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.
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.
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
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.
1. James MJ, et al. Dietary polyunsaturated fatty acids and inflammatory mediator production. Am J Clin Nutr 2000; 71(Suppl):343S-348S.
2. Endres S, et al. The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumour necrosis factor by mononuclear cells. N Engl J Med 1989; 320:265-71.
3. Arita M, et al. Stereochemical assignment, antiinflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1. J Exper Med 2005; 201(5):713-22.
4. Clandinin MT, et al. Intrauterine fatty acid accretion rates in human brain: implications for fatty acid requirements. Early Hum Dev 1980; 4(2):121-9.
5. Martinez M. Developmental profiles of polyunsaturated fatty acids in the brain of normal infants and patients with peroxisomal diseases: severe deficiency of docosahexaenoic acid in Zellweger?s and Pseudo-Swllweger?s Syndrome. In: Simopolous AP, Kifer RR, Martin RE, Marlow SM, editors. Health effects of omega-3 polyunsaturated fatty acids in seafood, World Rev Nutr Diet, Vol 66. Basel: Karger, 1991:87-102.
6. Smith W, et al. Dietary fat and fish intake and age-related maculaopathy. Arch Ophthalmol 2000; 118:401-4.
7. Olsen SF, et al. Intake of marine fat, rich in (n-3) polyunsaturated fatty acids, may increase birthweight by prolonging gestation. Lancet 1986; 2(8503):367-9.
8. Olsen SF, et al. Does fish consumption during pregnancy increase fetal growth? A study of the size of the newborn, placental weight and gestational age in relation to fish consumption during pregnancy. Int J Epidemio. 1990; 19(4):971-7.
9. Committee to study the prevention of low birth weight. Preventing low birth weight. Washington DC: National Academy Press, 1985.
10. Hornstra G, et al. Essential fatty acids in pregnancy and early human development. Eur J Obstet Gynecol Reprod Biol 1995; 61(1):57-62.
11. Daniels JL, et al. Fish intake during pregnancy and early cognitive development of offspring. Epidemiology 2004; 15(4):383-4.
12. Helland IB, et al. Similar effects on infants of n-3 and n-6 fatty acids supplementation to pregnant and lactating women. Pediatrics 2001; 108(5):E82.
13. Clin Nutr 2002 Feb; 75(2S):40-65.
14. Dunstan JA, Prescott SL. Does fish oil supplementation in pregnancy reduce the risk of allergic disease in infants? Curr Opin Allergy Clin Immunol. 2005; 5(3):215-21.
15. Denburg JA, et al. Fish oil supplementation in pregnancy modifies neonatal progenitors at birth in infants at risk of atopy. Pediatr Res. 2005; 57(2):276-81.
16. Cheruku RS, et al. Higher maternal plasma docosahexaenoic acid during pregnancy is associated with more mature neonatal sleep-state patterning. Am J Clin Nutr 2002; 76:608-13.
17. Hibbeln JR. Seafood consumption, the DHA content of mothers? milk and prevalence rates of postpartum depression: a cross-national, ecological analysis. J Affect Disord 2002; 69(1-3):15-29.
18. Llorente AM, et al. Effect of maternal docosahexaenoic acid supplementation on postpartum depression and information processing. Am J Obstet Gynecol 2003; 188(5):1348-53.
19. Horrobin DF. Low prevalences of coronary heart disease (CHD), psoriasis, asthma and rheumatoid arthritis in Eskimos: are they caused by high dietary intake of eicosapentaenoic acid (EPA), a genetic variation of essential fatty acid (EFA) metabolism or a combination of both? Med Hypotheses 1987; 22(4):421-8.
20. Hodge L, et al. Consumption of oily fish and childhood asthma risk. Med J Aust 1996; 164(3):137-140.
21. Satomi H, et al. An epidemiological study of the preventive effect of dietary fish on bronchial asthma. Koshu Eisei In Kenkyu Hokoku 1994; 43(3):305-314.
22. Schwartz J, Weiss ST. Dietary factors and their relation to respiratory symptoms. The Second National Health and Nutrition Examination Survey. Am J Epidemiol 1990;132(1):67-76.
23. Dunstan JA, et al. Fish oil supplementation in pregnancy modifies neonatal allergen-specific immune responses and clinical outcomes in infants at high risk of atopy: a randomized, controlled trial. J Allergy Clin Immunol. 2003; 112(6):1178-84.
24. Woods RK, et al. Dietary marine fatty acids (fish oil) for asthma. Cochrane Databawse Syst Rev 2000(2):CD001283.
25. Kirsch CM, et al. Effect of eicosapentaenoic acid in asthma. Clin Allergy 1988; 18(2):177-187.
26. Hodge L, et al. Effect of dietary intake of omega-3 and omega-6 fatty acids on severity of asthma in children. Eur Respir J 1998; 11(2):361-5.
27. Machura E, et al. [The effect of dietary fish oil supplementation on the clinical course of asthma in children]. Pediatr Pol 1996; 71(2):97-102.
