Immunomodulatory Effects of Polyunsaturated ω-3 Fatty Acids in Old Patients With Polyvascular Disease: a Double-blind, Randomized, Controlled, Factorial 2x2 Trial ("OMEGA3" Study)

Medical Background

Declines in immune function with age and an imbalance between pro- and anti-inflammatory mechanisms lead to a high incidence of infectious and cardiovascular disease among older individuals. ω-3 polyunsaturated fatty acids (EPA and DHA) are anti-inflammatory and represent a substrate of potent mediators, termed specialized proresolving mediators (SPMs). Specialized proresolving mediators (SPMs) are known to limit excessive neutrophil and monocyte migration and stimulate the uptake of apoptotic neutrophils and microbes, thus promoting the resolution of inflammation. Increases in SPM concentrations are linked with decreased uptake of oxidized low-density lipoproteins . Phagocyte functional decline with senescence has been well established. Aged macrophages exhibit functional changes such as compromised chemotaxis, impaired ability to phagocytose pathogenic bacteria, reduced expression of MHC class II molecules and decreased capacity for antigen presentation. However, how phagocyte dysfunction changes with the acquisition of a senescence phenotype is currently unknown.

Some components, such as polyunsaturated fatty acids (n-3 PUFAs), also prevent the induction of senescence and atherosclerosis but also have extensive immunomodulatory effects. The supplementation of fish oil (4 g n-3 PUFA/d) for 3 weeks in healthy older subjects induced dynamic reshaping of human CD4+ T cells and plasma membrane organization. Additionally, 5 days of n-3 PUFA supplementation was associated with an increase in the phagocytic activity of peripheral blood monocytes and neutrophils. The utility of n-3 PUFA-enriched supplements in the prevention of cardiovascular disease has been highlighted. Recently, the EVAPORATE study revealed that the combination of icosapentethyl, a highly purified form of eicopentaenoic acid ethyl ester, and statins might increase the regression of low-attenuation plaque volume on multidetector computed tomography compared with a placebo over 18 months. Specialized proresolving mediators (SPMs), bioactive lipids derived from n-3 PUFAs and leading to the resolution of inflammation, seem to be potential biomarkers for determining the immune regulatory potential of n-3 PUFAs. While native and mox LDL induce the release of inflammatory cytokines and mediators derived from docosahexaenoic acid (DHA) resolvin D1 from young endothelial cells, the effect of mox-LDL in senescent cells on SPM production is unknown. Eicosapentaenoic acid (EPA) and DHA significantly reduce H2O2-induced senescence-associated β-galactosidase activity in cells (by 31% and 22%, respectively). The consumption of fish oil, the main source of n-3 PUFAs, increases phagocytosis and the population of CD4+ and CD8+ lymphocytes in forty-five older healthy Caucasian women.

Drug profile

The substances evaluated will be polyunsaturated fatty acids such as eicosapentaenoic acid (EPA or C20: 5ω-3) and docosahexaenoic acid (DHA or C22: 6 ω-3).