Omega-3 fatty acid

Omega−3 fatty acids, also called Omega−3 oils, ω−3 fatty acids or n−3 fatty acids,

Mammals are unable to synthesize the

There is no high-quality evidence that dietary supplementation with omega−3 fatty acids reduces the risk of cancer or cardiovascular disease.^[8][9][10] Fish oil supplement studies have failed to support claims of preventing heart attacks or strokes or any vascular disease outcomes.^[11][12][13]

History

In 1929, George and Mildred Burr discovered that fatty acids were critical to health. If fatty acids were absent from the diet, a life-threatening deficiency syndrome ensued. The Burrs coined the phrase "essential fatty acids".^[14] Since then, researchers have shown a growing interest in unsaturated essential fatty acids as they form the framework for the organism's cell membranes.^[15] Subsequently, awareness of the health benefits of essential fatty acids has dramatically increased since the 1980s.^[16]

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".^[17] 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."^[18]

Historically,

The terms ω−3 ("omega−3") fatty acid and n−3 fatty acid are derived from the

In the expressions n−x or ω−x, the symbol is a minus sign rather than a hyphen (or dash), although it is never read as such. Also, the symbol n (or ω) represents the locant of the methyl end, counted from the

Although n and ω (omega) are synonymous, the IUPAC recommends that n be used to identify the highest carbon number of a fatty acid.^[20] Nevertheless, the more common name – omega−3 fatty acid – is used in both the lay media and scientific literature.

Example

For example, α-linolenic acid (ALA; illustration) is an 18-carbon chain having three double bonds, the first being located at the third carbon from the methyl end of the fatty acid chain. Hence, it is an omega−3 fatty acid. Counting from the other end of the chain, that is the

α-Linolenic acid is polyunsaturated (containing more than one double bond) and is also described by a lipid number, 18:3, meaning that there are 18 carbon atoms and 3 double bonds.^[20]

Chemistry

An omega−3 fatty acid is a fatty acid with multiple double bonds, where the first double bond is between the third and fourth carbon atoms from the end of the carbon atom chain. "Short-chain" omega−3 fatty acids have a chain of 18 carbon atoms or less, while "long-chain" omega−3 fatty acids have a chain of 20 or more.

Three omega−3 fatty acids are important in human physiology, α-linolenic acid (18:3, n-3; ALA), eicosapentaenoic acid (20:5, n-3; EPA), and docosahexaenoic acid (22:6, n-3; DHA).

Omega−3 fatty acids occur naturally in two forms, triglycerides and phospholipids. In the triglycerides, they, together with other fatty acids, are bonded to glycerol; three fatty acids are attached to glycerol. Phospholipid omega−3 is composed of two fatty acids attached to a phosphate group via glycerol.

The triglycerides can be converted to the free fatty acid or to methyl or ethyl esters, and the individual esters of omega−3 fatty acids are available.^{[clarification needed]}

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

In 1964, it was discovered that enzymes found in sheep tissues convert omega−6 arachidonic acid into the inflammatory agent, prostaglandin E₂,^[24] which is involved in the immune response of traumatized and infected tissues.^[25] By 1979, eicosanoids were further identified, including thromboxanes, prostacyclins, and leukotrienes.^[25] The eicosanoids typically have a short period of activity 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 have deleterious effects.^[25] Researchers found that certain omega−3 fatty acids are also converted into eicosanoids and docosanoids,^[26] but at a slower rate. If both omega−3 and omega−6 fatty acids are present, they will "compete" to be transformed,^[25] so the ratio of long-chain omega−3:omega−6 fatty acids directly affects the type of eicosanoids that are produced.^[25]

Interconversion

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%.^[27][28] The omega−3 conversion efficiency is greater in women than in men, but less studied.^[29] 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.^[30]

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.^[31] 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.^[32] 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.^[33]

The conversion of ALA to EPA and further to DHA in humans has been reported to be limited, but varies with individuals.^[2][34] Women have higher ALA-to-DHA conversion efficiency than men, which is presumed^[35] to be due to the lower rate of use of dietary ALA for beta-oxidation. One preliminary study showed that EPA can be increased by lowering the amount of dietary linoleic acid, and DHA can be increased by elevating intake of dietary ALA.^[36]

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.^[37] 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.^[38] This is commonly believed to be the reason why modern diets are correlated with many inflammatory disorders.^[37] 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.^[33][39]

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.^[40]

Metabolites of omega−6 are more inflammatory (esp. arachidonic acid) than those of omega−3. However, in terms of heart health omega-6 fatty acids are less harmful than they are presumed to be. A meta-analysis of six randomized trials found that replacing saturated fat with omega-6 fats reduced the risk of coronary events by 24%.^[41]

A healthy ratio of omega-6 to omega-3 is needed; healthy ratios, according to some authors, range from 1:1 to 1:4.^[42] Other authors believe that a ratio of 4:1 (4 times as much omega−6 as omega−3) is already healthy.^[43][44]

Typical Western diets provide ratios of between 10:1 and 30:1 (i.e., dramatically higher levels of omega−6 than omega−3).

