Omega-3 fatty acid

Omega-3 fatty acids are a family of polyunsaturated fatty acids which have in common a carbon-carbon double bond in the ω-3 position. (See Nomenclature for terms and discussion of ω (omega) nomenclature.)

Important omega-3 fatty acids in nutrition are: α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). For a more complete list see List of omega-3 fatty acids. The human body cannot synthesize omega-3 fatty acids de novo, but can synthesize all the other necessary omega-3 fatty acids from the simpler omega-3 fatty acid α-linolenic acid. Therefore, α-linolenic acid is an essential nutrient which must be obtained from food, and the other omega-3 fatty acids which can be either synthesized from it within the body or obtained from food are sometimes also referred to as essential nutrients.

Chemistry

 * For detail on omega (ω) nomenclature and numbering, see EFA Nomenclature.

The term omega-3 (aka "n-3", "ω-3") signifies that the first double bond exists as the third carbon-carbon bond from the terminal methyl end (ω) of the carbon chain.

Omega-3 fatty acids which are important in human nutrition are: α-linolenic acid (18:3, ALA), eicosapentaenoic acid (20:5, EPA), and docosahexaenoic acid (22:6, DHA). These three polyunsaturates have either 3, 5 or 6 double bonds in a carbon chain of 18, 20 or 22 carbon atoms, respectively. All double bonds are in the cis-configuration, i.e. the two hydrogen atoms are on the same side of the double bond.

Biological significance

 * The biological effects of the ω-3 fatty acids are largely mediated by their interactions with the ω-6 fatty acids, see Essential fatty acid interactions for detail.

A 1992 article by biochemist William E.M. Lands provides an overview of the research into omega-3 fatty acids, and is the basis of this section.

The 'essential' fatty acids were given their name when researchers found that they were essential to normal growth in young children and animals. (Note that the modern definition of 'essential' is more strict.) A small amount of omega-3 in the diet (~1% of total calories) enabled normal growth, and increasing the amount had little to no additional benefit.

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

In 1963 it was discovered that the omega-6 arachidonic acid was converted by the body into pro-inflammatory agents called prostaglandins. By 1979 more of what are now known as eicosanoids were discovered: thromboxanes, prostacyclins and the leukotrienes. 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. Researchers found that omega-3 is also converted into eicosanoids, but at a much slower rate. Eicosanoids made from omega-3 fats often have opposing functions to those made from omega-6 fats (ie, anti-inflammatory rather than inflammatory). If both omega-3 and omega-6 are present, they will "compete" to be transformed, so the ratio of omega-3:omega-6 directly affects the type of eicosanoids that are produced.

This competition was recognized as important when it was found that thromboxane is a factor in the clumping of platelets, which leads to thrombosis. The leukotrienes were similarly found to be important in immune/inflammatory-system response, and therefore relevant to arthritis, lupus, and asthma. These discoveries led to greater interest in finding ways to control the synthesis of omega-6 eicosanoids. The simplest way would be by consuming more omega-3 and fewer omega-6 fatty acids.

Cardiovascular health
On September 8, 2004, the U.S. Food and Drug Administration gave "qualified health claim" status to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) omega-3 fatty acids, stating that "supportive but not conclusive research shows that consumption of EPA and DHA omega-3 fatty acids may reduce the risk of coronary heart disease."

A 2006 report in the Journal of the American Medical Association concluded that their review of literature covering cohorts from many countries with a wide variety of demographic characteristics failed to demonstrate a link between omega-3 fatty acids and cancer prevention. 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 omega-3 fats on total mortality, combined cardiovascular events and cancer.

In April 2006, a team led by Lee Hooper at the University of East Anglia in Norwich, UK, published a review of almost 100 separate studies into omega-3 fatty acids, found in abundance in oily fish. It concluded that they do not have a significant protective effect against cardiovascular disease.

The above stands in stark contrast with two different reviews also performed in 2006 by the American Journal of Clinical Nutrition and a second JAMA review that both indicated decreases in total mortality and cardiovascular incidents (i.e. myocardial infarctions) associated with the regular consumption of fish and fish oil supplements. Of particular importance is that no or very few complications were documented.

Research in 2005-06 has suggested that the in-vitro anti-inflammatory activity of omega-3 acids translates into clinical benefits. Cohorts of neck pain patients and of rheumatoid arthritis sufferers have demonstrated benefits comparable to those receiving standard NSAIDs.

Those who follow a Mediterranean-style diet tend to have higher HDL ("good") cholesterol levels. Similar to those who follow a Mediterranean diet, Arctic-dwelling Inuit - who consume high amounts of omega-3 fatty acids from fatty fish - also tend to have increased HDL cholesterol and decreased triglycerides (fatty material that circulates in the blood). In addition, fish oil supplements containing EPA and DHA have been shown to reduce LDL ("bad") cholesterol and triglycerides. Finally, walnuts (which are rich in ALA) have been shown to lower total cholesterol and triglycerides in people with high cholesterol.

