Novel health benefits for marine omega-3s

Research continues to advance evidence for new areas of fish oil?s benefits — and new areas of opportunity for marketers of EPA and DHA fatty acids. Todd Runestad explores the possibilities

Health benefits for the entire spectrum of life — from prenatal brain and visual development to postpartum depression to childhood asthma, weight loss, cancer prevention, arthritis and cognitive decline — are being explored with omega-3 fatty acids. Truly, the goodness runs far afield from their claim-minted cardiovascular healthiness.

Inflammation reduction is thought to be a prime mechanism of action for omega-3s? efficacy. The long-chain polyunsaturated fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) also help cell membranes, intracellular metabolism and regulation of gene expression. Excess omega-6 oils compete for the same cells or enzyme systems and can lead to chronic inflammation, and certainly omega-3s help balance this ratio and can help tame inflammation.1 In addition, omega-3s lower the content of pro-inflammatory omega-6 substrate, arachidonic acid, in cell membranes.

Pro-inflammatory eicosanoids and cytokines are produced from arachidonic acid, and omega-3s have been shown to inhibit arachidonic acid metabolism, hence less pro-inflammatory synthesis.2

A recent study discovered a new class of bioactive lipids, called resolvins, which are made from omega-3 fatty acids by cellular enzymes and can reduce inflammation, at least in a mice model. Resolvin appears to inhibit inflammatory cells from migrating to target sites and also inhibits the turning on of other inflammatory cells.3

Even without a precise known mechanism, a large, growing and diverse number of studies advocate for fish oils? use, in particular the long-chain polyunsaturated fatty acids EPA and DHA. Of note, the Food and Drug Administration-sanctioned health claim explicitly left out alpha-linolenic acid from flaxseed oil as part of its heart-health claim.

Here are some new avenues of research benefits:

Researchers continue to learn about the importance of foetal exposure to omega-3s. Studies have linked fish diets and fish oils with high birth weights, improved newborn neurobehavioral function, visual acuity, brain development and cognitive assessment — sometimes up to eight years after birth.

Benefits to neonates are predicated on high concentrations of DHA in neurological tissues, including the brain and retina, which continue for the first 18 months after birth.4,5 The human brain contains about one-third fat, with a grey matter DHA content of approximately 40 per cent. Brain DHA content increases three to five times during the last trimester of pregnancy and again during the first 12 weeks of postnatal life.6

Several studies find a benefit of omega-3 supplementation for visual or mental development, but others find no benefit. Likely contributors to these mixed results include dosage, functional outcomes and sample size. Specific subcategories of neonatal and postnatal development include the following: Birth weight: Results of epidemiological studies suggest that marine diets, which contain omega-3 fatty acids, increase birth weight either by prolonging pregnancy or increasing the foetal growth rate.7,8 In addition, observational and interventional studies have demonstrated a direct association between foetal growth and maternal intake of omega-3 fatty acids.9,10 Proposed mechanisms have included the delayed timing of spontaneous delivery or an increased foetal growth rate, which results from enhanced placental blood flow associated with decreased blood viscosity.8

Development: Omega-3s are also heralded as improving cognitive development of infants. In an epidemiological study of 7,421 British children, fish intake by the mother during pregnancy, and by the infant postnatally, was associated with higher mean developmental scores, particularly among those who consumed fish four or more times per week.11

Cognitive development: One randomised, controlled trial addressed the question regarding influence of maternal intake of omega-3s during pregnancy on the cognitive development in infants. At 4 years of age, the supplemented group of mothers who had taken cod liver oil (DHA + EPA) during pregnancy and lactation had children with significantly higher scores than the control corn oil group. Scores used the Kaufman Assessment Battery for Children, which is a measurement of intelligence and achievement designed for children between 2.5 and 12.5 years.12 There was, however, no difference in scales measuring sequential processing, simultaneous processing and nonverbals.

