• Research Summaries - Omega-3 Fatty Acids

• OmegaAdvance_FAQs

Balancing Omega Fats for Better Health

EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) are the two main fatty acids found in fish, especially oily fish such as salmon, sardines and tuna. They belong to a family of essential nutrients known as omega-3 fatty acids.

While studies have shown that a balanced intake of omega-6 and omega-3 fatty acids is health promoting, Americans tend to consume about 5 times more omega-6 fats than is recommended, mostly from common cooking oils, vegetable margarine and meats. Therefore, health experts advise a greater intake of omega-3 fats to achieve a better balance between these two omega families. Improving that balance promotes a healthier cardiovascular system. Emerging research suggests that it may benefit visual health as well.

Omega-3 Fats and Visual Wellness

EPA and DHA play a pivotal role in protecting the nerve cells and vessels in the eye’s retina 1. The omega-3 fatty acids function normally to help decrease production of damaging free radicals and fight inflammation – a process that has been implicated in declining macular health.

Over the past few years, a number of population health studies report that consuming higher levels of EPA and DHA or fish may improve the odds of retaining a healthy macula 1,2. Participants in the AREDS clinical trial with the highest intake of DHA and EPA, for example, were found to have a better chance of maintaining macular health 3. While further study is needed to confirm these initial findings, consuming more dietary omega-3 fats is recommended by leading health authorities to support cardiovascular health.

Heart Healthy Omega-3 Fats

A recent review confirms that a regular intake of omega-3 fats can help keep the heart and arteries healthy 4,5. The ways that omega-3 fatty acids support cardiovascular function are still being studied, but research has shown that they promote regular heart beat rhythm, help maintain healthy triglyceride levels and help slow the growth rate of plaque in blood vessels. How much omega-3 fat is recommended? The American Heart Association suggests that healthy people eat a variety of fish, preferably fatty fish, at least twice weekly. For those that do not eat coldwater fish regularly, supplemental fish oil can help fill the dietary omega-3 gap.

How is OmegaAdvance Unique?

The fish oil in OmegaAdvance is sourced from the purest wild sardine, anchovy and mackerel fished in pristine, deep waters where there are significantly less environmental impurities. This fish oil, which undergoes further purification to help eliminate mercury and other marine contaminants, has achieved verification by the US Pharmacopoeia, the most rigorous quality assurance verification.

OmegaAdvance contains vitamin E and polyphenols from standardized olive leaf extract to help protect EPA and DHA from oxidation. The polyphenols in olive leaf extract have been shown to act as antioxidants in the body 6. OmegaAdvance also contributes lutein and zeaxanthin, providing a level that nearly doubles the typical dietary intake of these nutrients. Plentiful in green leafy vegetables, lutein and zeaxanthin work to filter out blue light that can be damaging to the eye’s retina 7. The absorption of lutein and zeaxanthin is enhanced by the fatty acids in OmegaAdvance.

OmegaAdvance is a perfect add-on to other ScienceBased Health formulations and provides the best benefit when incorporated into an overall healthy lifestyle.

1. Augood C, et al. Oily fish consumption, dietary docosahexaenoic acid and eicosapentaenoic acid intakes, and associations with neovascular age-related macular degeneration. Am J Clin Nutr 88:398-406, 2008.
2. SanGiovanni JP and Chew EY. The role of omega-3 long-chain polyunsaturated fatty acids in health and disease of the retina. Prog in Retinal Eye Res 24:87-138, 2005.
3. Chua B, et al. Dietary fatty acids and the 5-year incidence of age-related maculopathy. Archives Ophthalmol 124:981-6, 2006.
4. Chew, E. Dietary lipid intake and incident advanced age-related macular degeneration (AMD) in the Age-Related Eye Disease Study (AREDS). Abs 2382, ARVO Annual Meeting, Ft. Lauderdale FL, May, 2005.
5. Wang C, et al. n-3 Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review. Am J of Clin Nutr 84:5-17, 2006.
6. O'Keefe JH, et al. Effects of omega-3 fatty acids on resting heart rate, heart rate recovery after exercise, and heart rate variability in men with healed myocardial infarctions and depressed ejection fractions. Am J Cardiology 97:1127-30, 2006.
7. Weinbrenner T, et al. Olive oils high in phenolic compound modulate oxidative/antioxidative status in men. J Nutr 134:2314-21, 2004.
8. Stahl. W. Review: Macular carotenoids: lutein and zeaxanthin. Dev Ophthalmol 38:70-88, 2005.
   

Trio of Nutrients May Help Combat Type 2 Diabetes
Trio of Nutrients May Help Combat Type 2 Diabetes
Take Positive Steps to Counter Type 2
When it comes to preventing type 2 diabetes – or controlling blood sugar in those who already have it – the factors with the biggest punch by far are pretty straight forward: lose weight if you need to, exercise regularly, and eat a healthy Mediterranean or low glycemic index diet.
In addition, researchers continue to explore the contribution of individual nutrients in combating type 2. This issue of Staying Healthy highlights recent findings related to omega-3 fats, magnesium and cinnamon.
New Understanding of Omega-3 Benefits
The American Diabetes Association (ADA) already recommends that people with diabetes eat 2-3 servings of fish weekly. That’s because studies have shown that consuming more omega-3s can help stave off coronary heart disease in diabetics, who have a greater risk of developing cardiovascular conditions than non-diabetics.
New research also points to a potential role for the omega-3 fatty acids EPA and DHA in helping to activate anti-diabetic genes (1). The study, carried out in animals, found that these omega-3 fatty acids activate genes that help regulate fat cells and maintain blood sugar balance. The factor activated by the omega-3s (transcription factor PPARy) is one that’s targeted by a number of anti-diabetic drugs. If the findings hold true in humans, it may mean additional benefits for those meeting ADA guidelines for omega-3 intake.
Study Underscores Importance of Magnesium
Low blood levels of magnesium occur in about 25-30% of people with type 2, and are more common in those with poorly controlled diabetes. Many studies have also reported that a better intake of this mineral can lower the risk of developing type 2. Results from a long term study appear to confirm that association (2).
Led by investigators at the University of North Carolina at Chapel Hill, the study recruited nearly 4,500 young adults 18-30 years of age who were free of diabetes and assessed their intake of dietary magnesium. Three hundred and thirty cases of diabetes developed over the next 20 years of follow-up.
People with the highest magnesium intake were 47% less likely to acquire type 2 compared to those eating the least. Those getting the most averaged about 200 mg of magnesium for every 1,000 calories consumed compared with the lowest intake group who got about 100 mg of the mineral per 1,000 calories.
High magnesium consumers also had lower blood levels of inflammatory markers, and less insulin resistance (the inability of some cells to respond to insulin). One of magnesium’s jobs is to help insulin move glucose out of the blood stream and into cells.
As mentioned in the March Staying Healthy, a recently published survey found that less than ½ of US adults consume recommended magnesium levels. Dietary sources include beans, whole grains, broccoli, squash, and green leafy veggies, seeds, and nuts (especially almonds). Dairy, meats, chocolate, and coffee also provide magnesium, as does "hard" water.
Cinnamon Useful for Some Diabetics
From the UK comes a study suggesting that cinnamon may be useful in patients with poorly controlled type 2 diabetes (3). Fifty eight type-2 patients with high HbA1c (a key measure of glucose control) were given 2 grams of cinnamon or placebo daily for 3 months. Compared to placebo-takers, those supplemented with cinnamon experienced a significant reduction in HbA1c as well as a decrease in blood pressure (both systolic and diastolic values).
According to the researchers, this spice could be a useful addition to conventional drugs for diabetics who have trouble controlling their blood sugar levels.
References
1. 1. Yu, YH et al. The function of PPARy and dietary fish oil effect on the expression of lipid and glucose metabolism related genes. J Nutr Biochem (Epub ahead of print) Oct, 2010.
2. 2. Kim DJ et al. Magnesium intake in relation to systemic inflammation, insulin resistance and the incidence of diabetes. Diabetes Care (Epub ahead of print ) Aug, 2010.
3. 3. Akilen R et al. Glycated hemoglobin and blood pressure-lowering effect of cinnamon in multi-ethnic Type 2 diabetic patients in the UK: a randomized, placebo-controlled, double-blind clinical trial. Diabetes Med 27:1159-67, 2010.
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Exploring New Frontiers in Fish Oil and Health
Exploring New Frontiers in Fish Oil and Health
Omega-3s May Play a Role in Joint Health
We know that fish-sourced omega-3 fats are good for the heart and eyes, but could they have a role in joint health too? The results of several small studies suggest that they might (1).
At the same time, many with osteoarthritis find that supplemental glucosamine has positive effects in reducing knee pain, despite some conflicting results from clinical trials. A study has now evaluated a combination of omega-3 fatty acids and glucosamine in people suffering from osteoarthritis, and the results, while preliminary, appear to be promising (2).
A total of 177 patients with moderate-to-severe hip or knee osteoarthritis were tested over a period of 26 weeks in a randomized, double-blind, comparison study. The aim was to see if a combination of glucosamine sulfate (1500 mg/day) plus EPA and DHA (200 mg/day) was the same, inferior or superior to glucosamine alone.
The authors report that the combination was better at reducing pain and morning stiffness, suggesting that the ingredients might act synergistically. They theorize that glucosamine sulfate supports the rebuilding of cartilage while the omega-3s target arthritis-associated inflammation.
Fish Oil and Mental Health in Young People
Many drugs used to treat mental illness come with substantial costs and side effects. Could a relatively inexpensive and safe alternative actually help prevent mental disorders in young people at risk of developing them? That’s the promise of new findings from researchers at the Medical University of Vienna (3).
Those investigators tested 1,200 mg of EPA and DHA daily or placebo in 81 young adults (aged 13-25) who showed early or low-level symptoms of a psychiatric disorder such as schizophrenia, or who had a close relative with a psychotic disorder. The participants took the supplements for 12 weeks and were followed for another 40 weeks – a year in total.
At the study’s end, only 5% of the fish oil group had gone on to develop a mental disorder compared to 28% among the placebo takers. Those taking fish oil also experienced fewer symptoms and improved their ability to function.
The researchers point out that these results compare favorably to those of clinical trials involving anti-psychotic medications for prevention of mental disorders. But they also caution that more studies are needed to see whether fish oil is effective for older people or for those who already have an existing psychiatric condition.
Fighting Inflammation, Not Fat
While it’s clear that we need to press full speed ahead with the fight against obesity, the unsettling reality is that many Americans are still losing the battle of the bulge. So some researchers are looking at ways to make the extra pounds we carry less harmful to health.
One approach is to blunt the pro-inflammatory effects of excess fat tissue. By tamping down the immune system’s response to obesity, we might be able to prevent inflammation that contributes to heart disease, diabetes and other chronic problems.
In one double-blind study, investigators looked at the potential of an ‘anti-inflammatory mix’ to counter inflammation in 36 overweight men (4). The dietary mix consisted of moderate levels of fish oil combined with green tea extract, resveratrol, vitamins C and E, and lycopene-rich tomato extract – all selected for their anti-inflammatory actions. They examined the mixture’s influence on a wide variety of genes, and report a multitude of subtle changes indicating that the mix favorably influences inflammation of fat tissue, oxidative stress, and the ability of arteries to expand when needed.
References
1. Rosenbaum CC, et al. Antioxidants and antiinflammatory dietary supplements for osteoarthritis and rheumatoid arthritis. Altern Ther Health Med 16:32-40, 2010.
2. Gruenwald J, et al. Effect of glucosamine sulfate with or without omega-3 fatty acids in patients with osteoarthritis. Adv Ther 26:858-71, 2009.
3. Amminger GP, et al. Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial. Arch Gen Psychiatry 67:146-54, 2010.
4. Bakker GCM, et al. An anti-inflammatory dietary mix modulates inflammation and oxidative and metabolic stress in overweight men: a nutrigenomics approach. Am J Clin Nutr 911044-59, 2010.
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In the News: Anti-aging effects of Blueberries, Omega-3s & Salt Reduction
In the News: Anti-aging effects of Blueberries, Omega-3s & Salt Reduction
Can Blueberries Aid Memory in Older Adults?
The Blueberry – and its Scandinavian counterpart, the Bilberry – are rich sources of flavonoids, particularly the kind known as anthocyanins. Researchers have long been interested in the effects of these flavonoids on brain functioning. Studies, for example, have shown positive mental gains in older animals when blueberries were added to their diet. [See: Staying Healthy, Jan, 2008 at sciencebasedhealth.com]. Now, results from a small pilot study conducted by the US Department of Agriculture and Tufts University suggest that these berries may support brain function in people too (1).
In this study, the first of its kind, older people with early memory problems and an increased risk of dementia and Alzheimer’s, took a daily drink of about 500 ml (17 ounces) of blueberry juice for a 3 month period. Results showed significant improvements in learning and word-list recall, a measure of short-term memory. A trend toward reduced symptoms of depression was also observed.
While the investigators stressed that these findings need to be confirmed in a larger and controlled trial, they were encouraged that consistent supplementation with blueberries could be a way to forestall brain aging. It’s believed that the flavonoids in blueberries and bilberries may enhance connections and communication between nerve cells, and stimulate nerve cell regeneration.
Omega-3 Linked to Younger Biological Age
Telomeres are the genetic material at the end of chromosomes that shorten as cells replicate (the process by which cells divide and make copies of themselves). With each replication telomeres get shorter, and when they are used up, the cells are destroyed. Many experts believe that telomere length may be a marker of biological aging.
Previous studies have shown that telomeres are vulnerable to oxidative stress, and certain antioxidant nutrients have been linked to maintaining telomere length. [See: Staying Healthy, Nov, 2009].
Researchers from the University of California, San Francisco recently reported that higher blood levels of the omega-3 fatty acids EPA and DHA are linked to a lower rate of telomere shortening over a 5 year period in people with stable coronary artery disease (2). Telomeres shortened more rapidly in those with the lowest blood levels of EPA and DHA, while they grew shorter more slowly in those with the highest levels of these 2 fatty acids. Omega-3s have been shown to reduce markers of oxidative stress and increase levels of antioxidant enzymes, which may account for their protective effect.
The researchers noted that several studies have shown that high dietary intake of marine omega-3s is associated with longer survival in people with cardiovascular disease. While it’s not established that the omega-3 and telomere connection plays a role in the better survival rate, it could be a contributing factor.
Less Salt, Big Benefits
A new report published in the New England Journal of Medicine concludes that lowering the amount of salt people eat by even a small amount could meaningfully reduce cases of heart disease, stroke and heart attacks (3). The report found that everyone would benefit from less salt, but people at higher risk for heart problems would benefit the most. If everyone consumed even ½ a teaspoon less salt daily, there would be between 54,000 and 99,000 fewer heart attacks each year according to the estimates.
The idea that only certain people need to limit salt is a misconception, since blood pressure increases with age. Nearly 1/3 of adults have hypertension, and another 1/3 currently have pre-hypertension. To cut back on salt intake use the salt shaker less, and more importantly, read the sodium content on labels of processed foods – the source of about 75% of our dietary salt intake.
References
1. Krikorian R, et al. Blueberry supplementation improves memory in older adults. J Agri Food Chem, Epub Jan 4, 2010.
2. Farzaneh-Far R, et al. Association of marine omega-3 fatty acid level with telomeric aging in patients with coronary heart disease. J American Medical Assoc 303:250-7, 2010.
3. Bibbins-Domingo K, et al. Projected effect of dietary salt reductions on future cardiovascular disease. N Engl J Med, Epub Jan 20, 2010.
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In the News: Med Diet & Mood, AMD, & Fish Tips
In the News: Med Diet & Mood, AMD, & Fish Tips
Can the Med-Style Diet Influence Mood?
Are you eating a diet packed with fruits and veggies, beans, cereals, nuts, olive oil and fish? Including a little red wine? Avoiding junk food and limiting meat and dairy?
If so, you’re following the Mediterranean style diet – a diet that’s good for the heart, the waistline, and for reducing the risk of diabetes and some cancers. Research now suggests that this way of eating might support a positive outlook as well.
Med-Style Diet May Help Battle Depression
Investigators from Spain examined the diets of over 10,000 participants, and each person was assigned a score that reflected how closely their eating habits adhered to a Med-style diet. All the volunteers were free of depression when the study began, and were followed for an average of nearly 4 ½ years. Individuals who followed the Med-style dietary pattern most closely were 30% less likely to suffer from depression than those with the lowest scores (1).
Since these findings simply represent an association between diet and mental outcome, clinical trials will be necessary to confirm them. However, many scientists are convinced that some of the damaging inflammatory and metabolic processes involved in cardiovascular disease also play a role in mental health. In addition, the kinds of fatty acids present in the Med-style diet support good nerve cell function, and the vitamin and minerals this diet provides are needed for the body’s manufacture of neurotransmitters.
Omega-3 Intake and Age-related Vision Loss
Age-related macular degeneration (AMD) is a degenerative disease of the retina that causes loss of central vision. One form, ‘wet’ AMD, occurs when blood vessels grow abnormally beneath the macula and leak, eventually scarring the macula. The other form, ‘dry’ AMD happens when normal tissue in the macular slowly disappears, resulting in a pale area called central geographic atrophy.
It’s known that the omega-3 fatty acids, EPA and DHA, play an important role in the inner layer of nerve cells in the retina, and some studies have already linked better intake of these fatty acids to AMD risk reduction. A new study, involving a sub-group of participants in the AREDS trial, supports these earlier findings.
All of the participants in the study were considered to be at moderate-to-high risk of advanced AMD. Over 12 years of study, the researchers found that intake of omega-3 fats were related to risk for both wet and dry AMD. Those who consumed the most EPA and DHA had a 30% lower risk of developing both types of AMD compared to those who ate the least (2).
How Fish Is Cooked Is Important
Seafood safely is an important consideration. It’s best to eat some of the larger species infrequently, as they may contain more heavy metals and other marine contaminants (see Staying Healthy “Be Savvy about Seafood Safety”, Nov 2009).
Also, be aware that how fish is prepared can influence the heart and eye health benefits of the omega-3 fats they contain. The high heat of frying, for example, can cause deterioration of EPA and DHA, and frying oil also leaches out these fatty acids. Steaming is a good method, and a recent study presented at the 2009 American Heart Association meeting in Orlando, Florida, suggests that baking delivers the heart health benefits of fish better than frying.
References
1. Sanchez-Villegas A, et al. Association of the Mediterranean dietary pattern with the incidence of depression. Arch of Gen Psych 66:1090-98, 2009.
2. SanGiovanni JP, et al. Omega-3 long-chain polyunsaturated fatty acid intake and 12-y incidence of neovascular age-related macular degeneration and central geographic atrophy: a prospective cohort study from the Age-Related Eye Disease Study. Am J of Clin Nutr 90:1601-1607, 2009. 
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Heart-Felt Nutrients
Heart-Felt Nutrients
Foundations of a Heart-healthy Lifestyle
It’s clear that the foundation for a healthy heart includes getting enough physical activity, keeping our weight down, and sticking as much as possible to a Mediterranean style diet which emphasizes fish, nuts, whole grains, fruits, vegetables, olive oil and moderate red wine, while limiting red meat and sugars. But there’s often a divide between what we know and what we actually do. Americans tend to eat an insufficient amount of fish, for example, and to go overboard on sugary foods and beverages.
Several papers published last month focus on the cardiovascular (CV) benefits of the omega-3 fats from fish and the perils of excess sugar. A third study gets to the heart of how vitamin D (from sunlight, oily fish and egg yolks) contributes to CV health in diabetics.
Review Endorses CV Benefits of Fish Oil
A new review – probably the most extensive ever – concludes that the evidence from three decades of research supports fish oils as beneficial for everyone (1). This applies to healthy people as well as those with heart disease – including patients who have had a heart attack, those with heart failure, atherosclerosis and those with many kinds of heart arrhythmias. One of the most significant benefits is seen in atrial fibrillation, the most common form of abnormal heart rhythm.
Though fish oil, or more specifically the omega-3 fats they contain, can both prevent and treat many aspects of cardiovascular disease, it is not promoted often enough by physicians to their patients, according to the authors of the review.
The authors also echo the recommendations of the American Heart Association (AHA) in advising that healthy people get at least 500 mg of EPA and DHA per day – equal to around 2 fatty fish meals weekly – and that those with coronary heart disease or heart failure get about 1000 mg daily. Fish oil supplements free of mercury and other contaminants are a good alternative, note the authors, as few people are going to consume therapeutic doses of fatty fish.
AHA Urges Major Cutbacks in Sugar Intake
Americans are swallowing 22 teaspoons of sugar each day on average, and it’s time to cut way back according to the AHA (2). The heart organization distinguished between naturally occurring sugars and sugars added to foods during processing, and picked out the later for attack. Added sugars are likely contributors to the obesity crisis and are associated with increased risks of high blood pressure and elevated triglyceride levels, as well as other causes of heart disease and stroke.
Women should be getting no more than 6 teaspoons of added sugar daily, according to AHA guidelines, while 9 teaspoons is the limit recommended for most men. Regular soft drinks are one of the biggest culprits for adding sugars, followed by candy, cakes, cookies and pie. The sugar in just one 12-ounce can of regular soda exceeds the daily limit for women! So sit back with a glass of water with a twist of lime and sprig of mint, and learn more about the amount of added sugars in common foods at the US Dept. of Agriculture database.
How Vitamin D Helps Diabetic Heart Health
Regular readers of this newsletter know that vitamin D research is booming, and that low blood levels of this essential nutrient are common in people, including diabetics who have a higher risk of heart disease. New research with diabetic subjects has found that vitamin D inhibits the ability of cholesterol to be taken up by cells called macrophages (3).
With vitamin D deficiency, macrophage cells gobble up more cholesterol than they can eliminate. Once they’re clogged with cholesterol, macrophages become foam cells – one of the earliest markers of atherosclerosis. This eventually leads to stiffened blood vessels and blocked blood flow. The researchers noted that it may be possible to delay or reverse the development of atherosclerosis by helping diabetics regain adequate vitamin D levels.


