Those Important Omega-3s and Omega-6s

The world of fatty acids is a complicated one. There are saturated fats and unsaturated fats, trans-fats and hydrogenated fats, essential fatty acids, polyunsaturated and monounsaturated fats. First things first – let’s sort these out.

Fatty acids in general are long chains of carbon atoms bonded together with either single or double bonds and with or without hydrogen atoms. Different fats have different lengths of atom chains, different numbers of hydrogen atoms and different shapes. Small differences in structure translate into crucial differences in function. Fatty acids are generally not found singly in nature. They usually exist as three fatty acids in combination with glycerol in the form of triglyceride. Fatty acids can be saturated fats, trans-fats, mono-unsaturated fats or poly-unsaturated fats.

Saturated fats have no double bonds between their carbon atoms and all their bonds are filled up (saturated) with hydrogen. They are solid at room temperature and come from animal sources such as meat, poultry and dairy products as well as a few plant sources such as coconut oil, cocoa butter and palm oil.

Trans-fats exist in small amounts in nature but by far the most common trans-fats are those artificially produced through a process called hydrogenation. This process turns oils into solids and prevents them from becoming rancid. The process involves heating vegetable oil in the presence of hydrogen gas and a heavy-metal catalyst such as palladium to allow hydrogen atoms to be added to the carbon chain. On food label ingredient lists, this manufactured substance is typically listed as “partially hydrogenated oil.” Trans-fats are very unhealthy and should be completely avoided as much as possible.

Unsaturated fats include monounsaturated fats and polyunsaturated fats and are liquid at room temperature. Most vegetable oils are a mixture of polyunsaturated and monounsaturated fatty acids.

Monounsaturated fats have one double bond between two of their carbon atoms and are missing some hydrogen. Double bonds introduce bends in the fatty acid that influence the structure and physical properties of a fatty acid molecule. Sources of monounsaturated fats are olive oil, peanut oil, canola oil, soybean oil, sesame oil, avocados and nuts such as almonds, cashews and peanuts as well as high-oleic safflower and sunflower oils.

Polyunsaturated fats have multiple double bonds between their carbon atoms and are also missing some hydrogen. Polyunsaturated fats include omega-3 and omega-6 fatty acids which play important roles in the human body. Polyunsaturated fatty acids are an integral part of cell membranes, important for vision and for proper brain and nervous system function and act as chemical messengers for the cardiovascular and immune systems (6). Omega-6 polyunsaturated fatty acids are also mediators of growth and inflammation, blood vessel constriction and platelet aggregation (clotting) while omega-3 poly-unsaturated fatty acids are anti-inflammatory, anti-clotting, antiarrhythmic, lipid lowering and blood vessel relaxing. Deficiencies in essential fatty acid can cause abnormalities in the liver and kidneys, reduced rate of growth, decreased immune function, depression and dry skin (11). Studies indicate that omega-6 and omega-3 fatty acids can change the way that genes are expressed, especially those involved with fatty acid metabolism and inflammation (7,8)

Omega-3 and omega-6 fatty acids are called essential fatty acids (EFAs). They are “essential” because the human body requires them for good health but cannot synthesize them so they must be obtained from food. The two essential short-chain fatty acids are;
1 Omega-3 type fatty acid: Alpha-linolenic acid (ALA) which is metabolized into long-chain omega-3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)
2 Omega-6 type fatty acid: Linoleic acid (LA) which is metabolized into long chain omega-6 fatty acids such as arachidonic acid (AA) and dihomo-γ-linolenic acid (DGLA) (6).

Omega-6 fatty acids

It is almost impossible to be low in omega-6 fatty acids. They are found in almost every food type – vegetable oils (such as corn, safflower, soybean, cottonseed, sesame, sunflower and olive oils), meats, dairy, eggs, nuts, seeds, leafy vegetables, legumes and grains. The amount of omega-6 fat required daily for human health is about 12 to 13 gm per day for women and 17 to 20 gm per day for men (1).

Whole plants contain far more fat than you might imagine. Here are some examples of the percentage of calories that comes from fat in plant foods (1,3).

