary ω-3 or ω-6 LCPUFAs. The lesion size and vascular leakage were significantly smaller in animals fed with ω-3 LCPUFAs. To gain mechanistic insight into the effect of dietary ω-3 LCPUFAs on CNV regression, researchers analyzed the lipid profiles of these mice and identified endogenous CYP-generated metabolites. Specifically, 17,18-EEQ and 19,20-EDP, derived from the CYP-pathway were identified by liquid chromatography- mass spectrometry (LC–MS/MS) and found to confer protection. Systemic immune-cell recruitment and adhesion-molecule regulation were significantly dampened in mice receiving ω-3s, thereby suppressing inflammation that is thought to exacerbate this disease. These findings provide a unique mechanism whereby specific CYP derived lipid metabolites regulate angiogenesis in a mouse model of AMD.

The researchers demonstrated that dietary supplementation of omega (ω)-3 long-chain polyunsaturated fatty acids (LCPUFAs) mediates choroidal neovessel regression in a well-characterized murine model of neovascular AMD. The cytochrome P450 (CYP) enzymes catalyze the epoxidation of these ω-3 LCPUFAs to form the eicosanoids 17,18-epoxyeicosatetraenoic acid (EEQ) and 19,20-epoxydocosapentaenoic acid (EDP), which were identified as key lipid mediators of disease resolution.

Their findings show promising therapeutic potential in AMD disease resolution.

"Given the prevalence of neovascular eye disease, the potential impact of this study is highly significant. We have identified unique endogenous lipid biometabolites that are able to inhibit pathologic retinal angiogenesis, a major driver of vision loss worldwide. It is our hope that future studies will allow us to develop specific therapeutics that harness this knowledge resulting in a greater visual outcome and quality of life for patients suffering from these sight-threatening diseases," said lead author Ryoji Yanai, M.D., Ph.D.

Omega-3 Reduces Risk of Age-Related Macular Degeneration

Regular consumption of fish and omega-3 fatty acids found in fish is associated with a significantly reduced risk of developing age-related macular degeneration in women, according to a report the June, 2011 issue of Archives of Ophthalmology, one of the JAMA/Archives journals.

"An estimated nine million U.S. adults aged 40 years and older show signs of age-related macular degeneration (AMD)," the authors write as background information in the article. "An additional 7.3 million persons have early age-related macular degeneration, which is usually associated with moderate or no vision loss but does increase the risk of progression to advanced age-related macular degeneration."

Using the Women's Health Study, William G. Christen, Sc.D., of Brigham and Women's Hospital and Harvard Medical School, Boston, and colleagues collected data on 38,022 women who had not been diagnosed with age-related macular degeneration. Information on women's eating habits was obtained via questionnaire at the beginning of the study and included information on intake of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) [Omega-3 fatty acids found in fish], and arachidonic acid and linoleic acid (omega-6 fatty acids). During ten years of follow-up, additional questionnaires tracked the women's eye health, with specific focus on diagnosis of age-related macular degeneration.

Over the course of follow-up, 235 cases of age-related macular degeneration were reported. In analyses that adjusted for age and treatment assignment, women who consumed the most DHA compared with women who consumed the lowest amount had a 38 percent lower risk of developing age-related macular degeneration. Similar results were observed for higher intake of EPA and for higher consumption of both types of acid together.

Results for fish intake showed that consumption of one or more servings of fish per week, when compared to less than one per month, was associated with a 42 percent lower risk of age-related macular degeneration. "This lower risk appeared to be due primarily to consumption of canned tuna fish and dark-meat fish."

For omega-6 fatty acids, higher intake of linoleic acid but not arachidonic acid was associated with an increased risk of age-related macular degeneration, however this association was non-significant after adjustment for other risk factors and fats.

"In summary, these prospective data from a large population of women with no prior diagnosis of AMD indicate that regular consumption of DHA and EPA and fish significantly reduced the risk of incident AMD," the authors conclude.

Omega 3's prevent several forms of blindness

Omega-3 fatty acids –fats commonly found in fish oil – wee shown several years ago to prevent retinopathy, a major form of blindness, in a mouse model of the disease. A follow-up study, from the same research team at Children's Hospital Boston, now reveals exactly how omega-3's provide protection, and provides reassurance that widely used COX-inhibiting drugs like aspirin and NSAIDs don't negate their benefit. The findings, published in the February 9, 2011 issue of Science Translational Medicine, also suggest that omega-3's may be beneficial in diabetes.

