Omega 3 fatty acids (popularly referred to as ω−3 fatty acids or n−3 fatty acids^{[citation needed]}) are fats commonly found in marine and plant oils. They are polyunsaturated fatty acids with a double bond (C=C) starting after the third carbon atom from the end of the carbon chain. The fatty acids have two ends—the acid (COOH) end and the methyl (CH3) end. The location of the first double bond is counted from the methyl end, which is also known as the omega (ω) end or the n end.

The health effects of n-3 fatty acids supplementation are controversial. They are considered essential fatty acids, meaning that they cannot be synthesized by the human body but are vital for normal metabolism. Though mammals cannot synthesize n−3 fatty acids, they have a limited ability to form the long-chain n−3 fatty acids including eicosapentaenoic acid (EPA, 20 carbons and 5 double bonds), docosahexaenoic acid (DHA, 22 carbons and 6 double bonds) and α-linolenic acid (ALA, 18 carbons and 3 double bonds).

Common sources of n–3 fatty acids include fish oils, algal oil, squid oil and some plant oils such as echium oil and flaxseed oil.

  Health effects

  Cancer

The evidence linking the consumption of fish to the risk of cancer is poor.^[1] Supplementation with omega-3 fatty acids does not appear to affect this risk either.^[2] A 2006 report in the Journal of the American Medical Association, in their review of literature covering cohorts from many countries with a wide variety of demographics, concluded that there was no link between n−3 fatty acids and cancer.^[3] This is similar to the findings of a review by the British Medical Journal of studies up to February 2002 that failed to find clear effects of long and shorter chain n−3 fats on total mortality, combined cardiovascular events and cancer.^[4][5]

A 2007 systematic review of n-3 fatty acids and cachexia found evidence that oral n-3 fatty acid supplements benefit cancer patients, improving appetite, weight, and quality of life.^[6] A 2009 trial found that a supplement of eicosapentaenoic acid (EPA) helped cancer patients retain muscle mass.^[7]

  Cardiovascular disease

Evidence does not support a beneficial role for omega-3 fatty acid supplementation in preventing cardiovascular disease or stroke.^[8]

A 2006 review of n−3 fatty acids found in abundance in oily fish concluded that they do not have a significant protective effect against cardiovascular disease.^[9] This meta-analysis was controversial and stands in stark contrast with two different reviews also performed in 2006 by the American Journal of Clinical Nutrition^[10] and a second JAMA review;^[11] both indicated decreases in total mortality and cardiovascular incidents (i.e., myocardial infarctions) associated with the regular consumption of fish and fish oil supplements.

Large amounts may increase LDL (see below), up to 46%, although LDL changes from small to larger, buoyant, less atherogenic particles.^[12]

N-3 fatty acids also have mild antihypertensive effects. When subjects consumed n-3 from oily fish on a regular basis, their systolic blood pressure was lowered by about 3.5-5.5 mmHg.^[13] The 18 carbon α-linolenic acid (ALA) has not been shown to have the same cardiovascular benefits that DHA or EPA may have.^[14]

Some evidence suggests that people with certain circulatory problems, such as varicose veins, may benefit from the consumption of EPA and DHA, which may stimulate blood circulation, increase the breakdown of fibrin, a compound involved in clot and scar formation, and, in addition, may reduce blood pressure.^[15][16] Evidently, n−3 fatty acids reduce blood triglyceride levels,^[17][18][19] and regular intake may reduce the risk of secondary and primary heart attack.^[20] ALA does not confer the cardiovascular health benefits of EPA and DHA.^[21]

Large amounts may increase the risk of hemorrhagic stroke (see below): Lower amounts are not related to this risk;^[22] 3 grams of total EPA/DHA daily are generally recognized as safe (GRAS) with no increased risk of bleeding involved^[23] and many studies used substantially higher doses without major side effects (for example: 4.4 grams EPA/2.2 grams DHA in 2003 study).^[24]

  Inflammation

Although not confirmed as an approved health claim, current research suggests that the anti-inflammatory activity of long-chain n−3 fatty acids may translate into clinical effects.^[25] For example, there is evidence that rheumatoid arthritis sufferers taking long-chain n−3 fatty acids from sources such as fish have reduced pain compared to those receiving standard NSAIDs.^[26] Some potential benefits have been reported in conditions such as rheumatoid arthritis.^[27]

  Developmental disorders

Although not supported by current scientific evidence as a primary treatment for ADHD, autism spectrum disorders, and other developmental differences,^[28][29] omega-3 fatty acids have gained popularity for children with these conditions.^[28]