 

FOOD	% CALORIES FROM FAT
Broccoli, cauliflower, green pepper and asparagus	10%
Peas, lentils, beans	3%
Soybeans	41%
Chickpeas	15%
Quinoa	14%
Corn	11%
Greens – spinach, kale	12% to 15%
Potatoes, sweet potatoes	1%
Peanuts, peanut butter	78%
Tree nuts (cashews, walnuts, brazil nuts, pecans, etc)	70%
Vegetable oils	100%

 

It is plain to see that if a person eats a variety of plant-based foods it is easy to consume enough fat. For example, calculating from a 2000 calorie plant-based diet with an average of 20% calories from fat a person would get 44 gm of total fat every day. Within this total fat, ample omega-6 fatty acids would be included. (The percentage of calories from fat in the standard Western diet is around 35%.)

Omega-3 fatty acids

Omega-3 fatty acids are not nearly as plentiful as omega-6s and so it is vital for humans to eat foods rich in omega-3 fatty acids every day. The amount of omega-3 fats required daily for human health is 1.1 gm for women and 1.6 gm for men (1,3).

The short-chain omega-3 fatty acid, ALA, can be found in many vegetables, beans, nuts, seeds and fruits. The best plant sources of ALA include flaxseeds, chia seeds, walnuts, wheat germ and oils such as canola, soybean, walnut and flaxseed oils. Corn, safflower, sunflower and cottonseed oils contain lower levels of omega-3s (11). Surprisingly half the fats in leafy greens are omega-3s. However, because greens are not high in fat, they are not a great source.

The best sources of long-chain omega-3s, DHA and EPA, are fatty fish, fish oil capsules, algae oil capsules or yeast-based omega-3 capsules.

Considerations about eating fish and fish oil for omega-3

The problem with regular consumption of fish is that it contains unhealthy contaminants – heavy metals such as mercury, persistent organic pollutants (POPs) and other environmental toxins (35,15,16), not to mention the potential health problems that come with eating animal protein. Because of these contaminants fish oil capsules may be better sources of pre-formed DHA and EPA than fish itself. Most fish oil supplements today do not contain the toxic heavy metal, mercury, because it can be removed during processing and purification (33). However, many still contain persistent organic pollutants (POPs) (34).

Another concern is the unstability of the omega-3s in fish oils, bringing up the possibility of the formation of free radicals and inflammation. ALA from plant sources such as nuts, seeds, beans, vegetables and fruits is present in a more stable form (18). More study on this aspect is needed to uncover its actual consequences, if any, to health (17).

Keep in mind that that fish do not produce omega-3s. They obtain them from their natural diet of plankton and other marine ingredients which contain the microalgae that actually produce omega-3s (21). As our beleaguered oceans are becoming depleted, farmed fish are evolving into a more important source of fish for food. The food that these fish eat is an important consideration if you are looking for omega-3s. You cannot obtain omega-3 from fish unless they are actually eating an omega-3 source themselves. Many fish farms have turned to inexpensive grain-sourced food which is full of omega-6 fatty acids, not omega-3s (31). If you are eating farmed fish, be sure you check out the omega-3 status of the fish food that your fish food ate.

Concerns about eating plants for omega-3

There is wide variability between people in their capacity to produce the long-chain omega-3 DHA from ALA, the extent of which has yet to be determined. Women, due to the effects of estrogen, can convert approximately 21% of dietary ALA to EPA and 9% to DHA while men convert approximately 8% of dietary ALA to EPA and up to 4% to DHA (6). Genetic variability also comes into play. It is thought that about 30% of the variance in blood levels of omega-3 and omega-6 fatty acids are due to genetic differences in the enzymes needed to produce long-chain omega-3s and omega-6s. Also, the action of these enzymes can be inhibited by too much dietary saturated fat and cholesterol and by deficiencies of some vitamins and minerals.

It appears that the conversion rate of ALA to DHA and EPA is greater in those eating a plant-based diet and that vegetarians readily convert ALA to DHA and EPA. The EPIC study showed that women on vegan diets have more long-chain omega-3s in their blood than fish-eaters, meat-eaters and lacto-ovo-vegetarians (19).

