Eicosapentaenoic acid in emotional well-being and brain aging: evidence boundaries, clinical heterogeneity, and a peripheral-to-central resolution-biology framework.

Emotional well-being and brain aging are increasingly understood as overlapping outcomes shaped by inflammatory, neuroimmune, vascular, and metabolic processes. This structured critical narrative review evaluates eicosapentaenoic acid (EPA) as a mechanistically distinct omega-3 fatty acid while explicitly separating EPA-specific evidence from mixed omega-3, fish-intake, and biomarker-status evidence. Particular attention is given to EPA-derived specialized pro-resolving mediators, especially E-series resolvins, and to the hypothesis that EPA may influence brain-relevant outcomes through peripheral inflammatory resolution, endothelial signaling, blood-brain barrier function, neurovascular pathways, and the peripheral immune-brain axis. The current evidence is heterogeneous and differs substantially in directness. EPA-predominant evidence is most developed for depressive symptoms, whereas brain-aging and imaging evidence is often based on fish intake, total omega-3 exposure, or red blood cell EPA+DHA status rather than isolated EPA intervention. This review therefore interprets such evidence as hypothesis-generating rather than as proof of EPA-specific effects. Differences in EPA dose, EPA:DHA ratio, formulation, placebo choice, duration, background diet, baseline omega-3 status, baseline inflammation, clinical phenotype, concomitant treatment, and endpoint selection are examined as potential sources of heterogeneity. The review proposes a testable peripheral-to-central resolution-biology framework for future biomarker-informed research, not a validated clinical decision pathway or universal intervention. EPA is best evaluated as a candidate research exposure whose relevance depends on biological context, verified exposure, inflammatory phenotype, and mechanism-aligned outcomes.