MOLECULAR ATLAS OF AGING. META-GROUP 19. NEUROTRANSMITTERS AND THEIR PRECURSORS: THE VOICE OF THE AUTONOMIC NERVOUS SYSTEM, DISTORTED BY AGE. INTEGRATIVE APPROACH IN THE CONTEXT OF META-MEDIUM THEORY AND META-REGULATORS

Relevance. Neurotransmitters and their precursors are the main communication channel between the brain and the body, providing adaptive regulation of all organs and systems through the autonomic nervous system. Adrenaline, norepinephrine, dopamine, serotonin, acetylcholine, GABA, and glutamate — trace amounts of them circulate in the blood and affect vascular tone, heart rate, intestinal motility, immune response, and cellular aging. With age, this balance is disrupted: the sympathetic nervous system becomes chronically overactive, the parasympathetic nervous system weakens, receptor sensitivity decreases, and precursor metabolism switches towards pro-inflammatory pathways. Norepinephrine in plasma increases, but its receptors lose sensitivity; serotonin increases in platelets, increasing vasoconstriction; tryptophan switches to the kynurenin pathway, depleting the serotonin pool; tyrosine accumulates, but its conversion to catecholamines slows down; GABA and glutamate are out of balance. Aim. To present age-related dysregulation of neurotransmitters and their precursors as the nineteenth level of molecular aging, i.e., a distortion of the voice of the autonomic nervous system, which turns adaptive signals into chaotic noise, disrupting the functioning of all organs and accelerating aging. To substantiate the need for systemic restoration of neurotransmitter balance through the tuning of meta-regulators. Results. It has been shown that with age, the concentration of norepinephrine in plasma increases, reflecting chronic sympathetic hyperactivation, while its receptor sensitivity decreases (desensitization of β-adrenoceptors). The peripheral level of serotonin in platelets increases, which increases vasoconstriction and contributes to hypertension, and its antioxidant function decreases. The kynurenine/tryptophan ratio increases with age, reflecting the activation of the inflammatory pathway and being a biomarker of fragility and mortality. The level of DOPA (dopamine precursor) significantly increases with age, indicating a slowdown in its conversion to dopamine. Monoamine oxidase (MAO) activity increases, accelerating the degradation of neurotransmitters and generating ROS. A multimodal approach (the Quatotron method) to the physiological restoration of neurotransmitter balance through the regulation of precursors, enzymes, receptor sensitivity and autonomic tone has been proposed. Conclusion. Neurotransmitters and their precursors are the nineteenth level of molecular aging, the main communication channel whose failure makes all other signals distorted and blocks systemic rejuvenation. Their systemic recovery through the control of meta-regulators opens up new opportunities for the prevention of age-associated diseases and healthy longevity.