Considerations about taking algae oil or yeast-derived DHA capsules for omega-3

Microalgae are the organisms that actually produce omega-3 in the first place. As any fish would tell you if it could, microalgae are an excellent plant source of these healthy oils. They are an environmentally friendly and entirely renewable source that is free of contaminants (64). DHA from algae has been found to be 100% bioequivalent to the DHA in fish flesh (62). Yeast is a relatively new source of DHA (63).

The following are some good sources of omega-3 fatty acids (1,3);

 

FOOD	SERVING SIZE	# GM OMEGA-3
Chia seeds,dried	1 tbsp	2.5
Flaxseeds, ground	1 tbsp	3.2
Canola oil, soybean oil	1 tbsp	0.8
Walnuts	1 ounce (28.35 gm)	2.6
Pacific herring	1.5 ounces	1
Salmon	2 to 3 ounces	1
Canned tuna, white	4 ounces	1
Rainbow trout	3.5 ounces	1

 

Benefits of omega-3 fatty acids

The status of omega-3s and their effect on prevention of disease is in a state of flux at the present time. The following information might be confusing but the practical outcome is actually quite simple. Omega-3 fatty acids are very important for general health regardless of their status in disease prevention. Make sure you have a daily source and you can rest assured that your essential fat needs are taken care of.

Cardiovascular disease

Research into the relationship between long-chain omega-3s and cardiovascular disease has travelled a rocky road.  Observational studies in the past consistently showed that higher consumption of fish and higher dietary or plasma levels of omega-3s were associated with lower risk of coronary disease and heart failure (58,59).  Randomized controlled trials corroborated these findings using fish intake (38) and using fish oil capsules (39) as omega-3 sources.  More recently however studies have become contradictory.  Some conclude that omega-3s from supplements do not provide the same cardiovascular protection as those obtained from foods (9,10,22,23,24,25,26).  Others show benefits from both omega-3 supplements and food sources (36,37,42,52,53,54,55,56,57).  Theories for these discrepancies include the steep increase in the use of statin drugs which might blunt the benefits of omega-3 supplementation through the heart protection offered by these medications (23,41) or that there might be an upper limit of omega-3 above which there is no further benefit (40).

However the most recent meta-analysis, published January 31, 2018 and involving over 77,000 participants followed for more than four years, concludes that there is no significant association with supplementation of fish-derived omega-3 fatty acids and fatal or non-fatal coronary events.  In other words, there is no supporting evidence that taking omega-3 supplements will prevent cardiovascular disease. (68).  To strengthen this evidence, in August, 2018, a study from Great Britain found no significant difference in the risk of serious vascular events between those taking omega-3 fatty acid supplements and those who weren’t (69).

Cognition and brain function

Cognition and brain health is an area where omega-3s show promise of beneficial effects. Observational studies suggest that diets high in long-chain omega-3s can be associated with reduced risk of cognitive decline, Alzheimer’s disease and dementia (27,44). Randomized, controlled studies and meta-analyses confirm the benefit of contaminant-free long-chain omega-3 intake for improved brain function and reduced brain shrinkage in healthy older adults as well as decreased risk of dementia and Alzheimer’s Disease (30,45). However, once again results are not consistent. Many randomized trials do not show any benefit of fish intake in healthy older adults (46,29). In fact observable deficits in neurobehavioral performance have been observed. This may be due to neurotoxic contaminants such as mercury and PCBs from fish (28,29). In the final analysis researchers have come to the conclusion that increases in long-chain omega-3s through fish or supplements do not affect cognitive function in healthy older adults or people with Alzheimer’s Disease. For people with mild cognitive impairment, some aspects of cognition function, including attention, processing speed and immediate recall may be improved (47,48,49).

Pregnancy

Pregnancy is an important time to ensure that adequate essential fatty acids are available as they are needed for proper growth and brain development of the fetus. Studies have shown that increased exposure to omega-3 while in the uterus and just after birth results in improved cognitive function and better vision that can be observed during the first few years of life (20,65,66,67). When a baby is breastfed, breast milk is the only source of essential fatty acids for that baby. Lactating mothers should make sure they are ingesting a good source of omega-3 fats.