Visual acuity: DHA plays a role in retinal cell signalling, and thus helps optimise visual function. A Canadian study was conducted on 83 infants who were exclusively breast fed for four months by mothers whose diets were supplemented to increase DHA content of their breast milk. The infants? visual acuity was tested at 2, 4, 6, 9 and 12 months. Their mental and motor skills were tested at 6 and 12 months, and language development at 9 and 14 months. Researchers found that DHA related favourably to visual acuity, vocabulary production and comprehension.13

Allergies: Taking omega-3 supplements when pregnant could protect infants from developing allergies. Although the effects of fish oil supplementation in established allergic disease are less convincing, there is accumulating evidence that dietary omega-3s may have greater effects before allergic responses are established.14

An Australian study supplemented 98 atopic pregnant women with 3.7g/day omega-3s from 20 weeks? gestation until delivery. Although there was no difference in the frequency of atopic dermatitis at 1 year of age, infants in the fish oil group had significantly less-severe disease states.15

Sleep: In a study of 17 women and their newborns, mothers with more DHA in their blood were found to have babies with healthier sleep patterns in the first 48 hours after delivery compared with those whose mothers consumed less DHA.16

Post-partum depression: A meta-analysis of 41 studies demonstrated a connection between lower fish consumption and breast milk DHA levels, and lower DHA levels with increased risk of post-partum depression.17 However, one study that supplemented women with a low DHA dose of 200mg/day had no effect on post-partum depression.18

Asthma is a disease of an inflammatory nature that has been the subject of a number of studies using omega-3s. Chronic inflammation occurs in the airways, leading to airway hyper-responsiveness and associated symptoms such as wheezing and coughing.

Interest in omega-3s as a potential therapeutic aid began with the first study that saw a connection between high omega-3-fat-eating Eskimos and low incidence of asthma (as well as rheumatoid arthritis, coronary heart disease and psoriasis).19

However, aside from an acceptable safety profile, repeated studies have failed to definitively conclude anything with respect to the value of using omega-3 supplementation in asthma for adults or children.

The picture of a protective effect has been seen for Australian and Japanese children.20,21 Yet it contradicts findings from an American study, which reported a non-significant association between fish intake (undefined fish types) and asthma prevalence in adult nurses.22 The difference between the findings may be related to sampling methods or the possibility that the American diet contains enough omega-6 fatty acid content to offset the benefits of eating fish, even in children.

Some data suggest that dietary fish consumption, including oily fish, may serve a protective role for children, while other studies report children whose mothers with asthma ate oily fish during pregnancy had a decreased risk of developing asthma and other allergies. In one randomised, controlled trial, 40 pregnant mothers with a history of hay fever or asthma who supplemented with 3.7g/day omega-3 fish oils gave birth to babies who, after one year, experienced significantly less-severe cases.23

In a review of eight randomised, controlled trials from 1986-98, reviewers discerned a lack of a consistent effect of asthma symptoms, FEV1 (used to assess pulmonary function), bronchial hyper-reactivity, use of asthma medication and peak flow.24 Adult randomised controlled trials revealed a somewhat contradictory picture of efficacy with respect to this review?s primary outcome, FEV1.25 Two children?s studies also observed no benefit in terms of FEV1.26,27 Clearly, more research is needed before anything definitive can be concluded about the impact of omega-3 fatty acids on FEV1.

Epidemiological evidence suggests that omega-3s can to some extent prevent the development of rheumatoid arthritis
Rheumatoid arthritis is another inflammatory disorder. Epidemiological evidence suggests omega-3s can to some extent prevent the development of rheumatoid arthritis. These studies involve fish consumption and decreased incidence, 28 less severe conditions 29 and decreased risk. 30

In intervention trials, 3-6g/day omega-3s have resulted in symptom improvement including the number of painful and swollen joints, morning stiffness and subjective feelings of improvement.31 Fish oil treatment also generally resulted in reduced use of anti-rheumatic drugs.32