The European Commission sponsored a working group to develop recommendations on dietary fat intake in pregnancy and lactation. In 2008, the working group published consensus recommendations,^[54] including the following:

• "pregnant and lactating women should aim to achieve an average dietary intake of at least 200 mg DHA/day"
• "women of childbearing age should aim to consume one to two portions of sea fish per week, including oily fish"
• "intake of the DHA precursor, α-linolenic acid, is far less effective with regard to DHA deposition in fetal brain than preformed DHA"

However, the seafood supply to meet these recommendations is currently too low in most European countries and if met would be unsustainable.^[55]

In the EU, the EFSA publishes the Dietary Reference Values (DRVs), recommending Adequate Intake values for EPA+DHA and DHA:^[56]

^1 AI, Adequate Intake

^2 i.e. the second half of the first year of life (from the beginning of the 7th month to the 1st birthday)

^3 in addition to combined intakes of EPA and DHA of 250 mg/day

The American Heart Association (AHA) has made 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 two times per week; and "Treatment is reasonable" for those having been diagnosed with coronary heart disease. For the latter the AHA does not recommend a specific amount of EPA + DHA, although it notes that most trials were at or close to 1000 mg/day. The benefit appears to be on the order of a 9% decrease in relative risk.^[57] The European Food Safety Authority (EFSA) approved a claim "EPA and DHA contributes to the normal function of the heart" for products that contain at least 250 mg EPA + DHA. The report did not address the issue of people with pre-existing heart disease. The World Health Organization recommends regular fish consumption (1-2 servings per week, equivalent to 200 to 500 mg/day EPA + DHA) as protective against coronary heart disease and ischaemic stroke.

Contamination

However, other contaminants (PCBs, furans, dioxins, and PBDEs) might be found, especially in less-refined fish oil supplements.^[60]

Throughout their history, the Council for Responsible Nutrition and the World Health Organization have published acceptability standards regarding contaminants in fish oil. The most stringent current standard is the International Fish Oils Standard.^{[61][non-primary source needed]} Fish oils that are molecularly distilled under vacuum typically make this highest-grade; levels of contaminants are stated in parts per billion per trillion.^{[citation needed][62]}

Rancidity

A 2022 study found that a number of products on the market used oxidised oils, with the rancidity often masked by flavourings. Another study in 2015 found that an average of 20% of products had excess oxidation. Whether rancid fish oil is harmful remains unclear. Some studies show that highly oxidised fish oil can have a negative impact on cholesterol levels. Animal testing showed that high doses have toxic effects. Furthermore, rancid oil is likely to be less effective than fresh fish oil.^[63][64]

Fish

The most widely available dietary source of EPA and DHA is oily fish, such as salmon, herring, mackerel, anchovies, and sardines.^[1] Oils from these fishes have around seven times as much omega−3 as omega−6. Other oily fish, such as tuna, also contain n-3 in somewhat lesser amounts.^[1][65] Although fish are a dietary source of omega−3 fatty acids, fish do not synthesize omega−3 fatty acids, but rather obtain them via their food supply, including algae or plankton.^[66]

In order for farmed marine fish to have amounts of EPA and DHA comparable to those of wild-caught fish, their feed must be supplemented with EPA and DHA, most commonly in the form of fish oil. For this reason, 81% of the global fish oil supply in 2009 was consumed by aquaculture.^[5] By 2019, two alternative sources of EPA and DHA for fish have been partially commercialized: genetically-modified canola oil and Schizochytrium algal oil.^[67]

Fish oil

Marine and freshwater fish oil vary in content of arachidonic acid, EPA and DHA.^[68] They also differ in their effects on organ lipids.^[68]

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.^[69][70]

Krill

Krill oil is a source of omega−3 fatty acids.^[71] The effect of krill oil, at a lower dose of EPA + DHA (62.8%), was demonstrated to be similar to that of fish oil on blood lipid levels and markers of inflammation in healthy humans.^[72] While not an endangered species, krill are a mainstay of the diets of many ocean-based species including whales, causing environmental and scientific concerns about their sustainability.^[73][74][75] Preliminary studies appear to indicate that the DHA and EPA omega−3 fatty acids found in krill oil may be more bio-available than in fish oil.^[76] Additionally, krill oil contains astaxanthin, a marine-source keto-carotenoid antioxidant that may act synergistically with EPA and DHA.^{[77][78][79][80][12]}