Cancer

Research is ongoing regarding the relationship between omega-3 fatty acids and the risk of cancer. Associations have been made for omega-3 fatty acids and decreased risk of breast cancer (13,14), while some other cancers seem to have increased risk with high omega-3 intake (61). Conclusive results remain to be seen.

Benefits of ALA itself

ALA, the short-chain omega-3 fatty acid, has also been studied for health benefits. Nine major studies using data gathered from large sample populations and over relatively long collection periods have found that high ALA tissue levels are associated with fewer cardiovascular events, strokes and cardiac death. Studies on high ALA diets show beneficial changes in cholesterol levels and types, reduction of triglycerides and lipoprotein(a), lower blood pressure and less inflammation (50). The need now is for randomized, controlled trials of dietary ALA sources such as flaxseed and their effects on subjects with symptoms of atherosclerotic heart disease.

The all-important ratio of omega-6 to omega-3

A crucial consideration regarding polyunsaturated fatty acids is the ratio between omega-6 and omega-3 fatty acids. Humans evolved eating approximately equal amounts of omega-6 and omega-3 fatty acids, a ratio of 1:1. The optimum ratio between omega-6s and omega-3s is between 1:1 and 4:1. Alarmingly, in most people eating the standard Western diet, this ratio is between 10:1 and 25:1. At this ratio any omega-3s available are completely overpowered by the huge amount of omega-6s that are flooding the system. Both fatty acids compete for the same enzymes in order to produce long-chain fatty acids. If one of them is at a dramatically lower concentration it will lose the competition (5). High omega-6 to omega-3 ratios are linked to numerous diseases, including cancer, heart disease and inflammatory conditions like arthritis (60). The level of inflammation in the body is markedly affected by the ratio between omega-6s and omega-3s (12). Higher concentrations of omega-3s can tip the balance to less inflammation (32). The main source of omega-6s today is from vegetable oils in our diet. One efficient way to improve your ratio? Cut back on vegetable oils.

Practical steps for good omega-3 status (51);

Include healthy sources of ALA in your daily food choices (flaxseeds, chia seeds, walnuts). One tablespoon of ground flaxseed daily in a smoothie or sprinkled onto cereal or a salad will easily supply enough ALA to provide your required omega-3s. Alternatively it can be sprinkled on a hot meal but wait until the cooking is over and the dish has cooled somewhat before adding your ground seeds. Heat can destroy omega-3s. It is important to grind flaxseed before eating it. Unground flaxseed can travel through the intestinal tract unchanged and its oil will remained locked inside the seed. Use a coffee or spice grinder and grind just before using. The shelf life of ground flaxseed is short although it can be frozen for longer storage. Chia seeds also benefit from grinding, although some of the oil from whole seeds will be liberated in the digestive tract.

Limit total fat intake, especially saturated and trans-fats. Use added oils sparingly. Avoid processed foods, full-fat dairy products and intake of tropical oils. If you must eat meat, do not eat it every day and consume only one serving that is smaller in size than a deck of cards.

If you use oil for cooking, use it very sparingly and stick to canola oil which has an omega-6 to omega-3 ratio of close to 2:1. Olive oil, a monounsaturated oil, can also be used although its ratio is 9:1. Also be aware that olive oil has a very low smoke point and should not be used for high-heat cooking.

Keep seeds that are low in omega-3 fatty acids down to less than 1 ounce a day. These include pumpkin, sesame and sunflower seeds. Avocados and most nuts (except for walnuts) should also be eaten in small amounts as they are high in omega-6s and very low in omega-3s.

Consider taking a direct source of DHA and EPA daily. A reasonable dose is 100 mg to 300 mg daily of DHA or DHA/EPA mix. DHA can be converted by the body to EPA so that DHA supplementation alone will lead to increased levels of both DHA and EPA. Fish oil capsules, algae oil capsules or yeast-sourced omega-3 capsules are all good DHA/EPA sources.

SOURCES:

1 US Department of Agriculture, Agricultural Research Service. Nutrient Intakes from Food: Mean Amounts Consumed per Individual, by Gender and Age. Available at: http://www.ars.usda.gov/ba/bhnrc/fsrg.

