Molecular Atlas of Aging. Meta-Group 12. Lipid Mediators and Eicosanoids: Conductors of Inflammation That Lose the Score. Integrative Approach in the Context of Meta-Medium Theory and Meta-Regulators

Relevance. Lipid mediators and eicosanoids are the conductors of the orchestra of inflammation and its resolution. They control the immune response, vascular tone, pain sensitivity, and tissue homeostasis. In youth, this orchestra plays smoothly: pro-inflammatory eicosanoids (prostaglandins, leukotrienes) quickly extinguish the infection, and then specialized pro-resolving mediators (SPMs) — resolvins, protectins, maresins — restore tissues. With age, the score is lost: pro-inflammatory mediators become chronically excessive, and resolving mediators become deficient. Inflammation ceases to resolve and becomes chronic. Aim. To present the age-related imbalance of lipid mediators and eicosanoids as the twelfth level of molecular aging — a switch between acute inflammation and chronic inflammation, turning the protective reaction into a destructive process that underlies most age-related diseases. To substantiate the need for systemic restoration of lipid balance through the tuning of meta-regulators. Results. Aging has been shown to be associated with a significant decrease in the SPM:LT ratio in various organs, including the spleen, which contributes to increased inflammation and senescent cell accumulation. In old mice, there is a decrease in the level of resolvin D1 (RvD1) in the spleen compared to young controls, and treatment with RvD1 suppresses the expression of senescence markers and SASP in macrophages and reduces spleen fibrosis. With age, the resolution of intestinal inflammation through the eicosanoid-immune-microbiotic axis is impaired: pharmacological inhibition of eicosanoid synthesis or blockade of the EP4 receptor eliminates age-related impaired resolution of inflammation. Prostaglandin E2 (PGE2) acts as a key mediator of age-related diseases, participating in neuroinflammation in Alzheimer's disease, sarcopenia, osteoporosis, and type 2 diabetes through dysregulation of biosynthesis, metabolism, and receptor-mediated signaling. Resolvin E1 (RvE1) and Marezin 1 (MaR1) reverse senescence-induced changes in fibroblasts, restoring their regenerative function. In the myocardium of patients with heart failure, increased expression of SPM synthesis enzymes and the LGR6 receptor was revealed, indicating activation of compensatory mechanisms. A multimodal approach (Quatotron technique) to physiological restoration of lipid balance through optimization of substrates, enzymes, and signaling pathways has been proposed. Conclusion. Lipid mediators and eicosanoids are the twelfth level of molecular aging — a switch between protective and destructive inflammation. Their systemic recovery through the control of meta-regulators opens up new opportunities for the prevention of age-associated diseases and healthy longevity.