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The two major classes of polyunsaturated fatty acids (PUFAs) are the omega-3 and omega-6 fatty acids. Like all fatty acids, PUFAs consist of long chains of carbon atoms with a carboxyl group at one end of the chain and a methyl group at the other. PUFAs are distinguished from saturated and monounsaturated fatty acids by the presence of two or more double bonds between carbons within the fatty acid chain.
ALA is present in plant oils, such as flaxseed, soybean, and canola oils [3]. DHA and EPA are present in fish, fish oils, and krill oils, but they are originally synthesized by microalgae, not by the fish. When fish consume phytoplankton that consumed microalgae, they accumulate the omega-3s in their tissues [3].
Omega-3s play important roles in the body as components of the phospholipids that form the structures of cell membranes [5]. DHA, in particular, is especially high in the retina, brain, and sperm [3,5,6]. In addition to their structural role in cell membranes, omega-3s (along with omega-6s) provide energy for the body and are used to form eicosanoids. Eicosanoids are signaling molecules that have similar chemical structures to the fatty acids from which they are derived; they have wide-ranging functions in the body's cardiovascular, pulmonary, immune, and endocrine systems [1,2].
The eicosanoids made from omega-6s are generally more potent mediators of inflammation, vasoconstriction, and platelet aggregation than those made from omega-3s, although there are some exceptions [3,7]. Because both classes of fatty acids compete for the same desaturation enzymes, ALA is a competitive inhibitor of linoleic acid metabolism and vice versa [8]. Similarly, EPA and DHA can compete with arachidonic acid for the synthesis of eicosanoids. Thus, higher concentrations of EPA and DHA than arachidonic acid tip the eicosanoid balance toward less inflammatory activity [9].
Intake recommendations for fatty acids and other nutrients are provided in the Dietary Reference Intakes (DRIs) developed by the Food and Nutrition Board of the Institute of Medicine (IOM) (now called the National Academy of Medicine) [5]. DRI is the general term for a set of reference values used for planning and assessing nutrient intakes of healthy people. These values, which vary by age and sex, include the following:
Table 1 lists the current AIs for omega-3s in grams per day. Human milk contains omega-3s as ALA, EPA, and DHA, so the IOM established an AI for infants from birth to 12 months that is equivalent to the mean intake of omega-3s in healthy, breastfed infants.
For infants, the AIs apply to total omega-3s. For age 1 and older, the AIs apply only to ALA because ALA is the only omega-3 that is essential. The IOM did not establish specific intake recommendations for EPA, DHA, or other LC omega-3s.
Some foods, such as certain brands of eggs, yogurt, juices, milk, and soy beverages, are fortified with DHA and other omega-3s. Since 2002, manufacturers have added DHA and arachidonic acid (the two most prevalent LC PUFAs in the brain) to most infant formulas available in the United States [28].
Several food sources of ALA, DHA, and/or EPA are listed in Table 2. The U.S. Food and Drug Administration (FDA) has established a Daily Value (DV) of 65 g for total fat but not for omega-3s. Thus, Table 2 presents the amounts of omega-3 fatty acids in grams per serving only and not the percent of the DV.
*Except as noted, the U.S. Department of Agriculture (USDA) database does not specify whether fish are farmed or wild caught.
**The USDA database does not specify whether beef is grass fed or grain fed.
The USDA's FoodData Central website [29] lists the nutrient content of many foods and provides a comprehensive list of foods containing ALA arranged by nutrient content and by food name, foods containing DHA arranged by nutrient content and by food name, and foods containing EPA arranged by nutrient content and by food name.
LC omega-3s are present in several dietary supplement formulations, including fish oil, krill oil, cod liver oil, and vegetarian products that contain algal oil. A typical fish oil supplement provides about 1,000 mg fish oil, containing 180 mg EPA and 120 mg DHA, but doses vary widely [30]. Cod liver oil supplements provide vitamin A and vitamin D in addition to LC omega-3s. Although seafood contains varying levels of methyl mercury (a toxic heavy metal) [31], omega-3 supplements have not been found to contain this contaminant because it is removed during processing and purification [32].
Dietary supplements can contain several different forms of omega-3s, including natural triglycerides, free fatty acids, ethyl esters, re-esterified triglycerides, and phospholipids [32-34]. Natural triglycerides are the form that occur naturally in fish oil, whereas ethyl esters are synthesized from natural triglycerides by replacement of the glycerol molecule of the triglyceride with ethanol. Re-esterified triglycerides are formed by the conversion of ethyl esters back to triglycerides. Omega-3s as re-esterified triglycerides, natural triglycerides, and free fatty acids have somewhat higher bioavailability than ethyl esters, but consumption of all forms significantly increases plasma EPA and DHA levels [33,35].
