MOLECULAR ATLAS OF AGING. META-GROUP 14. COMPLEMENT SYSTEM: TWO-FACED JANUS, PROTECTING AND DESTROYING AT THE SAME TIME. INTEGRATIVE APPROACH IN THE CONTEXT OF THE THEORY OF META-ENVIRONMENTS AND META-REGULATORS

Relevance. The complement system is a cascade of more than 50 plasma and tissue proteins that provides rapid protection against pathogens, the removal of damaged cells, and the connection between innate and adaptive immunity. In youth, it works as a verified mechanism: it recognizes the foreign, activates the cascade, destroys the threat, and shuts down. However, with age, this mechanism fails. Chronic inflammation (inflamaging) keeps the complement system in a state of constant activation. Levels of key components — C3, C4, C5, C9 — increase. Anaphylatoxins C3a and C5a become chronically elevated. The membrane-attack complex C5b-9 accumulates in tissues. The complement system acquires a Janus two-face: on the one hand, it continues to protect — elevated levels of complement proteins in the elderly can suppress neuroinflammation and autoimmunity; On the other hand, its chronic activation becomes an independent driver of inflammation, destroying blood vessels, brain, kidneys and accelerating all age-related diseases. Aim. To present age-related dysregulation of the complement system as the fourteenth level of molecular aging, the main amplifier that turns local age-related damage into a systemic fire. To substantiate the need for systemic restoration of the regulatory balance of complement through the tuning of meta-regulators. Results. It was shown that systemic complement activation occurs with age: the levels of C1q, C4, C3, C5 and C9, as well as anaphylatoxins C3a and C5a and the soluble membrane attack complex sC5b-9 increase. The level of expression of complement proteins correlates not with chronological age, but with the "actionable-time aging", determining the rate of inflammatory aging. Activation occurs mainly through the classical pathway, which indicates the accumulation of immune complexes. Anaphylatoxins C3a and C5a bind to receptors on a variety of cells, triggering inflammation, chemotaxis, neuronal damage, and inducing a senescent phenotype through epigenetic mechanisms (DNA methylation). The membrane-attacking complex C5b-9 damages the endothelium, neurons, and epithelium. At the same time, the complement system demonstrates a paradoxical two-facedness: its hyperactivation enhances pathologies, but increased complement levels in the elderly can suppress neuroinflammation and autoimmunity. A multimodal approach (the Quatotron method) to the physiological restoration of the regulatory balance of complement through the reduction of systemic inflammation and the restoration of endogenous regulatory mechanisms has been proposed. Conclusion. The complement system is the fourteenth level of molecular aging, the main amplifier that turns local damage into a systemic inflammatory fire. Its systemic recovery through the control of meta-regulators opens up new opportunities for the prevention of age-associated diseases and healthy longevity.