February 1, 2007
Fish oils, algae-derived DHA and flaxseed are the leading providers of essential fatty acids. Their popularity has given rise to a broad swath of up-and-coming omega-3 ingredients, from fruit to nuts, said to provide the same benefits. Todd Runestad provides an overview of ingredients and their potential for the healthy-foods industry
So, you're a food manufacturer, and a savvy one at that. That means you know the difference between a fad and a trend — good thing you stayed on the sidelines of the low-carb fad, right? And if there's one unmistakable nutritional trend driving the food world today, you don't need to be a marketing whiz to know that it is omega-3 fatty acids. The US Food and Drug Administration gave them a health claim — it's like 2001 in the soy industry all over again! Only your staff scientist is confusing you because she's telling you it's not omega-3s per se but rather the omega-3 fatty acids DHA and EPA. And you say, aren't they all the same?
Chemistry — the arrangement of molecules — has, perhaps, never been so important as with the case of essential fatty acids. A fatty-acid molecule is a long hydrocarbon chain (hydrogen and carbon) capped by a carboxyl group (oxygen and hydrogen). Along that 18- to 22-carbon molecular chain, at least two bonds connect each carbon atom to one another. If the remaining two carbon bonds are linked with hydrogen atoms, that fatty acid is called saturated, and the resulting fat is solid at room temperature. If a carbon atom in that chain is double bonded, however, there will be room for only one hydrogen atom and, because of the missing hydrogen atom in the chain, the fatty acid is called unsaturated — liquid at room temperature. An unsaturated fatty acid containing just one double bond is called mono-unsaturated. More than one double bond — polyunsaturated.
Even smaller molecular differences can have profound health effects.
Take your garden-variety polyunsaturated hydrocarbon fatty-acid chain. If hydrogen atoms at two different double bonds along the chain are on the same side, the molecule is called a 'cis' configuration. But if hydrogen atoms at the double bonds are on opposite sides, it is called a 'trans' configuration. That simple change — the position of a single hydrogen atom at one point in an otherwise identical pair of 18-link hydrocarbon chains — can mean the difference between a relatively benign fat, and the cholesterol bomb known as a trans fat.
With omega-3 fatty acids, the number three represents the number of carbon atoms from the last double bond. Classic upstream metabolite alpha-linolenic acid (ALA), which converts to the all-important fatty acids eicosapentaenoic acid (20:5) and docosahexaenoic acid (22:6) — EPA and DHA — is often referred to as 18:3(n-3), meaning it has 18 carbon atoms with three double bonds.
It's a meaningful distinction because linoleic acid, which metabolises to omega-6 fatty acids gamma-linolenic acid and arachidonic acid, is routinely referred to as 18:2(n-6). The difference between an omega-6 and an omega-3 fatty acid — that is, an extra double bond with the number of carbon atoms from the last double bond at the sixth carbon instead of the third — can make all the difference in the world to a consumer interested in heart health, or any of a half-dozen other health benefits ascribed to EPA and DHA.
Know thy fats
These fats are called essential because the body cannot create them on its own; it needs to get them from dietary sources. Essential fatty acids are needed in order to manufacture body lipids, biological membranes and hormonelike substances such as prostaglandins. Only two fatty acids are truly essential — linoleic acid and alpha-linolenic acid — with the remaining polyunsaturated fatty acids (PUFAs) derived from these by a sequence of desaturation and elongation steps. Linoleic acid is the precursor for the n-6 series of fatty acids, found primarily in plant oils, whereas alpha-linolenic acid is the precursor for the omega-3 series of fatty acids EPA and DHA that occur mainly in oily fish and, to a lesser extent, green leafy vegetables.
It is now well understood — certainly among the nutritional set, and to a lesser extent among consumers — that there are 'good' fats and 'bad' fats. Trans fats: bad. Omega-3 fats: good. But even that distinction does not clear the waters.
To receive the benefits of the n-3 fatty acids EPA and DHA, a human would have to get them from fish/fish oils or preformed DHA from algae sources as well as fortified foods (with EPA and DHA) — flaxseed oil has an inefficient conversion rate of linolenic acid to EPA and DHA of levels ranging from about 5-15 per cent for EPA and 2-5 per cent or even less for DHA.1,2,3,4,5,6 Indeed, the reason the FDA granted a qualified health claim for EPA and DHA from fish sources and explicitly not for flax is because of the fairly large evidence base for EPA and DHA compared to ALA. The main reason why ALA is so poorly converted to the longer-chain EPA and DHA is because it is mostly used for energy, and thus quickly removed from the blood, whereas EPA and DHA are not.