References
1. Lavie DJ, et al. Omega-3 polyunsaturated fatty acids and cardiovascular disease. J Am Coll Cardiol 54:585-94, 2009.
2. Johnson RK, et al. Dietary Sugars Intake and Cardiovascular Health: A Scientific Statement from the American Heart Association. Circulation [Epub ahead of print, Aug 24] 2009.
3. Oh J, et al. 1,25(OH)2 vitamin D inhibits foam cell formation and suppresses macrophage cholesterol uptake in patients with type 2 diabetes mellitus. Circulation 120:687-98, 2009.
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New Findings on Nutrients & Mental Function
Diet, Exercise Help Preserve Brain Function
Cognition refers to our ability to process, retrieve and apply information. Cognitive skills are those that people use every day such as memory, learning, reasoning, and decision-making. Though a gradual decline in cognitive function occurs naturally as we grow older, evidence indicates that staying physically active and getting a good supply of essential nutrients are both critical factors in staying mentally sharp.
Studies, for example, have shown that older adults who maintain their level of physical activity with age can slow down their rate of cognitive decline, and that low blood levels of vitamins B12 and folic acid can compromise brain function. Now, preliminary findings from several new studies suggest a potential role for omega-3 fatty acids, vitamin D and flavonoids in helping to counter age-related cognitive impairment.
Omega-3 Boosts Memory for Healthy Adults
The results from two studies were presented in July at the Alzheimer's Association 2009 International Conference in Vienna. One of the studies, which examined the effects of the omega-3 fatty acid DHA in healthy older people with age-related memory complaints, reported improved memory function and heart health.
Nearly 500 people took part in this double-blind, 6 month, multi-site trial. Compared to those receiving a placebo, participants taking supplemental DHA had almost double the reduction in errors on a test that measures learning and memory performance (1). In addition, the researchers noted a decrease in heart rate in the DHA group, while blood pressure and weight did not change.
In contrast to the improvements observed in healthy older individuals, a second study presented at the Conference found that DHA did not benefit mental function in patients with Alzheimer's compared to those getting a placebo (2). The investigators did, however, observe a slower rate of decline on a sub-group of people who carried a gene (the e4 version of ApoE gene) that increases the risk of developing Alzheimer's but doesn't affect progression of the disease. Though more research is needed, it may be that nutritional interventions must occur very early in the disease to make any real difference.
Vitamin D & Mental Function in Older Men
Several recent studies have linked low blood levels of vitamin D with reduced cognitive abilities in older adults. Newly reported results from the European Male Aging Study are in agreement with these previous findings (3). In this study, over 3000 men age 40-79 underwent evaluation of their cognitive skills and vitamin D status.
Lower blood concentrations of vitamin D were associated with poorer performance on a test that measures how fast information is processed and visual short-term memory. This observation underscores the need for health professionals to routinely test blood levels of vitamin D, especially in older people.
Wine, Chocolate & Tea for Better Cognition?
Foods like fruits, wine, tea and chocolate are high in polyphenols, particularly flavonoid compounds. Intakes of flavonoids have been linked to a lower risk for age-related cognitive decline and dementia. In a newly published study (4), about 2000 men and women took a battery of tests evaluating learning, memory, attention, and verbal fluency. Their intake of wine, chocolate and tea was also determined.
Performance on the cognitive tests was higher in people consuming up to 10 grams per day of chocolate (typically less than of a chocolate bar) and 2-3 ounces of wine, with the effects stronger for wine consumption. Importantly, the effects were most pronounced for people consuming all three foods.
References

1. Yurko-Mauro K, et al. Results of the MIDAS Trial: Effects of docosahexaenoic acid on physiological and safety parameters in age-related cognitive decline. Alzheimer's Assoc 2009 Inter Conf Presentation #01-04-01, July 2009.
2. Quinn JF, et al. A clinical trial of docosahexaenoic acid for the treatment of Alzheimer's disease. Assoc 2009 Inter Conf Presentation #01-04-02, July 2009.
3. Lee DM, et al. Association between 25-hydroxyvitamin D levels and cognitive performance in middle-aged and older European men. J Neurol Neurosurg Psychiatry 80:722-9, 2009.
4. Nurk E, et al. Intake of flavonoid-rich wine, tea, and chocolate by elderly men and women is association with better cognitive test performance. J Nutr 139:120-7, 2009.
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In the News: Omega-3s, Antioxidants and GLA
Omega-3s, Zinc & "C" May Ease Asthma
Results of new research suggest that a combination of fish oil, zinc and vitamin C can improve the symptoms of bronchial asthma in children (1). Asthma, which affects nearly 20 million Americans, is on the rise according to the American Lung Association.
In this double-blind study, 60 asthmatic children were supplemented with 300 mg of EPA and DHA, 15 mg of zinc, 200 mg of ascorbic acid, a combination of all the nutrients or a placebo for 6 week periods. Lung function was measured, as were markers of inflammation. Symptoms such as wheezing, shortness of breath and the use of rescue inhalers were measured in a standardized test.
The researchers found significant improvement in all the tests when the nutrients were given one at a time. However all three nutrients combined produced the best results.
Omega-3s & Better Blood Pressure in Dieters
One of the many benefits of weight loss is often blood pressure reduction, and results of a recent study suggest that the omega-3s can result in even better reductions - at least in those who have low levels of the omega-3 DHA stored in their cell membranes (2). Low levels of cellular omega-3 are believed to reflect infrequent intake of these important fatty acids.
All of the 324 overweight study participants, aged 20-40, were put on weight loss diets and divided into 4 different groups. One group ate salmon 3 times weekly, while another consumed cod, which is lower in omega-3 content. The third group was given supplements providing about 495 mg of EPA and DHA daily, while the forth group was assigned to a placebo and ate no seafood.
All of the study subjects lost weight - a little over 11 pounds on average. Blood pressure also went down overall, but reductions were greater in those eating salmon or receiving the daily omega-3 supplement compared to people in the cod-consuming group and in placebo-takers who had low stores of the omega-3 to begin with. These observations are in line with a number of other study findings that indicate blood pressure reductions with greater EPA and DHA intake.
GLA Makes Contact Wear More Comfortable
Contact lens wearers commonly experience a feeling of dryness in their eyes. As a result, many people wear their lenses less often or discontinue their use altogether. A recent double-blind, placebo-controlled study examined the effects of 300 mg of supplemental GLA daily in 76 women with contact lens-related dry eye (3). The participants all wore soft contact lens.
The women in the GLA group experienced significant improvement in the sensation of dryness and overall lens comfort at 3 months and at 6 months, when the study ended. Tear meniscus height - a relatively new measurement of tear production - was also greater in the GLA supplementers compared to placebo.
Antioxidants, Exercise Boost Bones in Women
The results of a pilot study in 34 post-menopausal women suggest that a combination of antioxidant supplements and resistance training may help protect against bone loss. The women were assigned to 1 of 4 groups: 1) antioxidants plus exercise; 2) antioxidants and no exercise; 3) placebo plus exercise; or 4) placebo and no exercise. The antioxidants consisted of 600 IU vitamin E and 1,000 mg of vitamin C daily.
At the end of 6 months, measures of bone density revealed that only those women not exercising and getting the placebo experienced significant bone loss in the spine. In contrast, the bone density of those who exercised or took the antioxidants remained constant. These preliminary findings are promising and lend support to previous links seen between higher intake of antioxidants (e.g. lycopene) and better bone density in the spine of women and, for men, in the hip.
References

1. Al Biltagi M, et al. Omega-3 fatty acids, vitamin C and zinc supplementation in asthmatic children: a randomized, self-controlled study. Acta Pediatrica 98:737-42, 2009.
   
2. Ramel A, et al. Moderate consumption of fatty fish reduces diastolic blood pressure in overweight and obese European young adults during energy restriction. Nutrition [Epub May 30, 2009].
   
3. Kokke KH, et al. Oral omega-6 essential fatty acid treatment in contract lens association dry eye. Contact Lens Anterior Eye 31:141-6, 2008.
   
4. Chuin A, et al. Effect of combined antioxidants compared to resistance training on BMD in elderly women: a pilot study. Osteoporosis Inter 20:1253-8, 2009.
   
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In the News: B12 & the Brain, Omega-3 & Broccoli for Ailing Hearts
B12 May Help Retain Brain Volume with Age
Maintaining optimal blood levels of vitamin B12 is important, as low levels appear to increase the risk for impaired mental function and neurological disorders. A new study now indicates that failure to get enough B12, or absorb it well, may actually cause the brain to shrink.
The participants in this study, who had an average age of 73 with no mental impairments at the beginning, were divided into 3 groups based on their B12 levels. They underwent MRI scans to measure brain volume and physical and mental exams annually. At the end of the 5-year study period, the group with the lowest B12 levels (below 308 pico-moles/L) lost twice as much brain volume as those with the highest levels. The same researchers are now conducting a study to see whether improving B12 levels will actually prevent brain shrinkage.
It's estimated that up to 25% of the elderly may be B12 deficient. Poor dietary intake or absorption of this vitamin, found only in foods of animal origin including meat, milk, eggs, as well as some fortified cereals, is usually the problem. Most commonly, the age-related decline in stomach acid makes it difficult to digest B12. In addition, some people don't make enough of a small protein called intrinsic factor, which is needed for efficient B12 absorption. The Institute of Medicine recommends supplemental B12 for those over 50, and those with a lack of intrinsic factor often need medical intervention.
Fish Oil Helps Survival Rates in Heart Failure
According to new research, a daily supplement of fish oil omega-3 reduced mortality and cardiovascular-related hospital admissions for patients with heart failure, while statin drugs had no beneficial effect in the same group of patients.
Years ago, a group of Italian researchers (the GISSI) documented the preventive benefits of fish oil in those who had a heart attack by reducing their subsequent risk of sudden death. This same research group has recently published the results of the first large-scale double blind trial investigating the effectiveness of fish oil in chronic heart failure.
In the first trial, 6,975 patients with symptomatic heart failure were randomized to receive either 1 gram daily of omega-3 (EPA and DHA in ethyl ester form) or placebo. After nearly 4 years of follow-up, the risk of mortality was reduced by 9% and hospitalization for cardiovascular causes decreased by 8%.
In contrast, chronic heart failure patients assigned to get 10 mg of a statin drug (rosuvastatin) fared no better in terms of survival or hospitalization rates than those getting placebo. Even though the statin lowered LDL cholesterol and the inflammation marker CRP, the investigators theorize that once heart failure is established, statins may not allow patients to escape the underlying heart-disease process.
Broccoli May Reverse Heart Vessel Damage
Researchers report that compounds such as sulforaphane in broccoli may help counter processes thought to lead to vascular disease in diabetes. The investigators concluded that sulforaphane may function as a "dietary activator", preventing dysfunctional responses of endothelial cells that line the interior of blood vessels caused by elevated blood sugar. Endothelial cell dysfunction is common in diabetics.
The research team found a 73% in reduction in free radicals, which are known to increase in diabetics. While this study was conducted in cultured human endothelial cells, it may help explain why large-scale studies have linked high intake of broccoli, Brussels sprouts and cabbage to a lower risk of developing diabetes.
References

1. Vogiatzoglou A, et al. Vitamin B12 status and rate of brain volume loss in community-dwelling elderly. Neurology 71:826-32, 2008.
2. GISSI-HF Investigators. Effect of n-3 poly-unsaturated fatty acids in patients with chronic heart failure: a randomized, double-blind controlled trial. Lancet Aug. 29, 2008 [epub ahead of print].
3. GISSI-HF Investigators. Effect of rosuvastatin in patients with chronic heart failure: a randomized, double-blind placebo-controlled trial. The Lancet 372:1231-9, 2008.
4. Xue M, et al. Activation of NF-E2-related factor-2 reverses biochemical dysfunction of endothelial cells induced by hyperglycemia linked to vascular disease. Diabetes 57:2809-17, 2008.
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In the News: Vitamins B6, C, & D, and the Omega-3 Fats
Supplemental Vitamin B6 Needed by Many
One of the largest population-health studies to evaluate B6 levels reports that inadequate blood concentrations of this B-vitamin are much more common than previously believed (1). Deficiencies of B6 were thought to be relatively rare except among the elderly. B6 is needed for red blood cell formation, protein metabolism, normal immune function and cardiovascular health.
In the study, Tuft's researchers analyzed blood levels of the active form of B6 in a large sample of the population. Four groups were identified as being particularly deficient: women of childbearing age, men who smoke, Afro-American men, and people over 65.
Among the women, current and former users of oral contraceptives had significantly lower levels then men in the same age group. In fact, 75% of those who used oral contraceptives, but did not take B6 supplements, were deficient. According to the study authors, some population groups need supplemental B6 in order to achieve adequate status.
Review Supports Heart Benefits of Vitamin C
While popularly known as a vitamin that helps lessen the symptoms and length of colds, vitamin C may have heart benefits as well. A recent meta-analysis or review, which included 13 double blind trials, concluded that vitamin C at a minimum dose of 500 mg daily can lower elevated LDL cholesterol by an average 5% and triglycerides by nearly 9% (2).
While these reductions are very modest, they translate to an estimated 7% lower risk of coronary heart disease (CHD). The researchers stated that even small changes can have beneficial effects on the incidence of CHD, especially in light of the low cost and safety of supplemental vitamin C within the range of 500-1000 mg daily. vitamin C may work by protecting LDL from damage so that it can be recognized by receptors in the liver and removed from the circulation.
Good Vitamin D Status Seems Heart-Essential
Inadequate levels of vitamin D have been associated with an increasing number of health conditions, and experts are calling for higher-than-RDA intakes to achieve healthier blood levels of D. The findings from several new studies add to the mounting evidence that the current RDA for vitamin D is set far too low.
In the first study, investigators from Harvard's School of Public Health reviewed the medical records and blood samples of men with a history of heart attack or heart disease (3). They found that men with low vitamin D levels were over 100% more at risk of heart attack compared to men with sufficient levels. A doubling of vitamin D blood levels was associated with halving the risk of a heart attack.
A second study from the University of Graz in Austria produced similar results. Higher vitamin D blood levels were linked with both lower overall death rates and deaths from cardiovascular causes (4). The cardio-protective effects of this vitamin might range from improving the health of smooth muscles in the vascular system to reducing inflammation and blood pressure.
Omega-3s Lower the Risk for AMD
Finally, a higher intake of the omega-3 fatty acids EPA and DHA cut the risk of age-related macular degeneration (AMD) by up to 38%, according to a new review of 9 population-health studies (5). In analyzing these studies, which included roughly 88,900 participants, researchers from Australia found that higher intakes of EPA and DHA cut the risk of early AMD substantially. In terms of advanced AMD, getting more of these omega-3 fats yielded a 38% risk reduction. While we await the findings of AREDS-2, which is testing the effects of the omega-3 on AMD progression, it's wise to eat cold-water fish at least 2-3 times weekly.
References

1. Morris MS, et al. Trends of vitamin B6 status in US population sample. AJCN 87:1446-54, 2008.
   
2. McRae MP. Vitamin C supplementation lowers serum low-density lipoprotein cholesterol and triglycerides: a meta-analysis of 13 randomized controlled trials. J of Chiropractic Med 7:48-58, 2008.
   
3. Giovannucci E, et al. 25-hydroxyvitamin D and risk of myocardial infarction in men-a prospective study. Arch of Intern Med 168:1174-80, 2008.
   
4. Dobnig H, et al. Independent association of low serum 25-hydroxyvitamin D and 125-dihydroxyvitamin D levels with all-cause and cardiovascular mortality. Arch of Intern Med 168:1340-49, 2008
   
5. Chong EW-T, et al. Dietary n-3 fatty acids and fish intake in the primary prevention of AMD-A systematic review and meta-analysis. Arch of Ophthalmol 126:826-833, 2008.
   
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Dietary Changes May Help Ease Pain
Investigating the Diet - Pain Connection
Pain is the number one cause of disability in adult Americans. It affects 1 in 3, or about 50 million people according to 2005 government figures. Many herbs or specialized nutrients such as Boswellia, Devil's Claw and glucosamine have been studied for arthritic pain, and willow bark was the botanical forerunner of today's aspirin. Yet only now are we beginning to investigate the pain-reducing effects of common foods and the nutrients they provide. Supplemental vitamin C, for example, has been shown to help prevent the debilitating neuropathic pain that can develop after trauma such as fractures and sprains.
Hippocrates advised: "Let food be thy medicine and let thy medicine be food". Although dietary strategies are not meant to take the place of appropriate OTC analgesics and prescribed medications, eating differently may well be a complimentary way to help cope with pain, according to a recent review.
Fish Fats Fight Pain
EPA and DHA from fish have the greatest evidence supporting their pain-relieving effects. Supplemental omega 3s may be as effective as ibuprofen for neck pain and back pain, as well as reducing inflammatory joint pain. Researchers have found that diets low in omega 3 fats are correlated with more severe menstrual pain, while omega 3 fatty acids have been shown to decrease that pain. Some evidence also suggests a protective effect of omega 3s against depression, which can worsen chronic pain.
The omega 3s may be helping in a number of ways. In addition to dampening inflammation, they may influence pain perception through their role in nerve signaling pathways. Though an optimal pain-relieving level of omega 3s is not known, clinicians at the McGill University Pain Centre in Montreal report that they typically use 1 gram daily - an amount found to be clinically effective in various pain conditions. Keep in mind that dietary changes are gradual and may not be noticeable for several weeks to months. Also, the omega-3 fatty acid in flaxseed is not the same as those from fish, and has not been extensively studied.
Cherries Counter Painful Gout, Sore Muscles
Cherries, which have been traditionally used to treat everything from sore throat to more serious pain, are rich in anti-inflammatory compounds called antho-cyanins. Daily consumption of cherries was recently shown to reduce pain in patients with gout by reducing inflammation and helping to eliminate excess uric acid.
In another study, drinking a 12 oz. cherry juice blend twice daily was superior to placebo in quelling post-exercise muscle pain. One professional hockey team, in fact, has reportedly added a tart cherry sports drink to its after-workout regimen to aid muscle soreness.