Formulations of omega-3 dietary supplements vary widely, so it is important to check product labels to determine the types and amounts of omega-3s in these products. The Dietary Supplement Label Database from the National Institutes of Health contains label information from many dietary supplements on the market that contain omega-3s.
Evidence that higher LC omega-3 levels are associated with a reduced risk of several chronic diseases, including coronary heart disease, suggests that many Americans could benefit from slightly higher intakes. However, classical essential fatty acid deficiency in healthy individuals in the United States is virtually nonexistent [5]. During periods of dietary-fat restriction or malabsorption accompanied by an energy deficit, the body releases essential fatty acids from adipose-tissue reserves. For this reason, clinical signs of essential fatty-acid deficiency are usually only found in patients receiving parenteral nutrition that lacks PUFAs. This was documented in case reports during the 1970s and 1980s [5], but all current enteral and parenteral feeding solutions contain adequate levels of PUFAs.
The potential health benefits of consuming omega-3s are the focus of a great deal of scientific research. By far, the majority of research has focused on EPA and DHA from foods (e.g., fish) and/or dietary supplements (e.g., fish oil) as opposed to ALA from plant-based foods.
Many observational studies link higher intakes of fish and other seafood with improved health outcomes. However, it is difficult to ascertain whether the benefits are due to the omega-3 content of the seafood (which varies among species), other components in the seafood, the substitution of seafood for other less healthful foods, other healthful behaviors, or a combination of these factors. Data from randomized clinical trials are needed to shed light on these questions.
This section focuses on areas of health in which omega-3s might be involved: CVD and its risk factors; infant health and neurodevelopment; cancer prevention; Alzheimer's disease, dementia, and cognitive function; age-related macular degeneration; dry eye disease; rheumatoid arthritis; and other conditions.
Results from the Japan EPA Lipid Intervention Study in 2007 supported the growing body of evidence that LC omega-3s reduce the risk of heart disease, especially in people with a history of coronary artery disease [56]. In this study, 18,645 people with hypercholesterolemia (total cholesterol of at least 251 mg/dL) with or without coronary artery disease received either 1.8 g/day EPA plus a statin or a statin only. After a mean of 4.6 years, the EPA group had 19% fewer major coronary events than the control group. The EPA group also experienced a significant reduction in rates of unstable angina and nonfatal coronary events but not in rates of sudden cardiac death or coronary death in comparison with the control group.
In an analysis of the primary prevention subgroup from this study (participants with no history of coronary artery disease), EPA supplementation had no significant effects on any outcome. However, for the secondary prevention subgroup (those with a history of coronary artery disease), the EPA group had a 28% reduction in the rate of unstable angina and a 19% reduction in that of major coronary events. A separate analysis of data from this study found that the EPA supplementation did not affect total stroke incidence but did reduce the risk of recurrent stroke by 20% in patients who had previously experienced a stroke [57].
Several subsequent clinical trials, however, had largely null findings [58-60]. For example, the 2012 Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial included 12,536 patients who had diabetes or a high risk of diabetes and a high risk of cardiovascular events. Supplementation with 1 g/day omega-3s (375 mg DHA and 465 mg EPA) for about 6 years significantly lowered triglyceride levels but had no effect on risk of myocardial infarction, stroke, or death from cardiovascular causes in comparison with placebo [59]. Similarly, in the 2010 Alpha Omega Trial, low-dose EPA and DHA supplementation (150 mg DHA and 226 mg EPA daily, supplied in a margarine) for 40 months also failed to reduce the rate of major cardiovascular events in comparison with placebo among 4,837 older men and women who had previously experienced a myocardial infarction and were receiving antihypertensive, antithrombotic, and/or lipid-lowering medications [60].
Scientists gained additional insight into the effects of omega-3s for the primary prevention of CVD, including in patients with diabetes, from two 2018 trials: VITamin D and OmegA-3 TriaL (VITAL) and A Study of Cardiovascular Events in Diabetes (ASCEND) [61,62]. Both trials compared the same 1 g/day omega-3 formulation (460 mg EPA and 380 mg DHA) with placebo, but in different populations. VITAL included 25,871 men age 50 and older and women age 55 and older with no previous heart attacks, strokes, or cancer, whereas ASCEND included 15,480 adults age 40 or older with diabetes but no evidence of CVD. VITAL also tested the omega-3 supplement with and without 2,000 International Units (IU)/day vitamin D.
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