That is not to say that flaxseed is unhealthy — au contraire. Flaxseed has demonstrated the ability to modestly reduce serum total and LDL cholesterol, reduce post-meal glucose absorption, decrease some markers of inflammation, and serve as a good source of soluble fibre. Flax lignans have also been investigated for their efficacy toward hormonal conditions such as prostate and breast health.7,8 But flax does not have the same health benefits as fish-derived DHA and EPA when it comes to preventing second heart attacks, lowering triglyceride levels and offering other n-3 cardiovascular benefits.9,10
That flax is an omega-3 but will not get consumers appreciable quantities of EPA and DHA has created some confusion among food manufacturers, some of which have used flax in their products to boast the content of omega-3s. Consumers who are more familiar with the omega-3 term may believe by buying omega-3 foods they are getting the benefits of EPA and DHA. Different sources of omega-3s have different benefits, so source wisely.
Another variable compounding the benefits of n-3 oils is the fact that in the last half century, Western diets have consisted of larger amounts of highly processed foods. These contained decreased levels of omega-3s and increased levels of omega-6s. There was a time when the ratio of omega-6s to omega-3s in our diets was near 1:1. Today the typical Western diet has a ratio said to be 15:1 or higher. This imbalance promotes a range of chronic diseases from inflammation to cardiovascular disease, cancer, osteoporosis and more.11 In addition, because of competition between n-6 and n-3 sources, the ratio between the two is likely more important than the absolute amount of n-6 or n-3.12
Recognition of the health benefits of omega-3 fatty acids has grown since the Inuit Eskimos' low incidence of heart disease was highlighted in the 1970s.13 Their high-fat diet, sourced from marine animals, helped establish that the omega-3 fatty acids found in fish play a unique and important role in preventing heart disease.
The Italian GISSI trial represents the clinical trial with the longest duration (3.5 years), and the largest sample size (n=11,324), and that measured both LDL cholesterol and CHD in a diseased population. It reported a 15 per cent decrease in relative risk of coronary heart disease in the diseased-population intervention group, which had already suffered one heart attack, that consumed 1g/day omega-3 fatty acids.14
Lower triglyceride levels and a reduction of abnormal thickening of arteries due to fatty plaque deposits on arterial inner walls seem to be two primary means of fish oils having their beneficial effect on cardiovascular health.15
Despite the FDA failing to throw its full weight behind omega-3 EFAs, in Europe there is no such hesitation. A recent International Herald Tribune article reported that every patient in the cardiac care unit at the San Filippo Neri Hospital in Rome who survives a heart attack goes home with a prescription for purified fish-oil capsules.
Of note to formulators, a 2006 human study discovered that a combined supplement containing omega-3s, vitamin E and niacin — all with documented cardiovascular effects — acts together at different levels of lipid-chain production to improve the lipid profile, inflammation and oxidative status, allowing researchers to reduce the dose of each compound. In niacin's case, the dosage was still effective without any of niacin's side effects.16
Stroke-risk reduction can also be conferred by fish consumption. Harvard researchers found that any fish consumption at all will decrease stroke risk by 12 per cent, with each additional single serving of fish per week further decreasing stroke risk by two per cent.17
Heart health is hardly the end of this fish tale. Many other benefits have also been associated with consumption of fish oils, spanning the entire life, from pregnancy and infants, to joint health, cognitive function and certain cancers.
Pregnancy and infants
DHA is a major structural fatty acid in the grey matter of the brain and the retina of the eye, comprising up to 20 per cent of total fatty acids in the brain and up to 50 per cent in the retina.18 It is naturally found in breast milk. DHA has been found to be important for visual and mental development of the infant in utero and throughout infancy.19
DHA was cited as the likely component of breast milk influencing the significantly higher cognitive outcomes of breast-fed infants through the first 18 years of life, as compared to non-DHA supplemented formula-fed infants.20 Indeed, a recent Harvard study estimates that increasing maternal DHA intake by 100mg/day increases child IQ by 0.13 points.21 DHA supplementation resulted in mental-development advantages in children including improved eye-hand co-ordination and improved attention skills as toddlers.22,23
The amount of time a foetus spends in utero can have profound implications for the health of the infant. A Danish study of 533 pregnant women who supplemented 2.7g/day n-3 fatty acids found the treated group had a significant four days extra gestation compared to placebo.24 Remaining in utero benefits the infant. And having the mother supplement with DHA can have positive effects on an infant's growth, visual acuity and multiple indices of development, according to a randomised, masked, controlled trial on mothers supplementing with arachidonic acid and DHA.25
Inflammation is part of the body's normal response to infection and injury. However, excessive or inappropriate inflammation contributes to a range of acute and chronic human diseases and is characterised by the production of inflammatory cytokines, arachidonic acid-derived eicosanoids (prostaglandins, thromboxanes, leukotrienes), and inflammatory free radicals.26 DHA and EPA are direct precursors for series-3 prostaglandins, which are hormonelike substances that can reduce platelet aggregation, or blood clotting, as well as improve blood flow and reduce inflammation.27
Omega-3s suppress the synthesis and release of pro-inflammatory cytokines such as tumour necrosis factor alpha, interleukin-1 and interleukin-2. In only 2000, researchers for the first time identified lipids within EPA and DHA, dubbed 'resolvins,' which are produced by EPA and directly reduce inflammation. 28 The precursor n-3 PUFA alpha-linolenic acid does not appear to exert anti-inflammatory effects at achievable intakes.