Soy, Fiber, Tea, Wine & the Occasional Sweet?
A number of healthful foods and beverages may hold pain-relief promise, although more research is needed. For example, a population-health study has linked higher fiber intake with lower levels of menstrual pain in young Japanese women. One theory is that fiber could decrease levels of estrogen, and suppressing estrogen has been associated with analgesic effects.
Soymilk has been reported to decrease menstrual cycle-related breast pain, as well as the pain and discomfort associated with osteoarthritis. And in a preliminary study, substituting high levels of soy for other protein and fat in the diet was found to provide meaningful pain relief for nearly 1/3 of participants who were recovering from surgery or trauma.
Caffeine alone is not very effective for pain. But it can significantly increase the effects of acetaminophen and ibuprofen. In one study, 100 mg of caffeine (about the amount in a cup of strong coffee) doubled the effect of a single dose of ibuprofen after oral surgery. In addition to caffeine, green tea contains a compound (EGCG) that has been experimentally shown to decrease levels of inflammatory markers that can occur in people with rheumatoid arthritis. Animal research, too, raises the possibility of a pain-relieving role for a compound in red wine called resveratrol.
Finally, can our craving for sweets be linked to pain relief? The answer is likely yes, since sucrose (sugar) has been shown to reduce crying and pain behavior after blood draws in newborns. It seems to be the sweet taste itself that brings a mild analgesic effect by stimulating the release of the body's endorphins.
Reference
Pereira J and Shir Y. Reducing pain through dietary changes. Clinical Nutrition Insight. 34:1-4, 2008.
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Update: Diet & Healthy Brain Function
Slowing Age-Related CNS Changes
With a large portion of our population growing older, researchers are exploring how dietary and lifestyle strategies might slow down the natural age-related decline in mental function that most of us experience. As we age, we become less able to remember newly acquired information for example. In addition, as the entire central nervous system (CNS) ages, balance, coordination and muscle strength are also affected.
While all the mechanisms involved in mental aging aren't fully understood, scientists believe that oxidative stress and inflammation play an important role. Antioxidant defense systems become less effective with age, leaving the brain more vulnerable to oxidative and inflammatory damage.
The good news is that there are things we can do to combat these changes. Strength conditioning has been shown to improve balance and coordination in older individuals, and special mental exercises can benefit memory, reasoning and how fast we process information [See February 2007 issue]. As the following research reveals, eating a diet rich in colorful fruits and vegetables as well as seafood, is a dietary strategy that may pay dividends as well.
Beta-Carotene May Help Men Keep Their Edge
For an average of 18 years, Harvard researchers followed 4000 participants in the Physicians' Health Study, half of whom took 50 mg of beta-carotene every other day and half who received a placebo. When that part of the study ended in 1998, another 2000 healthy men were recruited, and all 6000 participants continued in the study for 3 more years (1).
Men who took the antioxidant for 3 years or less showed no improvement on standard tests of memory, but those taking beta-carotene for 15 years or more scored consistently higher on all the tests.
The key finding is that long term intake of beta-carotene - the amount in about 4 carrots daily - may help memory as we get older. This makes sense, since the underlying changes that lead to impaired memory appear to occur over many years, if not decades. Remember that those who smoke should avoid high levels of beta-carotene since evidence suggests an increased risk of lung cancer in smokers with high beta-carotene intake.
"Brainberries" May Counter Aging Declines
Berries such as blueberries and their European cousin, the bilberry, are a good source of antioxidant and anti-inflammatory compounds. Researchers at the Center on Aging at Tufts have shown in many experiments that blueberry, spinach and strawberry extracts can reverse age-related brain and behavioral deficits in aged animals (2).
While all of the supplemented diets showed positive mental gains, blueberries produced the greatest benefits on motor functions such as balance and coordination. A more recent study showed cognitive benefits even when blueberry extracts were added to an already balanced diet in older animals.
According to the researchers, supplemental blueberries improved the ability of old nerve cells to communicate with one another. Their findings suggest that berries may actually reduce the signals created by oxidative stress, and increase signals that are important in facilitating learning and memory.
Study Duo Support Fish for Brain Health
Two new studies suggest that consuming fish, and the omega-3 fatty acids they contain, support mental function. In the first study, Dutch researchers analyzed data from participants in the FACIT trial and report that increased blood levels of omega-3 fatty acids were associated with significantly less decline in how fast we process and react to external stimuli (3).
The second study examined the relation between consumption of seafood and cognitive performance in elderly Norwegians. The researchers report that those eating at least 10 grams (.35 oz) of fish daily performed better in tests for mental performance than people eating less. However, the best scores occurred in individuals consuming about 75 grams (2.6 oz) daily (4).
References

1. Grodstein F, et al. A randomized trial of beta-carotene supplementation and cognitive function in men. Arch Int Med 167:2184-90, 2007.
2. Joseph JJ, et al. Brainberries and aging. Clin Nutr Insight 34:1-4, Jan, 2008.
3. Dullemeijer C, et al. N-3 fatty acids proportions in plasma and cognitive performance in older adults. AJCN 86:1479-85, 2007.
4. Nurk E, et al. Cognitive performance among the elderly and dietary fish intake. AJCN 86:1470-78, 2007.
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Healthful Eating for Better Lung Function
Diet May Keep Chronic Lung Disorders at Bay
You don't smoke, and you avoid second hand smoke and air pollution as much as possible. Are there other steps you can take to help maintain healthy airways and lung function? Well, research suggests that your diet can influence the risk of chronic bronchitis and asthma, and may lessen symptoms for those who already suffer from such conditions.
Mediterranean-Style Diet Fends Off COPD
Consuming a "Med"-style diet rich in fruits, veggies and fish may halve the risk of chronic obstructive pulmonary disease (COPD), the umbrella term for chronic bronchitis and emphysema (1).
Harvard researchers tracked more than 42,000 male health professionals for 12 years, ranking them by how closely they followed a Med style diet or how much they stuck to a Western dietary pattern. After adjusting for age, smoking and other factors, greater adherence to the Med diet was associated with a 50% decrease in COPD risk compared to men with the lowest adherence. At the same time, men who followed a Western style diet most closely were about four and a half times more likely to suffer from newly diagnosed COPD as those who ate the least from that menu.
The Western diet was defined as one high in processed foods, refined grains, cured and red meats, French fries and deserts. The researchers noted that this diet contains nitrites used to preserve or color foods such as bacon, corned beef, luncheon meats, sausage and ham. Nitrites generate free radical compounds that could contribute to progressive deterioration of pulmonary function. A high-glycemic diet like the Western eating pattern has also been linked to impaired lung function.
In contrast, a Med-style diet is rich in beta-carotene, vitamins C and E, polyphenols (bioflavonoids), omega-3s, and essential minerals. It is these antioxidants and polyphenols that appear to offer protection. According to the study authors, their findings are consistent with previous study results suggesting a beneficial effect for antioxidants on COPD - particularly vitamin C and, to a lesser extent, vitamin E.
Fish & Whole-Grains Guard Against Asthma
A study published late last year also supports components of the Med-style diet as helpful for young asthmatics (2). With the assistance of their parents, Dutch public health researchers assessed the diets of nearly 600 children 8-13 years old.
The investigators found that whole grains and fish intake were most closely linked with asthma risk. High intakes of whole grains and fish were associated with a 54% and 66% reduction in the odds of having asthma, respectively. Kids who consumed a high intake of both foods experienced significantly less wheezing. Only 4.2% of children who ate the most grains and fish suffered wheezing, while 20% of those eating the least exhibited this symptom.
It's also worth noting that a diet rich in antioxidants found in fruits and veggies is important for expectant moms. A study conducted by Harvard researchers found that higher maternal intakes of antioxidants during pregnancy decrease the risk for wheezing illnesses in early childhood (3).
Fish Oil Helps Exercisers with Asthma
Exercise is a powerful trigger of asthma symptoms in about 80% of asthmatics. Vigorous exercise can cause airways to narrow, resulting in shortness of breath, wheezing and chest tightness. Recently, researchers from Indiana University tested the ability of fish oil to reduce the severity of these symptoms (4). They found that when asthmatics were given high dose fish oil supplements instead of placebos, they had better pulmonary function and needed to use a bronchodilator less frequently after a bout of exercise.
References

1. Varraso R, et al. Prospective study of dietary patterns and chronic obstructive pulmonary disease among US men. Thorax (Br Med J) E pub online, May 15, 2007.
2. Tabak C, et al. Diet and asthma in Dutch school children (ISAAC-2). Thorax (Br Med J) 61:1048-53, 2006.
3. Litonjua AA, et al. Maternal antioxidant intake in pregnancy and wheezing illnesses in children at 2 y of age. Am J Clin Nutr 84:903-11, 2006.
4. Mickleborough TD, et al. Protective effect of fish oil supplementation on exercise-induced bronco-constriction in asthma. Chest 129:39-49, 2006.
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Fish Oil Omega-3s: New Research Findings
EPA & DHA: Beyond Heart & Brain Benefits
The long chain fats in fish oil, EPA and DHA, are best known for their cardiovascular benefits. They help guard arteries by quelling chronic inflammation, keeping levels of triglycerides in check, and making vessels more elastic. Factor in their ability to improve electrical communication between heart cells and prevent arrhythmia, and it's easy to understand why omega-3s are a standard part of cardiac care in European countries.
The evidence for an Omega-3 role in fending off mental aging is also increasing [see the February 2007 and December 2006 newsletter issues]. Several new areas of potential benefit for these fatty acids are also emerging: visual, prostate and colon health.
Preventing Retinopathy?
In addition to being studied in the AREDS-2 trial for AMD, the omega-3s may help protect against retinopathy, a deterioration of the retina that affects about 4 million diabetics and 40,000 premature infants. This disease is a 2-part process that starts with a loss of blood vessels. With the vessel loss, the retina becomes oxygen deprived and reacts by spurring new vessel growth. However, the low-oxygen triggered vessels grow abnormally and are malformed, leaky and over-abundant.
Collaborating researchers from the NEI, Harvard, the University of Göteborg in Sweden and other institutions, recently examined the effects of omega-3 and omega-6 in an animal model of retinopathy (1). Animals were fed EPA and DHA from fish oil, or arachidonic acid - an omega-6 typically found in meats and dairy, and made in the body from other fats present in many vegetable oils. The investigators found that mice on the omega-3 diet initially lost 40-50% less retinal vessels compared to the omega-6 group. As a result, the omega-3 fed group had a 40-50% reduction in abnormal vessel growth.
One of the study's authors said: "If clinical trials find that supplementing with omega-3 s is as effective in protecting humans against retinal disease as demonstrated by the findings of this study, this cost effective intervention could benefit millions of people".
Better Colon Health?
Findings from a new study published in the American Journal of Epidemiology, add to a growing body of science linking omega-3 and fatty fish consumption to a reduced risk of colorectal cancer (2). Scottish researchers examined the type and amounts of fats in the diets of 1,455 subjects with colorectal cancer and the same number of matched healthy individuals.
Increased intake of EPA was associated with a 41% reduction in risk, while a 37% lower risk was linked to DHA intake, comparing highest against lowest average intakes. The omega-3s have been shown to reduce the body's inflammatory response (3). This is very important, because chronic inflammation is believed to be the culprit in about 20% of all cancers.
Healthier Prostates?
In addition to colorectal cancer, prostate cancer is also believed to be influenced by chronic inflammation. The incidence of prostate cancer has been increasing over the past 15 years, with over a half million new cases diagnosed every year worldwide.
Higher intake of the omega-3s DHA and EPA could cut the risk of developing this cancer by 40% according to a new study from Harvard (4). The investigators compared blood levels of fatty acids in 476 men with prostate cancer and the same number of healthy controls. The results tally with other studies reporting that regular intake of fatty fish like salmon is associated with a prostate-protective effect.
References

1. Connor KM, et al. Increased dietary intake of 3-poly-unstaturated acids reduces pathological retinal angiogenesis. Nature Medicine 13:868-874, 2007.
2. Theodoratou E, et al. Dietary fatty acids and colorectal cancer: a case-control study. American Journal of Epidemiology 166:181-195, 2007.
3. Wada M, et al. Enzymes and receptors of prostaglandin pathways with arachidonic acid-derived versus eicosapentaenoic acid-derived substrates and products. Journal of Biological Chemistry 282: 22254-66. 2007.
4. Chavarro JE, et al. A prospective study of polyunsaturated fatty acid levels in blood and prostate cancer risk. Cancer Epidemiology, Biomarkers and Prevention. 16:1364-70 ,2007.
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Fending Off Mental Aging
A flurry of recent research suggests that there may be ways to improve our odds of preventing Alzheimer's or age-related mental decline through diet and life-style. Here's a look at some of the promising findings.
Mental Exercises for Brain Gain
Lead researchers from Pennsylvania State University report that mental exercise may play a key role in staving off age-related loss of mental agility (1). The research team divided the 2,800+ subjects aged 65 and older into four groups of roughly 700 to receive training in either memory, reasoning or speed of processing, and a control group that received no instruction. Memory training consisted of strategies to remember word lists or texts, such as associating various words, visualizing them or organizing them in specific ways. Reasoning training taught subjects how to spot the pattern in a series of letters or numbers. Processing speed was enhanced by repeated practice in identifying an object on a screen after increasingly shorter visual exposures.
Training Yields Long Term Improvements
Participants were asked to appraise their own skills, and indicate whether the training helped with every-day tasks. Practical skills like finding items in a medicine cabinet were also independently evaluated by the scientists. After training, 87% of the speed trainees, 74% of the reason trainees and 26% of the memory trainees showed immediate improvement.
That advantage over their untrained peers persisted over the next 5 years. Compared to controls, the memory group, for example, was able to remember about 3-4 more words from a list of 12-15. Some who got refresher training 1and 3 years after the initial instruction performed best of all, especially those in the speed-processing group. Tasks like making change for a purchase or reading medication labels were performed more quickly and efficiently.
Most impressively, the training seemed to largely offset the cognitive decline experienced by nearly of the control subjects. By the end of 5 years, a significant gap had opened between those in the instruction groups and controls. According to one of the study's authors, "to drive this effect, you have to practice things you don't necessary like or things you don't regularly practice". In other words, it may not be quite as simple as doing crossword or sudoku puzzles. In the future, the authors hope to make these training programs more widely available. It's not hard to envision mental exercise programs in senior centers nationwide to help prevent mind decline as we age.
Dietary Strategies for Brain Fitness
Research shows that brain levels of DHA decrease with age, and that getting more DHA later in life increases brain content. The December, 2006 issue of Staying Healthy describes a Tufts study which links higher blood levels or intake of DHA (from fish) to a significantly lower risk of Alzheimer's and dementia. A second double-blind study from Sweden found that omega-3 supplements slowed mental decline in people with very mild Alzheimer's, though the group with mild disease was small and no effect was seen in people with more advanced forms (2). In addition, a small study from Japan reports improvements in immediate memory and attention in patients with mild cognitive impairment after taking DHA and arachidonic acid supplements (vs. placebo) for 3 months (3).
Since the Mediterranean diet is abundant in seafood, it's no surprise that it would also show promise in protecting mental function. But that diet's potential benefits may extend beyond its fish content. Scientists report that subjects most closely following a "Med" style diet consisting mostly of vegetables, legumes, fruits, cereals and some fish were almost 40% less likely to develop Alzheimer's than those with the poorest adherence (see the August, 2006 issue).
Lastly, a series of studies conducted at Tufts have shown that diets enriched with antioxidant-rich blueberries, strawberries, cranberries or grape juice can reduce or reverse declines in brain function in laboratory animals.
References

1. Willis SL, et al. Long-term effects of cognitive training on everyday function outcomes in older adults. JAMA 296:2805-14, 2006.
2. Freund-Levi Y, et al. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD Study. Arch Neurol 63:1402-8, 2006.
3. Kotani S, et al. Dietary supplementation of arachidonic and docosahexaenoic acids improves cognitive dysfunction. Neurosci Res 56:159-64, 2006.
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News Bites: Fish as Food for the Brain & Exercise for Eye Health
DHA, Fish Lower Risk for Alzheimer's
Coldwater, fatty fish are a concentrated source of the omega-3 fats docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). Population health studies have consistently shown positive health effects from fish consumption and, now, a study published in the November issue of The Archives of Neurology, links greater fish intake to a lower risk of developing Alzheimer's and other dementias (1). And in this study, DHA was most important for cutting risk.
Using data from the Framingham Heart study, researchers followed about 900 healthy participants for an average of more than 9 years. During that time, 99 people developed dementia including 71 cases of Alzheimer's. Researchers quantified the amount of DHA and fish the participants typically consumed by dietary questionnaires, and measured the level of fatty acids in their blood.
DHA Cuts Risk of Dementia by Nearly 50%
The top 25% of study volunteers with the highest blood levels of DHA reduced their risk of developing dementia by 47%. They were about half as likely to develop dementia as the 75% of participants with lower levels of DHA in their blood. The risk reduction was seen even after controlling for other known or suspected risk factors for dementia such as smoking, overweight, high blood pressure and diabetes.
Participants who ate two or more servings of fish weekly reduced their dementia risk by 39%, while those who ate less had no risk reduction.
According to the study's authors, the observation that DHA seems to be key in lowering dementia risk is consistent with earlier data showing high levels of DHA in healthy brain tissue and low levels in the brains of people with Alzheimer's. The next step will be to conduct placebo controlled trials of DHA in people who don't yet have Alzheimer's to see whether DHA can help protect against this disease.
Active Lifestyle Could Protect Against AMD
Exercise may help protect against age-related macular degeneration (AMD) according to the results of a large study supported by the NIH and published in the British Journal of Ophthalmology (2). The authors examined the relationship between physical activity and AMD because heart disease and AMD appear to share common risk factors. And regular exercise, as we all know, is good for the heart and arteries.
Participants in the Beaver Dam Eye Study were followed for 15 years. During that time they were given eye exams periodically, and they filled out questionnaires at the beginning of the study to assess their level of activity. They were asked how many flights of stairs they climbed daily, how many city blocks they walked each day, and how often each week they engaged in physical activity that involved working up a sweat.
Compared with sedentary people, those who participated in regular activity 3 times weekly were less likely to develop wet AMD. Those with an active lifestyle - defined as engaging in an activity that resulted in sweating 3 or more times each week - reduced their risk of wet AMD by 70%. Walking 12 or more blocks daily lowered that risk by 30%.
Walk Daily, Put More Fish on Menu
Can't get to the gym or participate in vigorous exercise? Try walking at least a mile daily. Though each city and each block vary in length, walking 8-12 city blocks is roughly equivalent to a mile. It's certainly good for heart and may help your eyesight as well.
For better mental function as we age, remember that fatty fish is best, and frying fish can cause some deterioration of its DHA content. You can also consider augmenting your intake of DHA and EPA with supplemental fish oil.
References

1. Schaefer EJ, et al. Plasma phosphatidylcholine docosahexaenoic Acid content and risk of dementia and Alzheimer disease: the Framingham Heart study. Arch Neurol. 63:1545-50, 2006.
2. Knudtson MD, et al. Physical Activity and the 15-year Cumulative Incidence of Age-related Macular Degeneration: The Beaver Dam Eye Study. British J of Ophthalmology, published online Oct. 31, 2006.
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Be Savvy about Fish Safety
Fish Provide Healthful Omega-3 Fats
Fish and shellfish are a good source of protein and provide the omega-3 fatty acids DHA and EPA, particularly fatty fish that dwell in colder waters. The omega-3's have well established heart benefits, and consuming them regularly has been linked in some studies to a lower risk for age-related macular degeneration and dry eye. Health authorities from the American Heart Association to the American Diabetes Association recommend eating at least 2 fish servings weekly.
It's important to select and store fish safely to avoid any chance of food borne illness and to minimize intake of any marine contaminants. Many of the following seafood safety tips and guidelines are from the Food and Drug Administration (FDA) and Center for Food Safety and Applied Nutrition (CFSAN). To learn more, you can visit their website at: http://www.cfsan.fda.gov/~lrd/seafsafe.html
Choose Wisely to Minimize Mercury
Nearly all fish and shellfish contain traces of mercury as the toxin methylmercury. However larger fish that have lived longer have the highest levels because they they've had more time to accumulate it. These large fish present the greatest risk, and the FDA and Environmental Protection Agency advise women who are pregnant or could become pregnant, nursing mothers and young children to reduce their exposure to the harmful effects of mercury by:
• Not eating shark, swordfish, king mackerel or tilefish because they contain high mercury levels;
  
• Eating up to 12 oz. weekly of a variety of fish that are lower in mercury; serve young children smaller portions. Five of the most commonly eaten fish that are low in mercury include: shrimp, canned light tuna, salmon, pollock and catfish. Commonly eaten albacore, or "white" tuna contains more mercury than canned light tuna.
• Checking local advisories about the safety of fish caught locally.
  