Omega-3 fatty acids offer a promising complementary approach to standard treatments for ADHD and developmental coordination disorder.^[29] Fish oils appear to reduce ADHD-related symptoms in some children.^[29] Double blind studies have shown "medium to strong treatment effects of omega 3 fatty acids on symptoms of ADHD".^[30]

There is not enough scientific evidence to support the effectiveness of n-3 fatty acids for autism spectrum disorders.^[31]

Fish oil has only a small benefit on the risk of early birth.^[32][33]

  Psychiatric disorders

Though there is some evidence that n-3 fatty acids are connected to a variety of mental disorders,^[34] there is limited evidence that may be useful as an add-on for the treatment of depression associated with bipolar disorder.^[35] There is preliminary evidence that EPA supplementation, either with DHA or medication, is helpful in cases of depression^[36]

  Adverse effects

In a letter published October 31, 2000,^[37] the United States Food and Drug Administration Center for Food Safety and Applied Nutrition, Office of Nutritional Products, Labeling, and Dietary Supplements noted that known or suspected risks of EPA and DHA consumed in excess of 3 grams per day may include the possibility of:

• Increased incidence of bleeding
• Hemorrhagic stroke
• Oxidation of omega-3 fatty acids, forming biologically active oxidation products
• Increased levels of low-density lipoproteins (LDL) cholesterol or apoproteins associated with LDL cholesterol among diabetics and hyperlipidemics
• Reduced glycemic control among diabetics

Subsequent advice from the FDA and national counterparts have permitted health claims associated with heart health.

  Chemistry

  Chemical structure of alpha-linolenic acid (ALA), an essential n−3 fatty acid, (18:3Δ9c,12c,15c, which means a chain of 18 carbons with 3 double bonds on carbons numbered 9, 12, and 15). Although chemists count from the carbonyl carbon (blue numbering), physiologists count from the n (ω) carbon (red numbering). Note that, from the n end (diagram right), the first double bond appears as the third carbon-carbon bond (line segment), hence the name "n−3". This is explained by the fact that the n end is almost never changed during physiologic transformations in the human body, as it is more energy-stable, and other carbohydrates compounds can be synthesized from the other carbonyl end, for example in glycerides, or from double bonds in the middle of the chain.

  Chemical structure of eicosapentaenoic acid (EPA).

  Chemical structure of docosahexaenoic acid (DHA).

N−3 fatty acids that are important in human physiology are α-linolenic acid (18:3, n−3; ALA), eicosapentaenoic acid (20:5, n−3; EPA), and docosahexaenoic acid (22:6, n−3; DHA). These three polyunsaturates have either 3, 5, or 6 double bonds in a carbon chain of 18, 20, or 22 carbon atoms, respectively. As with most naturally-produced fatty acids, all double bonds are in the cis-configuration; in other words, the two hydrogen atoms are on the same side of the double bond.

  List of n−3 fatty acids

This table lists several different names for the most common n−3 fatty acids found in nature.

  History

Although omega-3 fatty acids have been known as essential to normal growth and health since the 1930s, awareness of their health benefits has dramatically increased since the 1990s.^[38]

The health benefits of the long-chain omega-3 fatty acids — primarily EPA and DHA are the best known. These benefits were discovered in the 1970s by researchers studying the Greenland Inuit Tribe. The Greenland Inuit people consumed large amounts of fat from fish, but displayed virtually no cardiovascular disease. The high level of omega-3 fatty acids consumed by the Inuit reduced triglycerides, heart rate, blood pressure, and atherosclerosis.^[39]

On September 8, 2004, the U.S. Food and Drug Administration gave "qualified health claim" status to EPA and DHA n−3 fatty acids, stating that "supportive but not conclusive research shows that consumption of EPA and DHA [n−3] fatty acids may reduce the risk of coronary heart disease."^[40] This updated and modified their health risk advice letter of 2001 (see below). As of this writing, regulatory agencies^[who?] do not accept that there is sufficient evidence for any of the suggested benefits of DHA and EPA other than for cardiovascular health, and further claims should be treated with caution.