Brain and behaviour
Results from controlled treatment trials investigating the efficacy of DHA/EPA on children's behavioural issues, in particular ADHD, are mixed, but the few studies in this area have involved different populations and treatment formulations. Dietary supplementation with fish oils appears to alleviate ADHD-related symptoms in at least some children, and one study of ADHD children also found benefits for academic achievement.29 In a preliminary trial to investigate which forms of fatty acids might work best, 30 adults with ADHD were randomly assigned to 12 weeks of supplementation with olive oil (which contains less than one percent omega-3 fatty acids), flax oil (a good source of alpha-linolenic acid), or fish oil (high in both EPA and DHA). Blood levels of fatty acids were measured at the start of the trial and again after 12 weeks. While flax oil supplementation resulted in an increase in ALA and a slight decrease in the ratio of omega-6 to omega-3 fatty acids, fish-oil supplementation brought about significant increases in EPA, DHA and total omega-3 fatty acids, as well as a decrease in the ratio of omega-6s to omega-3s. This suggests that fish oil may be more effective in improving fatty-acid profiles and therefore alleviating the symptoms of ADHD.30
In a placebo-controlled, double-blind study on physical aggression in children nine to 12 years old, 3.6g/day fish oils for three months reduced physical aggression in girls, but not boys.31
Autism is a condition characterised by a marked impairment in social interaction, delayed language use and restrictred patterns of behaviour. One recent study gave 13 autistic children five to 17 years old 1.5 g/day PUFAs of placebo for six weeks. The supplementing children had significant decreases in hyperactivity and repetitive movements compared to placebo.32
Low omega-3 levels have been linked to depression in elderly people.33 EPA may be more important than DHA in treating depression. This was teased out of a double-blind, placebo-controlled study in the US.34 Another interesting study found a low-dose omega-3 supplement had better results than a high-dose supplement.35 While additional research comes in, provocative new evidence has shown that DHA and arachidonic acid may help slow cognitive decline in the elderly.36 Other research from 2006 shows the n-3 oils may slow mental decline in people with very mild Alzheimer's disease — but no effect on people with more advanced forms.37 Although there is no known cause for Alzheimer's as of yet, researchers speculate that because DHA is the most abundant fat in the brain, low levels of the fatty acid may somehow play a role in disease formation.
Animal studies, and now recent human studies, suggest a role in bone health as well, particularly in relation to abnormally high levels of omega-6 fatty acids. A long-term study in California tracked the ratio of dietary omega-6 fats to omega-3s in relation to bone-mineral density (BMD) in middle- and older-age individuals. They tested BMD by dual-energy X-ray absorptiometry?the gold standard for assessing bone loss?and found that the higher the ratio of linoleic acid (omega-6) to alpha-linolenic acid (omega-3), the lower the BMD. These results were independent of age, body mass index and various lifestyle factors.38
Evidence is beginning to accumulate that the omega-3s work on a genetic level to prevent cancer development by increasing the expression of tumour suppression genes BRCA1 and BRCA2, which help repair damaged DNA. Some animal studies show that diets high in n-6 fatty acids — which roughly correlate to the highly processed current Western diets — set the stage for cancer later in life. If these animal studies are extrapolated to humans, it may explain the link among diet, early puberty onset and breast-cancer risk, and indicate that an in utero exposure to a diet high in n-6 PUFAs may affect later breast-cancer risk.39
This research is both preliminary and equivocal — some rat studies show that although prepubertal exposure to a low-fat n-3 PUFA diet reduced later mammary tumorigenesis in rats, high levels of this fatty acid can have adverse effects on the prepubertal mammary gland and increase subsequent breast-cancer risk. 40
More to come
Evidence has also emerged showing benefits from n-3 fatty acid consumption in health conditions such as lupus and asthma.41,42 A cross-sectional study in Australia showed an inverse association between fish consumption and age-related maculopathy (ARM) — a leading cause of blindness in older adults. Subjects who ate fish more than once per week reduced their risk of having ARM by half compared to those who ate fish less than once per month.43 Patients with rheumatoid arthritis, who received fish-oil supplements in addition to background medication, had a significant decrease in the number of tender joints and morning stiffness.44 The continued study of n-3 fatty acids will lead to further understanding of their effects on development, health and disease-risk reduction.
