Omega-3 EPA/DHA — Essential Marine Fatty Acids
Omega-3 fatty acids, specifically EPA and DHA, are essential polyunsaturated fats primarily sourced from marine life. They are critical for maintaining cellular membrane integrity, resolving systemic inflammation, and supporting cardiovascular and cognitive health, making them foundational to longevity protocols.
Mechanism of Action
EPA and DHA are incorporated into cell membrane phospholipids, modulating membrane fluidity and the function of embedded receptors. They act as precursors to specialized pro-resolving mediators (SPMs), including resolvins, protectins, and maresins, which actively resolve inflammation. Omega-3s also reduce the production of pro-inflammatory eicosanoids derived from arachidonic acid by competing for cyclooxygenase (COX) and lipoxygenase (LOX) enzymes. Additionally, they lower hepatic triglyceride synthesis by downregulating SREBP-1c and upregulating PPAR-alpha, which enhances fatty acid beta-oxidation.
Human Trial Evidence
Omega-3s are among the most extensively studied molecules in human clinical trials. The REDUCE-IT trial demonstrated that 4 g/day of highly purified EPA (icosapent ethyl) significantly reduced major adverse cardiovascular events in high-risk patients. However, the VITAL trial showed that 1 g/day of combined EPA/DHA did not significantly reduce the primary endpoints of major cardiovascular events or cancer in a general population, though it did reduce total myocardial infarction. Evidence for cognitive decline prevention remains mixed and highly dose-dependent.
Dosing Protocol
1–4 g/day of combined EPA and DHA is the most studied range in humans. Prescription forms (e.g., icosapent ethyl) are used at 4 g/day for severe hypertriglyceridemia and cardiovascular risk reduction. Best taken with a fat-containing meal to maximize absorption. Phospholipid forms (krill oil) may have higher bioavailability than ethyl esters.
Safety & Contraindications
Generally well tolerated. High doses (>3 g/day) may increase the risk of bleeding, particularly in individuals taking anticoagulants or antiplatelet medications. Recent trials have also noted a dose-dependent increased risk of incident atrial fibrillation with high-dose supplementation. Gastrointestinal side effects, such as fishy burps or mild diarrhea, are common but often mitigated by taking the supplement with meals or using enteric-coated formulations. Prescription forms require medical supervision.