Polyunsaturated fatty acids (PUFAs) are categorized as n-6 PUFA and n-3 PUFA [1]. Long-chain n-3 PUFAs serve as precursors for endocannabinoids, oxylipins, and eicosanoids, which are important regulators of adipogenesis, inflammation, insulin action, and neurological function (Fig. 1) [2]. Since n-3 PUFA and n-6 PUFAs compete for enzymes responsible for the production of long-chain n-3 PUFAs, their balance influences the production of eicosanoids and oxylipins [3].

Among the n-3 PUFAs, alpha-linolenic acid (ALA; 18:3n3) is an essential fatty acid which cannot be synthesized in humans, and must therefore be obtained through diet [14]. Thus, a lack of ALA in the diet results in clinical symptoms of deficiency, such as scaly dermatitis and reduced growth [5]. In addition, ALA acts as a precursor for the long-chain n-3 PUFAs, eicosapentaenoic acid (EPA; 20:5n3) and docosahexaenoic acid (DHA; 22:6n3), through elongation and desaturation [6]. The major food sources for EPA and DHA are fatty fish, fish oils, and products fortified with fish oils, which help reduce the risk of cardiovascular disease (CVD) [7].

Because of their cardioprotective effects, dietary recommendations for EPA, DHA, and ALA have been issued globally. Due to limited evidence, Korea set a Dietary Reference Intake (DRI) for n-3 PUFA for the first time in 2020 [8]. This paper describes the process and evidence used to create the DRI of ALA and EPA + DHA for Koreans.

Various global organizations have suggested dietary recommendations for n-3 PUFA, including ALA, EPA, and DHA, mainly for reducing the risk of CVD and hypertriglyceridemia (Table 4) [42028]. Additionally, recommendations for DHA intake have been made for infants. The Institute of Medicine (IOM) of the National Academies has set an AI for ALA based on an intake that supports normal growth and neural development, with no nutrient deficiency. Although IOM of the National Academies had no DRI for EPA and DHA, the recommended macronutrient distribution range for n-3 PUFA is 0.1–0.2%. The American Heart Association, American Dietetic Association, and Dietitians of Canada recommend 500 mg/day EPA + DHA provided by 2 servings of fatty fish/week (1 serving is 112 g cooked) [10]. The Food and Agriculture Organization (2010) recommends 200 mg/day DHA or 300 mg/day DHA + EPA, and the World Health Organization recommends regular fish consumption (1 to 2 servings per week; each serving should provide an equivalent of 200–500 mg EPA + DHA) [11].

The EFSA proposes to set an AI for ALA of 0.5%E, based on the lowest estimated mean intakes of various population groups from numerous European countries, where overt deficiency symptoms of ALA are absent (Table 4) [20]. Based on cardiovascular considerations, the EFSA recommends an AI of 250 mg EPA + DHA for adults. When considering CVD, prospective epidemiological and dietary intervention studies indicate that oily fish consumption or dietary n-3 long-chain PUFA supplements (equivalent to 250 to 500 mg/day EPA + DHA) decreases the risk of mortality from CVD and sudden cardiac death. In infants, DHA intakes of 50 to 100 mg/day are found to be effective for visual function and considered to be adequate in the complementary feeding period. Thus, EFSA proposes an AI of 100 mg DHA for infants (> 6 mon of age) and young children below the age of 24 mon (Table 4).

In Japan, the AI of n-3 PUFA was established on the median intake determined from epidemiological studies that estimated the intake of healthy individuals [28]. For infants, AI was computed on the n-3 PUFA concentration present in human milk, and the amount consumed by the infant was used for calculation.

There is no convincing evidence that high intakes of ALA and n-3 PUFA have detrimental effects on health [420]. Supplemental intake of EPA and DHA combined at doses up to 5 g/day, supplemental intake of EPA alone up to 1.8 g/day, and supplemental intake of DHA up to 1,000 mg/day do not raise safety concerns for adults [11]. Thus, no global dietary recommendation is set for the UL of n-3 PUFA.

N-3 PUFA is known to exert cardioprotective effects via antiarrhythmic, anti-inflammatory, hematologic, and endothelial mechanisms [29]. In multiple prospective cohort studies, including the Physicians’ Health Study, a significant association was obtained between the dietary intake of n-3 PUFA and a lower risk of fatal CVD events, especially sudden cardiac death [3031323334].

In particular, a dose-dependent association was observed between very low to moderate intake and lower risk of sudden cardiac death, thereby indicating that consuming 1 to 2 fatty fish meals per week is associated with a 50% lower risk of sudden cardiac death, as compared with little or no seafood intake [3233]. In contrast, intake of n-3 PUFA was not found to be associated with a lower risk of sudden cardiac death in the Japanese population [3536]. Interestingly, the dietary intake of fish among Japanese was 3 to 4 times higher than most Western countries, and similar to the Korean consumption [37]. Current evidence suggests that the association between long-chain n-3 PUFA from seafood and the risk of sudden cardiac death may be not linear, but a modest consumption of seafood (1–2 servings per week) may be better, compared with little or no seafood intake.

Clinical trials have presented the benefits of both fish and n-3 PUFA supplements in CVD. The Diet and Reinfarction Trial reported that fish (or fish oil) consumption significantly reduces all-cause mortality and CVD in men who had recovered from a myocardial infarct [38]. The Gruppo Italiano per la Sperimentazione della Strepto-chinasi nell’Infarto Miocardico trial enrolled patients who had survived a myocardial infarct. They reported that supplementation of approximately 867 mg/day EPA + DHA (1:2 ratio, or about 289 mg EPA and 578 mg DHA) reduces the risk for CVD by 11–20%, and a 47% decrease in sudden cardiac death [39]. In the prospective randomized open-label trial of the Japan EPA Lipid Intervention Study, supplementation with 1,800 mg/day EPA resulted in a 19% relative reduction in major coronary events in patients who were taking statins [40]. Two very recent trials also reported some benefits of n-3 PUFA supplementation in high-risk patients. The REDUCE-IT trial involved patients with established CVD or with diabetes and other risk factors who were taking statins. They found that 4 g/day EPA lowered the risk of ischemic events, including cardiovascular death among patients with elevated TG levels despite the use of statins [41]. However, the STRENGTH trial determined the impact of 4 g/day EPA + DHA in patients receiving statins with mildly elevated triglyceride levels, and found no significant effect on major adverse cardiac events, including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, and unstable angina requiring hospitalization [42].

As a rule, subjects to whom the DRI is applied are healthy individuals or groups of healthy individuals, but the previous randomized clinical trials included only at risk of CVD and CVD populations. The VITAL trial is a study for the primary prevention of CVD in men aged 50 yrs or older and women aged 55 yrs or older in the US [43]. This study reported that supplementation of 1 g/day EPA + DHA did not affect a lower incidence of major cardiovascular events, but significantly reduced death from myocardial infarction and total CVD. Since there is insufficient evidence demonstrating the effect of n-3 PUFA on clinical CVD outcomes, particularly in healthy populations, dietary guidelines of n-3 PUFA for disease reduction cannot be recommended.

Global organizations have suggested dietary recommendations for n-3 PUFA, including ALA, EPA, or DHA, for the prevention of deficiency and reducing the risk of CVD. Based on the national health and nutrition survey, the AI for ALA and EPA + DHA were established for the first time for Koreans aged 1 yr and older. For Korean infants aged 0–11 mon, AI was based on the observed human maternal milk content of ALA and DHA. Future RCTs and other research on n-3 PUFA are required to establish the EAR, RNI, and recommendations for disease reduction, particularly for the healthy Korean population.