While these advisories are directed to women of childbearing age and children, many people may want to avoid the large fish identified as high in mercury or least eat them infrequently. The FDA and CFSAN website offers more information about the mercury content in a variety of fish and shellfish.
Shopping for & Storing Fresh or Frozen Fish
It's important to look for freshness when choosing seafood. In some species, if the catch has been left out in the sun too long - or the fish haven't been transported under proper refrigeration - toxins known as scombrotoxin, or histamine, can develop. Eating spoiled fish that have high levels of these toxins can cause illness. Fish should smell fresh and mild, not fishy, sour, or ammonia-like. A fish's eyes should be clear and bulge a little (except for a few naturally cloudy-eyed fish types, such as walleye pike).
Whole fish and filets should have firm, shiny flesh that springs back when pressed. Fish fillets that have been previously frozen may have lost some of their shine, but are fine to eat. Fillets should not be dark around the edges, discolored, or appear dry or mushy in any area.
Don't buy frozen packages that are positioned above the "frost line" or top of the freezer case in the store's freezer. If the package cover is transparent, look for signs of frost or ice crystals which could mean the fish has been stored a long time or thawed and refrozen.
Put seafood on ice or in the refrigerator or freezer soon after buying it. If you're going to use the seafood within 2 days after purchase, store it in the refrigerator. If not, wrap it tightly in moisture-proof freezer paper or foil to protect it from air leaks and store it in the freezer.
Omega-3 Supplements
For those who can't eat fish regularly, supplemental sources of omega-3 from fish oil are a viable alternative to augment fish intake. Most of these softgel supplements pose no practical concern about mercury, containing trace levels often scant enough to be undetectable by the standard testing limits employed.
It's wise to choose fish oils sources that have undergone molecular distillation to help remove impurities, and testing for mercury and other potential marine contaminants such as dioxins, PCB's, arsenic and lead. As with all supplements, pregnant women should check with their doctor before taking omega-3 supplements.
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The Second Age-Related Eye Disease Study (AREDS 2)
AREDS 2 Slated to Get Underway
One of the most influential studies of the past decade is about to have a sequel. The Age-Related Eye Disease Study (AREDS), published in late 2001, was the first large-scale trial to demonstrate that supplementation with antioxidant nutrients can help slow the progression of age-related macular degeneration (AMD) and it's associated vision loss.
AREDS found that a combination of vitamins C, E, beta-carotene, zinc and copper lowered the risk of advanced AMD by 25% in high-risk patients. No effects of this antioxidant combination were observed in people without signs of the disease or with early AMD. Subjects without AMD didn't receive zinc - a mineral that also lowered the risk of AMD progressing when given alone to higher risk patients.
Lutein, Zeaxanthin and Omega-3 Fatty Acids
Now, researchers at the National Eye Institute (NEI) are gearing up to assess the impact of other nutrients that have emerged as potentially beneficial since the first AREDS study began: lutein, zeaxanthin and the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). lutein and zeaxanthin are thought to shield the macula and retina from oxidative stress generated by exposure to light.
EPA and DHA, fatty acids that are present in cold-water fish, also play important roles in the eye. According to a review by the NEI, these fatty acids lessen the effects of exposure to light, stress, inflammation and other factors. DHA is also a major component of photoreceptors (rods and cones).
AREDS Analysis
When researchers analyzed the dietary intake of participants in the original AREDS trial, they found that those with the highest intake of DHA had a 50% lower risk of advanced AMD, and those consuming the most EPA had nearly the same 50% decrease in their risk of developing advanced geographic atrophy (a severe form of "dry" AMD). The investigators also studied patients' intake of lutein and zeaxanthin, finding that those with the highest intake had a 50% lower risk of developing new AMD during the trial compared to the control group. For people with high intakes and elevated blood levels of lutein and zeaxanthin, a decreased risk of both neovascular (wet AMD) and dry AMD was observed.
Wet AMD, characterized by leaky blood vessels behind the retina, is considered advanced-stage AMD, while the dry AMD develops slowly over time as light sensitive macular cells degenerate. There are several stages of dry AMD, including early, intermediate and advanced. Dry AMD is more common than the wet form, though wet AMD is usually more severe.
The Next Phase: AREDS 2
The new trial will be a multi-center, randomized study of 4000 participants aged 55 to 80 who have large drusen (yellow-white "spots under the retina) or advanced AMD in one eye. Participants will receive one of four supplements: either placebo, 10 mg of lutein along with 2 mg of zeaxanthin, 1 g of DHA and EPA, or a combination of the lutein, zeaxanthin, DHA and EPA.
AREDS 2 will start recruiting patients in 2006, with a 24-month recruiting period and 5 years of following participants. In addition, the investigators will evaluate a new version of the original AREDS supplements with a reduced level of zinc and without beta-carotene. While the main focus of AREDS II will be on AMD and cataract, the researchers also hope to learn more about the effects of EPA and DHA on mental function.
We won't know the results of AREDS 2 for a number of years. But in the meantime, it makes good sense to keep eating a diet rich in fruits and vegetables for antioxidant nutrients, especially dark green leafy veggies which are good sources of lutein, and to eat fish at least 2-3 times weekly for their heart-healthy omega-3 fats. And if your eye care practitioner has recommended that you take supplements of the original AREDS nutrients, be sure to follow that advice.
References

1. Chew, EY. AREDS links higher intake of DHA, EPA, lutein and zeaxanthin with decreased risk of AMD. Presented at ARVO Minisymposium, Bethesda, Maryland, May, 2005.
2. SanGiovanni JP and Chew EY. The role of omega-3 long-chain polyunsaturated fatty acids in health and disease of the retina. Prog in Retinal Eye Res 24:87-138, 2005.
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Part II. Anti-Inflammatory Action Plan
Once thought to be a simple problem of too much cholesterol, it is now widely accepted that inflammation also plays a central role in the atherosclerotic process. Inflammation, measured by a factor in blood called C-reactive protein (CRP), can lead to heart attack or stroke. Inflammation may also raise the risk of hypertension, obesity and eye disease.
Inflammation, High Blood Pressure & AMD
Picture your blood vessels as a system of pliable pipes. When more blood needs to flow through them in a hurry, they have the flexibility to expand. When less flow is required, they can contract-except, apparently, when they're subject to inflammation. New research suggests that with inflammation, vessels become stiff and less flexible. So when a high volume of blood has to push through the constricted arteries, it creates more pressure against the artery walls and results in high blood pressure. Over time, hypertension weakens vessel walls and paves the way for heart attacks and stroke.
The inflammation-high blood pressure connection recently emerged in a Harvard University study. CRP was measured in 20,000 women who were followed for an average of 8 years. Those with the highest level of CRP at the start were about 50% more likely to end up with hypertension compared to those who started out with the lowest levels. Even women who began with relatively low blood pressure were more apt to develop hypertension if their CRP was on the high side. A CRP over 3.5 mg/L was considered quite high and was most strongly linked with developing hypertension. But even CRP in the range of 1.7-3.5 was associated with greater hypertension risk (1). CRP levels appear to raise the risk for age-related macular degeneration (AMD) as well. In the AREDS trial, those with advanced AMD had significantly higher CRP than those without this condition. Higher CRP levels were also observed in those with intermediate stage AMD (2).
Steps to Lower Inflammation
Shed extra weight. A recent study suggests that one of the most important ways to keep CRP levels down is to lose extra weight. A Tufts University study compared the weight-loss effectiveness of four different diets: Weight Watchers, Atkins, Zone and Ornish. All four diets reduced CRP, though the low-fat Ornish diet lowered it the most and promoted the greatest weight loss (3). According to the Tufts investigators, one of the best predictors of CRP is abdominal fat, and losing weight around the middle works well for lowering CRP.
Go with a lower fat, produce-rich diet. What you eat might be as important as eating to lose weight. A large scale study compared two diet patterns: one was the typical Western style diet, with more red meat, processed meat, french fries, high-fat dairy, refined grains and sweets. The other diet was high in fruits and vegetables, poultry, fish, whole grains and beans. There was only a modest difference between the two diets in terms of total, LDL and HDL cholesterol. But compared to the healthier diet, men eating the crummy diet had higher levels of CRP (4).
Fold in more fish. The omega-3 fatty acids in fish (EPA, DHA) can create more of the prostaglandins that suppress inflammation, while other fats (mostly omega-6) create prostaglandins that encourage it. A number of studies have shown that fish oil supplements or diets high in fish, can reduce the symptoms of inflammatory rheumatoid arthritis. Many scientists think that eating a better balance of omega-3 to omega-6 fatty acids could also potentially cut the risk of heart disease.
Take a "multi" supplement. Research suggests that inflammation may deplete antioxidant stores. Lower blood levels of lutein, lycopene, carotenes, vitamin C and selenium were significantly related to higher CRP levels in a recent study. This association held even after adjusting for many other factors that can affect CRP such as smoking, aspirin use, age, exercise, etc. Preliminary findings also indicate that vitamin E may be useful in lowering CRP (6).
References

1. Sesso HD et al. C-reactive protein and the risk of developing hypertension. JAMA 290:3000-2, 2003.
2. Seddon JM et al. Association between C-reactive protein and age-related macular degeneration. JAMA 291:704-10, 2004.
3. Schaefer EJ et al. Tufts University Health and Nutrition Letter. February, 2004.
4. Kerver JM. Dietary patterns associated with risk factors for CVD in healthy US adults. AJCN 78:1103-10, 2003.
5. Ford ES et al. C-reactive protein concentration and concentrations of blood vitamins, carotenoids, and selenium among US adults. Eur J Clin Nutr. 57:1157-63, 2003.
6. Devaraj S and Jialal L. Alpha tocopherol supplementation decreases serum C-reactive protein and monocyte interleukin-6 levels in normal volunteers and type 2 diabetic patients. Free Radic Biol Med 29:790-2, 2000.
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In the News: Recent Omega-3 Research Findings
In the News: Recent Omega-3 Research Findings
Omega-3 Reduces Risk of Irregular Heartbeat In Older Individuals
Atrial fibrillation (AF) is the most common type of chronic arrhythmia in adults, and the risk for AF increases considerably with age.
Animal studies and short-term clinical trials suggest that increased intake of omega-3 fatty acids might improve cardiac function by influencing blood pressure, systemic vascular resistance, and myocardial efficiency, and/or via anti-inflammatory and anti-fibrotic effects. Omega-3 may also increase electrical stability by modulating ion channels.
Although some studies have assessed the association of omega-3s with incident AF, nearly all have estimated dietary intake via dietary questionnaires – with inconsistent results. Also, prior studies have focused on predominantly middle-aged populations rather than older adults, who are most at risk.
Now, findings from the Harvard School of Public Health provide evidence that omega-3 fatty acids may also protect against onset of atrial fibrillation (AF) later in life (1). The researchers looked at circulating levels of omega-3 – a more objective and accurate measure of omega-3 intake – among 3326 participants over 65 and free of AF or heart failure at baseline.
The highest average levels of total omega-3 fatty acids as well as DHA were associated with a reduction in AF risk of about 25%. Additionally, when evaluated as percent of all fatty acids, each 1% higher level of total omega-3s was linked to a 9% lower risk of AF.
Omega-3 May Reduce Key Inflammatory Biomarker Linked to Cardiovascular Disease & Cancer Risks
Two new studies published in the American Journal of Nutrition suggest that higher intakes of omega-3s may confer both cardiac and anti-cancer benefits through decreasing levels of an inflammatory biomarker, soluble intercellular adhesion molecule-1 or sICAM-1. Accumulating evidence suggests that low circulating levels of sICAM-1 contribute to a decrease in atherosclerosis risk.
The first study (2), a meta-analysis, analyzed 18 randomized trials that involved omega-3 supplementation and provided data on sICAM-1 concentrations. Results showed that supplemental omega-3 was associated with sICAM-1 reductions in both healthy individuals and people with abnormal levels of blood lipids.
According to the researchers, the findings suggest that omega-3s reduce inflammation by selectively inhibiting monocyte activation rather than endothelial activation. Since the protective effects were observed in both healthy subjects and those with dyslipidemia, it’s possible that supplemental omega-3 may help prevent the development of atherosclerosis as well as slow its progression.
In the second study (3), a team from the National Institute of Health and Medical Research in Paris investigated whether omega-3 intakes might alter sICAM-1 concentrations and cancer risk by comparing 408 cancer cases with 760 healthy people with similar characteristics.
Levels of sICAM-1 were indeed related to omega-3 levels, and this association was seen for different types of cancer, including prostate and breast cancer. In addition, sICAM-1 was positively linked with cancer risk in people who had below average omega-3 intakes.
Two mechanisms may explain the observations. First, the omega-3s may be decreasing the expression of adhesion molecules like sICAM-1. Secondly, the omega-3s may act by intervening in the pro-cancer pathway stimulated by sICAM-1.
While more research is needed, the two studies taken together support the idea that supplemental omega-3 can reduce the biomarker sICAM-1, resulting in potential cardiovascular and anti-cancer benefits.
References
1. Wu JHY, et al. Association of plasma phospholipid long-chain omega-3 fatty acids with incident atrial fibrillation in older adults: The Cardiovascular Health Study. Circulation 125:1084-93, 2012.
2. Yang Y, et al. Effects of n-3 PUFA supplementation on plasma soluble adhesion molecules: a meta-analysis of randomized controlled trials. Am J Clin Nutr 95:972-80; Epub Feb 29, 2012.
3. Touvier M, et al. Modulation of the association between plasma intercellular adhesion molecule-1 and cancer risk by n-3 PUFA intake: a nested case-control study. Am J Clin Nutr 95:944-50; Epub Feb 29, 2012.
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In the News: Folic acid, B12 & Vision in Astronauts | Omega-3s & Brain Volume
In the News
Folic acid, B12 & Vision in Astronauts | Omega-3s & Brain Volume
Visual Changes Post-Space Flight May be Due to Altered Folic Acid & B12 Metabolism
About 20% of astronauts who’ve been on International Space Station (ISS) missions have developed ophthalmic changes after flight, including optic disc edema, globe flattening, choroidal folds, hyperopic shifts, and cotton wool spots. But why are some but not other astronauts affected? NASA researchers in collaboration with several universities have conducted experiments on ISS since 2006 to answer this question.
The investigative team found biochemical differences in crewmembers with vision issues, which strongly suggest that their folate and vitamin B12 dependent 1-carbon transfer metabolism was affected before, during, and after flight. One-carbon metabolites, including homocysteine, were 25-45% higher (P, 0.001) in those with ophthalmic changes than in those without them, and crewmembers with vision issues had consistently lower serum folate during flight. Pre-flight levels of homocysteine and cystathionine, and in-flight levels of folate, correlated with changes in refraction observed after flight (1).
The researchers believe that common polymorphisms in enzymes of this pathway (e.g. MTHFR 677C/T) interact with the shift in cranial fluids encountered at “zero” gravity in space to cause these ophthalmic changes.
While it’s not likely that you’ll encounter an astronaut in your waiting room anytime soon, these findings may have clinical import to those on Earth as well.
One of the most studied polymorphisms in this pathway is MTHFR 677C/T, which has an allele frequency of 30% in many ethnic groups. Heterozygotes (C/T) have a 30% decrease in the activity of the enzyme MTHFR and homozygotes (T/T) a 60% decrease in this critical enzyme. Evidence suggests that individuals with these polymorphisms may require more folic acid to maintain their status of this B-vitamin.
While Americans are getting more dietary folic acid than ever due to food fortification, getting some extra folic acid via a multi-vitamin supplement may be a good idea considering the high frequency of the polymorphisms, and that elevated homocysteine is a risk factor for ischemic stroke, inter-cranial aneurysms, migraine headaches, and possibly occlusive retinal vascular disease and some types of glaucoma. Many could also benefit from supplemental B12 due to the difficultly of its absorption in older people.
Brain Volume Tied to Omega-3 Intake
According to new findings, low blood concentrations of the omega-3s are associated with smaller brain volume and poorer performance on mental acuity tests (2).
Researchers from UCLA looked at the fatty acid content of red blood cells from over 1,500 men and women who were free of dementia and averaged 67 years of age. MRI scans were used to measure brain volume and white matter hyperintensities, a radiological finding that indicates vascular damage.
Study participants in the lowest quartile of omega-3 blood levels were observed to have significantly smaller total cerebral brain volume compared to those in the top quartile – a finding that held even after adjusting for age, smoking, body mass index and other variables.
Those with low omega-3 also fared poorer on tests of visual memory, abstract memory and executive function, defined as the control and management of other cognitive processes.
The investigators believe that the omega-3’s reduce vascular pathology and thus slow down the rate of brain aging. Too little omega-3 could promote accelerated brain aging.
Few people in the study used fish oil supplements, so the benefits were due to consuming more oily, cold-water fish. It may be that omega-3 supplementation could benefit brainpower – as well as cardiovascular health and perhaps vision maintenance – for those getting insufficient omega-3s from diet alone.
References
1. Zwart SR, et al. Vision changes after spaceflight are related to alterations in folate and vitamin B-12 dependent one-carbon metabolism. J Nutr 142: 427–31, 2012.
2. Tan ZS, et al. Red blood cell omega-3 fatty acid levels and markers of accelerated brain aging. Neurology 78:658-64, 2012.
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Omega-3s & Vitamin A Help Preserve Vision in Retinitis Pigmentosa
Omega-3s & Vitamin A Help Preserve Vision in Retinitis Pigmentosa
Omega-3s, Vitamin A & Retinitis Pigmentosa
Retinitis pigmentosa is a group of inherited disorders affecting about 2 million people worldwide. Research suggests that the course of this condition may respond to nutrient intervention.
Three clinical trials conducted by a Harvard research team between 1984 and 2008, provided evidence that vitamin A supplementation (15,000 IU daily) alone or combined with an omega-3 rich diet could slow rate of decline in retinal function. In these trials, each lasting 4-6 years, a slower rate of decline was observed for electroretinograms (ERGs) or visual field. No significant slowing in decline of distance or retinal acuity was reported. However, Visual acuity usually declines very slowly in retinitis pigmentosa patients.
Eligibility criteria for the three trials were comparable, and test methods were the same for measuring acuity and estimating omega-3 intake. This enabled the team to combine data from all three trials to increase the statistical power and clarify whether dietary omega-3 had any effect on acuity over a 4-6 year period.
Methods
Dietary intake was calculated from questionnaires completed annually by 357 adult retinitis pigmentosa patients from the three randomized trials who were all receiving 15,000 IU vitamin A daily for 4 to 6 years. Rates of visual acuity decline were compared between those with high (> 200 mg omega-3 fatty acids/day) versus low (> 200 mg daily) intake of omega-3. The analyses took age of the participants into account.
Some patients were excluded from the ERG analyses primarily because their initial values were too low. Thus, the annual rate of decline of 163 patients with high omega-3 intake was compared with the rate of decline of 103 patients with low intake.
Results
Mean annual rates of acuity decline were slower among those with higher omega-3 intake. Mean rates of change in distance acuity (ETDRS) were -0.59 letter per year amongst the high intake group compared with -1.00 letter in the low intake group (p = .001). For retinal acuity (Snellen), a 1.5% decline per year versus a 2% yearly decline was seen with high vs. low consumers, respectively (p = .03). There was no effect of age on either distance or retinal acuity decline.