2 IOM. Dietary Reference Intakes for Energy, Carbohydrates, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, DC: National Academies Press; 2002.

3 http://nutritiondata.self.com/facts/vegetables-and-vegetable-products/2526/2

4 Lands, W.E., Morris, A., Libelt, B. Quantitative effects of dietary polyunsaturated fats on the composition of fatty acids in rat tissues. Lipids. 1990; 25:505-516.

5 Simopoulous, A.P. The importance of the omega-6/omega-3 fatty acid ratio in cardiovascular disease and other chronic diseases. Exp Biol Med (Maywood). 2008; 233:674-688.

6 Linus Pauling Institute, Oregon State University. http://lpi.oregonstate.edu/mic/other-nutrients/essential-fatty-acids

7 Price, P.T., Nelson, C.M., Clarke, S.D. Omega-3 polyunsaturated fatty acid regulation of gene expression. Curr Opin Lipidol. 2000; 11(1):3-7.

8 Calder, P.C. Dietary modification of inflammation with lipids. Proc Nutr Soc. 2002; 61(3):345-358.

9 Hooper, L., Thompson, R.L., Harrison, R.A. et al. Risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: systemic review. BMJ. 2006.

10 Kwak, S.M., Myung, S.K., Lee, Y.J. Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials. Arch Intern Med. 2012; 172:986-994.

11 http://www.pcrm.org/health/health-topics/essential-fatty-acids

12 Simopoulos, A.P.. Essential fatty acids in health and chronic disease. Am J Clin Nutr. 1999; 70:560S-569S.

13 Thiébaut, A.C., Chajés, V., Gerber, M., et al. Dietary intakes of omega-6 and omega-3 polyunsaturated fatty acids and the risk of breast cancer. Int J Cancer. 2009; 124:924-931.

14 Yee, L.D., Lester, J.L., Clinton, S.K., et al. ω-3 Fatty acid supplements in women at high risk of breast cancer have dose-dependent effects on breast adipose tissue fatty acid composition. Am J Clin Nutr. 2010; 91:1185-1194.

15 Masley, S.C., Masley, L.V., Gualtieri, C.T.. Effect of Mercury Levels and Seafood Intake on Cognitive Function in Middle-aged Adults. Integrative Medicine • Vol. 11, No. 3 • June

16 Wallin, A., Di Giuseppe, D., Orsini, N., Patel, P.S., Forouhi, N.G., Wolk. A. Fish consumption, dietary long-chain n-3 fatty acids, and risk of type 2 diabetes: systematic review and meta-analysis of prospective studies. Diabetes Care. 2012 Apr; 35(4):918-29.

17 Matsuo, N. Studies on the toxicity of fish oil. The Journal of Biochemistry, vol. 41, pp. 481–487, 1954.

18 Odeleye, O.E., Watson, R.R. Health implications of the n-3 fatty acids. Am J Clin Nutr. 1991; 53:177-178.

19 Welch, A.A., Shakya-Shrestha, S., Lentjes, M.A.H., Wareham, N.J., Khaw, K.T. Dietary intake and status of n-3 polyunsaturated fatty acids in a population of fish-eating and non-fish-eating meat-eaters, vegetarians, and vegans and the precursor-product ratio of a-linolenic acid to long-chain n-3 polyunsaturated fatty acids: results from the EPIC-Norfolk cohort. Am J Clin Nutr. 2010; 92:1040-1051.

20 Makrides, M., Gibson, R.A., McPhee, A.J. et al. Neurodevelopmental outcomes of preterm infants fed high-dose docosahexaenoic acid: a randomized controlled trial. JAMA. 2009; 301:175–182.

21 Harris, W.S.. Omega-3 fatty acids. In: Coates PM, Betz JM, Blackman MR, et al., eds. Encyclopedia of Dietary Supplements. 2nd ed. London and New York: Informa Healthcare; 2010:577-86.

22 Roncaglioni, M.C., Tombesi, M., Silletta, M.G. n-3 fatty acids in patients with cardiac risk factors. N Engl J Med 2013; 369:781-782.

