The inner fire: the shifting paradigm of complement system in aging

The complement system (CS) is a key component of innate immune system that could be activated through pathways converging in activating C3 to cell-specific targeting. Besides its first-line defense against infection, CS serves as a bridge to adaptive immunity by modulating T-cell function and enhancing B-cell-mediated responses, thereby strongly contributing to the overall immune homeostasis. While deficiencies of CS components often result in increased susceptibility to infection, dysregulation of CS activation is associated with autoimmunity and chronic inflammation. Given the ability of the CS to rapidly respond to pathogen-associated molecular patterns along with its redundancy, it also relies on strictly regulated checkpoints to prevent unintended host damage. During aging, the CS undergoes a relevant shift: in elderly, the persistent low-grade inflammation leads to the continuous activation of CS that in turn contributes to the sustained chronic inflammation ("inflammaging"): CS thus might correlate with the increasingly well-known age-related degenerative diseases. However, during aging, CS might act like a two-faced Janus: on one hand, CS drives persistent chronic inflammation by acting as a mediator of inflammation; on the other, elevated levels of CS proteins may act as immunomodulatory agents and prevent disorders associated with CS abnormalities, such as neuroinflammation and autoimmune diseases. This review synthesizes the emerging evidence of potential protective role of the aging-related CS dysregulation in elderly. We explore how CS in elderly people modulates a sophisticated network in immunosenescence, neuroinflammation and autoimmunity. Understanding this "switch" of CS during aging will be essential for designing novel strategies for therapeutic modulation of CS-driven inflammation and damage while preserving its potential role in defense and repair.