Graph courtesy of Archives of Ophthalmology
Comment
This appears to be the first report of omega-3 intake slowing, though modestly, the yearly rate of visual acuity decline in retinitis pigmentosa.
DHA / vitamin A interactions may account for the observed benefits of this combination. It’s thought rods give cones vitamin A via Muller cells, and DHA is required for releasing vitamin A from the protein (IRBP) that transports it between Muller cells. Further, rod degeneration can lead to shortages of both nutrients.
No significant difference in annual rates of decline for full-field cone ERGs was detected. Since this measure is generated predominately by mid- and far peripheral cones, this observation suggests that omega-3 benefit is limited to acuity and central field preservation.
Based on their findings, the authors estimate that the combined vitamin A and omega-3 rich diet would result in an additional 18 years of vision if the nutritional intervention begins at age 37, the average age of the participants in the combined trials.
Reference: Berson EL, et al. Omega-3 intake and visual acuity in patients with retinitis pigmentosa receiving vitamin A. Arch Ophthalmol, Published online ahead of print Feb 13, 2012.
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Omega-3s Influence Macular Pigment
Omega-3s Influence Macular Pigment
Investigating the role of omega-3s in macular pigment formation
High dietary intake of lutein and zeaxanthin, or their oral supplementation, is known to increase their accumulation within the macula to form protective macular pigment (there is evidence that this accumulation relies on specific carotenoid binding proteins).
Omega-3 fatty acids and particularly DHA, are abundant in the human retina where they play structural, functional and neuroprotective roles. A number of epidemiological studies have observed decreased AMD risk with higher intake of the omega-3s EPA and DHA.
Since lutein and zeaxanthin are fat soluble, their metabolism is strongly interlinked with lipids. It has been suggested, in fact, that dietary omega-3 intake enhances retinal accumulation of lutein and zeaxanthin.
To better understand the factors influencing macular pigment accumulation, French investigators recently looked at the relationship between MPOD and plasma levels of lutein, zeaxanthin and omega-3s in a homogeneous population of healthy volunteers. The researchers report a significant correlation between MPOD and all of these dietary nutrients.
The results of this study suggest that omega-3 fatty acids may act synergistically with lutein and zeaxanthin in constituting the macular pigment, and could be an added reason for concurrent supplementation of these nutrients. Such supplementation is currently being tested in the ongoing AREDS 2 clinical trial.
Results
MPOD within 6° correlated with plasma levels of lutein and zeaxanthin (r=0.35, p<0.001 and r=0.30, p<0.005, respectively).
MPOD also significantly correlated with total plasma omega-3 polyunsaturated fatty acids (PUFAs) (r=0.22, p<0.05).
Among the different omega-3 PUFAs, docosapentaenoic acid (DPA) had the highest correlation with MPOD (r=0.31, p<0.001), while correlation with EPA was moderate (r=0.21, p<0.05), and did not reach significance for DHA.


Scatter plots depicting the correlations between macular pigment optical density (MPOD) at one degree of eccentricity with (A) lutein and zeaxanthin (L+Z); with (B) total omega-3 long chain polyunsaturated fatty acids (LCPUFAs); with (C) EPA (eicosapentaenoic acid) and with (D) DPA (docosapentaenoic acid)
Graphic courtesy of Investigative Ophthalmology & Visual Science

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Comments
In this study, MPOD correlated not only with plasma lutein/zeaxanthin, but also with the omega-3 long chain fatty acids – particularly EPA and DPA. DPA, a metabolic intermediate between EPA and DHA, is the second most abundant long chain omega-3 found within the retina.
While the mechanisms by which the omega-3 may influence MPOD remain to be determined, it is possible that they: 1) modulate the gastro-intestinal uptake of lutein and zeaxanthin; 2) enhance transport of these carotenoids to the eye by lipoproteins; or 3) affect the concentration or utilization of lutein and zeaxanthin in the macular area.
Reference: Delyfer MN, et al. Association of macular pigment density with plasma omega-3 fatty acids: the PRIMAVOSA study. Invest Ophthalmol Vis Sci. Epub ahead of print, Jan 24, 2012.
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Meta-Analysis: Omega-3 Fatty Acids Reduce Artery Stiffness
Meta-Analysis: Omega-3 Fatty Acids Reduce Artery Stiffness
Arterial Stiffness and Cardiovascular Events
Arteries stiffen and become less flexible as a consequence of aging and arteriosclerosis. Age-related stiffness occurs when the elastic fibers within the arterial wall (elastin) begin to fray due to mechanical stress. Stiffer arteries require a greater amount of force in order to expand and take up the blood ejected from the heart. This, in turn, causes the heart to contract harder to accommodate the artery.
Arterial stiffness, in fact, has recently emerged as a significant predictor of cardiovascular disease. For example, a recent meta-analysis of 17 longitudinal studies confirmed that aortic stiffness is a significant predictor of future cardiovascular events and all-cause mortality (1). Thus, evidence-based approaches to reducing arterial stiffness are of significant clinical importance.
Omega-3 Fatty Acids and Arterial Flexibility
One candidate for helping to alleviate arterial stiffness is the omega-3 fatty acids found in fish oil – EPA and DHA. Fish oils have long been known to mildly reduce elevated blood pressure, and evidence suggests that they may lower heart rate and prevent arrhythmia. They are also known to benefit those with coronary heart disease by reducing mortality. But do they have an effect on arterial stiffness?
Although current evidence from randomized and controlled human clinical trials suggests that fish oils may be beneficial in reducing arterial stiffness, no quantitative synthesis of this data has been conducted. This gap in knowledge led a team of researchers from Melbourne, Australia to conduct the first systematic review and meta-analysis of controlled trials to assess whether fish oils are of benefit in arterial stiffness (2).
Study Design
Multiple databases and clinical trial registries were systematically searched up until September 2010 for randomized and controlled adult human clinical trials to investigate the effects of long-chain n-3 fatty acids on arterial stiffness. No limits were set on dosage sizes or sample characteristics.
A total of 10 omega-3 trials met the final inclusion criteria; 4 using pulse wave velocity and 6 using arterial compliance, measured as capacitive compliance or systemic arterial compliance, as respective outcome measures.
Results
Meta-analysis revealed that omega-3 was statistically significant in effectively improving both pulse wave velocity (P<0.01) and arterial compliance (P<0.001). There was no evidence of heterogeneity or publication bias. Results were not influenced by changes in blood pressure, heart rate or BMI.
Comments
The findings of the present analysis suggest that high dose supplementation with EPA and DHA offers a scientifically supported means of reducing arterial stiffness, and may account for some of the cardio-protective effects of these omega-3 fatty acids, according to the authors.
One possible limitation of this analysis is that none of the studies included used carotid-femoral pulse wave velocity, which is regarded as the ‘gold standard’ in the measurement of arterial stiffness. However, the measures used in the present meta-analysis such as brachial-ankle pulse wave velocity and systemic arterial compliance are also valid and predictive of CVD and or mortality.
In terms of any potential impact on ocular health, associations between arterial stiffness and AMD and arterial stiffness and glaucoma have been reported in some epidemiologic investigations, though not others.
References
1. Vlachopoulos C, et al. Prediction of cardiovascular events and all-cause mortality with arterial stiffness. A systematic review and meta-analysis. Journal of American College of Cardiology 55:1318–27, 2010.
2. Pase M, et al. Review Article. Do long-chain n-3 fatty acids reduce arterial stiffness? A meta-analysis of randomised controlled trials. British Journal of Nutrition, Epub July 6, 2011.
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Protective Role for Omega-3s in Macular Health?
Role for Omega-3s in Prevention of AMD?
Omega-3s May Reduce Risk of AMD in Women
While an AREDS-tested antioxidant supplement has been shown to slow progression in people with intermediate AMD, there is no recognized means of prevention for those currently free of the disease or the estimated 7.3 million Americans with early AMD.
Evidence from observational studies suggests that regular dietary intake of fish, DHA and EPA may reduce AMD risk. In fact, the randomized trial, AREDS-2, is currently evaluating whether supplemental DHA and EPA can lower the risk of progression to advanced AMD. However, the available data for early AMD are limited and inconsistent.
To increase that evidence base, a team of Harvard University researchers has examined the relationship between omega-3, fish consumption and AMD in a large cohort of women health professionals who were free of the disease at the study’s start.
The researchers now report that regular consumption of EPA, DHA and fish is associated with a 34-42% risk reduction of visually significant AMD incidence. They conclude that consistent omega-3 consumption may be of benefit in the primary prevention of AMD.
Design
In this prospective study, dietary information was obtained by food-frequency questionnaire at baseline for 39,876 health professionals who participated in the Women’s Health Study. A total of 38,022 women, 54 years of age on average and free of a diagnosis of AMD, completed the questionnaire and were followed for an average of 10 years.
The main outcome measure was incident AMD responsible for a reduction in best corrected visual acuity to 20/30 or worse, based on self-report confirmed by medical record review.
Results
A total of 235 cases of AMD, most characterized by some combination of drusen and retinal pigment epithelial changes, were confirmed during an average 10 years of follow-up.
Women in the highest 1/3 of intake for DHA, compared with those in the lowest, had a multivariate-adjusted 38% lower risk of AMD (RR 0.62, 95% confidence interval 0.44-0.87).
For EPA, women in the highest tertile had a 34% reduced risk (RR 0.66, 95% confidence interval 0.48-0.92).
Consistent with the findings for DHA and EPA, a 42% lower risk was observed in women who consumed 1 or more servings of fish weekly compared to those consuming less than 1 serving monthly (RR 0.58 95% confidence interval, 0.38-0.87).
Comments
There are many mechanisms by which omega-3s could affect AMD occurrence. For example, they have been shown to protect against the damaging effects of blue light in the parafovea.

DHA and EPA may also contribute to macular protection by modulating inflammatory and immune processes thought to play a role in AMD pathogenesis. They enhance production of resolvins and neuroprotectins—compounds thought to dampen and resolve inflammatory responses. EPA and DHA also affect the expression of signal transduction genes and genes for pro-inflammatory cytokines.
These findings by WG Christen and his colleagues are broadly consistent with previously published findings, and appear to be the strongest observational evidence to date in support of a role for omega-3 and fish intake in the primary prevention of AMD.
Because early AMD is associated with an increased risk of developing advanced AMD, these data also suggest that regular omega-3 intake could ultimately reduce the number of persons who have advanced AMD.
References
1. Christen WG et al. Dietary omega-3 Fatty Acid and Fish Intake and Incident Age-Related Macular Degeneration in Women. Archives of Ophthalmology, Published online March 14, 2011.
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Lutein, Zeaxanthin & Omega-3s and Blue Light Damage
Lutein, Zeaxanthin & Omega-3s Shown to Protect Against Blue Light Damage
Lutein, Zeaxanthin, Omega-3 and AMD Risk
The low values of macular pigment density seen in some people, coupled with the age-related decline of natural defenses in the retina and RPE can increase oxidative stress, a risk factor for AMD. AMD risk is thought to be further increased by exposure to blue (short-wavelength) light, although the results of observational studies have been conflicting.
One of the observational studies reports that estimated lifetime blue light exposure increased the risk of neovascular AMD specifically in individuals with low plasma levels of antioxidants, including zeaxanthin. However, experiments to evaluate the relationship of the macular pigment xanthophylls (lutein and zeaxanthin) to light damage and macular disease have been few, due to a lack of appropriate animal models. Only higher primates have a macula lutea, with its high foveal concentration of macular pigment.
Working with a unique set of rhesus monkeys raised on lutein and zeaxanthin-free diets, a research team has now looked at the effects of macular pigment absence – followed by xanthophyll supplementation – on blue light damage. The researchers also examined whether a deficiency of omega-3 fatty acids affects sensitivity to blue light as well.
Study Design and Methods
The study included 8 rhesus monkeys with no lifelong intake of xanthophylls and no detectable macular pigment. Four of the monkeys had low omega-3 intake and 4 had adequate dietary intake.
Retinas received 150 μm-diameter exposures of low-power 476 nm laser light either at 0.5 mm [~2(o)] eccentricity, adjacent to the macular pigment peak, or parafoveally at 1.5 mm [~6(o)]. Exposures of xanthophyll-free animals were repeated after supplementation with pure lutein or zeaxanthin for 22-28 weeks.
Visible lesion areas were plotted as a function of exposure energy, with greater slopes of the regression lines indicating greater sensitivity to damage. The results were compared to data from control animals with typical levels of xanthophylls and omega-3 in their diets and retinas.
Results
For control animals with normal macular pigment, the fovea was less sensitive to blue light damage than the parafovea. However in the monkeys lacking macular pigment, fovea and parafovea were equally vulnerable.
After supplementation, foveal protection in xanthophyll-free animals did not differ from controls. And, like controls, the fovea was now less sensitive to damage than the parafovea.
In the parafovea (but not the fovea), animals low in omega-3 fatty acids showed greater sensitivity to damage compared to those with adequate omega-3.
Comments
These findings confirm the photo-protective effect of lutein and zeaxanthin in the fovea where their con-centration is greatest, and indicate that omega-3 fatty acids lessen damage in the parafovea. Although the study showed protection against acute blue light damage, it seems probable that these nutrients would also protect the macula against chronic blue light exposure.
The omega-3 fatty acid DHA is present at exceptionally high levels in the retina, particularly in photoreceptor outer segment membranes. There are a number of ways by which DHA could act to lessen blue light damage: it serves as the precursor for neuroprotective factors and helps counter inflammation. In addition DHA helps block abnormal vessel growth (see EduFacts Vol. 12 No. 1).
“Our results”, conclude the study authors, “offer hope that good nutrition, augmented by supplementation when appropriate, can contribute to reduction of risk for AMD, especially for persons with reduced macular xanthophyll levels due to retinal disease, poor diet, or genetic predisposition”.
References
Barker FM, et al. Nutritional Manipulation of Primate Retinas. V: Effects of Lutein, Zeaxanthin and n–3 Fatty Acids on Retinal Sensitivity to Blue Light Damage. IOVS Papers in Press. Published on January 18, 2011 as Manuscript iovs.10-5898
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Omega-3s Work and Retinopathy
Revealing How Omega-3s Work against Retinopathy
Deciphering Pathways Could Pay Dividends
The omega-3 fatty acids EPA and DHA appear to play an important role in thwarting the new growth of irregular blood vessels in the retina. For example, the omega-3s have been shown to protect against retinal angiogenesis in an animal model of retinopathy and higher omega-3 intake has also been found to correlate with decreased neovascularization in AREDS participants. However, we still don’t know exactly which lipid pathways and which molecules govern specific protective effects.
Deciphering the pathways by which omega-3s block abnormal vessel growth in the eye could lead to the development of new targeted treatments to augment the currently used anti-VEGF approaches to treating retinopathy. It could also tell us whether common inhibitors of omega-3 related enzymes such as aspirin and NSAIDs can be used without losing the beneficial effect of these dietary fatty acids.
Background: Meet the COX and LOX Families
The principal enzymatic pathways that convert the omega-3 and omega-6 fatty acids into bioactive metabolites are the cyclooxygenases (COXs) and the lipoxygenases (LOXs).
The COXs play a primary role in producing prostaglandins (which mediate inflammatory and anaphylactic reactions), thromboxanes (mediators of vessel constriction), and prostacyclins (which are involved in the resolution phase of inflammation).
The LOXs, on the other hand, generate biologically active products such as the leukotrienes, lipoxins, and the recently identified omega 3–derived resolvins and protectins. Resolvins and (neuro)protectins, which can be formed from both EPA and DHA, have very potent anti-inflammatory and immune-regulating actions.
Bottom line is that the beneficial effects of the omega-3s are mostly mediated by these hormone-like compounds derived via the COX and LOX enzymes.
Study Details
Montreal, UC Berkeley, the NEI and elsewhere, sought to clarify the overall contribution of COX and LOX enzymes in blocking destructive neovascularization.
In brief, omega-3 diets were fed to 4 lines of mice, each of which were deficient in one of the 4 main enzymes that convert omega-3s to active metabolites (COX 1 or 2, or LOX 5 or 12/15). Retinopathy was then induced by oxygen exposure.
Results
The research team found that protection against retinopathy required the 5-LOX enzyme. Specifically, the protective effect was due to 5-LOX oxidation of DHA to the metabolite 4-HDHA (4-hydroxy-DHA).
4-HDHA directly inhibited endothelial cell proliferation and sprouting angiogenesis.
This action was independent of 4-HDHA’s anti-inflammatory effects. Instead, 4-HDHA worked by activating PPAR gamma, a transcription factor that regulates the expression of genes.
In addition, the investigators found significant concentrations of 4-HDHA in healthy human subjects, suggesting that their findings may apply to the way omega-3s block angiogenesis in humans.
The fact that COX 1 and 2 were not involved in inhibiting angiogenesis suggests that COX inhibitors such as aspirin and ibuprofen can be used without negating the beneficial effect of dietary omega-3s.
In contrast, clinical use of 5-LOX inhibitors (e.g. the drug zileuton) in patients at risk of ocular neovascular disease warrants closer investigation in light of these findings.
This new information about omega-3s could make them a promising new treatment option considering that the monthly cost of omega-3 supplementation is a fraction of the up to $4,000 cost per month of anti-VEGF therapy.
Reference
1. Sapieha P,et al. 5-Lipoxygenase metabolite 4-HDHA is a mediator of the antiangiogenic effect of w-3 polyunsaturated fatty acids. Sci Transl Med 3, 69ra12 (2011).
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EPA & DHA and Macular Health in AREDS 2
EPA & DHA Linked to Lower AMD Risk in AREDS 2
AREDS 2 Basics
AREDS 2 is a nationwide study to determine whether high dose carotenoids (lutein and zeaxanthin) and omega-3 fatty acids (DHA and EPA) can slow vision loss in people at moderate to high risk for the progression of AMD. The study began in the fall of 2006, and is expected to be completed in 2013.
The 3 interventions arms for the carotenoids and omega-3s are: 1) 10 mg of lutein and 2 mg of zeaxanthin plus placebo; 2) 350 mg of DHA and 650 mg of EPA plus placebo; and 3) a combination of the DHA/EPA and lutein/ zeazanthin. In addition, all participants are offered the original AREDS formula (now considered standard of care) or 3 variations of this formula: (1) no beta-carotene; (2) lower amounts of zinc; and (3) no beta-carotene and lower zinc.
At the Association for Research in Vision and Ophthalmology's meeting in May, researchers presented the baseline demographic and dietary characteristics of AREDS 2 participants, and their associations with AMD (1). They report that people consuming the most DHA or EPA had the lowest rating of AMD severity.
Study Design
Baseline fundus photographs were centrally graded with a standardized protocol using drusen size and pigment characteristics to assign the AREDS 5 level simple scale score of severity. Participants completed a dietary assessment at baseline, and nutrient density values were classified into quintiles. Data were adjusted for age, gender and
Results
Demographic characteristics are shown in Table 1. Dietary DHA and EPA were inversely related to AMD severity score in energy-adjusted comparisons of highest versus lowest quintile intake (p<0.05 for both nutrients, see Table 2). Trend tests on quintile median nutrient values yielded a p-value of <0.01 for both EPA and DHA. The association of lutein and zeaxanthin intake with severity score was in the direction of benefit, but did not achieve statistical significance.