Health risks
In a letter dated October 31, 2000 entitled Letter Regarding Dietary Supplement Health Claim for omega-3 Fatty Acids and Coronary Heart Disease, the United States Food and Drug Administration Center for Food Safety and Applied Nutrition, Office of Nutritional Products, Labeling, and Dietary Supplements noted that the known or suspected risks of EPA and DHA omega-3 fatty acids may include:


 * Increased bleeding can occur if overused (normally over 3 grams per day)
 * The possibility of 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
 * Suppression of immune and inflammation responses, and consequently, to decreased resistance to infections and increased susceptibility to opportunistic bacteria

The following risks have been attributed to the FDA but are not mentioned in the above letter:


 * A significant potential risk is the possibility of vitamin poisoning from taking large doses of supplements which contain large quantities of vitamins (particularly vitamin A) in addition to omega-3 fatty acids. For this reason, the primary source of omega-3, if taken as a supplement, should be from fish body oil and not from a fish liver based oil.

Warning for persons with CHF
Persons with congestive heart failure, chronic recurrent angina or evidence that their heart is receiving insufficient blood flow are advised to talk to their doctor before taking omega-3 fatty acids. It may be prudent for such persons to avoid taking omega-3 fatty acids or eating foods that contain them in substantial amounts.

In congestive heart failure, cells that are only barely receiving enough blood flow become electrically hyperexcitable. This, in turn, can lead to increased risk of irregular heartbeats, which, in turn, can cause sudden cardiac death. Omega-3 fatty acids seem to stabilize the rhythm of the heart by effectively preventing these hyperexcitable cells from functioning, thereby reducing the likelihood of irregular heartbeats and sudden cardiac death. For most people, this is obviously beneficial and would account for most of the large reduction in the likelihood of sudden cardiac death. Nevertheless, for people with congestive heart failure, the heart is barely pumping blood well enough to keep them alive. In these patients, omega-3 fatty acids may eliminate enough of these few pumping cells that the heart would be no longer able to pump sufficient blood to live, causing an increased risk of cardiac death.

Autism
According to an internet survey approximately 30% of parents use omega-3 supplements as a therapy for autistic children. There are currently only a few studies on the effectiveness of essential fatty acid supplementation as a treatment of autism and none of these have been well-controlled. Bell and colleagues reported that parents of 18 autistic children who had been supplemented with fish oil for six months described improvements in overall health, cognition, sleep patterns, social interaction, and eye contact. Another case report found that an autistic child given 540 mg of EPA per day over a four week period experienced a complete elimination of his previous anxiety about everyday events as reported by his parents and clinician.

Low birth weight
In a study of nearly 9,000 pregnant women, researchers found women who ate fish once a week during their first trimester had 3.6 times less risk of low birth weight and premature birth than those who ate no fish. Low consumption of fish was a strong risk factor for preterm delivery and low birth weight.

Psychological disorders
Omega-3s are known to have membrane-enhancing capabilities in brain cells. One medical explanation is that omega-3s play a role in the fortification of the myelin sheaths. Not coincidentally, omega-3 fatty acids comprise approximately eight percent of the average human brain according to Dr. David Horrobin, a pioneer in fatty acid research. Ralph Holman of the University of Minnesota, another major researcher in studying essential fatty acids, who gave it the name, surmised how omega-3 components are analogous to the human brain by stating that "DHA is structure, EPA is function."

A benefit of omega-3s is helping the brain to repair damage by promoting neuronal growth. In a six-month study involving people with schizophrenia and Huntington's disease who were treated with EPA or a placebo, the placebo group had clearly lost cerebral tissue, while the patients given the supplements had a significant increase of grey and white matter.

Consequently, the past decade of omega-3 fatty acid research has procured some Western interest in omega-3s as being a legitimate 'brain food.' Still, recent claims that one's intelligence quotient, psychological tests measuring certain cognitive skills, including numerical and verbal reasoning skills, are increased on account of omega-3s consumed by pregnant mothers remain unreliable and controversial. An even more significant focus of research, however, lies in the role of omega-3s as a non-prescription treatment for certain psychiatric and mental diagnoses and has become a topic of much research and speculation.

In 1999, Andrew L. Stoll, MD and his colleagues at Harvard University conducted a small double-blind placebo-controlled study in thirty patients diagnosed with bipolar disorder. Over the course of nine months, he gave 15 subjects capsules containing olive oil, and another 15 subjects capsules containing nine grams of pharmaceutical-quality EPA and DHA. In doing so, he was able to make the general distinction between the placebo group failing to improve while the Omega-3 group experienced a noticeable degree of recovery. Though Stoll believes that the 1999 experiment was not as optimal as it could have been and has accordingly pursued further research, the foundation has been laid for more researchers to explore the theoretical association between absorbed omega-3s and signal transduction inhibition in the brain.