Recent food innovations are conveniently allowing consumers the choice of healthier foods, in particular those fortified with omega-3 fatty acids. DHA-infused eggs are created by feeding chickens flaxseed, kelp, canola or other nonanimal fats. New technologies allow the easy integration of fish oils into a range of foods and beverages. Seed oils already have a relatively simple way of getting into baked goods. Ultimately, through a combination of supplementation of clean, high-quality fish-oil capsules as well as pumping up foods with various sources of omega-3 fatty acids, may the health of consumers finally begin to improve.
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2. Thompson LU, et al. Dietary flaxseed alter tumor biological markers in postmenopausal breast cancer. Clin Cancer Research 2005 May;11:3828-35.
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4. Layne KS, et al. Normal subjects consuming physiological levels of 18:3(n-3) and 20:5(n-3) from flaxseed or fish oils have characteristic differences in plasma lipid and lipoprotein fatty acid levels. J Nutr 1996 Sep;126(9):2130-40.
5. Francois CA, et al. Supplementing lactating women with flaxseed oil does not increase docosahexaenoic acid in their milk. Am J Clin Nutr 2003 Jan;77(1):226-33.
6. Young GS, et al. Effect of randomized supplementation with high dose olive, flax or fish oil on serum phospholipid fatty acid levels in adults with attention deficit hyperactivity disorder. Reprod Nutr Dev 2005 Sep-Oct;45(5):549-58.
7. Arterburn LM, et al. Distribution, interconversion and dose response of n-3 fatty acids in humans. Am J Clin Nutr 2006 Jun;83(6 Suppl):1467S-1476S.
8. Kaasgaard SG, et al. Effects of dietary linseed oil and marine oil on lipid peroxidation in monkey liver in vivo and in vitro. Lipids 1992 Oct;27(10):740-5.
9. Emken EA, et al. Dietary linoleic acid influences desaturation and acylation of deuterium-labeled linoleic and linolenic acids in young adult males. Biochem Biophys Acta 1994;1213:277-88.
10. Davis BC, Kris-Etherton PM, Achieving optimal essential fatty acid status in vegetarians: current knowledge and practical implications. Am J Clin Nutr 2003 Sep;78(3 Suppl):640S-646S.
11. Simopoulos AP. Evolutionary aspects of diet, the omega-6/omega-3 ratio and genetic variation: nutritional implications for chronic diseases. Biomed Pharmacother 2006 Nov;60(9):502-7.
12. Khor GL. Dietary fat quality: a nutritional epidemiologist's view. Asia Pac J Clin Nutr 2004 Aug;13(Suppl):S22.
13. Bang HO, et al. The composition of the Eskimo food in northwestern Greenland. Am J Clin Nutr 1980 Dec;33:2657-61.
14. No authors listed. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Lancet 1999 Aug 7;354(9177):447-55.
15. Von Schacky C, et al. The effect of dietary n-3 fatty acids on coronary atherosclerosis. Ann Intern Med 1999;130:554-62.
16. Accinni R, et al. Effects of combined dietary supplementation on oxidative and inflammatory status in dyslipidemic subjects. Nutr Metab Cardiovasc Dis 2006 Mar;16(2):121-7.
17. Bouzan C, et al. A quantitative analysis of fish consumption and stroke risk. Am J Prev Med 2005 Nov;29(4):347-52.
18. Uauy R, et al. Essential fatty acids in visual and brain development. Lipids 2001;36:885-95.
19. Lauritzen L, et al. The essentiality of long chain n-3 fatty acids in relation to development and function of the brain and retina. Prog Lipid Res 2001;40:1-94.
20. Horwood LJ, Fergusson DM. Breast-feeding and later cognitive and academic outcomes. Pediatrics 1998;101:e9.
21. Cohen JT, et al. A quantitative analysis of prenatal intake of n-3 polyunsaturated fatty acids and cognitive development. Am J Prev Med 2005 Nov;29(4):366-74.