Comments
At baseline, AREDS 2 participants had good visual function in their study eye(s). The majority had large drusen and/or pigmentary changes in the retinal pigment epithelium, risk factors for progression to advanced AMD. The authors conclude that those with the highest intake of DHA or EPA were significantly less likely than their peers to have higher AMD severity scores.
References
1. Chang JR, et al. Demographic and dietary characteristics of the Age-Related Eye Disease Study 2 (AREDS2) participants and their associations with age-related macular degeneration (AMD). ARVO May 2-6, 2010, Ft. Lauderdale, FL, e-Abs 97.
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Review: Lutein & Zeaxanthin Metabolism
Review: Lutein & Zeaxanthin Metabolism
Metabolism is Key to Lutein’s Protective Role
Growing evidence suggests lutein and zeaxanthin play an important role in protection against AMD by filtering out blue light or quenching free radicals. While much remains to be learned, researchers from Waterford Institute and Regional Hospital in Ireland and the University of Utah’s Moran Eye Center have reviewed mechanisms involved in absorption and transport of these carotenoids, their uptake by the retina and how they are stabilized (1). Below are highlights of these findings, along with editorial comment on implications for diet, lifestyle and supplement use.
Absorption of Lutein and Zeaxanthin
Dietary fat is important for the absorption of xanthophyll carotenoids like lutein and zeaxanthin. Fat stimulates bile flow from the gall bladder to emulsify fat-soluble vitamins into lipid micelles – microscopic fat droplets – so they can be absorbed in the small intestine. Inadequate fat intake can result in reduced absorption of carotenoids, even if the diet is carotenoid-rich. Experimental data suggest absorption of lutein is mediated by a non-specific transporter protein (this protein, scavenger receptor class B type I, appears to play a primary role in intestinal absorption, but other proteins or passive diffusion may also be involved). Of note, some competition for absorption is seen when similarly structured carotenoids like beta-carotene and lutein are consumed together.
Comments: Though different carotenoids compete for absorption, some evidence suggests that balanced amounts of various carotenoids consumed together over time don’t interfere with each other in terms of bioavailability (2). Importantly, doses of lutein (10 mg) and zeaxanthin (2 mg) now being used in the AREDS 2 trial, did not reduce serum levels of other important carotenoids in a dosing study (3).
Transport of Lutein and Zeaxanthin
Dietary lutein and zeaxanthin are delivered to the retina via plasma lipoproteins, chiefly LDL and HDL cholesterol. While LDL is the primary carrier for most carotenoids, LDL and HDL carry about equal amounts of lutein and zeaxanthin. Several studies suggest relatively low HDL levels could hinder transport and capture of these carotenoids. Lower HDL levels have been found in overweight and obese individuals, for example, and higher body fat percentage is linked to risk of AMD progression as well as to lower macular pigment density. Lipoproteins also include protein components known as apolipoproteins. Researchers are investigating whether a person’s apolipoprotein profile might influence transport and delivery of these carotenoids to the retina. Of many apolipoproteins types, ApoE has the strongest link with AMD.
Comments: Lower levels of HDL have been found in overweight individuals, consistent with the possibility that a relative lack of HDL may impair transport and/or retinal capture of the carotenoids. Obesity has been identified as a risk factor for AMD. Take home message? Aerobic exercise, which aids weight loss and increases HDL, may prove useful in lowering AMD risk.
Retinal Uptake of the Xanthophyll Carotenoids
The mechanisms governing retinal capture and accumulation of lutein and zeaxanthin to the exclusion of other carotenoids are still poorly understood. However, retinal capture of xanthophyll carotenoids is performed by xanthophyll-binding proteins (XBP). XBPs may also be involved in: a) stabilizing xanthophylls in cell membranes, the cytosol or the cytoskeleton, b) mediating inter-conversion of lutein, zeaxanthin and various metabolites within the retina, and c) facilitating antioxidant activity of macular carotenoids. Importantly, it has been found that XBPs can become saturated, with implications for xanthophyll carotenoid supplementation.
Comments: Macular pigment density often increases dramatically in the first 4 weeks of supplementation, and then levels off. In a number of studies testing 10-12 mg of lutein, macular pigment density reached a plateau after the first month. This may be due to saturation of binding proteins, and suggests higher doses may not further enhance macular pigment over time.
References
1. Loane E, et al. Transport and retinal capture of lutein and zeaxanthin with reference to age-related macular Degeneration. Surv Ophthalmol 53:68-81, 2008.
2. Tyssandier V, et al. Vegetable-borne lutein, lycopene, and beta-carotene compete for incorporation into chylomicrons, with no adverse effect on the medium-term (3-wk) plasma status of carotenoids in humans. Am J Clin Nutr 75:526–34 2002.
3. Rosenthal JM, et al. Dose-ranging study of lutein supplementation in persons aged 60 years or older.Invest Ophthalmol Vis Sci 47:5227–233, 2006.
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Omega-3 Rich Diet May Help Preserve Macular Health & Vision
Strategies to Prevent AMD Urgently Needed
Age-related macular degeneration (AMD) is a major cause of irreversible vision loss among people of Western European ancestry. It’s estimated that 3.35 million Europeans and 1.75 million Americans are living with sight-threatening AMD. Over the next 20 years these numbers are expected to increase by 50% if preventive interventions aren’t identified. Finding low cost ways to prevent progression to advanced AMD is particularly important since treatments for wet AMD are limited in scope, invasive, costly and may result in complications as severe as end-stage disease.
National Eye Institute researchers have examined whether omega-3 intake is associated with a reduced likelihood of developing central geographic atrophy and neovascular AMD in a cohort within AREDS – a multicenter clinical trial, which ran from 1992 to 2005. The investigators report that participants with the highest omega-3 intake were 30% less likely than their peers to develop dry or wet AMD.
Study Design
The research team looked at a sub-group of 1,837 AREDS participants considered to be at moderate-to-high risk of advanced AMD. Baseline data of omega-3 intake was obtained using a validated food-frequency questionnaire. Trained fundus graders ascertained AMD status from annual stereoscopic color photos by using standardized methods at a single reading center across a 12-year period.
Results
Nearly 20% of participants progressed to dry AMD, and about 32% progressed to wet AMD over the 12-year period. Those in the highest quintile of combined EPA and DHA intake were 30% less likely to develop dry and wet AMD than their peers in the lowest intake quintile. Median intake in the highest quintile was 11% of total calories, based on 2000 kcal daily.

Comments
“If these results are generalizable, they may guide the development of low-cost and easily implemented preventive interventions for progression to advanced AMD”, according to the researchers led by John Paul SanGiovanni. A 4000-person, 5-year randomized clinical trial designed to test the efficacy of omega-3 for this purpose is now underway (www.areds2.org). The omega-3 fatty acids may work by multiple mechanisms. For example, AMD appears to have an inflammatory etiology, and the omega-3s have the capacity to affect pathologic inflammatory processes in the retina.
Reference
SanGiovani et al. ω-3 Long-chain polyunsaturated fatty acid intake and 12-y incidence of neovascular age-related macular degeneration and central geographic atrophy: a prospective cohort study from the Age-Related Eye Disease Study. Am J Clin Nutr [Epub Oct, 2009].
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Omega-3s in an Animal Model of AMD
Volume 10 - Number 3
Omega-3s Slow AMD in Animal Model
It is known that omega-3 fatty acids, particularly DHA, play an important role in the layer of nerve cells in the retina, and studies have already reported that omega-3 may protect against the onset of AMD. A meta-analysis, for example, reported in the June, 2008 issue of the Archives of Ophthalmology found that a high intake of omega-3s and fish may reduce the risk of AMD by up to 38%. The Australian authors of this review noted that the benefits of omega-3 were most pronounced against more advanced AMD, while twice weekly fish consumption was associated with a lower risk of both early and late AMD (1).
In line with the epidemiologic data, are the results of a new National Eye Institute study which found that omega-3 fatty acids could retard the progression of lesions in a murine mouse model of AMD (2). Even more intriguing are the findings that mice in the high omega-3 group displayed some reversion of the lesions.
Study Design and Methods
The study evaluated the effects of a high omega-3 diet on the retinas of Cc12 - / - / Cx3cr1- / - mice - a model that develops AMD-like retinal lesions that include focal deep retinal lesions, abnormal retinal pigment epithelium, photoreceptor degeneration, and accumulation of A2E, a component of human retinal lipofuscin (an aging pigment and likely product of lipid peroxidation).
The mice were raised on low or high omega-3 diets, and clinical endpoints were measured using fundus photography, histopathology, transmission electron microscopy, A2E extraction and enzyme-linked immunoabsorbant assay to evaluate serum prostaglandin levels.
Results
Mice that were fed the high omega-3 diet showed a slower progression of lesions compared to the low omega-3 fed mice. Some mice ingesting the high omega-3 diet exhibited regression of lesions. No retinal lesions were noted in the normal wild mice used as controls and fed a regular diet.

Compared to the low omega-3 group, mice consuming the omega-3 enriched diet had lower levels of inflammatory molecules such as prostaglandin E2 and leukotriene B4, and higher levels of anti-inflammatory mediators such as prostaglandin D2. Higher omega-3 also resulted in lower IL-6 transcript levels and concentrations of ocular TNF-alpha, an inflammatory cytokine.
Comments
In summary, a diet enriched in EPA and DHA ameliorated the progression of retinal lesions in this useful animal model of AMD. These results are supportive of the findings from population health studies, and await further confirmation in humans by the AREDS 2 trial in progress.
EPA and DHA are concentrated in the retina and retinal vascular endothelium, and DHA accounts for about 50% of the lipids in photoreceptor rod outer segments. Vital retinal functions, including damage repair, depend on the existence of adequate levels of DHA.
In the eye, the omega-3 fatty acids and their derivatives play an extensive role in many biologic processes such as the inflammatory cascade, apoptosis and neuroprotection. In this study, the researchers focused on the function of the omega-3s in inflammation, since the role of inflammation in the pathogenesis of AMD is evident. Arachidonic acid, an omega-6 fatty acid, is the starting material for the synthesis of pro-inflammatory mediators such as various cytokines. When fish oil is provided, EPA and DHA are incorporated into cellular membranes at the expense of arachidonic acid.
References

1. Chong EW, et al. Dietary omega-3 fatty acid and fish intake in the primary prevention of age-related macular degeneration: a systematic review and meta-analysis. Archives of Ophthalmology 126:826-33, 2008.
2. Tuo J, et al. A high omega-3 fatty acid diet reduces retinal lesions in a murine model of macular degeneration. American Journal of Pathology 175:799-807, 2009.
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Inadequate Omega-3 Intake Contributes to 84,000 U.S. Deaths Annually
Prioritizing Preventable Causes of US Deaths
Modifiable risk factors responsible for many premature or preventable deaths fall into three main categories: Lifestyle factors such as smoking and physical inactivity; Dietary risk factors such as a high salt intake and a low intake of fruits and vegetables; And "metabolic" risk factors, such as obesity and hypertension, which shorten life expectancy by increasing the odds of developing CVD and diabetes.
With health care costs skyrocketing, it's important to know how many deaths are caused by each risk factor before developing policies and programs to improve the nation's health. Although previous studies have provided some information, they have not used consistent and comparable methods to estimate the number of deaths attributable to different risk factors. In addition, previous studies have rarely considered dietary and metabolic risk factors.
In a new study, jointly funded by the CDC and the Association of Schools of Public Health, Harvard researchers estimated the number of deaths due to 12 different modifiable risk factors.
Study Methods and Findings
The researchers used a method called "comparative risk assessment." They retrieved data on exposures to the 12 selected risk factors from US national health surveys, and obtained information on deaths from different diseases from the US National Health Center for Health Statistics. They also used previously published studies to estimate how much each risk factor increased the risk from a disease, and applied a mathematical model to estimate the number of deaths related to each factor.
Smoking and high blood pressure, which both have effective interventions, are responsible for the largest number of preventable deaths, followed by obesity, physical inactivity and high salt intake. Notably, 84,000 deaths were attributable to insufficient omega-3 intake, slightly higher than high trans fatty acid intake (82,000).
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Comment
Though the study focused upon the most common causes of death such as cancer, heart disease and respiratory diseases, the findings that inadequate consumption of omega-3, and fruits and vegetables are important risk factors may be notable for visual health as well. EPA and DHA (from fish), as well as lutein and zeaxanthin (from produce), have been strongly linked to the risk of AMD and, possibly, other ocular conditions. The typical intake of EPA and DHA for example is 100-200 mg daily, while the AREDS-2 trial is testing 1,000 mg. In addition, 10 mg of lutein and 2 mg of zeaxanthin are being employed in AREDS-2, while the average daily consumption of these carotenoids is 2 mg.

Reference
Danaei G, et al. The Preventable Causes of Death in the United States: Comparative Risk Assessment of Dietary, Lifestyle, and Metabolic Risk Factors. PLoS Med 6(4): e1000058.
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Nutrition Impacts AMD Risk & Health Costs
Preventive Steps May Lower AMD Costs
Preventing Age-Related Macular Degeneration (AMD) and delaying its progression would best preserve people's quality of life while containing health care system costs. The results from two new analyses suggest that adopting dietary habits or using supplements that slow progression from early to late stages, could ease the future burden of this disease.
Combined Dietary Factors Reduce AMD Risk
Foods provide many nutrients that may interact to modify the risk for AMD. Therefore, instead of looking at isolated nutrients, researchers from Tufts University developed a composite scoring system to examine the combined effect of dietary nutrients on AMD risk.
Study Design and Results
Data was analyzed for 4,003 Age-Related Eye Disease Study (AREDS) participants, involving 7,934 eyes. Levels of AMD-protective nutrients, including vitamins C and E, zinc, lutein, zeaxanthin, omega-3 fatty acids (DHA and EPA), as well as low-GI (Glycemic Index) foods, were assessed using participants' food intake reports. Each dietary factor was assigned a percentile score, and factor scores were added up to find each participant's compound score. Compound scores were related to participants' AMD risk, based on stereoscopic fundus photographs of the macula taken when they joined AREDS.
Participants whose diets included higher levels of these protective nutrients and of low-GI foods were at substantially lower risk for early and advanced AMD. Validation analyses showed the relationships to be robust.
Conclusion and Comments
The results suggest that the compound score summarizing the overall effect of diets rich in the AREDS trial nutrients (vitamin C, vitamin E, and zinc), the AREDS 2 trial nutrients (DHA, EPA, lutein and zeaxanthin), and low-GI foods are independently associated with lower risk for prevalent drusen and advanced AMD. Beta-carotene did not affect risk levels. The findings are in accord with earlier research linking low GI-diets with reduced risk of AMD and cataract, and further research is warranted.
New Therapies May Mitigate Rise in AMD
The Vision Health Cost-Effectiveness Study Group - encompassing investigators from the CDC, the National Center for Chronic Disease and Prevention and other institutions - report that while the prevalence of AMD will increase substantially by 2050, the use of new therapies can mitigate its effects.
Study Design and Results
The study simulated cases of early AMD, choroidal neovascularization (CNV), geographic atrophy (GA), and AMD-attributable visual impairment and blindness with five possible scenarios:
(1) No treatment; (2) Focal laser and photodynamic therapy (PDT) for CNV; (3) Vitamin prophylaxis at early-AMD incidence with focal laser/PDT for CNV; (4) No vitamin prophylaxis followed by focal laser treatment for extra and juxtafoveal CNV and anti-vascular endothelial growth factor treatment; (5) Vitamin prophylaxis at early-AMD incidence followed by CNV treatment, as in scenario (4).
Cases of early AMD nearly doubled, increasing from 9.1 million in 2010 to 17.8 million in 2050 across all scenarios. In non-vitamin-receiving scenarios, cases of CNV and GA increased from 1.7 million in 2010 to 3.8 million in 2050 (25% lower in vitamin-receiving scenarios). Cases of visual impairment and blindness increased from 620,000 in 2010 to 1.6 million in 2050 when given no treatment and were 2%, 22%, 17%, and 35% lower in scenarios 2, 3, 4, and 5, respectively (see Figure 2E).

Figure 2E
Number of Americans with pre-vision-threatening age-related macular degeneration (AMD) and blindness, with 5 alternative treatment scenarios from 2010 to 2050. Scenario 1 indicates no treatment (baseline); scenario 2, focal laser or photodynamic therapy (PDT) for CNV; scenario 3, universal vitamin prophylaxis at early AMD incidence with focal laser or PDT for CNV treatment; scenario 4, no vitamin prophylaxis followed by focal laser treatment for extrafoveal and juxtafoveal CNV and anti-vascular endothelial growth factor (anti-VEGF) treatments for subfoveal CNV for 2 years followed by PDT; scenario 5, universal vitamin prophylaxis followed by focal laser and anti-VEGF treatments for subfoveal CNV for 2 years followed by PDT.
Conclusion and Comments
The authors found that use of vitamins and existing therapies could reduce AMD by as much as 35%, translating to 565,000 fewer cases of visual impairment and blindness in 2050.
A 23% reduction in cases of visual impairment and blindness could be achieved using only vitamin prophylaxis in conjunction with focal laser and PDT therapies for patients who develop CNV - which amounts to a reduction of 375,000 cases of visual impairment and blindness five decades from now.
According to the authors, additional efforts to expand the use of AREDS level dietary supplements Is a cost-effective method of delaying AMD progression and cost-effective use of health care resources. However, research indicates it is not widely used among patients with early-stage disease and the correct dosage is seldom used. For example, though 68% of patients with early AMD who visited a retinal specialty practice in Edmonton, Canada, took some form of AREDS-recommended antioxidant supplement, no patients were taking the correct dosage of all 4 recommended vitamins. Public prevention efforts should focus on expanding the use of antioxidant vitamins in people with early AMD, and ensuring that these patients use the correct dosage.
References
1. Chiu, C-J, et al. Dietary compound score and risk of age-related macular degeneration in the AREDS. Ophthalmology 116:939-46, 2009.
2. Rein DB et al. Forecasting age-related macular degeneration through the year 2050: the potential impact of new treatments. Arch Ophthalmol 127:533-40, 2009.
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Drinking Wine Linked to Higher Omega-3 Levels
Alcohol, Omega-3 Fats, and Heart Health
The heart benefits of the traditional Mediterranean diet high in fish, fresh produce and red wine, have been well documented. A new study, part of the European IMMIDIET project, has shed new light on one of red wine's positive cardiovascular benefits.
The aim of the IMMIDIET project, funded by the European Union's initiative on food nutrition and health, is to examine the role of genetic and lifestyle factors in CVD prevention in Italians living at home, as wells as Italian immigrants to other countries.
High dietary and plasma concentrations of the marine fatty acids EPA and DHA are known to be protective against coronary heart disease (CHD) and sudden cardiac death. Alcohol, too, lowers the risk of ischemic stroke and CHD via a number of proposed pathways: increasing HDL, decreasing platelet aggregation and coagulation factors and exerting beneficial effects on endothelial function and inflammation.
Evidence also suggests that alcohol influences fatty acid metabolism. Low alcohol intake appears to increase long-chain fatty acid concentrations, while high alcohol decreases their concentration. Alcohol-induced increases in marine fatty acids might be a unique cardio-protective mechanism of alcohol.
In IMMIDIET, the researchers examined whether the heart benefits of alcohol extend to healthy men and women as well as male patients with cardiovascular disease as was shown in a previous study, the Lyon Diet Heart Study. They also examined whether various alcoholic beverages might affect marine lipid concentrations differently.
Study Design and Methods
In the framework of IMMIDIET, 1,604 men and women aged 26-65 years were enrolled in Italy, Belgium and England. A food frequency questionnaire was used to evaluate dietary and beverage intake. Blood samples were obtained, and plasma and red blood cell omega-3 fatty acids were assessed by gas chromatography.
Results
In fully adjusted multivariate analyses, alcohol intake In fully adjusted multivariate analyses, alcohol intake was positively associated with plasma EPA, DHA and EPA + DHA concentrations (p < 0.0001, p < 0.036 and p < 0.002 respectively) in women. EPA and EPA + DHA index in red blood cells were also positively associated with alcohol intake in females (p < 0.0001 and p < 0.037 respectively). In men, only plasma and red blood cell EPA concentrations were linked with intake of alcohol (p < 0.003 and p < 0.004 respectively).
In wine drinkers, stratified analyses revealed a statistically significant positive association between alcohol intake and both plasma and red cell EPA, DHA and the EPA + DHA index. In contrast, no association was found in those who drink beer and spirits.
Comments
This study examined three different populations with different dietary habits who consumed different types of alcoholic beverages. Analyses carried out on different beverages showed that the link between alcohol and omega-3 fatty acids was present in both wine drinkers and beer or spirits drinkers. However, adjusting for alcohol content of alcoholic beverages abolished the association with omega-3s in beer or spirits drinkers, while the associations with EPA and DHA were maintained or strengthened in wine drinkers.
These findings suggest that components in wine other than alcohol may be responsible for the higher omega-3 concentrations observed. The study authors propose that the polyphenol antioxidant components of wine may stimulate the synthesis of EPA and DHA from the precursor alpha-linolenic acid. Polyphenols may also be involved in that process by preventing alcohol-induced oxidation of long chain fatty acids, thus delaying their breakdown.
Reference
de Giuseppe R, et al. Alcohol consumption and n-3 polyunsaturated fatty acids in healthy men and women from 3 European populations. Am J Clin Nutr 89:354-62, 2009.
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EPA and DHA Again Linked with AMD Risk Reduction
EPA and DHA Again Linked with AMD Risk
According to a meta-analysis (1) published in the June issue of Archives of Ophthalmology, a higher intake of the omega-3 fatty acids EPA and DHA reduced the risk of age-related macular degeneration (AMD). In analyzing 9 studies that included roughly 88,900 participants, the Australian authors report that higher intakes of EPA and DHA cut the risk of early AMD substantially and yielded a 38% risk reduction for advanced AMD.
Most recently, a study published in the August issue of the American Journal of Clinical Nutrition is the first in Europeans to show a beneficial association between neovascular AMD and the consumption of oily fish (e.g. mackerel, tuna, salmon, sardines, and herring) (2). The study, funded in part by the European Commission and the Macular Disease Society UK, is consistent with results from studies in the US and Australia.
Study Design and Methods
The EUREYE study is a cross-sectional population-based study in persons aged 65 years or older in 7 centers located from north to south Europe. Participants in the cross-sectional population-based EUREYE study underwent fundus photography and were interviewed by using a food-frequency questionnaire. Fundus images were graded by the International Classification System for Age Related Maculopathy.
Questionnaire data were converted to nutrient intakes with the use of food-composition tables. Survey logistic regression was used to calculate odds ratios (ORs) and 95% CIs of energy-adjusted quartiles of EPA or DHA with neovascular AMD, taking into account potential confounders.
Results
Dietary intake data and fundus images were available for 105 cases with neovascular AMD and for 2170 controls without any features of early or late AMD.
Eating oily fish at least once per week compared with less than once per week was associated with a halving of the odds of neovascular AMD (OR = 0.47; 95% CI: 0.33, 0.68; P = 0.002). Compared with the lowest quartile, there was a significant trend for decreased odds with increasing quartiles of either DHA or EPA. Odds ratios in the highest quartiles were 0.32 (95% CI: 0.12, 0.87; P = 0.03) for DHA and 0.29 (95% CI: 0.11, 0.73; P = 0.02) for EPA.
In short, habitual consumption of oily fish at least once a week was linked to a 50% reduction in the risk of developing wet AMD. Further, people who consumed at least 300 mg per day of DHA and EPA were 69% less likely to have wet AMD then those consuming less.