23 Bosch, J., Gerstein, H.C., Dagenais, G.R., Diaz, R., Dyal, L. et al. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med 2012; 367:309-18.

24 Kromhout, D., Giltay, E.J., Geleijnse, J.M. Alpha Omega Trial Group. n-3 fatty acids and cardiovascular events after myocardial infarction. N Engl J Med 2010; 363:2015-26.

25 Writing Group for the AREDS Research Group, Bonds, D.E., Harrington, M., Worrall, B.B., Bertoni, A.G., Eaton, C.B., et al. Effect of long-chain omega-3 fatty acids and lutein + zeaxanthin supplements on cardiovascular outcomes: results of the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA Intern Med 2014; 174:763-71.

26 Rizos, E.C., Ntzani, E.E., Bika, E., Kostapanos, M.S., Elisaf, M.S., Association Between Omega-3 Fatty Acid Supplementation and Risk of Major Cardiovascular Disease Events: A Systematic Review and Meta-analysis. JAMA. Sept. 2012. 308(10).

27 Sydenham, E., Dangour, A.D., Lim, W.S. Omega 3 fatty acid for the prevention of cognitive decline and dementia. Cochrane Database Syst Rev. 2012 Jun 13 ;6:CD005379.

28 Danthiir, V., Hosking, D., Burns, N.R., Wilson, C. et al. Cognitive performance in older adults is inversely associated with fish consumption but not erythrocyte membrane n-3 fatty acids. J Nutr. 2014 Mar; 144(3):311-20.

29 Laurin, D., Verreault, R., Lindsay, J., Dewailly, E., Holub, B.J. Omega-3 fatty acids and risk of cognitive impairment and dementia. J Alzheimers Dis. 2003 Aug; 5(4):315-22.

30 Witte, A.V., Kerti, L., Hermannstädter, H.M., et al. Long-chain omega-3 fatty acids improve brain function and structure in older adults. Cereb Cortex. 2014 Nov; 24(11):3059-68.

31 Sprague, M., Dick, J.R., Tocher, D.R. Impact of sustainable feeds on omega-3 long-chain fatty acid levels in farmed Atlantic salmon, 2006-2015. Sci Rep. 2016 Feb 22; 6:21892.

32 James, M., Proudman, S., Cleland, L. Fish oil and rheumatoid arthritis: past, present and future. Proc Nutr Soc 2010;69:316-23.

33 ConsumerLab.com. Product review: fish oil and omega-3 fatty acid supplements review (including krill, algae, calamari, green-lipped mussel oil).

34 Bengtson Nash, S.M., Schlabach, M., Nichols, P.D. A Nutritional-Toxicological Assessment of Antarctic Krill Oil versus Fish Oil Dietary Supplements. Nutrients. 2014 Sep; 6(9): 3382–3402.

35 Bonito, L.T., Hamdoun, A., Sandin, S.A. Evaluation of the global impacts of mitigation on persistent, bioaccumulative and toxic pollutants in marine fish. 2016. PeerJ 4:e1573

36 Djousse, L., Akinkuolie, A.O., Wu, J.H., Ding, E.L., Gaziano, J.M. Fish consumption, omega-3 fatty acids and risk of heart failure: a meta-analysis. Clin Nutr 2012; 31:8468-53.

37 Del Gobbo, L.C., Imamura, F., Aslibekyan, S., Marklund, M., Virtanen, J.K., Wennberg, M., et al. Omega-3 polyunsaturated fatty acid biomarkers and coronary heart disease: pooling project of 19 cohort studies. JAMA Intern Med 2016;176:1155-1166.

38 Burr, M.L., Fehily, A.M., Gilbert, J.F., Rogers, S., Holliday, R.M., Sweetnam, P.M., et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: Diet and Reinfarction Trial (DART). Lancet 1989; 2:7577-61.

39 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; 354:447-455.