Retinopathy – an eye disease caused by the proliferation of tortuous, leaky blood vessels in the retina – is a leading cause of blindness, affecting 4.1 million Americans with diabetes (a number expected to double over the next 15 years) and many premature infants. Another 7 million-plus Americans have age-related macular degeneration (AMD); this too will increase as the population ages. The most common "wet" form of AMD is also caused by abnormal blood vessel growth.

The ability to prevent these "neovascular" eye diseases with omega-3 fatty acids could provide tremendous cost savings, says Children's ophthalmologist Lois Smith, MD, PhD, senior investigator on the study. "The cost of omega-3 supplementation is about $10 a month, versus up to $4,000 a month for anti-VEGF therapy," she says, referring to drugs such as Macugen and Lucentis used in AMD and diabetic retinopathy. "Our new findings give us new information on how omega-3s work that makes them an even more promising option."

Omega-3 fatty acids, highly concentrated in the retina, are often lacking in Western diets, which tend to be higher in omega-6 fatty acids. In Smith's previous study mice fed diets rich in omega-3 fatty acids by Smith's team had nearly 50 percent less pathologic vessel growth in the retina than mice fed omega-6-rich diets. Smith and colleagues further showed that the omega-3 diet decreased inflammatory messaging in the eye.

In the new study, they document another protective mechanism: a direct effect on blood vessel growth (angiogenesis) that selectively promotes the growth of healthy blood vessels and inhibits the growth of abnormal vessels.

In addition, Smith and colleagues isolated the specific compound from omega-3 fatty acids that has these beneficial effects in mice (a metabolite of the omega-3 fatty acid DHA, known as 4-HDHA), and the enzyme that produces it (5-lipoxygenase, or 5-LOX). They showed that COX enzymes are not involved in omega-3 breakdown, suggesting that aspirin and NSAIDs – taken by millions of Americans -- will not interfere with omega-3 benefits.

"This is important for people with diabetes, who often take aspirin to prevent heart disease, and also for elderly people with AMD who have a propensity for heart disease," says Smith. (One drug used for asthma, zileuton, does interfere with 5-LOX, however.)

Finally, the study demonstrated that 5-LOX acts by activating the PPAR-gamma receptor, the same receptor targeted by "glitazone" drugs such as Avandia, taken by patients with type 2 diabetes to increase their sensitivity to insulin. Since these drugs also increase the risk for heart disease, boosting omega-3 intake through diet or supplements might be a safer way to improve insulin sensitivity in patients with diabetes or pre-diabetes. "There needs to be a good clinical study in diabetes," Smith says.

Smith works closely with principal investigators at the National Eye Institute who are conducting an ongoing multicenter trial of omega-3 supplements in patients with AMD, known as AREDS2. The trial will continue until 2013. An earlier retrospective study, AREDS1, found higher self-reported intake of fish to be associated with a lower likelihood of AMD.

In addition, Smith is collaborating with a group in Sweden that is conducting a clinical trial of omega-3 fatty acids in premature infants, who are often deficient in omega-3. That study will measure infants' blood levels of omega-3 products and follow the infants to see if they develop retinopathy. If results are promising Smith will seek FDA approval to conduct a clinical trial in premature infants at Children's.

Meanwhile, in her lab work, Smith plans to continue seeking beneficial lipid pathways, while looking for the most harmful omega 6 metabolites. "We found the good guys, now we'll look for the bad ones," says Smith. "If we find the pathways, maybe we can selectively block the bad metabolites. We would hope to start with drugs that are already available."

Omega-3s in fish, seafood may protect seniors' eyes

Seniors interested in lifestyle choices that help protect vision will be encouraged by a Johns Hopkins School of Medicine study, and people concerned about glaucoma can take heart from work on early detection by the University of Miami Miller School of Medicine. Both studies are published in the December, 2010 issue of Ophthalmology, the journal of the American Academy of Ophthalmology.

Researchers at Wilmer Eye Institute, Johns Hopkins School of Medicine, wanted to know how the risk of age-related macular degeneration (AMD) would be affected in a population of older people who regularly ate fish and seafood, since some varieties are good sources of omega-3 fatty acids. A diet rich in omega-3s probably protects against advanced AMD, the leading cause of blindness in whites in the United States, according to the Age-Related Eye Disease Study (AREDS) and other recent studies. High concentrations of omega-3s have been found in the eye's retina, and evidence is mounting that the nutrient may be essential to eye health. The new research, led by Sheila K. West, PhD, was part of the Salisbury Eye Evaluation (SEE) study.

Food intake information with details on fish and shellfish consumed was collected over one year using a validated questionnaire for 2,391 participants aged 65 to 84 years who lived along Maryland's Eastern Shore. After dietary assessment was complete, participants were evaluated for AMD. Those with no AMD were classified as controls (1,942 persons), 227 had early AMD, 153 had intermediate-stage disease, and 68 had advanced AMD. In the advanced AMD group, the macular area of the retina exhibited either neovascularization (abnormal blood vessel growth and bleeding) or a condition called geographic atrophy. Both conditions can result in blindness or severe vision loss.