On another front, UK researchers described a mechanism by which omega-3s modulate the expression and activity of degradative and inflammatory factors that cause cartilage destruction during arthritis. Specifically, omega-3s reduce the activity of enzymes that degrade connective tissue components and also can reduce pro-inflammatory cytokines.33 The improvements seen have generally been modest, though consistent.34

Adipose tissue contains the highest concentration of fatty acids. New research shows that fish consumption in a calorie-restricted diet among overweight subjects with high blood pressure enhances the beneficial effects of weight loss. With both caloric restriction and daily fish consumption, reductions in blood pressure and improvements in fat profile, heart rate and sugar metabolism are greater than with weight loss alone.

In a recent animal study, EPA/DHA was shown to reduce accumulation of body fat by limiting both increased size and increased numbers of fat cells. The fish oil concentrates given to mice not only caused weight reduction, but also stopped the animals from gaining weight when given free access to food.35

Researchers believe the omega-3s have an effect on gene expression that leads to increased metabolism and decreased fat storage. Although preliminary, research — and marketing — will continue to assess omega-3s for their potential for entering the weight-management category.

Cognitive disorders
DHA?s role in brain health is not limited to the early years — it is of paramount importance throughout life. DHA is key to brain metabolism and both DHA and EPA are beneficial in neuropsychiatric conditions. It promotes neuronal survival through its capacity to increase phosphatidylserine, the major acidic phospholipid in cell membranes.36 There is recent evidence that fish oils slow the ageing of the brain by reducing inflammation.37

Low fish consumption has been associated with development of Alzheimer?s disease, and countries with high rates of fish oil consumption have low rates of depressive disorders.38,39 This association is believed due to the anti-thrombotic and anti-atherogenic properties of omega-3s.40 The range of cognitive benefits are many.

Stress: Humans have been stressing since the dawn of time. Japanese researchers gave 1.5g/day DHA for nine weeks to 14 medical students during final exams. At the end of the trial, plasma levels of the stress hormone norepinephrine were significantly reduced.41

In a follow-up, the same researchers supplemented 21 healthy, unstressed subjects with 762mg/day EPA + DHA for two months. Even at this smaller dose, plasma norepinphrine levels dropped significantly.42

Another Japanese trial, this one double-blind, placebo-controlled and randomised, of subjects 50-60 years old who took 1.5g/day DHA for two months found significantly decreased aggression, but only among the white-collar workers and not with the Thai villagers.43

A cross-sectional observational study (as part of an ongoing cohort study) of 3,581 urban white and black young adults in Oakland, California, found that consumption of any fish rich in omega-3s was correlated with a lower likelihood of high hostility, compared with no fish consumption.44

Depression: Studies have both supported and contested the association between depression and low plasma cholesterol levels, be it by diet or medications. Evidence suggests that responsibility may lie in an imbalance in the ratio of omega-6 to omega-3 fatty acids, and/or a deficiency in n-3 fatty acids. These relationships may also help explain the inconsistent findings in trials of cholesterol-lowering interventions and depression.45

Israeli doctors used the ethyl ester of EPA (E-EPA, a pure EPA form) as an adjunct to treatment for depressive episodes occurring in 20 patients with recurrent unipolar depressive disorder who were receiving maintenance antidepressant therapy. By week three of the four-week study, this parallel-group, double-blind study found significant benefits with the addition of the omega-3 oils. The researchers were not able to distinguish whether E-EPA augmented the antidepressant action in the manner of lithium (which inhibits neuronal signal transduction pathways) or if it had independent antidepressant properties of its own.46

Alzheimer?s: Unsaturated fatty acids are important constituents of neuronal cell membranes and have neuroprotective, antioxidant and anti-inflammatory properties. Intake of omega-3s could also significantly reduce the chances of developing Alzheimer?s disease, as low serum DHA levels are significantly correlated with the disease.47 In a sample of adults aged 65-94, those who ate fish at least once a week had a 60 per cent lower risk of developing the disease compared to those who never or rarely ate fish.48

