The complement system was first identified as a heat-sensitive factor in fresh serum that ‘complemented’ the effects of specific antibody in the lysis of bacteria and red blood cells.The serum complement system, which represents a chief component of innate immunity, not only participates in inflammation but also acts to enhance the adaptive immune response. Specific activation of complement via innate recognition proteins or secreted antibody releases cleavage products that interact with a wide range of cell surface receptors found on myeloid, lymphoid and stromal cells. This intricate interaction among complement activation products and cell surface receptors provides a basis for the regulation of both B and T cell responses.
Complement C1q is an activator of Wnt signaling. C1q activates canonical Wnt signaling by binding to Fz receptors and subsequently inducing C1s-dependent cleavage of the ectodomain of LRP6. Serum C1q concentration and the expression of C1q in various tissues are increased with aging, which are associated with increased Wnt signaling activity in serum and in multiple tissues during aging.
Wnt signaling plays critical roles in development of various organs and pathogenesis of many diseases, and augmented Wnt signaling has recently been implicated in mammalian aging and aging-related phenotypes. Recent studies have revealed a role of Wnt signaling in the regulation of mammalian aging. Wnt/b-catenin signaling is augmented in a mouse model of accelerated aging, and inhibition of canonical Wnt signaling reverses the aging-associated impairment of skeletal muscle regeneration. Moreover, this age-related activation of Wnt signaling was attributed to the substance(s) in the serum that binds to the extracellular cysteine-rich domain (CRD) of Fz. However, because Wnt proteins tightly bind to the cell surface and/or extracellular matrix and are thought to act in a short-range manner, the substance(s) in the serum that activates Wnt signaling was assumed to be distinct from classical Wnt proteins.