40 Trikalinos, T.A., Lee, J., Moorthy, D., Yu, W.W., Lau, J., Lichtenstein, A.H., et al. Effects of eicosapentanoic acid and docosahexanoic acid on mortality across diverse settings: systematic review and meta-analysis of randomized trials and prospective cohorts. Nutritional Research Series vol. 4. In. Rockville (MD): Agency for Healthcare Research and Quality (US); 2012

41 Chen, Q., Cheng, L.Q., Xiao, T.H., Zhang, Y.X., Zhu, M., Zhang, R., et al. Effects of omega-3 fatty acid for sudden cardiac death prevention in patients with cardiovascular disease: a contemporary meta-analysis of randomized, controlled trials. Cardiovasc Drugs Ther 2011; 25:259-265.

42 Agency for Healthcare Research and Quality. Omega-3 fatty acids and cardiovascular disease: an updated systematic review. 2016.

43 Dangour, A.D., Whitehouse, P.J., Rafferty, K., Mitchell, S.A., Smith, L., Hawkesworth, S., et al. B-vitamins and fatty acids in the prevention and treatment of Alzheimer’s disease and dementia: a systematic review. J Alzheimers Dis 2010; 22:205-224.

44 van Gelder, B.M., Tijhuis, M, Kalmijn, S.,Kromhout, D. Fish consumption, n-3 fatty acids, and subsequent 5-y cognitive decline in elderly men: the Zutphen Elderly Study. Am J Clin Nutr 2007; 85:1142-1147.

45 Zhang, Y., Chen, J., Quiu, J., Li, Y., Wang, J., Jiao, J. Intakes of fish and polyunsaturated fatty acids and mild-to-severe cognitive impairment risks: a dose-response meta-analysis of 21 cohort studies. Am J Clin Nutr. 2016 Feb; 103(2):330-340.

46 Dangour, A.D., Allen, E., Elbourne, D., Fasey, N., Fletcher, A.E., Hardy, P., et al. Effect of 2-y n-3 long-chain polyunsaturated fatty acid supplementation on cognitive function in older people: a randomized, double-blind, controlled trial. Am J Clin Nutr 2010; 91:1725-1732.

47 Jiao, J., Li, Q., Chu, J., Zeng, W., Yang, M., Zhu, S. Effect of n-3 PUFA supplementation on cognitive function throughout the life span from infancy to old age: a systematic review and meta-analysis of randomized controlled trials. Am J Clin Nutr 2014; 100:1422-36.

48 Yurko-Mauro, K., Alexander, D.D., Van Elswyk, M.E. Docosahexaenoic acid and adult memory: a systematic review and meta-analysis. PLoS One 2015; 10:e0120391.

49 Mazereeuw, G., Lanctot, K.L., Chau, S.A., Swardfager, W., Herrmann, N. Effects of omega-3 fatty acids on cognitive performance: a meta-analysis. Neurobiol Aging 2012; 33:1482 e17-29.

50 Rodriguez-Leyva, D., Bassett, C.M.C., McCullough, R., Pierce, G.N. The cardiovascular effects of flaxseed and its omega-3 fatty acid, alpha-linolenic acid . Can J Cardiol. 2010 Nov; 26(9): 489–496.

51 Davis, Brenda, RD. Vegetarian’s Challenge – Optimizing Essential Fatty Acid Status. Today’s Dietician. February 2010; 12(2): p22

52 Einvik, G.,Klemsdal, T.O., Sandvik, L., Hjerkinn, E.M. A randomized clinical trial on n-3 polyunsaturated fatty acids supplementation and all-cause mortality in elderly men at high cardiovascular risk. Eur J Cardiovasc Prev Rehabil. 2010 Oct; 17(5):588-92.

53 Virtanen, J.K., Mozaffarian, D., Chiuve, S.E., Rimm, E.B. Fish consumption and risk of major chronic disease in men. Am J Clin Nutr. 2008 Dec; 88(6):1618-25.

54 Strøm, M., Halldorsson, T., Mortensen, E.L., Torp-Pedersen, C., Olsen, S.F. Fish, n-3 fatty acids, and cardiovascular diseases in women of reproductive age: a prospective study in a large national cohort.
Hypertension. 2012 Jan; 59(1):36-43.