"Our study corroborates earlier findings that eating omega-3-rich fish and shellfish may protect against advanced AMD." Dr. West said. "While participants in all groups, including controls, averaged at least one serving of fish or shellfish per week, those who had advanced AMD were significantly less likely to consume high omega-3 fish and seafood," she said.

The study also looked at whether dietary zinc from crab and oyster consumption impacted advanced AMD risk, but no significant relationship was found. Zinc is also considered protective against AMD and is included in an AMD-vitamin/nutrient supplement developed from the AREDS study. Dr. West speculated that her study found no effect because the levels of zinc obtained from seafood/fish were low compared to supplement levels.

A side note: fish and shellfish were part of the normal diet of the study population, rather than added with the intention of improving health. The links between fish consumption, omega-3s and healthy lifestyles were not widely known in the early 1990s when the dietary survey was conducted. In fact, some of the study participants who consumed the most seafood were also smokers and/or overweight, two factors usually associated with AMD and other health risks.

 Omega-3 Supplements Protect Eyes

Omega-3 fatty acids found in fatty fish such as tuna and salmon may protect against progression of age-related macular degeneration (AMD), but the benefits appear to depend on the stage of disease and whether certain supplements are taken, report researchers at the Laboratory for Nutrition and Vision Research (LNVR), Jean Mayer USDA Human Nutrition Research Center on Aging (HNRCA) at Tufts University.

The researchers calculated intakes of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) from dietary questionnaires administered to 2,924 men and women, aged 55 to 80 years, participating in an eight-year supplement trial, the Age-Related Eye Disease Study (AREDS) of the National Eye Institute (NEI). The AREDS trial results suggest taking supplements of antioxidants plus zinc prevents progression of late-stage AMD. AREDS study participants were randomly allocated to receive either a placebo or supplements containing the antioxidants vitamins C and E and beta carotene, the minerals zinc and copper, or a combination of both.

"In our study, we observed participants with early stages of AMD in the placebo group benefited from higher intake of DHA, but it appears that the high-dose supplements of the antioxidants and/or the minerals somehow interfered with the benefits of DHA against early AMD progression," says senior author Allen Taylor, PhD, director of the LNVR at the USDA HNRCA. Taylor is also a professor at the Friedman School of Nutrition Science and Policy at Tufts and Tufts University School of Medicine (TUSM).

The antioxidant supplements did not seem to interfere with the protective effects of DHA and EPA against progression to advanced stages of AMD. Participants who consumed higher amounts of DHA and EPA appeared to have lower risk of progression to both wet and dry forms of advanced AMD. The results are published in the British Journal of Ophthalmology.

"Data from the present study also shows the supplements and omega-3 fatty acids collaborate with low-dietary glycemic index (dGI) diets against progression to advanced AMD," says corresponding author Chung-Jung Chiu, DDS, PhD, a scientist in the LNVR and an assistant professor at TUSM. "Our previous research suggests a low-GI diet may prevent AMD from progressing to the advanced stage. We hypothesize that the rapid rise of blood glucose initiated by high-GI foods results in cellular damage that retinal cells cannot handle, thus damaging eye tissues."

dGI is a scale used to determine how quickly carbohydrates are broken down into blood sugar, also known as blood glucose. Foods such as sweetened drinks, sodas and white bread are high-GI because they trigger a sharp rise and fall of blood sugar. Low-GI foods, such as whole grain versions of pasta and bread, have a milder effect on blood sugar response. Earlier data published by Taylor and Chiu suggests that daily substitution of five slices of whole grain bread for white bread out of a total intake of 250 g of carbohydrate might cut out almost 8% of advanced AMD over five years. This is readily achievable with little diet behavior modification.

Eating two to three servings of fatty fish such as salmon, tuna, mackerel, shellfish, and herring every week would achieve the recommended daily intake of DHA and EPA. However, the majority of AREDS participants and Americans eat a much lower level than recommended. "If changing dietary habits is not easy, supplementation is an option," says Chiu.

The authors stress it is still premature to conclude dietary recommendations for people with AMD and more studies are warranted. "Taken together, these data indicate that consuming a diet with higher levels of omega-3 fatty acids, antioxidants and low-GI foods may delay compromised vision due to AMD," says Taylor. "The present study adds the possibility that the timing of a dietary intervention as well as the combination of nutrients recommended may be important."