"Several epidemiological studies suggest covariation between seafood consumption and rates of mood disorders. Biological marker studies indicate deficits in omega-3 fatty acids in people with depressive disorders, while several treatment studies indicate therapeutic benefits from omega-3 supplementation. A similar contribution of omega-3 fatty acids to coronary artery disease may explain the well-described links between coronary artery disease and depression. Deficits in omega-3 fatty acids have been identified as a contributing factor to mood disorders and offer a potential rational treatment approach." (American Journal of Psychiatry 163:1098-1100, June 2006)

Daily values
As macronutrients, fats are not assigned recommended daily allowances. Macronutrients have AI (Acceptable Intake) and AMDR (Acceptable Macronutrient Distribution Range) 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.

"A growing body of literature suggests that higher intakes of α-linolenic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) may afford some degree of protection against coronary heart disease. Because the physiological potency of EPA and DHA is much greater than that for α-linolenic acid, 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."

There was insufficient evidence as of 2005 to set a UL (upper tolerable limit) for n-3 fatty acids.

Researchers believe the ideal omega-6 intake should be no more than 4-5 times that of our omega-3 intake. The National Institutes of Health recently published recommended daily intakes of fatty acids, specific recommendations include 650 mg of EPA and DHA, 2.22 g/day of alpha-linolenic acid and 4.44 g/day of linoleic acid.

The greatest risk of fish oil omega-3 supplementation is heavy metal poisoning by the body's accumulation of traces of heavy metals, in particular mercury, lead, nickel, arsenic and cadmium as well as other contaminants (PCBs, furans, dioxins), which may be found especially in less refined fish oil supplements. For these reasons, the FDA recommends that total dietary intake of omega-3 fatty acids from fish be limited to 3 grams per day, of which no more than 2 grams per day are from nutritional supplements.

Historically, the Council for Responsible Nutrition (CRN) and the World Health Organization (WHO) have published acceptable standards regarding contaminants in fish oil. The most stringent current standard is the International Fish Oils Standard (IFOS). Fish oils that typically make this highest grade are those that are molecularly distilled under vacuum, and have virtually no measurable level of contaminants (measured parts per billion and parts per trillion).

Fish
Early humans evolved eating inter-tidal shellfish, while living a shoreline existence in Africa. Now, as then, inter-tidal herbivorous shellfish such as mussels and clams can help people reach a healthy balance of omega-3 and omega-6 fats in their diets, instead of the current (Western diets) 1:17. [[37]

The most widely available source of EPA and DHA is cold water oily fish such as wild salmon, herring, mackerel, anchovies and sardines. The oil from these fish have a profile of around seven times as much omega-3 as omega-6. Farmed salmon, being grain fed, have a higher proportion of omega-6 than wild salmon. Other oily fish such as tuna also contain omega-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 may accumulate up the food chain. Some supplement manufacturers remove heavy metals and other contaminants from the oil through various means, such as molecular distillation (see above), which increases purity, potency and safety.

Even some forms of fish oil may not be optimally digestible. Of four studies that compare bioavailability of the triglyceride form of fish oil vs. the ester form, two have concluded that the natural triglyceride form is better, and the other two studies did not find a significant difference. No studies have shown the ester form to be superior although it is cheaper to manufacture.

Although fish is a dietary source of omega-3 fatty acids, fish do not synthesize them; they obtain them from the algae in their diet. For this reason, there is often a significant difference in EPA and DHA concentrations in farmed vs wild caught fish.

Flax
Flax (aka linseed) (Linum usitatissimum) and its oil are perhaps the most widely available botanical sources of omega-3. Flaxseed oil consists of ca. 55% ALA (alpha-linolenic acid). Flax, like chia, contains approximately three times as much omega-3 as omega-6.

15 grams of flaxseed oil provides ca. 8 grams of ALA, which is converted in the body to EPA and then DHA at an efficiency of (5%-10%), and (2%-5%) respectively.

Eggs
Eggs produced by chickens fed a diet of greens and insects produce higher levels of omega-3 fatty acids than chickens fed corn or soybeans.

Other sources
Farmland Dairies has made a 1% Milk Plus Omega-3 which is sold in NY-NJ-PA area.

Krill, a small, shrimp-like zooplankton, is a less-known source of omega-3. Oil extracted from the krill contains omega-3 fatty acids, such as EPA and DHA, and antioxidants, such as astaxanthin and flavonoids. One advantage of extracting omega-3s from krill is that they are at the bottom of the food chain and do not contain nearly the amount of heavy metals and PCBs as predatory fish. Thus they require little or no distillation. However in comparison to fish, krill contain much lower amounts of omega-3 fatty acids per gram.