Plant sources

Linseed (or flaxseed) (Linum usitatissimum) and its oil are perhaps the most widely available

Some transgenic initiatives have transferred the ability to make EPA and DHA into existing high-yielding crop species of land plants:[91]

• Camelina sativa: In 2013, Rothamsted Research reported two genetically modified forms of this plant. Oil from the seeds of this plant contained on average 15% ALA, 11% EPA, and 8% DHA in one development and 11% ALA and 24% EPA in another.^[92][93]
• Canola: In 2011, CSIRO, GRDC, and Nufarm developed a version of canola that produces DHA in seeds; the oil contains 10% DHA and almost no EPA. In 2018, it was approved as an animal feed additive in Australia.^[94] In 2021, the US FDA acknowledged it as a New Dietary Ingredient for humans.^[95] Separately, Cargill has commercialized a different strain of canola that produces EPA and DHA for fish feed. The oil contains 8.1% EPA and 0.8% DHA.^[91]

Eggs

Eggs produced by hens fed a diet of greens and insects contain higher levels of omega−3 fatty acids than those produced by chickens fed corn or soybeans.^[96] In addition to feeding chickens insects and greens, fish oils may be added to their diets to increase the omega−3 fatty acid concentrations in eggs.^[97]

The addition of flax and canola seeds, both good sources of alpha-linolenic acid, to the diets of laying chickens, increases the omega−3 content of the eggs, predominantly DHA.^[98] However, this enrichment could lead to an increment of lipid oxidation in the eggs if the seeds are used in higher doses, without using an appropriate antioxidant.^[99]

The addition of green algae or seaweed to the diets boosts the content of DHA and EPA, 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".^[100]

Meat

Omega−3 fatty acids are formed in the chloroplasts of green leaves and algae. While seaweeds and algae are the sources of omega−3 fatty acids present in fish, grass is the source of omega−3 fatty acids present in grass-fed animals.^[101] 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.^[102]

The omega−6: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.^[103]

In a 2009 joint study by the USDA and researchers at Clemson University in South Carolina, grass-fed beef was compared with grain-finished beef. The researchers found that grass-finished 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 octadecenoic acid, a conjugated linoleic acid, which is a potential cancer fighter), 90% higher in vaccenic acid (which can be transformed into CLA), lower in the saturated fats, and has a healthier ratio of omega−6 to omega−3 fatty acids (1.65 vs 4.84). Protein and cholesterol content were equal.^[103]

The omega−3 content of chicken meat may be enhanced by increasing the animals' dietary intake of grains high in omega−3, such as flax, chia, and canola.^[104]

Kangaroo meat is also a source of omega−3, with fillet and steak containing 74 mg per 100 g of raw meat.^[105]

Seal oil

Seal oil is a source of EPA,

A trend in the early 21st century was to fortify food with omega−3 fatty acids.^[88][109]

Health effects of omega-3 supplementation

The association between supplementation and a lower risk of all-cause mortality is inconclusive.^[11][110]

Cancer

There is insufficient evidence that supplementation with omega−3 fatty acids has an effect on different cancers.^{[1][9][40][111]} Omega-3 supplements do not improve body weight, muscle maintenance or quality of life in cancer patients.^[112]

Cardiovascular disease

Moderate and high quality evidence from a 2020 review showed that EPA and DHA, such as that found in omega−3 polyunsaturated fatty acid supplements, does not appear to improve mortality or cardiovascular health.^[8] There is weak evidence indicating that α-linolenic acid may be associated with a small reduction in the risk of a cardiovascular event or the risk of arrhythmia.^[2][8]

A 2018 meta-analysis found no support that daily intake of one gram of omega−3 fatty acid in individuals with a history of coronary heart disease prevents fatal coronary heart disease, nonfatal myocardial infarction or any other vascular event.^[11] 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.^[113] No protective effect against the development of stroke or all-cause mortality was seen in this population.^[113] A 2021 meta-analysis found that supplementation was associated with a reduced risk of myocardial infarction and coronary heart disease.^[114]

A 2019 review found that omega-3 fatty acid supplements make little or no difference to cardiovascular mortality and that people with myocardial infarction have no benefit in taking the supplements.[124] A 2021 review found that omega-3 supplementation did not affect cardiovascular disease outcomes.^[10]

