MOLECULAR ATLAS OF AGING. META-GROUP 3. PRO-INFLAMMATORY CYTOKINES: A CHRONIC FIRE THAT BURNS THE BODY FROM THE INSIDE OUT. INTEGRATIVE APPROACH IN THE CONTEXT OF META-MEDIUM THEORY AND META-REGULATORS

Background. Chronic, low-intensity systemic inflammation that increases with age even in the absence of an overt infection — a phenomenon known as inflammaging — is one of the most active areas of research in modern gerontology. In previous works, we proposed the theory of 20 meta-environments — distributed systems of the body, 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 all meta-environments. Aim. To present pro-inflammatory cytokines (IL-6, TNF-α, IL-1β) as the third level of molecular aging, a chronic inflammatory fire that occurs after energy collapse and loss of regenerative signals, but then becomes an independent driver of aging. To substantiate the need to restore cytokine balance through systemic tuning of meta-regulators. Results. It was shown that IL-6, TNF-α and IL-1β form an autocatalytic inflammatory network supported by senescence cells via SASP (senescence-associated secretory phenotype). IL-6 is a major marker and driver of aging associated with cardiovascular disease, sarcopenia, and cognitive decline. TNF-α is a key mediator of muscle proteolysis, insulin resistance, and neuroinflammation. IL-1β, activated via the NLRP3 inflammasome, serves as an "igniter" of the cascade. With age, the threshold for activation of the inflammasome decreases, and the number of DAMP signals increases, leading to chronic hyperproduction of IL-1β. Chronic DAMP-TLR-MyD88-NF-κB signaling supports the production of all three cytokines simultaneously, creating a self-sustaining inflammatory circuit. A multimodal approach (the Quatotron technique) to the physiological restoration of cytokine balance through the tuning of immuno-inflammatory (No7), redox- (No2) and neuro-autonomic (No8) meta-regulators has been proposed. Conclusion. Pro-inflammatory cytokines are the third level of molecular aging. Their restoration through the systemic management of meta-regulators opens up new opportunities for the prevention of age-associated diseases and healthy longevity.