The Canadian Government has recognized the importance of DHA omega-3 and permits the following biological role claim for DHA: "DHA, an omega-3 fatty acid, supports the normal development of the brain, eyes and nerves."^[41]

  Mechanism of action

The 'essential' fatty acids were given their name when researchers found that they are essential to normal growth in young children and animals, though the modern definition of 'essential' is stricter. A small amount of n−3 in the diet (~1% of total calories) enabled normal growth, and increasing the amount had little to no additional effect on growth.^[42]

Likewise, researchers found that n−6 fatty acids (such as γ-linolenic acid and arachidonic acid) play a similar role in normal growth. However, they also found that n−6 was "better" at supporting dermal integrity, renal function, and parturition. These preliminary findings led researchers to concentrate their studies on n−6, and it is only in recent decades that n−3 has become of interest.^[42]

In 1964, it was discovered that enzymes found in sheep tissues convert n−6 arachidonic acid into the inflammatory agent called prostaglandin E₂,^[43] which both causes the sensation of pain and expedites healing and immune response in traumatized and infected tissues.^[42] By 1979, more of what are now known as eicosanoids were discovered: thromboxanes, prostacyclins, and the leukotrienes.^[42] The eicosanoids, which have important biological functions, typically have a short active lifetime in the body, starting with synthesis from fatty acids and ending with metabolism by enzymes. However, if the rate of synthesis exceeds the rate of metabolism, the excess eicosanoids may have deleterious effects.^[42] Researchers found that certain n−3 fatty acids are also converted into eicosanoids, but at a much slower rate. Eicosanoids made from n−3 fatty acids are often referred to as anti-inflammatory, but in fact they are just less inflammatory than those made from n−6 fats. If both n−3 and n−6 fatty acids are present, they will "compete" to be transformed,^[42] so the ratio of long-chain n−3:n−6 fatty acids directly affects the type of eicosanoids that are produced.^[42]

This competition was recognized as important when it was found that thromboxane is a factor in the clumping of platelets, which can both cause death by thrombosis and prevent death by bleeding. Likewise, the leukotrienes were found to be important in immune/inflammatory-system response, and therefore relevant to arthritis, lupus, asthma, and recovery from infections. These discoveries led to greater interest in finding ways to control the synthesis of n−6 eicosanoids. The simplest way would be by consuming more n−3 and fewer n−6 fatty acids.^[42]

  Interconversion

  Conversion efficiency of ALA to EPA and DHA

The short-chain n−3 fatty acids are converted to long-chain forms (EPA, DHA) with an efficiency below 5%^[44][45] in men, and at a greater percentage in women which may be due to the importance for meeting the demands of the fetus and neonate for DHA.^[46]

These conversions occur competitively with n−6 fatty acids, which are essential closely related chemical analogues that are derived from linoleic acid. Both the n−3 α-linolenic acid and n−6 linoleic acid must be obtained from food. Synthesis of the longer n−3 fatty acids from linolenic acid within the body is competitively slowed by the n−6 analogues. Thus, accumulation of long-chain n−3 fatty acids in tissues is more effective when they are obtained directly from food or when competing amounts of n−6 analogs do not greatly exceed the amounts of n−3.^{[citation needed]}

The conversion of ALA to EPA and further to DHA in humans has been reported to be limited, but varies with individuals.^[47][48] Women have higher ALA conversion efficiency than men, it is presumed due to the lower rate of use of dietary ALA for beta-oxidation. This suggests that biological engineering of ALA conversion efficiency is possible. Goyens et al. argue that it is the absolute amount of ALA, rather than the ratio of n−3 and n−6 fatty acids, that controls the conversion efficiency.^[49]

  The n−6 to n−3 ratio

Some clinical studies^[42][50][51] indicate that the ingested ratio of n−6 to n−3 (especially linoleic vs alpha-linolenic) fatty acids is important to maintaining cardiovascular health. However, two studies published in 2005 and 2007 found that while n−3 polyunsaturated fatty acids are extremely beneficial in preventing heart disease in humans, the levels of n−6 polyunsaturated fatty acids (and therefore the ratios) were insignificant.^[52][53]

Both n−3 and n−6 fatty acids are essential; i.e., humans must consume them in the diets. N−3 and n−6 eighteen-carbon polyunsaturated fatty acids compete for the same metabolic enzymes, thus the n−6:n−3 ratio will significantly influence the ratio of the ensuing eicosanoids (hormones), (e.g., prostaglandins, leukotrienes, thromboxanes, etc.), and will alter the body's metabolic function.^[54] In general, grass-fed animals accumulate more n−3 than do grain-fed animals, which accumulate relatively more n−6.^[55] Metabolites of n−6 are more inflammatory (esp. arachidonic acid) than those of n−3. This necessitates that n−3 and n−6 be consumed in a balanced proportion; healthy ratios of n−6:n−3 range from 1:1 to 1:4 (an individual needs more n−3 than n−6).^[56] Studies suggest the evolutionary human diet, rich in game animals, seafood, and other sources of n−3, may have provided such a ratio.^[57][58]

