Omega-3

Omega-3 polyunsaturated fatty acids include alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). ^[1] EPA and DHA are found in oily fish and fish oil supplements, whereas ALA is derived from plants. ^{[2] [3]} Because the body does not efficiently produce EPA and DHA from marine sources, it is necessary to obtain adequate amounts through fish and fish-oil products. ^[4]

EPA and DHA partly inhibit many aspects of inflammation, including leucocyte chemotaxis, adhesion molecule expression, and production of pro-inflammatory cytokines. ^[2] EPA and DHA give rise to anti-inflammatory and inflammation-resolving mediators called resolvins, protectins, and maresins. ^[2] Mechanisms underlying their anti-inflammatory action include altered cell membrane phospholipid composition and inhibition of activation of the pro-inflammatory transcription factor nuclear factor kappa B, reducing expression of inflammatory genes. ^[2]

The most extensive Cochrane systematic assessment to date included 86 randomized controlled trials with 162,796 participants and found high-certainty evidence of little or no effect of increasing long-chain omega-3 on all-cause mortality. ^[3] That review concluded that increasing long-chain omega-3 slightly reduces the risk of coronary heart disease mortality and events and reduces serum triglycerides, with triglycerides reduced by about 15% in a dose-dependent way. ^[3] Treatment of at-risk patients with omega-3 formulations has produced disparate results in large clinical trials: low-dose EPA/DHA mixtures routinely failed to prevent cardiovascular events in the STRENGTH and OMEMI trials, whereas EPA-only formulations significantly reduced cardiovascular events in high-risk patients in JELIS, REDUCE-IT, and RESPECT-EPA. ^[5] A meta-analysis incorporating 48 longitudinal studies with 103,651 participants found moderate-to-high-level evidence that dietary intake of omega-3 fatty acids could lower the risk of all-cause dementia or cognitive decline by about 20%. ^[6] A systematic review and meta-analysis of 90 randomized controlled trials found that omega-3 supplementation was relatively safe, with higher odds of diarrhea, dysgeusia, and bleeding tendency but no report of definite omega-3-related serious adverse events.

Elevated omega-3 fatty acid levels are associated with lower incident risk for cardiovascular disease, yet the ability of supplementation to reduce cardiovascular risk has been highly inconsistent across trials. ^{[5] [8]} The inconsistent cardiovascular outcomes may be attributable to variations in dosage, formulation, and composition, and event reduction with EPA appears related to achieved EPA blood levels beyond triglyceride lowering. ^[9] Omega-3 fatty acids have been linked to healthy aging throughout life, with EPA and DHA associated with cardiovascular function and Alzheimer's disease. ^[4]