28. Horrobin EF. Low prevalences of coronary heart disease (CHD), psoriasis, asthma and rheumatoid arthritis in Eskimos: are they caused by high dietary intake of eicosapentaenoic acid (EPA), a genic variation of essential fatty acid (EFA) metabolism or a combination of both? Med Hypothesis 1987; 22:421-8.
29. Recht L, et al. Hand handicap and rheumatoid arthritis in a fish-eating society (the Faroe Islands). J Int Med 1990; 227:49-55.
30. Shapiro J, et al. Diet and rheumatoid arthritis in women: a possible protective effect of fish consumption. Epidemiology 1996; 7:256-63.
31. Fortin P, et al. Validation of a meta-analysis: the effects of fish oil in rheumatoid arthritis. J Clin Epidemiol 1995; 48:1379-90.
32. Lau CS, et al. Effects of fish oil supplementation on non-steroidal anti-inflammatory drug requirement in patients with mild rheumatoid arthritis ? a double-blind, placebo-controlled study. Br J Rheumatol 1993; 32(1):982-9.
33. Curtis CL, et al. N-3 fatty acids specifically modulate catabolic factors involved in articular cartilage degradation. J Biol Chem 2000; 275(2):721-4.
34. Kremer JM. Effects of modulation of inflammatory and immune parameters in patients with rheumatic and inflammatory disease receiving dietary supplementation of n-3 and n-6 fatty acids. Lipids 1996; 31 Suppl:S243-7.
35. Ruzickova J, et al. Omega-3 PUFA of marine origin limit diet-induced obesity in mice by reducing cellularity of adipose tissue. Lipids 2004; 39(12):1177-85.
36. Akbar M, et al. Docosahexaenoic acid: A positive modulator or Akt signaling in neuronal survival. Proc Natl Acad Sci USA 2005; 102(31):10858-63.
37. Whalley LJ, et al. Cognitive aging, childhood intelligence, and the use of food supplements: possible involvement of n-3 fatty acids. Am J Clin Nutr 2004; 80(6):1650-7.
38. Conquer JA, et al. Fatty acid analysis of blood plasma of patients with Alzheimer?s disease, other types of dementia and cognitive impairment. Lipids 2000; 35(12):1305-12.
39. Fenton WS, et al. Essential fatty acids, lipid membrane abnormalities, and the diagnosis and treatment of schizophrenia. Biol Psychiatry 2000;47(1):8-21.
40. Kalmijn S, et al. Polyunsaturated fatty acids, antioxidant and cognitive function in very old men. Am J Epidemiol 1997; 145:33-41.
41. Sawazaki S, et al. The effect of docosahexaenoic acid on plasma catecholamine concentrations and glucose tolerance during long-lasting psychological stress: a double-blind placebo-controlled study. J Nutr Sci Vitaminol (Tokyo) 1999; 45(5):655-65.
42. Hamazaki K, et al. Effect of omega-3 fatty acid-containing phospholipids on blood catecholamine concentrations in healthy volunteers: a randomized, placebo-controlled, double-blind trial. Nutrition 2005; 21(6):705-10.
43. Hamazak T, et al. The effect of docosahexaenoic acid on aggression in elderly Thai subjects ? a placebo-controlled double-blind study. Nutr Neurosci 2002; 5(1):37-41.
44. Iribarren C, et al. Dietary intake of n-3, n-6 fatty acids and fish: relationship with hostility in young adults ? the CARDIA study. Eur J Clin Nutr 2004; 58(1):24-31.
45. Bruinsma KA, Taren DL. Dieting, essential fatty acid intake,and depression. Nutr Rev 2000; 58(4):98-108.
46. Nemets B, et al. Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Am J Psychiatry, 2002; 159(3):477-9.
47. Kyle DJ, et al. Low serum docosahexaenoic acid is a significant risk factor for Alzheimer?s dementia. Lipids. 1999; 34 Suppl:S245.
48. Friedland RP. Fish consumption and the risk of Alzheimer?s disease: is it time to make dietary recommendations? Arch Neurol 2003; 60(7):923-4.
49. Emsley R, et al. Randomized, placebo-controlled study of ethyl-eicosapentaenoic acid as supplemental treatment in schizophrenia. Am J Psychiatry 2002; 159(9):1596-8.
50. Gillum RF, et al. The relationship between fish consumption and stroke incidence: the NHANES I Epidemiologic Follow-up Study (National Health and Nutrition Examination Survey). Arch Intern Med 1996; 27:204-9.
51. Whiting CV, et al. Dietary n-3 polyunsaturated fatty acids reduce disease and colonic proinflammatory cytokines in a mouse model of colitis. Inflamm Bowel Dis 2005; 11(4):340-9.
52. Arita M, et al. Resolvin E1, an endogenous lipid mediator derived from omega-3 eicosapentaenoic acid, protects against 2,4,6-trinitrobenzene sulfonic acid-induced colitis. Proc Natl Acad Sci USA 2005; 102(21):7671-6.
53. Siddiqui RA, et al. Anticancer properties of propofol-docosahexaenoate and propofol-eicosapentaenoate on breast cancer cells. Breast Canc Res 2005;7:R645-R654.