MOLECULAR ATLAS OF AGING. META-GROUP 17. METABOLITES: A FUEL MIXTURE THAT CHANGES ITS COMPOSITION EVERY YEAR. INTEGRATIVE APPROACH IN THE CONTEXT OF META-MEDIUM THEORY AND META-REGULATORS

Relevance. Metabolites are not just "fuel". Glucose, fatty acids, amino acids, and ketone bodies are signaling molecules, modulators of gene expression, substrates for synthesis, and building blocks. Their balance determines whether a cell will thrive or wither. Aging represents a fundamental metabolic rearrangement: metabolite levels change dramatically, creating a metabolic environment conducive to cellular aging and age-associated diseases. Glucose becomes more variable, insulin resistance increases. Fatty acid oxidation decreases. Branched-chain amino acids (BCAAs) accumulate, becoming a marker and driver of cellular aging. Ketone bodies, especially β-hydroxybutyrate, play a dual role: they protect proteostasis, but their depletion with age deprives the brain and muscles of alternative fuel. Aim. To present age-related dysregulation of metabolites as the seventeenth level of molecular aging — the final common path through which most age-related disorders are realized. To substantiate the need for systemic restoration of metabolic homeostasis through the tuning of meta-regulators. Results. Two key metabolic shifts have been shown to occur with age: early ketogenesis (around 40 years of age) and gluconeogenesis (around 60 years of age). The triglyceride-glucose index (TyG) is positively correlated with the acceleration of biological aging, and insulin resistance is associated with distal steps of the insulin signaling cascade and mitochondrial ROS. BCAA levels increase with age, and BCAA metabolism disorders are not a consequence of, but a cause of, cellular senescence and the SASP phenotype. Long-chain acylcarnitines (C18:1, C14:1) are markers of age-related decline in muscle quality. β-hydroxybutyrate, the level of which decreases with age, acts as an endogenous regulator of proteostasis by interacting with misfolded proteins, including amyloid β. A multimodal approach (Quatotron method) to the physiological restoration of metabolic homeostasis through the optimization of nutrition, physical activity and restoration of mitochondrial function is proposed. Conclusion. Metabolites are the seventeenth level of molecular aging, the final common pathway through which most age-related disorders are realized. Their systemic recovery through the control of meta-regulators opens up new opportunities for the prevention of age-associated diseases and healthy longevity.