Meat from grass-fed animals is often higher in omega-3 than meat from the corresponding grain-fed animal. The omega-6 to omega-3 ratio of grass-fed beef is about 2:1, making it a more useful source of omega-3 than grain-fed beef, which usually has a ratio of 4:1. Commercially available lamb is almost always grass-fed, and subsequently higher in omega-3 than other common meat sources. Milk and cheese from grass-fed cows may also be good sources of omega-3. One UK study showed that half a pint of milk provides 10% of the recommended daily intake (RDI) of ALA, while a piece of organic cheese the size of a matchbox may provide up to 88%".

The microalgae Crypthecodinium cohnii and Schizochytrium are rich sources of DHA (22:6 ω-3) and can be produced commercially in bioreactors. Oil from brown algae (kelp) is a source of EPA.

Acai palm fruit also contains omega-3 fatty acids.

Omega-3 capsules are sold in bottles for daily intake as supplements.

The omega-6 to omega-3 ratio
Clinical studies indicate that the ingested ratio of omega-6 to omega-3 (especially Linoleic vs Alpha Linolenic) fatty acids are important to maintaining cardiovascular health.

Both omega-3 and omega-6 fatty acids are essential, i.e. humans must consume them in the diet. Omega-3 and omega-6 compete for the same metabolic enzymes, thus the omega-6:omega-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. Generally, grass fed animals provide more omega 3 than do grain fed animals which produce relatively more omega 6. Metabolites of omega-6 are significantly more inflammatory (esp. arachidonic acid) than those of omega-3. This necessitates that omega-3 and omega-6 be consumed in a balanced proportion; the ideal ratio of omega-6:omega-3 being from 3:1 to 5:1. Studies suggest that the evolutionary human diet, rich in seafood, nuts and other sources of omega-3, may have provided such a ratio.

Simopoulos, et al recommend daily intakes of three omega-3 forms: 650 mg of EPA and DHA, and 2.22 grams of ALA, and one omega-6 form: 4.44 grams of LA. This translates to a 3:2 omega-6 to omega-3 ratio. (i.e. 1.5:1)

Typical Western diets provide ratios of between 10:1 and 30:1 - i.e., dramatically skewed toward omega-6. Here are the ratios of omega-6 to omega-3 fatty acids in some common oils: canola 2:1, soybean 7:1, olive 13:1, sunflower (no omega-3), flax 1:3 cottonseed (almost no omega-3), peanut (no omega-3), grapeseed oil (almost no omega-3) and corn oil 46 to 1 ratio of omega-6s to omega-3s. It should be noted that olive, peanut and canola oils consist mainly of monounsaturated fatty acids, approx 80% monounsaturated fatty acids, (i.e. neither omega-6 nor omega-3) meaning that they contain relatively small amounts of omega (3 & 6) fatty acids. Consequently, the omega-6 to omega-3 ratios for these oils (i.e. olive, canola and peanut oils) are not as significant as they are for corn, soybean and sunflower oils.

Notes and references
37. Robson, A. 2006. "Shellfish view of omega-3 and sustainable fisheries." Nature 444, 1002 Shellfish in NATURE

Bell, J.G., et al. 2004. "Essential fatty acids and phospholipase A2 in autistic spectrum disorders." Prostaglandins Leukot.Essent.Fatty Acids 71(4):201-204.

Genuis, S.J.a.G.K.S. 2006. "Time for an oil check: the role of essential omega-3 fatty acids in maternal and pediatric health." Journal of Perinatology 26:359-365.

Green, V.A., K.A. Pituch, J. Itchon, A. Choi, M. O'Reilly, J. Sigafoos, "Internet survey of treatments used by parents of children with autism," Res Dev Disabil, 2006, 27(1):70-84.

Johnson, S.M., and E. Hollander. 2003. "Evidence that eicosapentaenoic acid is effective in treating autism." J Clin Psychiatry 64(7):848-849.

Richardson, A.J. 2006. "Omega-3 fatty acids in ADHD and related neurodevelopmental disorders." Int.Rev.Psychiatry 18(2):155-172.

Richardson, A.J., and M.A. Ross. 2000. "Fatty acid metabolism in neurodevelopmental disorder: a new perspective on associations between attention-deficit/hyperactivity disorder, dyslexia, dyspraxia and the autistic spectrum." Prostaglandins Leukot.Essent.Fatty Acids 63(1-2):1-9.

Young, G., and J. Conquer. 2005. "Omega-3 fatty acids and neuropsychiatric disorders." Reprod.Nutr.Dev 45(1):1-28.