AMD is a progressive disease that attacks central vision, resulting in a gradual loss of eyesight and, in some cases, blindness. The NEI reports that AMD is the most common causes of non-remediable vision loss in Americans over 60.

In another study, Archives of Ophthalmology recently published a meta analysis on omega-3 fatty acid and fish intake and its effect on the prevention of age-related macular degeneration (AMD). This study identified 274 abstracts, 3 prospective cohort, 3 case-control, and 3 cross-sectional studies.

Using quantitative methods, a high dietary intake of omega-3 fatty acids was associated with a 38% reduction in the risk of late AMD. Fish intake (2x per week) was associated with reduced risk of early and late AMD.


More omega-3 and AMD specific studies need to be conducted to further investigate omega-3¹s effect on AMD.

Ref: Arch Ophthalmol. 2008;126(6):826-833. 

Higher intake of fish and vitamin D levels linked to lower risk of age-related macular disease

Individuals who have higher dietary intake of foods with omega-3 fatty acids and higher fish consumption have a reduced risk of advanced age-related macular degeneration, while those with higher serum levels of vitamin D may have a reduced risk of the early stages of the disease, according to two reports in the May , 2007issue of Archives of Ophthalmology, one of the JAMA/Archives journals.

Age-related macular degeneration (AMD) occurs when the macula, the area at the back of the retina that produces the sharpest vision, deteriorates over time. It is the most common cause of blindness among older adults in the United States, affecting more than 7 million individuals older than 40 years, according to background information in the articles. The prevalence of AMD is likely to increase as the population ages. There is currently no known way to prevent the condition, but research has begun to identify potentially modifiable risk factors and nutrient-based treatments.

The Age-Related Eye Disease Study Research Group assessed 4,519 individuals who were age 60 to 80 when they enrolled in 1992 through 1998. At that time, photographs were taken of their retinas to determine if they had AMD, and if so, to which of four stages the condition had progressed. The participants also completed a food frequency questionnaire that measured how often they consumed foods rich in certain vitamins, minerals and other nutrients, such as omega-3 fatty acids commonly found in tuna, salmon and other fish.

A total of 1,115 participants did not have any symptoms of AMD at the beginning of the study, and were compared with those who did, including 658 individuals with neovascular (severe) AMD. "Dietary total omega-3 long-chain polyunsaturated fatty acid intake was inversely associated with neovascular AMD, as was docosahexaenoic acid," or DHA, a fatty acid that previous evidence suggests affects the retina, the authors write. "Higher fish consumption, both total and broiled/baked, was also inversely associated with neovascular AMD." Eating more than two medium (4-ounce) servings of fish per week or more than one medium serving of broiled or baked fish was associated with the lowest risk for advanced AMD.

Omega-3 fatty acids may influence processes involved in the development of blood vessel– and nerve-related diseases of the retina, the authors write. For instance, DHA may protect the retina by influencing which genes turn on and off, while fatty acids overall may eventually form compounds that promote cell survival and proper blood vessel function, reduce inflammation and maintain energy balance.

"These results and those from other observational analytic investigations suggest that modifying diet to include more foods rich in omega-3 long-chain polyunsaturated fatty acids could result in a reduction in the risk of having neovascular AMD," the authors conclude. Clinical trials would provide further information about whether diet changes or supplements could prevent the development of advanced AMD.

In a related study, Niyati Parekh, Ph.D., R.D., of the University of the Medicine and Dentistry of New Jersey, New Brunswick, and the University of Wisconsin–Madison, and colleagues analyzed data from 7,752 individuals (including 11 percent with AMD) who were part of the National Health and Nutrition Examination Survey, a large study designed to represent the entire U.S. population. Participants were enrolled in the study between 1988 and 1994. They had physical examinations that included blood and urine samples, photographs of the retinas, and interviews and questionnaires regarding sociodemographics, lifestyle habits and food intake.

"Levels of serum vitamin D were inversely associated with early AMD but not advanced AMD," the authors write. When participants were split into five groups based on level of vitamin D in the blood, those in the highest group had a 40 percent lower risk of early AMD than those in the lowest group. "Milk intake was inversely associated with early AMD. Fish intake was inversely associated with advanced AMD."

Vitamin D may reduce the risk of AMD by reducing inflammation or by preventing the growth of new blood vessels in the retina, which contributes to some forms of AMD, the authors speculate. "This study provides evidence that vitamin D may protect against AMD," the authors conclude. "However, at this time there is insufficient epidemiologic evidence of the relationship between vitamin D level and AMD to make recommendations regarding optimum serum vitamin D levels or milk and fish intake to protect against AMD or its progression. The results of the present research warrant further investigation for confirmation of the vitamin D-AMD association in other population studies."