A 2021 review concluded that use of omega-3 supplements was associated with an increased risk of atrial fibrillation in people having high blood triglycerides.^[125] A meta-analysis showed that use of marine omega-3 supplementation was associated with an increased risk of atrial fibrillation, with the risk appearing to increase for doses greater than one gram per day.^[126]

Chronic kidney disease

In people with

A 2022 Cochrane review of controlled trials did not find clear evidence that marine-derived omega-3 supplementation improves cognitive and physical recovery or social, and emotional wellbeing following stroke diagnosis, nor prevents stroke recurrence and mortality.[13] In this review, mood appeared to worsen slightly among those receiving 3g fish oil supplementation for 12 weeks; psychometric scores changed by 1.41 (0.07 to 2.75) points less than those receiving palm and soy oil.^[13] However, this represented only a single small study and was not observed in a study lasting more than 3 months. Overall, the review was limited by the low number of high-quality evidence available.

Inflammation

A 2013 systematic review found tentative evidence of benefit for lowering inflammation levels in healthy adults and in people with one or more

For rheumatoid arthritis, 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.^[132] The American College of Rheumatology 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.^[133] The National Center for Complementary and Integrative Health has concluded that "supplements containing omega−3 fatty acids ... may help relieve rheumatoid arthritis symptoms" but warns that such supplements "may interact with drugs that affect blood clotting".^[134]

Developmental disabilities

One meta-analysis concluded that omega−3 fatty acid supplementation demonstrated a modest effect for improving ADHD symptoms.

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.[139] A 2018 Cochrane systematic review with moderate to high quality of evidence suggested that omega−3 fatty acids may reduce risk of perinatal death, risk of low body weight babies; and possibly mildly increased LGA babies.^[140]

A 2021 umbrella review with moderate to high quality of evidence suggested that "omega-3 supplementation during pregnancy can exert favorable effects against pre-eclampsia, low-birth weight, pre-term delivery, and post-partum depression, and can improve anthropometric measures, immune system, and visual activity in infants and cardiometabolic risk factors in pregnant mothers."^[141]

Mental health

Omega-3 supplementation has not been shown to significantly affect symptoms of

A 2015 study concluded that there are multiple factors responsible for depression and deficiency of omega 3 fatty acids can be one of them. It further stated that only those patients who have depression due to insufficient omega-3 fatty acids can respond well to the omega 3 supplements while others are unlikely to get any positive effects.[147] Meta-analysis suggest that supplements with higher concentration of EPA than DHA are more likely to act as anti-depressants.^[148][149]

In contrast to dietary supplementation studies, there is significant difficulty in interpreting the literature regarding dietary intake of omega−3 fatty acids (e.g. from fish) due to participant recall and systematic differences in diets.^[150] 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.^[151][152] A significant correlation between shorter treatment trials was associated with increased omega−3 efficacy for treating depressed symptoms further implicating bias in publication.^[152]

Cognitive aging

A 2016 Cochrane review found no convincing evidence for the use of omega‐3 PUFA supplements in treatment of Alzheimer's disease or dementia.^[153] There is preliminary evidence of effect on mild cognitive problems, but none supporting an effect in healthy people or those with dementia.^[154][155] A 2020 review suggested that omega 3 supplementation has no effect on global cognitive function but has a mild benefit in improving memory in non-demented adults.^[156]

A 2022 review found promising evidence for prevention of cognitive decline in people who regularly eat long-chain omega 3 rich foods. Conversely, clinical trials with participants already diagnosed with Alzheimer's show no effect.^[157] A 2020 review concluded that long-chain omega-3 supplements do not deter cognitive decline in older adults.^[158]

Brain and visual functions

Brain function and vision rely on dietary intake of DHA to support a broad range of cell membrane properties, particularly in grey matter, which is rich in membranes.^[159][160] A major structural component of the mammalian brain, DHA is the most abundant omega−3 fatty acid in the brain.^[161][162] Omega 3 PUFA supplementation has no effect on macular degeneration or development of visual loss.^[163]

Atopic diseases

Results of studies investigating the role of LCPUFA supplementation and LCPUFA status in the prevention and therapy of

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.^[165]

Asthma

As of 2015, there was no evidence that taking omega−3 supplements can prevent asthma attacks in children.^[166]

Diabetes

A 2019 review found that omega-3 supplements have no effect on prevention and treatment of type 2 diabetes.^[167][168] A 2021 meta-analysis found that supplementation with omega-3 had positive effects on diabetes biomarkers, such as fasting blood glucose and insulin resistance.^[169]

See also

Notes

References