Typical Western diets provide ratios of between 10:1 and 30:1 (i.e., dramatically higher levels of n−6 than n-3).^[59] The ratios of n−6 to n−3 fatty acids in some common vegetable oils are: canola 2:1, soybean 7:1, olive 3-13:1, sunflower (no n−3), flax 1:3,^[60] cottonseed (almost no n−3), peanut (no n−3), grapeseed oil (almost no n−3) and corn oil 46:1 ratio of n−6 to n−3.^[61]

  Dietary sources

  Daily values

As macronutrients, fats are not assigned Dietary Reference Intakes. Macronutrients have acceptable intake (AI) levels and acceptable macronutrient distribution ranges (AMDRs) instead of RDAs. The AI for n−3 is 1.6 grams/day for men and 1.1 grams/day for women, while the AMDR is 0.6% to 1.2% of total energy.^[62]

A growing body of literature suggests that higher intakes of α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) may afford some degree of protection against coronary disease. Because the physiological potency of EPA and DHA is much greater than that of ALA, it is not possible to estimate one AMDR for all n−3 fatty acids. Approximately 10 percent of the AMDR can be consumed as EPA and/or DHA."^[62] There was insufficient evidence as of 2005 to set an upper tolerable limit for n−3 fatty acids.^[62]

Heavy metal poisoning by the body's accumulation of traces of heavy metals, in particular mercury, lead, nickel, arsenic, and cadmium, is a possible risk from consuming fish oil supplements. Also, other contaminants (PCBs, furans, dioxins, and PBDEs) might be found, especially in less-refined fish oil supplements. In reality, however, heavy metal toxicity from consuming fish oil supplements is highly unlikely, because heavy metals selectively bind with protein in the fish flesh rather than accumulate in the oil. An independent test in 2005 of 44 fish oils on the US market found all of the products passed safety standards for potential contaminants.^[63] The FDA recommends that the total dietary intake of n−3 fatty acids from fish not exceed 3 grams per day, with no more than 2 grams per day from nutritional supplements.^[40]

Throughout their history, the Council for Responsible Nutrition and the World Health Organization have published acceptable standards regarding contaminants in fish oil. The most stringent current standard is the International Fish Oils Standard.^[64] Fish oils that are molecularly distilled under vacuum typically make this highest-grade, and have measurable levels of contaminants (measured parts per billion and parts per trillion).

A recent trend has been to fortify food with n−3 fatty acid supplements. Global food companies have launched n−3 fatty acid fortified bread, mayonnaise, pizza, yogurt, orange juice, children's pasta, milk, eggs, popcorn, confections, and infant formula.

The American Heart Association has set up dietary recommendations for EPA and DHA due to their cardiovascular benefits: Individuals with no history of coronary heart disease or myocardial infarction should consume oily fish or fish oils two times per week; those having been diagnosed with coronary heart disease after infarction should consume 1 g EPA and DHA per day from oily fish or supplements; those wishing to lower blood triglycerides should consume 2-4 g of EPA and DHA per day in the form of supplements.^[65]

  Fish

The most widely available dietary source of EPA and DHA is cold water oily fish, such as salmon, herring, mackerel, anchovies, and sardines. Oils from these fish have a profile of around seven times as much n−3 as n−6. Other oily fish, such as tuna, also contain n−3 in somewhat lesser amounts. Consumers of oily fish should be aware of the potential presence of heavy metals and fat-soluble pollutants like PCBs and dioxins, which are known to accumulate up the food chain. After extensive review, researchers from Harvard's School of Public Health in the Journal of the American Medical Association (2006) reported that the benefits of fish intake generally far outweigh the potential risks. Although fish is a dietary source of n−3 fatty acids, fish do not synthesize them; they obtain them from the algae (microalgae in particular) or plankton in their diets.^[66]

  Fish oil

Not all forms of fish oil may be equally digestible. Of four studies that compare bioavailability of the glyceryl ester form of fish oil vs. the ethyl ester form, two have concluded the natural glyceryl ester form is better, and the other two studies did not find a significant difference. No studies have shown the ethyl ester form to be superior, although it is cheaper to manufacture.^[70][71]

  Krill

Krill oil is a newly^[when?] discovered source of n−3 fatty acids. Various claims are made in support of krill oil as a superior^{[citation needed]} source of n−3 fatty acids. The effect of krill oil, at a lower dose of EPA + DHA (62.8%), was demonstrated to be similar to that of fish oil.^[72]

  Plant sources

  Flax seeds produce linseed oil, which has a very high ALA content

These tables are incomplete.