55 Takata, Y., Zhang, X., Li, H., Gao, Y.T., Yang, G., Gao, J., Cai, H., Xiang, Y.B., Zheng, W., Shu, X.O. Fish intake and risks of total and cause-specific mortality in 2 population-based cohort studies of 134,296 men and women. Am J Epidemiol. 2013 Jul 1; 178(1):46-57.

56 Yamagishi, K., Iso, H., Date, C., Fukui, M., Wakai, K., Kikuchi, S., Inaba, Y., Tanabe, N., Tamakoshi, A. Japan Collaborative Cohort Study for Evaluation of Cancer Risk Study Group. Fish, omega-3 polyunsaturated fatty acids, and mortality from cardiovascular diseases in a nationwide community-based cohort of Japanese men and women the JACC (Japan Collaborative Cohort Study for Evaluation of Cancer Risk) Study. J Am Coll Cardiol. 2008 Sep 16; 52(12):988-996.

57 Mozaffarian, D., Lemaitre, R.N., King, I.B., Song, X., Huang, H., Sacks, F.M., Rimm, E.B., Wang, M., Siscovick, D.S. Plasma phospholipid long-chain ω-3 fatty acids and total and cause-specific mortality in older adults: a cohort study. Ann Intern Med. 2013 Apr 2; 158(7):515-525.

58 Mozaffarian, D., Gottdiener, J.S., Siscovick, D.S. Intake of tuna or other broiled or baked fish versus fried fish and cardiac structure, function, and hemodynamics. Am J Cardiol. 2006 Jan 15; 97(2):216-22.

59 Kris-Etherton, P.M., Harris, W.S., Appel, L.J.; American Heart Association. Nutrition Committee. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation. 2002 Nov 19; 106(21):2747-57.

60 American Institute for Cancer Research. How Omega-3 Fats May Protect against Cancer.
Newsletter 84, Summer 2004

61 Brasky, T.M., Till, C., White, E., Neuhouser, M.L., Song, X. et al. Serum Phospholipid Fatty Acids and Prostate Cancer Risk: Results from the Prostate Cancer Prevention Trial. American Journal of Epidemiology. 2015.

62 Arterburn, L.M., Oken, H.A., Hoffman, J.P., Bailey-Hall, E., Chung,G, Rom,D., Hamersley, J., McCarthy, D. Bioequivalence of Docosahexaenoic acid from different algal oils in capsules and in a DHA-fortified food. Lipids, 42(11):1011-1024, 2007.

63 Ratledge, C. Single cell oils for the 21st century. In: Cohen Z., Ratledge C., editors. Single Cell Oils. AOCS Press; Champaign, IL, USA: 2005. pp. 1–20.

64 Nichols, P.D., Petrie, J., Singh, S. Long-Chain Omega-3 Oils–An Update on Sustainable Sources Nutrients. 2010 Jun; 2(6): 572–585.

65 Innis, S.M., Friesen, R.W. Essential n-3 fatty acids in pregnant women and early visual acuity maturation in term infants. Am J Clin Nutr 2008; 87(3):548-557.

66 Judge, M.P., Harel, O., Lammi-Keefe, C.J. Maternal consumption of a docosahexaenoic acid-containing functional food during pregnancy: benefit for infant performance on problem-solving but not on recognition memory tasks at age 9 mo. Am J Clin Nutr 2007; 85(6):1572-1577.

67 Birch, E.E., Garfield, S., Castañeda, Y., Hughbanks-Wheaton, D., Uauy, R., Hoffman, D. Visual acuity and cognitive outcomes at 4 years of age in a double-blind, randomized trial of long-chain polyunsaturated fatty acid-supplemented infant formula. Early Hum Dev 2007; 83(5):279-284.

68 Aung, T., Halsey, J., Kromhout, D., Gerstein, H.C., Marchioli, R. et al. Associations of Omega-3 Fatty Acid Supplement Use With Cardiovascular Disease Risks – Meta-analysis of 10 Trials Involving 77 917 Individuals. JAMA Cardiol. January 31, 2018.

69 Bowman, L., Effects of n−3 Fatty Acid Supplements in Diabetes Mellitus; The ASCEND Study Collaborative Group. August 26, 2018. DOI: 10.1056/NEJMoa1804989