References
1. Chong EW-T, et al. Dietary n-3 fatty acids and fish intake in the primary prevention of AMD-A systematic review and meta-analysis. Arch of Ophthalmol 126:826-833, 2008.
2. Augood C, et al. Oily fish consumption, dietary docosahexaenoic acid and eicosapentaenoic acid intakes, and associations with neovascular age-related macular degeneration. Am J Clin Nutr 88:398-406, 2008.
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Omega-3 & Antioxidants Support Visual Acuity in Dry AMD
Antioxidants, Omega-3 and Dry AMD
Dry, atrophic, or non-exudative, age-related macular degeneration (AMD) is the most common form of the disease, and is characterized by progressive devitalization of retinal pigment epithelium (RPE) and the formation of fatty deposits under the RPE known as soft drusen. Patients not receiving treatment have demonstrated a loss of visual acuity at 6 months of at least 0.8 lines and up to 1.5 lines.
Studies have suggested that nutritional factors can play a significant role in slowing the onset or limiting the effects of AMD. In 2004, the Lutein Antioxidant Supplementation Trial (LAST) demonstrated that nutritional supplementation with lutein or lutein together with antioxidants, vitamins and minerals improved visual function and symptoms in male patients with atrophic AMD (1). Currently, the 2nd Age-Related Eye Disease Study (AREDS II) is examining the effects of carotenoids and omega-3 fats on AMD.
The Taurine, Omega-3 Fatty Acids, Zinc, Antioxidant, Lutein (TOZAL) study was conducted to investigate the impact of combined omega-3, antioxidants, and other nutrients on visual function in those with atrophic AMD (2). The results suggest that such a nutritional approach may help maintain visual acuity.
Study Design and Methods
The primary objective of this prospective, open case-controlled study was to measure the change from baseline in visual function - Best-Corrected Visual Acuity (BCVA) via the ETDRS chart, contrast sensitivity, central 10 degree visual fields and retinal imaging (angiograms and photographs) at 6 months in subjects with atrophic (dry) AMD treated with a targeted nutritional supplement.
Thirty seven mixed gender patients with a mean age of 76.3 +/- 7.8 years were enrolled at 5 independent study sites and received standard of care along with a nutritional supplement containing lutein; zeaxanthin; vitamins A, C and E; beta-carotene; taurine; zinc, copper; EPA and DHA. Results were compared to a placebo cohort constructed from the literature that was matched for inclusion and exclusion criteria. A paired t-test was used to test a null hypothesis and a two-sided alpha level of 0.05 was used to determine statistical significance.
Results
Seventy-six percent of subjects receiving the nutritional supplement demonstrated stabilization or improvement of BCVA at 6 months. Subjects gained an average of 0.0541 logMAR or one-half of a line of visual acuity (VA) over the 6-month period. There was a statistically significant improvement in VA from baseline (p = .045).
Comments
"The results provide strong evidence that the treatment being studied produces an improvement in VA" according to the authors. Supplementation increased VA above the expected baseline decrease in the majority of patients in this population. The results of the TOZAL study agree with the LAST and CARMIS studies and are predictive for positive visual acuity outcomes in the AREDS II trial. However, supplementation for longer than 6 months is likely required to effect changes in additional visual parameters.