However, the next year a South African study using 3g/day E-EPA for 12 weeks as an add-on treatment with antipsychotic treatment for chronic, severe schizophrenics found significantly greater reduction in syndrome total scores and dyskinesia scores than the placebo group.49

New frontiers
The emerging benefits of fish oils do not stop here. Other research points to an association between omega-3s and cerebral infarctions, or stroke.50 They can reduce the severity of chronic inflammatory bowel disease, potentially by means of reducing immune cell activation or enhancing the epithelial barrier.51 They also can protect against colitis via resolvin, the anti-inflammatory lipid mediator derived from EPA.52

On the cancer front, omega-3s have demonstrated an ability to inhibit cancer cell migration and reduce their metastatic activity, and they work synergistically with existing anticancer drugs.53 There is an association between fish oil intake and risk of developing prostate and colorectal cancers.

Fish oil manufacturers and marketers will certainly see additional benefits to promote, or even a future health claim in any of these areas, as well as others. Indeed, a new study published in October 2005 noted that the cardioprotective benefits of omega-3s are similar to that of aspirin. New delivery systems — from seamless integration into foods without taste or odour issues to high-bioavailable gel paks — consumers will have even more reasons to raise their consumption of nature?s most nearly perfect food.

Convergence of science and regulations boosts sector
More than 6,000 scientific papers published on the benefits of long-chain polyunsaturated fatty acids such as DHA and EPA have contributed to a positive regulatory environment, manifest in the 2004 FDA qualified health claim for fish oils.

Physician and consumer awareness has also helped reach an unmet health care need in a variety of areas where fish oils show benefit. Toxicity from polychlorinated biphenyls (PCBs) like methylmercury in food sources of fatty acids such as Atlantic salmon has directed the way toward supplemental forms. And diligence on behalf of the fish oil supplement sector in establishing industrywide quality standards have maintained an aura of quality on the supplements side — which can hardly be said of the rest of the US supplements world.

The final issue — taste and odour of fish — is also being overcome. Ocean Nutrition Canada, after 15 years, has perfected microencapsulation, which eliminates those final two issues and has paved the way for fish oil integration into processed foods.

Already, the Canadian concern has sourced its microencapsulated fish oil into Australian UpBread by Tip Top (sold at a 55 per cent price premium). In the US, Arnold Foods is putting Ocean Nutrition?s Meg-3 branded ingredient in its premium breads. A host of other foods including yoghurts is on tap.

Also competing for the food share is Martek Biosciences, which essentially owns the infant formula market with its algae-sourced preformed DHA. In 2001, no baby formula contained DHA, whereas today about 90 per cent of the US products do. Martek also recently entered an agreement with cereal giant Kellogg?s.

In the supplements arena, Coromega has licensed a patented technology from Pronova that brings an emulsified, flavoured fish oil in single-serving packs. Internal, independent human studies show this next-gen delivery system increases DHA and EPA levels faster and increases levels to a greater extent over a two-day study period than regular fish oil softgels.

Why fish oils landed a heart-health claim
In 2000, and then again in late 2004, the FDA agreed: fish oils, in particular the omega-3 fatty acids EPA and DHA, seem to protect against a range of cardiovascular risk factors. These include: reduced risk of heart attack and cardiovascular disease, prevention of unwanted blood clots, reduction in incidence of abnormal heart beats, reduction of circulating blood fats, protection against high blood pressure and improved blood vessel health.

