Omega 3 fatty acid

Health effects

Supplementation does not appear to be associated with a lower risk of all-cause mortality.

Cancer

The evidence linking the consumption of fish to the risk of cancer is poor. Supplementation with omega-3 fatty acids does not appear to affect this either.

A 2006 review concluded that there was no link between omega-3 fatty acids consumption and cancer. This is similar to the findings of a review of studies up to February 2002 that failed to find clear effects of long and shorter chain omega-3 fats on total risk of death, combined cardiovascular events and cancer. In those with advanced cancer and cachexia, omega-3 fatty acids supplements may be of benefit, improving appetite, weight, and quality of life. There is tentative evidence that marine omega-3 polyunsaturated fatty acids reduce the risk of breast cancer but this is not conclusive.

The effect of consumption on prostate cancer is not conclusive. There is a decreased risk with higher blood levels of DPA, but an increased risk of more aggressive prostate cancer with higher blood levels of combined EPA and DHA (found in fatty fish oil).

Cardiovascular disease

Evidence, in the population generally, does not support a beneficial role for omega-3 fatty acid supplementation in preventing cardiovascular disease (including myocardial infarction and sudden cardiac death) or stroke. However, omega-3 fatty acid supplementation greater than one gram daily for at least a year may be protective against cardiac death, sudden death, and myocardial infarction in people who have a history of cardiovascular disease. No protective effect against the development of stroke or all-cause mortality was seen in this population. Eating a diet high in fish that contain long chain omega-3 fatty acids does appear to decrease the risk of stroke. Fish oil supplementation has not been shown to benefit revascularization or abnormal heart rhythms and has no effect on heart failure hospital admission rates. Furthermore, fish oil supplement studies have failed to support claims of preventing heart attacks or strokes.

Evidence suggests that omega-3 fatty acids modestly lower blood pressure (systolic and diastolic) in people with hypertension and in people with normal blood pressure. 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 and increase the breakdown of fibrin, a protein involved in blood clotting and scar formation. Omega-3 fatty acids reduce blood triglyceride levels but do not significantly change the level of LDL cholesterol or HDL cholesterol in the blood. ALA does not confer the cardiovascular health benefits of EPA and DHAs.

The effect of omega-3 polyunsaturated fatty acids on stroke is unclear, with a possible benefit in women.

Inflammation

Some research suggests that the anti-inflammatory activity of long-chain omega-3 fatty acids may translate into clinical effects. A 2013 systematic review found tentative evidence of benefit. Consumption of omega-3 fatty acids from marine sources lowers markers of inflammation in the blood such as C-reactive protein, interleukin 6, and TNF alpha.

For rheumatoid arthritis (RA), one systematic review found consistent, but modest, evidence for the effect of marine n-3 PUFAs on symptoms such as "joint swelling and pain, duration of morning stiffness, global assessments of pain and disease activity" as well as the use of non-steroidal anti-inflammatory drugs. The American College of Rheumatology (ACR) has stated that there may be modest benefit from the use of fish oils, but that it may take months for effects to be seen, and cautions for possible gastrointestinal side effects and the possibility of the supplements containing mercury or vitamin A at toxic levels. The National Center for Complementary and Integrative Health has concluded that "[n]o dietary supplement has shown clear benefits for RA", but that there is preliminary evidence that fish oil may be beneficial, and called for further study.

Developmental disabilities

Although not supported by current scientific evidence as a primary treatment for ADHD, autism, and other developmental disabilities, omega-3 fatty acid supplements are being given to children with these conditions.

One meta-analysis concluded that omega-3 fatty acid supplementation demonstrated a modest effect for improving ADHD symptoms. A Cochrane review of PUFA (not necessarily omega-3) supplementation found "there is little evidence that PUFA supplementation provides any benefit for the symptoms of ADHD in children and adolescents", while a different review found "insufficient evidence to draw any conclusion about the use of PUFAs for children with specific learning disorders". Another review concluded that the evidence is inconclusive for the use of omega-3 fatty acids in behavior and non-neurodegenerative neuropsychiatric disorders such ADHD and depression.