References
1. Richer S et al. Double-masked, placebo-controlled, randomized trial of lutein and antioxidant supplementation in the intervention of atrophic age-related macular degeneration: the Veterans LAST study. Optometry 75:216-230, 2004.
2. Cangemi FE, et al. TOZAL Study: An open case control study of an oral antioxidant and omega-3 supplement for dry AMD. BMC Ophthalmology 7:3, 2007.
3. Sartore M et al. CARMIS Research Group: Effects of short-term supplementation with carotenoids and antioxidants on visual acuity and visual function in age related macular degeneration. Presented at: ARVO; April 30-May 4, 2006; Fort Lauderdale, FL.
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Meta-Analysis: Omega-3 Intake and AMD Risk
Omega-3 Fatty Acids and Risk of AMD
According to AMD Alliance International, AMD affects approximately 25-30 million people worldwide, and the incidence of this disease is projected to triple by 2025. New treatments for AMD are limited to patients with exudative AMD and are not without risks. Thus, primary prevention of AMD by modifying risk factors remains an important public health strategy.
Insufficient intake of certain dietary components may be one of those risk factors. There is growing interest in the long - chain omega-3 fatty acids EPA and DHA since they play an important role in the layer of nerve cells in the retina and may be involved in the prevention or progression of AMD.
Epidemiological studies have generally shown inverse associations between intake of these fatty acids from fish and AMD. Now, a systematic review and meta-analysis from the University of Melbourne reports that higher intakes of EPA and DHA significantly decrease the risk of both early and late AMD (1).
Study Design and Methods
Seven databases were systematically searched using standardized criteria, with no limits on publication year or language. Randomized controlled trials and prospective cohort, case-control, and cross-sectional studies were included. Of 2,754 abstracts identified, 3 prospective cohort, 3 case-control, and 3 cross-sectional studies met the criteria. Measures of associations were pooled quantitatively using meta-analytic methods.
Results
Nine studies provided data on a total sample of 88,974 people including 3,203 AMD cases.
A high dietary intake of omega-3 fatty acids was associated with a 38% reduction in the risk of late AMD, when the highest intake was compared with the lowest (pooled odds ratio [OR], 0.62; 95% confidence interval [CI], 0.48-0.82).
Fish intake at least twice weekly was associated with a 24% and 33% reduced risk of early and late AMD respectively (pooled OR, 0.76; 95% CI, 0.64-0.90; and pooled OR, 0.67; 95% CI, 0.53-0.85).
Combining the results from all 9 studies also showed that a high dietary intake of EPA was linked to a 23% lower risk of early AMD, while DHA was associated with a 30% reduction.
In contrast, a high intake of the omega-3 alpha linolenic acid was associated with a 49% increase in risk.
Comments
In this study the definition of 'early AMD' included vision loss, and hence might be more indicative of an intermediate stage of AMD. However, the findings suggest that a greater intake of EPA and DHA can slow AMD progression. In addition, results from the current analysis are consistent with another systematic review in which the authors critically reviewed 6 observational studies for evidence that omega-3 fatty acids prevent AMD (2).
While the benefits of EPA and DHA require confirmation in long-term intervention trials such as AREDS-2, the authors underscore the strong underlying biological rationale of these fatty acids.
DHA plays an essential structural role in the membrane of the retina and is found in high concentrations. Further, the outer photoreceptor cell segments of the retina are constantly shed in the normal visual cycle and deficiency of DHA could initiate AMD.
According to the authors: "There is also evidence that such long-chain fatty acids protect against oxygenic, inflammatory, and age-associated pathology of the vascular and neural retina, which are possible pathogenic factors for AMD development."
References
1. W-T Chong E, et al. Dietary omega-3 fatty acid and fish intake in the primary prevention of age-related macular degeneration. A systematic review and meta-analysis. Arch Ophthalmol 126:826-33, 2008.
2. Hodge WG, et al. Efficacy of omega-3 fatty acids in preventing age-related macular degeneration: a systematic review. Ophthalmology 113:1165-1172, 2006.
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AREDS Analyses: Higher Omega-3 & Lutein - AMD Likelihood
AREDS Reports Numbers 20 and 22
Dietary data was collected from participants when they enrolled in the AREDS trial so that investigators could later examine the relationship of AMD case groups with intake levels of individual nutrients.
To explore these relationships, AREDS subjects were divided into four groups based on increasing severity of drusen or type of AMD. The dietary information from those four groups was then compared with that from AREDS participants categorized as being 'free' of AMD. AMD-free was defined as having no drusen or less than 15 small drusen. Nutrient intake values were adjusted for energy intake then stratified into quintiles.
Results of the analyses were published in the May and September issues of the journal Archives of Ophthalmology. The first of these case-control studies reports on the relationship of dietary lipids and AMD (1), while the second study assessed whether nutrients such as carotenoids, vitamins A, C and E and others, were related to AMD risk (2).
Omega-3 and Fish Intake Lower AMD Risk
The researchers found that only higher intake of total long chain omega-3 and fish (the primary dietary source of EPA and DHA), were linked to a decreased likelihood of having neovascular AMD. Benefit was not seen for the other AMD groups.
Arachidonic acid was the only dietary lipid directly associated with neovascular AMD prevalence. Participants getting the most arachidonic acid in their diets were 54% more likely to have late AMD. Arachidonic acid, an omega-6 fat abundant in meat and dairy, is a precursor for inflammatory eicosinoids.
No statistically significant relationships were seen for other dietary lipids such as the monounsaturates, found in olive oil for example, or saturated fats.
It's interesting to note that the omega-3 fat alpha-linolenic acid, found in flaxseed oil for example, was associated with decreased AMD risk only when it was included along with EPA and DHA as part of the total intake of long chain polyunsaturated fats. Assessed alone, alpha-linolenic was not related to AMD. Alpha-linolenic acid must first be metabolized to EPA to provide anti-inflammatory activity, and this conversion is only 10-20% effective.
Comparing the highest to lowest quintiles, those consuming the most total omega-3 fats were about 39% less likely to have neovascular AMD. Risk reduction for greater fish intake was the same. A 46% lower chance of having late AMD was linked with the highest consumption of DHA.
EPA, DHA and arachidonic acid are major fatty acids in the diet. Both arachidonic acid and DHA (which can be formed from EPA), are key components of retinal photoreceptor outer segments and vascular tissue. While all three of these lipids are essential, a better balance of EPA and DHA to arachidonic acid is recommended for cardiovascular health. This study strongly suggests that improving that balance can favorably influence retinal health as well.
Only Lutein / Zeaxanthin Independently Linked to AMD
Higher dietary intake of lutein and zeaxanthin was independently associated with a reduced likelihood of having neovascular AMD, geographic atrophy, and large or extensive intermediate drusen. No other nutrients were independently related to AMD.
After adjusting for total energy intake and other non-nutritional risk factors, subjects consuming the highest amount of lutein and zeaxanthin were 35% less likely to have neovascular AMD and 55% less likely to have geographic atrophy than those eating the least. Those whose diets provided the most of these two carotenoids also had a 26% reduced likelihood of having large or extensive drusen.
The findings from both of these AREDS case-control studies are, in part, the basis for testing 10 mg of lutein, 2 mg of zeaxanthin, 650 mg EPA and 350 mg of DHA in the AREDS 2 trial currently underway.
References
1. AREDS Report No. 20: The relationship of dietary lipid intake and age-related macular degeneration in a case-control study. Arch Ophthalmol 125:671-9, 2007.
2. AREDS Report No. 22: The relationship of dietary carotenoids with age-related macular degeneration in a case-control study. Arch Ophthalmol 125:1225-32, 2007.
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DHA and EPA May Support Health in Retinopathy
Retinopathy and Omega-3 Fatty Acids
Retinopathy affects an estimated 4 million diabetic patients and about 40,000 premature infants in the US. Retinopathy has two critical phases: loss of vessels in the retina which leads to hypoxia, followed by new vessel growth spurred by the lack of oxygen. The new vessels grow abnormally, are malformed, leaky and over-abundant. In the later stages of the disease, the abnormal vessels pull the retina away from its supporting layer, and the detachment ultimately results in blindness.
The role of omega-3 lipids in angiogenesis is beginning to be defined, and it appears that EPA and DHA are involved in regulating vessel loss and neo-vascularization.
In a study published in the July issue of Nature Medicine, omega-3 fatty acids protected against the development and progression of retinopathy in mice. It was found that increasing tissue levels of EPA and DHA decreases the area of vascular loss in the retina by increasing normal vessel regrowth after injury, and by reducing the hypoxic stimulus for growth of abnormal vessels.
The study was a collaborative effort by researchers at Children's Hospital Boston, Brigham and Women's Hospital, Massachusetts General Hospital, the University of Göteborg in Sweden, and the National Eye Institute. The authors concluded that "supplementing omega-3 polyunsaturated fatty acid intake may be of benefit in preventing retinopathy".
Study Summary
Mice subjected to oxygen-induced retinopathy were fed isocaloric diets enriched with 2% fatty acids - either omega-3 (EPA and DHA) or omega-6 (arachidonic acid). Additionally, the researchers also examined retinopathy in the Fat-1 model. Fat-1 mice are genetically altered to convert omega-6 to omega-3 - a conversion that humans and other mammals cannot do.
Mice receiving the omega-3 rich diet were observed to have 40-50% less initial retinal vessel loss compared to omega-6 fed mice. As a result, the omega-3 group had a similar 40-50% reduction in pathological vessel growth. The results were virtually identical in the Fat-1 mice, confirming that increased retinal omega-3 levels inhibited neo-vascularization.
Omega-3 Protective Mechanism
The investigators demonstrated that the omega-3 diet suppressed production of the cytokine called TNF-alpha, reducing the inflammatory response in the retina. In contrast, the arachidonic enriched diet increased TNF-alpha production. The retinas of the omega-3 group also had higher levels of neuroprotectin D1 and resolvin D1 (both derived from DHA), and resolvin E1, which is derived from EPA. These compounds also potently protected against pathological vessel growth, and were not detected in retinas of the omega-6 fed mice.
Commentary
"It is remarkable that with only a 2% change in dietary omega-3 intake, we observed an approximate 40-50% decrease in retinopathy severity", commented one of the study's lead authors Dr. Kim Connor. "Our studies suggest that after initial loss, vessels re-grew more quickly and efficiently in the omega-3 fed mice", said Connor. "This increased the oxygen supply to retinal tissue, resulting in a dampening of the inflammatory alarm signals that lead to pathological vessel growth".
According to the other lead author, Dr. John Paul SanGiovanni, "this is a major conceptual advance in the effort to identify modifiable factors that may influence inflammatory processes implicated in the development of common sight-threatening retinal disease".
The American Diabetic Association currently advises people with diabetes to consume more omega-3 to lower their risk of heart disease. If the findings of this study are confirmed in humans, fish oil may also lessen the risk for one of the long-term complications of diabetes, retinopathy. A clinical trial at Children's Hospital Boston is set to test the effects of omega-3 supplementation in premature infants at risk of retinopathy.
Reference
1. Connor KM et al. Increased dietary intake of 3-polyunsaturated fatty acids reduces pathological retinal angiogenesis. Nature Medicine 13:868-874, 2007.
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Update: Nutrients & Retinitis Pigmentosa
Nutrient Supplementation for RP
Retinitis pigmentosa (RP) refers to a group of inherited progressive retinal dystrophies characterized by photoreceptor degeneration. The rods are affected initially, followed by gradual death of the cones. It's estimated that 1 in 4,000-5,000 people have RP worldwide. Since no generally accepted medical or surgical treatment can stop the course of the disease, researchers have undertaken studies with various nutritional supplements in hopes of improving visual function or slowing disease progression. Along with vitamin A , DHA and an omega-3 rich diet, lutein has recently been reported to be of potential benefit in RP.
Lutein May Benefit Visual Field and Acuity
Spurred by previous studies suggesting lutein as a potential treatment with positive effects on macular pigment density, researchers from the Wilmer Eye Institute conducted a double-blind, randomized placebo-controlled trial with a cross-over design (1). Thirty-four adult RP patients were randomized to 2 groups and followed for 48 weeks. One group received lutein supplements (10 mg/day for 12 weeks followed by 30 mg/day) for the first 24 weeks, then placebo for the following 24 weeks. The second group received placebo prior to lutein. Both groups were given a multi-vitamin and mineral supplement.
Lutein supplementation had a significant effect on central visual field. Visual acuity also improved slightly, though no effect on contrast sensitivity was observed. Comparing the development of vision measures against the natural loss expected to occur over 48 weeks, most measures showed reduced decline. These reductions were significant for normal illumination visual acuity and contrast sensitivity. The results, according to the authors, suggest that lutein supplementation improves visual field and may also modestly improve visual acuity.
Vitamin A Helps Preserve Visual Function
In 1993, Harvard investigators reported that 15,000 IU of vitamin A palmitate slowed the rate of decline of retinal function over 5 years as measured by ERG (2). In this study of 600 RP patients, high dose vitamin A helped preserve retinal function, while those getting high dose vitamin E (400 IU) were more likely to show a functional decline. A later study following adult RP patients taking high dose vitamin A for about 12 years concluded that prolonged intake is considered safe in this age group (3), although routine monitoring of liver function and fasting serum vitamin A levels are advised. Women of childbearing age should not take high dose vitamin A, which may raise the risk of birth defects.
Antioxidants Protect Cones in Animal Model
Why the negative affect of high dose vitamin E on RP function? It is possible that high dose vitamin E might have inhibited the absorption or transport of vitamin A, since patients receiving high doses had slight but significant decreases in serum A levels compared with those receiving lower doses in the 1993 Harvard study.
However, further exploratory studies of combined antioxidants in RP patients may be warranted. A recent study in an animal model of RP found that high dose antioxidants (vitamins E, C, alpha lipoic acid others) significantly reduced oxidative damage in cones, increased cone cell density and preserved cone function. These results, according to the Johns Hopkins authors, suggest that the gradual cone death that occurs after rod cells die is due to oxidative damage, and that antioxidants could provide benefit (4).
Omega-3 Fatty Acids Support Visual Field
While a 4 year long study published in 2004 reported that 1,200 mg of supplemental DHA along with high dose vitamin A did not slow the course of RP overall, further subgroup analysis showed benefit for those starting vitamin A supplementation for the first time (5,6). In addition, those study participants taking vitamin A (but not DHA) who also had a higher dietary omega-3 intake experienced substantial benefit. The rate of visual field decline was retarded by 40-50% yearly in those whose omega-3 intakes were equivalent to 1-2 servings of fatty fish weekly.
References
1. Bahrami H, et al. Lutein supplementation in retinitis pigmentosa: PC-based vision assessment in a randomized double-masked placebo-controlled clinical trial. BMC Ophthalmology 6:23, 2006.
2. Berson EL, et al. A randomized trial of vitamin A and vitamin E supplementation for retinitis pigmentosa. Arch Ophthalmol 111:761-72, 1993.
3. Sibulesky L, et al. Safety of <7500 RE (<25,000 IU) vitamin A daily in adults with retinitis pigmentosa. Am J Clin Nutr 69:656-63, 1999.
4. Komeima K, et al. Antioxidants reduce cone cell death in a model of retinitis pigmentosa. PNAS 103:1130-35, 2006.
5. Berson EL, et al. Clinical trial of docosahexaenoic acid in patients with retinitis pigmentosa receiving vitamin A treatment. Arch Ophthalmol 122:1297-305, 2004.
6. Berson EL, et al. Further evaluation of docosahexaenoic acid in patients with retinitis pigmentosa. 12:1306-14, 2004.
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From Inuit to Implementation: Omega-3s Have Come of Age
Omega-3s: From Inuit to Implementation
While the relationship between the omega-3 fatty acids and age related cognition and retinal function have only recently begun to emerge, the cardio-vascular effects of EPA and DHA have been studied for nearly three decades. Interest in these fatty acids from cold water fish began in the late 1970's when studies revealed that Greenland's indigenous Inuits had a significantly lower rate of heart attack compared with Western control subjects. These observations generated an estimated 5000 studies to explore this and other effects of omega-3 fats, and ultimately led to the American Heart Association's recommendations for regular omega-3 consumption in 2002. Research continues to support the cardio-protective role of these fatty acids as evidenced by the findings of several newly published studies.
Fish Fatty Acids More Effective Than Defibrillators
Omega-3 fatty acids may prevent more sudden deaths than automated external defibrillators (AED) in homes and public places or implanted defibrillators according to results of a study supported by the Centers for Disease Control (1). Researchers compared these preventive strategies in a computer-simulated community of 100,000 people that resembled the population of Olmsted County, Minnesota.
Raising the omega-3 fatty acid levels among the cyber-Olmsted citizens resulted in lowering overall mortality rates by 6.4%. In contrast, AEDs reduced death rates by 0.8% and implanted defibrillators (ICDs) lowered the rates by 3.3%. Three-quarters of the reduction in deaths from increased omega-3 levels would come from raising them among the healthy portion of the population.
Raising blood levels of the omega-3 in people after a heart attack could save 58 lives yearly according to the simulation's predictions, while only 7 lives were saved by AEDs and implanted defibrillators prevented 30 deaths yearly. While heart attack survivors are routinely given omega-3 supplements in some European countries, this is generally not the case in the U.S., though the evidence supports it. According to a study published in the September issue of the Journal of the American Board of Family Medicine, only 17% of family doctors were likely to advise patients - including those who had suffered a heart attack - to take omega-3 supplements (2). There is a great need, the authors concluded, to "improve awareness of this important advice."
Heart Benefits Confirmed In Systematic Review
A recently published systematic review of randomized controlled trials, prospective cohort and case-control studies, concludes that the evidence suggests that fish or fish oil supplements reduces the rates of all cause mortality, cardiac and sudden death, and possibly stroke(3). The evidence was stronger for secondary than primary prevention.
Commissioned by the NIH, the review found that increased consumption of EPA and DHA - but not the omega-3 fatty acid alpha linolenic (ALA) - reduces the rates of these CVD outcomes. Data on the effects of ALA, found in flaxseed and other vegetable oils, were reportedly limited and typically of poor quality.
Future Directions: An Omega-3 Index
A second review published online in August ahead of print in the journal Cardiovascular Research, also concludes that the majority of the evidence supports the benefits of omega-3 intake for heart health. The authors, from Saint Luke's Hospital, University of Missouri-Kansas City School of Medicine, have proposed an omega-3 index as a modifiable risk factor for CVD. The Index measures the sum of EPA+DHA in the membrane of erythrocytes as the percent of all fatty acids in the red blood cell membrane. The authors also determined that membrane EPA+DHA index equal to or exceeding 8% is associated with the greatest cardio-protection. In the future, this measure of EPA/DHA status could help physicians tailor advice to their patients to help them achieve levels of omega-3 scientifically reported to provide CVD benefits.
References
1. Kottke TE, et al. Preventing sudden death with n-3 (omega-3) fatty acids and defibrillators. Am J Prev Med 31:316-23, 2006.
2. Oh RC, et al. The fish in secondary prevention of heart disease (FISH) survey-primary care physicians and omega-3 fatty acid prescribing behaviors. J Am Board Fam Med 19:459-67, 2006.
3. Wang C, et al. n-3 Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review. Am J Clin Nutr 84:5-17, 2006.
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Oily Fish Consumption & AMD Risk
Support for Macular Benefits of Omega-3
Reviewers from the National Eye Institute recently summarized the functions of the omega-3 fatty acids eicosapentenoic acid (EPA) and docosapentaenoic acids (DHA) in retinal tissues. [See EduFacts, Vol. 5 No 7]. According to the reviewers, studies looking at the relationship of the omega-3 fats to the prevalence of advanced AMD have generally observed a protective effect. A new study by Australian researchers adds to this growing body of evidence, and suggests that regularly consuming omega-3 fat, especially from fish, protects against early and late AMD in older individuals (1).
Design and Methods
To assess longitudinal associations between dietary fat and incident AMD, dietary intakes were measured by food frequency questionnaires at baseline in 2895 participants of the Blue Mountains Eye Study (BMES). Since the questionnaires can under- or over-report food consumption, dietary data were verified in a sub- group of participants who completed 4-day weighed food records 3 times over the course of a year. The results were generally in good agreement with the questionnaire data. Seventy five percent of the BMSE cohort (2335 persons) was re-examined after 5 years. Presence of AMD was graded from retinal photographs (Wisconsin ARM Grading System). Logistic regression adjusted for age, sex, vitamin C intake and smoking.
Results
The researchers examined the risk of incident AMD participants in the lowest and highest quintiles of dietary fat intakes with respect to the 60% of the population who represent a moderate, normal intake, or those in the middle 3 quintiles. Participants in the highest vs. the lowest quintiles of omega-3 fat intake had a lower risk of incident early AMD (odds ratio 0.41 [0.22-0.75])
A 40% reduction of incident early ARM was associated with fish consumption at least once a week (odds ratio 0.58 [0.37-0.90]). Consuming fish at least 3 times weekly resulted in about a 70% reduction in the incidence of late AMD (odds ratio 0.25 [0.06-1.00]). (See Table)
When the intake of specific types of fats was calculated, a trend toward increased risk of developing early AMD was noted for people with the lowest intake of monounsaturated fats and omega-3 including alpha-linolenic acid.
Comments
Though several population health studies have linked high dietary fat intake from any source to increased AMD risk, this study found no evidence that dietary fat of any kind raised that risk. The findings are largely in agreement with other studies showing that diets high in omega-3 fatty acids, particularly DHA derived largely from fish, may protect against retinal oxidation and degeneration, according to the authors. They propose that insufficient omega-3 intake could cause abnormal metabolism in the retina and affect cell renewal.
ORs and CIs of Early and Late ARM with Increasing Frequency of Certain Food Types in BMES Participants*
		5-y Incidence, OR (95% CI)
		Early ARM (n = 130)	Late ARM (n = 22)
Margarine
	<1/wk	1.00 (Reference)	1.00 (Reference)
	1-6/wk	.89 (0.57-1.38)	1.55 (0.44-5.40)
	Daily	0.87 (0.58-1.29	0.85 (0.33-2.22)
Butter
	<1/wk	1.00 (Reference)	1.00 (Reference)
	1-6/wk	0.48 (0.22-1.02)	0.82 (0.18-3.76)
	Daily	0.77 (0.48-1.24)	0.85 (0.27-2.66)
Total Fish †
	< 1/mo	1.00 (Reference)	1.00 (Reference)
	≥1/wk	0.48 (0.37-0.90)	0.44 (0.16-1.21)
	≥3/wk	0.62 (0.38-1.03)	0.25 (0.06-1.00)
Nuts
	Never	1.00 (Reference)	1.00 (Reference)
	≥ 1/wk	0.80 (0.52-1.25)	0.82 (0.29-2.34)
	≥ 1/wk	0.79 (0.46-1.34)	0.55 (0.14-2.16)
Abbreviations: ARM, age-related maculopathy; BMES, Blue Mountains Eye Study; CI, confidence interval; OR, odds ratio. *Food types are categorized by frequency of servings. † Includes sardines, tuna, and other fish.
References
1. Chua B, et al. Dietary fatty acids and the 5-year incidence of age-related maculopathy. Archives Ophthalmol 124:981-6, 2006.
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Discoveries Shed Light on How DHA Helps Protect Macular Health
DHA and Cell Survival
A paper E-published in March, 2006 reports on the role that the omega-3 fatty acid docosahexaenoic acid (DHA) in fish oil plays in protecting cells in the retina from degenerative diseases like age-related macular degeneration and retinitis pigmentosa (1).
In both of these blinding eye diseases, photoreceptors (rods and cones) degenerate and die. Although this process can be triggered by many different things, one of the most significant protective factors may be the close association of retinal pigment epithelial cells (RPE) and the amount of DHA they contain.
The main role of RPE cells is photoreceptor maintenance. RPE cells conduct the daily shedding, internalization and degradation of the tips of photo-receptor outer segments. Now it appears that RPE cells are also crucial to the survival of photoreceptor cells.
Closer to Solving a Complex Riddle
Both RPE and photoreceptor cells are exposed to potentially damaging factors such as sunlight and high oxygen tension on a daily basis. It's known that antioxidants such as lutein afford some protection, but exactly how these cells avoid harm from these and other factors, has been somewhat of a mystery up to now. However, Nicolas Bazan, MD, PhD, Director of the Neuroscience Center of Excellence at LSU Health Sciences Center in New Orleans, working in col-
laboration with Harvard researchers, has made several important discoveries that are beginning to provide answers to this complex question.
One of the answers is the importance of DHA. RPE cells cope with UV and oxidative stress, as well as trauma, by using antioxidants like vitamin E present in cellular membranes. Part of the RPE cells' response to these insults is to activate the synthesis of a major neuroprotective compound called neuroprotectin D1 or NPD1. Oxidative stress and other triggers turn on genes that lead to inflammation and cell death. NPD1 inhibits these genes. RPE cells contain DHA, which has been found to be the precursor to NPD1.
The DHA - NPD1 Connection
RPE cells regulate the uptake, conservation and delivery of DHA to photoreceptor cells. In addition to stimulating the production of NDP1, DHA promotes protective cell signaling by facilitating the expression of helpful rather than destructive proteins. DHA and NPD1 also decrease the production of damaging free radicals.
DHA is known to be in short supply in patients with retinitis pigmentosa and Usher's syndromes, and an oral supply of DHA has been shown to improve the condition of retinitis pigmentosa patients with chronic progressive neurodegeneration (2). Additionally, studies have found that higher dietary intake of DHA is associated with AMD risk reduction. DHA has been shown to promote the survival and inhibit cell death not only of photoreceptor cells, but also of neurons in an experimental model of Alzheimer's disease.
Other important questions remain, including the identification of another receptor believed to be an important pathway for NPD1, and more information is needed about the signals that control NPD1 formation. It's important to define these initial events, notes Dr. Bazan, since early clinical manifestations of retinal degeneration precedes massive photoreceptor cell death.
Physiological and pathological features of DHA in photoreceptors Photoreceptor outer segments have the highest DHA content of any cell and have unusual DHA-retention ability. Prolonged dietary deprivation of omega-3 fatty acids is required to reduce DHA content. Only then do function impairments occur. During outer-segment renewal, the retinal pigment epithelium (RPE) recycles DHA back to the inner segments. DHA-supplemented infant formulas enhance: Maturation of retinal function Visual acuity Overall neurological performance in pre-term and term infants Blood DHA levels are decreased in various forms of retinitis pigmentosa, in Usher's syndrome, and in animal models of inherited retinal degeneration. Rodents with rhodopsin mutations that are homologous to mutations in human retinitis pigmentosa display decreased levels of DHA in photoreceptors. In age-related macular degeneration, there is an inverse relationship between diets high in DHA and risk for the disease
References
1. Bazan NG. Review. Cell survival matters: docosahexaenoic acid signaling neuroprotection and photoreceptors. Trends in Nueroscience. [Epub ahead of print], March 30, 2006.
2. Berson EI, et al. Further evaluation of DHA in patients with retinitis pigmentosa receiving vitamin A treatment subgroup analyses. Arch Ophthalmol 122:457-64, 2004.
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AREDS Analysis: Antioxidants, Omega-3 and the AMD-CVD Connection
CVD & AMD Share Common Risks, Processes
A Harvard research team led by Dr. Johanna Seddon notes that age-related macular degeneration (AMD) and cardiovascular disease (CVD) share common risk factors, such as smoking and higher body mass index (BMI). They propose that mechanisms involved in developing AMD could be better understood by evaluating biomarkers of CVD. A number of analyses, in fact, have shown that systemic biomarkers for inflammation and artery damage, including C-reactive protein (CRP) and homocysteine (HCY), are related to AMD. Basic research also demonstrates that inflammatory, immune and atherosclerotic processes are related to AMD development.
To further explore mechanisms related to AMD pathogenesis, these researchers evaluated the relationships between CRP, HCY and other known risk or protective factors for AMD in subjects from the original AREDS trial (1). According to Dr. Seddon, the findings indicate that "sick eyes may occur in sick bodies related to smoking, overweight, inadequate nutrient intake, and other unhealthy behaviors".
Study Design
After randomization for AREDS, 934 subjects from two clinical sites underwent blood draws, measurements, photographs of the macula and answered questionnaires. Dietary, behavioral and medical risk, and protective factors for AMD were evaluated for their associations with blood values of CRP and HCY. This original data provided information on intake of fish as well as antioxidants such as vitamins C and E, alpha- and beta-carotene and lutein/zeaxanthin. In addition, serum nutrient values obtained from participants at one of the sites were also evaluated for their association with CRP and HCY. Multivariable regression analyses were performed after adjusting for age, gender and AREDS treatment.
Results
Higher levels of serum antioxidants vitamin C and lutein/zeaxanthin and higher fish intake (a source of omega-3 fats) were associated with lower serum CRP levels. CRP levels decreased 2 milligrams per litre for every 1000 microgram per decilitre increase in blood levels of lutein/zeaxanthin. A 0.2 milligram per litre decrease in CRP was also associated with more than 2 servings of fish weekly.
Increased BMI and smoking were associated with increased CRP, while serum alpha-carotene, dietary intake of antioxidants and vitamin B6 were associated with lower levels of plasma HCY. Levels of HCY were observed to be higher in those with hypertension. While serum vitamin E was linked to lower concentrations of HCY, it was unexpectedly linked to higher levels of CRP.
Comments
Factors reported to be related to AMD, namely antioxidants, smoking, BMI, HCY (2) and fish intake, are also associated with inflammatory, immune, or other CVD mechanisms. These results are consistent with previous findings associating smoking, BMI, and the biomarkers CRP and interleukin-6 with AMD in a different study cohort of AMD patients (3).
The relationship between fish intake, BMI, and levels of inflammatory markers have been previously reported in other "non-ocular" study populations. These data support and expand on these associations. The positive link between higher vitamin E and CRP deserves further study, according to the authors. This finding disagrees with the recent Rotterdam study, which found that vitamin E significantly lowered AMD risk [EduFacts Vol.6 No.1].
Overall, the Harvard study adds to a growing body of data showing a protective effect of antioxidants such as lutein/zeaxanthin, and omega-3 fats against AMD.
References
1. Seddon JM et al. C-reactive protein and homocysteine are associated with dietary and behavioral risk factors for age-related macular degeneration. Nutrition 22:441-43, 2006.
2. Seddon JM et al. Evaluation of homocysteine and risk of age-related macular degeneration. Am J Ophthalmol 141:201-3, 2006.
3. Seddon JM et al. Progression of age-related macular
   degeneration: prospective assessment of C-reactive protein, interleukin-6, and other cardiovascular biomarkers. Arch Ophthalmol 123:774-82, 2005.
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NEI Review: Role of Omega-3 in Retinal Health & Disease
Introduction
The omega-3 fats EPA and DHA are mainly obtained from coldwater fish, while the more commonly consumed omega-6 fats primarily come from vegetable oils, meats and dairy products. Evidence suggests that the high ratio of omega-6 fats to low levels of omega-3 fats currently consumed in the U.S. promotes a number of chronic diseases (1). For example, the cardio-protective benefits of consuming more omega-3 are well established. Studies looking at the relationship of omega-3 to the prevalence of advanced AMD have also observed a protective effect [see table below].
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Omega-3 & Major Retinal Diseases
A newly published review of omega-3 functions in the retina from the NEI Division of Epidemiology and Clinical Research supports those observations. According to the reviewers, consistent evidence suggests that the omega-3 play a pivotal role in protecting the vascular and neural retina (2).
The authors discuss omega-3 related bioactive compounds in relation to three retinal diseases of major public health significance: ARMD, diabetic retinopathy and retinopathy of prematurity EPA and DHA may protect against factors and processes involved in the pathology of the retina's vasculature and nerve cells such as ischemia, damage from light exposure, reactive oxygen species and free radicals, inflammation and age-related retinal changes.
General Function of the Omega-3
Lipids found in cellular membranes reflect the type of dietary fats we consume. Tissue status of long-chain omega-3 can be modified by - and is dependent on - our dietary intake of these fatty acids. In nerve cell membranes omega-3 serve structural and function roles. They maintain membrane fluidity and flexibility, and modulate ion channels, receptors and ATPases. They also serve as precursors for the formation of eicosanoids, a family of hormone-like agents that act locally in the cells that make them or in adjacent cells. Eicosanoids influence processes such as inflammation, vessel dilation and constriction, clotting, the movement of calcium in and out of cells, and cell division and growth (1).
Omega-3 Role in the Retina
DHA is a major structural component of retinal photoreceptor outer segment membranes, and it affects the permeability, fluidity and thickness of these membranes. The omega-3 can influence such key processes as retinal cell signaling, gene expression, differentiation and retinal cell survival.
Omega-3 also affect the production and activation of angiogenic growth factors, vasoregulatory eicosinoids, and other factors implicated in abnormal retinal neovascularization, vascular permeability and inflammation. The formation of new and abnormal blood vessels, or angiogenesis, is common to 'wet' AMD, proliferative diabetic retinopathy and retinopathy of prematurity. Clarifying the role of omega-3 in retinal health and disease is important since tissue stores can be increased by consuming a better balance of omega-3 to omega-6.
References
1. Rand Evidence Report 114, commissioned by US Health Department. Effects of omega-3 fatty acids on cognitive function with aging, dementia and neurological diseases. AHRQ No. 05- E011-2, 2005
2. SanGiovanni JP and Chew EY. The role of omega-3 long-chain polyunsaturated fatty acids in health and disease of the retina. Prog in Retinal Eye Res 24:87-138, 2005
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