MOLECULAR ATLAS OF AGING. META-GROUP 1. GAS TRANSMITTERS AS A FUNDAMENTAL TARGET OF AGING: INTEGRATIVE APPROACH IN THE CONTEXT OF THE THEORY OF META-ENVIRONMENTS AND META-REGULATORS

Relevance. The global burden of age-associated diseases continues to grow, remaining the main cause of mortality and disability in developed countries. Modern medicine, which preserves the organo- and cell-centric paradigm, is not able to offer effective strategies for systemic rejuvenation and prevention of chronic diseases. In previous works, we proposed the theory of meta-environments — 20 distributed systems of the body (blood, endothelium, interstitium, extracellular matrix, glycocalyx, etc.), the pathology of which underlies up to 65% of the burden of chronic diseases, as well as the concept of ten meta-regulators — integrative control circuits that set the fundamental parameters of the operation of all meta-environments. Objective: To present gas transmitters (NO, H₂S, CO) as a zero level of molecular aging, i.e., a primary failure that triggers a cascade of systemic disorders, and to substantiate the need for their restoration through the system tuning of meta-regulators. Results. It has been shown that age-related decline in the production of NO, H₂S and CO begins in middle age, long before the clinical manifestations of aging. Each of the three gases performs unique but complementary functions: NO regulates endothelial function and vascular tone; H₂S provides mitochondrial protection, activates Nrf2-dependent antioxidant pathways, and inhibits cellular senescence through Sirt3/SOD2 signaling; CO exhibits cytoprotective and anti-inflammatory properties by modulating heme oxygenase activity and ROS production. Sirt6 has been found to prevent age-related decline in H₂S through the control of one-carbon metabolism, and mitochondrial-directed H₂S increases survival and preserves mitochondrial structure. Three gases form a single signaling network ("Gasotransmitter Trio Network"), and their synergistic protective effect is lost with aging. A multimodal approach (Quatotron technique) to the physiological restoration of the gasotransmitter network is proposed through the tuning of meta-regulators — redox regulator (No2), immuno-inflammatory (No7) and neuro-autonomic (No8) — without the introduction of exogenous donors. Conclusion. Gas transmitters are a fundamental target of aging. Their recovery through the systematic management of meta-regulators opens up new opportunities for the prevention of age-associated diseases and healthy longevity.