22. Jensen CL, et al. Effects of maternal docosahexaenoic acid intake on visual function and neurodevelopment in breast-fed term infants. Am J Clin Nutr 2005;82(1):1579-86.
23. Jensen C, et al. Effect of maternal DHA supplementation on neuro-phsychological and visual status of former breast-fed infants at five years of age. Pediatr Res 2004;49:181a.
24. Olsen SF, et al. Randomised controlled trial of effect of fish-oil supplementation on pregnancy duration. Lancet 1992;339:1003-7.
25. O'Connor DL, et al. Growth and development in preterm infants fed long-chain polyunsaturated fatty acids: a prospective, randomized controlled trial. Pediatrics 2001 Aug;108(2):359-71.
26. Calder PC. n-3 polyunsaturated fatty acids, inflammation, and inflammatory diseases. Am J Clin Nutr 2006 Jun;83(6 Suppl):1505S-1519S.
27. Roman AS, et al. Omega-3 fatty acids and decidual cell prostaglandin production in response to the inflammatory cytokine IL-1beta. Am J Obstet Gynecol 2006 Dec;195(6):1693-9.
28. Serhan CN, et al. Resolvins, docosatrienes, and neuroprotectins, novel omega-3-derived mediators, and their aspirin-triggered endogenous epimers: an overview of their protective roles in catabasis. Prostaglandins Other Lipid Mediat 2004 Apr;73(3-4):155-72.
29. Richardson AJ. Omega-3 fatty acids in ADHD and related neurodevelopmental disorders. Int Rev Psychiatry 2006 Apr;18(2):155-72.
30. Young GS, et al. Effect of randomized supplementation with high dose olive, flax or fish oil on serum phospholipid fatty acid levels in adults with attention deficit hyperactivity disorder. Reprod Nutr Dev 2005 Sept-Oct;45(5):549—58.
31. Itomura M, et al. The effect of fish oil on physical aggression in schoolchildren — a randomized, double-blind, placebo-controlled trial. J Nutr Biochem 2005 Mar;16(3):163-71.
32. Richardson AJ. Long-chain polyunsaturated fatty acids in childhood development and psychiatric disorders. Lipids 2004;39:1215-22.
33. Tiemeier H, et al. Plasma fatty acid composition and depression are associated in the elderly: the Rotterdam Study. Am J Clin Nutr 2003 Jul;78(1):40-6.
34. Marangell LB, et al. A double-blind, placebo-controlled study of DHA in the treatment of depression. Inform 2000;11:578-82.
35. Peet M, et al. A dose-ranging study of the effects of EPA in patients with ongoing depression despite apparently adequate treatment with standard drugs. Arch Gen Psychiatry 2002;59:913-9.
36. Kotani S. Dietary supplementation of arachidonic and docosahexaenoic acids improves cognitive dysfunction. Neurosci Res 2006;56(2):159-64.
37. Freund-Levy Y, et al. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer's disease: OmegAD study: a randomized double-blind trial. Arch Neurol 2006 Oct;63(10):1402-8.
38. Weiss LA, et al. Ratio of n-6 to n-3 fatty acids and bone mineral density in older adults: the Rancho Bernardo Study. Am J Clin Nutr 2005;81(4): 934-8.
39. Hilakivi-Clarke L, et al. A maternal diet high in n - 6 polyunsaturated fats alters mammary gland development, puberty onset, and breast cancer risk among female rat offspring. Proc Natl Acad Sci USA 1997 Aug 19;94(17):9372-7.
40. Olivo SE, Hilakivi-Clarke L. Opposing effects of prepubertal low- and high-fat n-3 polyunsaturated fatty acid diets on rat mammary tumorigenesis. Carcinogenesis 2005 Sep;26(9):1563-72.
41. Reifen R, et al. Flax reduces antibody levels. Lupus 1998; 7(3):192-7.
42. Koumenis IL, et al. Inhibition of leukotriene biosynthesis by a novel dietary fatty acid formulation in patients with atopic asthma: a randomized, placebo-controlled, parallel-group, prospective trial. Clin Ther Mar 2003; 25(3):972-9.
43. Smith W, et al. Dietary fat and fish intake and age-related maculopathy. Arch Ophthalmol 2000;118:401-404.
44. Kremer JM. n-3 fatty acid supplements in rheumatoid arthritis. Am J Clin Nutr 2000;71: 349S-351S.
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