Fish oil has only a small benefit on the risk of early birth. A 2015 meta-analysis of the effect of omega-3 supplementation during pregnancy did not demonstrate a decrease in the rate of preterm birth or improve outcomes in women with singleton pregnancies with no prior preterm births. A systematic review and meta-analysis published the same year reached the opposite conclusion, specifically, that omega-3 fatty acids were effective in "preventing early and any preterm delivery".

Mental health

There is some evidence that omega-3 fatty acids are related to mental health, including that they may tentatively be useful as an add-on for the treatment of depression associated with bipolar disorder. Significant benefits due to EPA supplementation were only seen, however, when treating depressive symptoms and not manic symptoms suggesting a link between omega-3 and depressive mood. There is also preliminary evidence that EPA supplementation is helpful in cases of depression. The link between omega-3 and depression has been attributed to the fact that many of the products of the omega-3 synthesis pathway play key roles in regulating inflammation such as prostaglandin E3 which have been linked to depression. This link to inflammation regulation has been supported in both in vitro and in vivo studies as well as in meta-analysis studies. The exact mechanism in which omega-3 acts upon the inflammatory system is still controversial as it was commonly believed to have anti-inflammatory effects.

There is, however, significant difficulty in interpreting the literature due to participant recall and systematic differences in diets. There is also controversy as to the efficacy of omega-3, with many meta-analysis papers finding heterogeneity among results which can be explained mostly by publication bias. A significant correlation between shorter treatment trials was associated with increased omega-3 efficacy for treating depressed symptoms further implicating bias in publication.

Very low quality evidence finds that omega-3 fatty acids might prevent psychosis.

Cognitive aging

Epidemiological studies are inconclusive about an effect of omega-3 fatty acids on the mechanisms of Alzheimer's disease. There is preliminary evidence of effect on mild cognitive problems, but none supporting an effect in healthy people or those with dementia.

Atopic diseases

Results of studies investigating the role of LCPUFA supplementation and LCPUFA status in the prevention and therapy of atopic diseases (allergic rhinoconjunctivitis, atopic dermatitis and allergic asthma) are controversial; therefore, at the present stage of our knowledge we cannot state either that the nutritional intake of n-3 fatty acids has a clear preventive or therapeutic role, or that the intake of n-6 fatty acids has a promoting role in context of atopic diseases.

Risk of deficiency

People with PKU often have low intake of omega-3 fatty acids, because nutrients rich in omega-3 fatty acids are excluded from their diet due to high protein content.

Chemistry

Omega-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; and the double bonds are interrupted by methylene bridges (-CH
2-), so that there are two single bonds between each pair of adjacent double bonds.

List of omega-3 fatty acids

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

Ethyl ester

Free fatty acid

Called "omega-3 carboxylic acids" (Epanova)

Biochemical forms

DHA is transported into the brain in the form of lysophosphatidylcholine.

Transporters

DHA in the form of lysophosphatidylcholine is transported into the brain by a membrane transport protein, MFSD2A, which is exclusively expressed in the endothelium of the blood–brain barrier.

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. The omega-3 fatty acid DHA, also known as docosahexaenoic acid, is found in high abundance in the human brain. It is produced by a desaturation process, but humans lack the desaturase enzyme, which acts to insert double bonds at the ω₆ and ω₃ position. Therefore, the ω₆ and ω₃ polyunsaturated fatty acids cannot be synthesized and are appropriately called essential fatty acids.

In 1964 it was discovered that enzymes found in sheep tissues convert omega-6 arachidonic acid into the inflammatory agent called prostaglandin E₂ which both causes the sensation of pain and expedites healing and immune response in traumatized and infected tissues. 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. If the rate of synthesis exceeds the rate of metabolism, the excess eicosanoids may, however, have deleterious effects. Researchers found that certain omega-3 fatty acids are also converted into eicosanoids, but at a much slower rate. Eicosanoids made from omega-3 fatty acids are often referred to as anti-inflammatory, but in fact they are just less inflammatory than those made from omega-6 fats. If both omega-3 and omega-6 fatty acids are present, they will "compete" to be transformed, so the ratio of long-chain omega-3:omega-6 fatty acids directly affects the type of eicosanoids that are produced.