One recent double-blind, placebo-controlled, randomised, crossover study examined DHA?s effect on cardiovascular risk factors in 32 postmenopausal women. After six weeks of supplementing with 2.8g/day DHA, the supplementing group had a 20 per cent decrease in blood triglyceride levels, a 28 per cent decrease in triglyceride to HDL ratio, an eight per cent increase in HDL levels, and a seven per cent decrease in resting heart rate.1 Fish oils? cardiovascular benefit profile includes the following mechanisms:
  • Prevent heart attacks: In a 2003 case-control study of men and women over age 65, higher intake of DHA and EPA was associated with a lower risk of fatal heart attacks, possibly due to their anti-arrhythmic properties or ability to stabilise atherosclerotic plaques.2
  • Prevent future heart attacks: The landmark GISSI Prevention Trial followed 11,324 Italians who had at least one previous episode of myocardial infarction. After three-and-a-half years, there was a 45 per cent reduction in sudden cardiac death, compared to no change with the placebo group.3 Notably, the benefit was slightly better than the statin drug pravastatin.4
  • Modulate heart arrhythmias: Fish oil has been shown to reduce ventricular arrhythmias and to be more beneficial than currently used pharmacologic agents.5 In one six-month trial with 65 people who took 1g/day, they had 46.9 per cent, 67.8 per cent, 71.8 per cent and 100 per cent fewer occurrences of the four types of arrhythmias monitored.6 The exact mechanism is unknown; DHA may accumulate into heart muscle cell membranes, resulting in a positive change in heart rhythm.
  • Lower triglyceride levels: Small elevations in triglyceride levels are associated with heart events, and there is a dose-dependent response between fish oil intake and triglyceride levels. About 4g/day has decreased serum triglyceride levels by 25-30 per cent.7 In particular, triglyceride levels drop significantly after meals when supplementing with 1g/day fish oils. However, there was no effect found when supplementing while adhering to a low-fat diet.8
  • Prevent atherosclerosis: Several mechanisms are proposed for omega-3s? ability to stave off the thickening and hardening of the arteries characterised by deposits in and fibrosis of the inner layer of the arteries. These include lowering effects on blood lipid levels and blood pressure, their anti-thrombotic properties and their ability to prevent cardiac arrhythmias.9
  • Improve arterial elasticity: This relatively new cardiovascular risk factor may predict future cardiovascular problems. An Australian study supplemented 41 subjects with either 3g/day DHA or EPA for seven weeks. The systemic arterial compliance, which reflects arterial elasticity, increased 36 per cent with EPA and 27 per cent with DHA.10


1. Stark KD, Holub BJ. Differential eicosapentaenoic acid elevations and altered cardiovascular disease risk factor responses after supplementation with docosahexaenoic acid in postmenopausal women receiving and not receiving hormone replacement therapy. Am J Clin Nutr 2004;79(5):765-73.
2. Lemaitre RN, et al. N-3 Polyunsaturated fatty acids, fatal ischemic heart disease, and nonfatal myocardial infarction in older adults: the Cardiovascular Health Study. Am J Clin Nutr 2003; 77(2):319-25.
3. Marchioli R, Schweiger C, et al. Efficacy of n-3 polyunsaturated fatty acids after myocardial infarction: results of GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell?Infarto Miocardico. Lipids 2001; 36 Suppl:S119-26.
4. [No authors listed] Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med. 1998 Nov 5; 339(19):1349-57.
5. Albert C. Fish oil ? an appetising alternative to anti-arrhythmic drugs? Lancet 2004 May 1; 363(9419):1412-3.
6. Mozaffarian D, et al. Fish intake and risk of incident atrial fibrillation. Circulation 2004; 110(4):368-73.
7. Harris WS. N-3 fatty acids and serum lipoproteins: human studies. Am J Clin Nutr 1997; 65(5 Suppl):1545S-1654S.
8. Roche HM, Gibney MJ. Postprandial triacylglycerolaemia: the effect of low-fat dietary treatment with and without fish oil supplementation. Eur J Clin Nutr 1996; 50(9):617-24.
9. Connor WE. Importance of n-3 fatty acids in health and disease. Am J Clin Nutr 2000; 71:171S-175S.
10. Nestel P, et al. The n-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid increase systemic arterial compliance in humans. Am J Clin Nutr 2002; 76(2):326-30.

Global fish oil suppliers

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