MOLECULAR ATLAS OF AGING. META-GROUP 2. PRO-INFLAMMATORY CYTOKINES (IL-6, TNF-α, IL-1β). INTEGRATIVE APPROACH IN THE CONTEXT OF META-MEDIUM THEORY AND META-REGULATORS

Relevance. Age-associated tissue degeneration is the result not only of the accumulation of damage, but also of the loss of regenerative signals. 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 the operation of all meta-environments. Aim. To present the signaling proteins of rejuvenation (GDF11, IGF-1, VEGF, oxytocin) as the second level of molecular aging — the architects of regeneration, whose age-related degradation deprives the body of the ability to systematically repair tissues. To substantiate the need for their restoration through the systemic tuning of meta-regulators. Results. Four key signaling proteins have been shown to form an integrative network that controls regeneration, angiogenesis, neurogenesis, and cellular homeostasis. GDF11, the level of which correlates with cardiovascular events and dementia, slows the aging of excitatory neurons through p21 repression and protects endothelial cells from oxidative stress through the activation of autophagy. IGF-1, which exhibits paradoxical duality (decreased signaling prolongs life, but its deficiency leads to sarcopenia and neurodegeneration), prevents cellular senescence through the activation of mitophagy. VEGF, whose signaling is suppressed with age through an increase in soluble trap receptors, is critical for the maintenance of vasculature and neurovascular health. Oxytocin, the level of which decreases with age due to hypermethylation in the hypothalamus, enhances neurogenesis and synaptic plasticity, and its combination with an Alk5 inhibitor (OT+A5i) prolongs the life of old mice by 73%. A multimodal approach (Quatotron technique) to physiological restoration of the signaling network through the tuning of regenerative-niche (No4), metabolome- (No6) and neuro-autonomic (No8) meta-regulators is proposed. Conclusion. Signaling proteins of rejuvenation are the second level of molecular aging. Their restoration through the systemic control of meta-regulators opens up new opportunities for the prevention of age-associated diseases and healthy longevity.