Conversion efficiency of ALA to EPA and DHA

Humans can convert short-chain omega-3 fatty acids to long-chain forms (EPA, DHA) with an efficiency below 5%. The omega-3 conversion efficiency is greater in women than in men, but less-studied. Higher ALA and DHA values found in plasma phospholipids of women may be due to the higher activity of desaturases, especially that of delta-6-desaturase.

These conversions occur competitively with omega-6 fatty acids, which are essential closely related chemical analogues that are derived from linoleic acid. They both utilize the same desaturase and elongase proteins in order to synthesize inflammatory regulatory proteins. The products of both pathways are vital for growth making a balanced diet of omega-3 and omega-6 important to an individual’s health. A balanced intake ratio of 1:1 was believed to be ideal in order for proteins to be able to synthesize both pathways sufficiently, but this has been controversial as of recent research.

The conversion of ALA to EPA and further to DHA in humans has been reported to be limited, but varies with individuals. Women have higher ALA conversion efficiency than men, which is presumed to be 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 the absolute amounts of ALA and LA each influence conversion rates separately, rather than simply the ratio between the two.

Omega-6 to omega-3 ratio

Human diet has changed rapidly in recent centuries resulting in a reported increased diet of omega-6 in comparison to omega-3. The rapid evolution of human diet away from a 1:1 omega-3 and omega-6 ratio, such as during the Neolithic Agricultural Revolution, has presumably been too fast for humans to have adapted to biological profiles adept at balancing omega-3 and omega-6 ratios of 1:1. This is commonly believed to be the reason why modern diets are correlated with many inflammatory disorders. While omega-3 polyunsaturated fatty acids may be beneficial in preventing heart disease in humans, the level of omega-6 polyunsaturated fatty acids (and, therefore, the ratio) does not matter.

Both omega-6 and omega-3 fatty acids are essential: humans must consume them in their diet. Omega-6 and omega-3 eighteen-carbon polyunsaturated fatty acids compete for the same metabolic enzymes, thus the omega-6:omega-3 ratio of ingested fatty acids has significant influence on the ratio and rate of production of eicosanoids, a group of hormones intimately involved in the body's inflammatory and homeostatic processes, which include the prostaglandins, leukotrienes, and thromboxanes, among others. Altering this ratio can change the body's metabolic and inflammatory state. In general, grass-fed animals accumulate more omega-3 than do grain-fed animals, which accumulate relatively more omega-6. Metabolites of omega-6 are more inflammatory (esp. arachidonic acid) than those of omega-3. This necessitates that omega-6 and omega-3 be consumed in a balanced proportion; healthy ratios of omega-6:omega-3, according to some authors, range from 1:1 to 1:4. Other authors believe that a ratio of 4:1 (4 times as much omega-6 as omega-3) is already healthy. Studies suggest the evolutionary human diet, rich in game animals, seafood, and other sources of omega-3, may have provided such a ratio.

Typical Western diets provide ratios of between 10:1 and 30:1 (i.e., dramatically higher levels of omega-6 than omega-3). The ratios of omega-6 to omega-3 fatty acids in some common vegetable oils are: canola 2:1, hemp 2-3:1, soybean 7:1, olive 3–13:1, 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 46:1 ratio of omega-6 to omega-3.

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 1980s.

On September 8, 2004, the U.S. Food and Drug Administration gave "qualified health claim" status to EPA and DHA omega-3 fatty acids, stating, "supportive but not conclusive research shows that consumption of EPA and DHA [omega-3] fatty acids may reduce the risk of coronary heart disease". This updated and modified their health risk advice letter of 2001 (see below).

The Canadian Food Inspection Agency has recognized the importance of DHA omega-3 and permits the following claim for DHA: "DHA, an omega-3 fatty acid, supports the normal physical development of the brain, eyes and nerves primarily in children under two years of age."