Table 1. ALA content as the percentage of the seed oil.^[73]

Table 2. ALA content as the percentage of the whole food.^[74][75]

Flaxseed (or linseed) (Linum usitatissimum) and its oil are perhaps the most widely available botanical source of the n−3 fatty acid ALA. Flaxseed oil consists of approximately 55% ALA, which makes it six times richer than most fish oils in n−3 fatty acids.^[76] A portion of this is converted by the body to EPA and DHA, though this may differ between men and women.^[77]

100 g of the leaves of Purslane contains 300-400 mg ALA.^[78]

  Eggs

Eggs produced by hens fed a diet of greens and insects contain higher levels of n−3 fatty acids than those produced by chickens fed corn or soybeans.^[79] In addition to feeding chickens insects and greens, fish oils may be added to their diets to increase the n-3 fatty acid concentrations in eggs.^[80]

The addition of flax and canola seeds to the diets of chickens, both good sources of alpha-linolenic acid, increases the omega-3 content of the eggs, predominantly DHA.^[81]

The addition of green algae or seaweed to the diets boosts the content of DHA and EPA content, which are the forms of omega-3 approved by the FDA for medical claims. A common consumer complaint is "Omega-3 eggs can sometimes have a fishy taste if the hens are fed marine oils."^[82]

  Meat

Omega 3 fatty acids are formed in the chloroplasts of green leaves and algae. While seaweeds and algae are the source of omega 3 fatty acids present in fish, grass is the source of omega 3 fatty acids present in grass fed meats.^[83] When cattle are taken off omega 3 fatty acid rich grass and shipped to a feedlot to be fattened on omega 3 fatty acid deficient grain, they begin losing their store of this beneficial fat. Each day that an animal spends in the feedlot, the amount of omega 3 fatty acids in its meat is diminished.^[84]

The n−6 to n−3 ratio of grass-fed beef is about 2:1, making it a more useful source of n−3 than grain-fed beef, which usually has a ratio of 4:1.^[55]

In a 2009 study which was a joint effort between the USDA and researchers at Clemson University in South Carolina grass-fed beef was compared with grain-finished beef and researchers found that grass-fed beef is: higher in moisture content, 42.5% lower total lipid content, 54% lower in total fatty acids, 54% higher in beta-carotene, 288% higher in vitamin E (alpha-tocopherol), higher in the B-vitamins thiamin and riboflavin, higher in the minerals calcium, magnesium, and potassium, 193% higher in total omega-3s, 117% higher in CLA (cis-9 trans-11) which is a potential cancer fighter, 90% higher in vaccenic acid (which can be transformed into CLA), lower in the saturated fats linked with heart disease, and has a healthier ratio of omega-6 to omega-3 fatty acids (1.65 vs 4.84). Protein and cholesterol content were equal. ^[55]

In most countries, commercially available lamb is typically grass-fed, and thus higher in n−3 than other grain-fed or grain-finished meat sources. In the United States, lamb is often finished (i.e., fattened before slaughter) with grain, resulting in lower n−3.^[85]

The omega-3 content of chicken meat may be enhanced by increasing the animals' dietary intake of grains high in n−3, such as flax, chia, and canola.^[86]

Kangaroo meat is also a source of n−3, with fillet and steak containing 74 mg per 100g of raw meat.^[87]

  Mammalian brains and eyes

The brains and eyes of mammals are extremely rich in DHA as well as other n-3 fatty acids.^[88] DHA is a major structural component of the mammalian brain, and is in fact the most abundant (n-3) fatty acid in the brain.^[89]

  Seal oil

Seal oil is a source of EPA, DPH Template:What is DPH? Link please!, and DHA. According to Health Canada, it helps to support the development of the brain, eyes and nerves in children up to 12 years of age.^[90] However, like all seal products, it is not allowed for import into the European Union^[91]

  Other sources

The microalgae Crypthecodinium cohnii and Schizochytrium are rich sources of DHA, but not EPA, and can be produced commercially in bioreactors.^{[citation needed]}.

Oil from brown algae (kelp) is a source of EPA.^{[citation needed]}

In 2006 a study was published in the Journal of Dairy Science entitled "The Linear Relationship between the Proportion of Fresh Grass in the Cow Diet, Milk Fatty Acid Composition, and Butter Properties". It was found that grass fed butter contains substantially more CLA, vitamin E, beta-carotene, and omega-3 fatty acids than butter from cows raised in factory farms or that have limited access to pasture. It was also found that the softer the butter, the more fresh pasture in the cow’s diet. Cows that get all their nutrients from grass have the softest butterfat of all.^[92]

  Notes and references

  Further reading

  External links

• University of Maryland Medical Center, omega-3 Fatty Acids
• MedlinePlus Herbs and Supplements: Omega-3 fatty acids, fish oil, alpha-linolenic acid