Complement C1q Activates Canonical Wnt Signaling and Promotes Aging-Related Phenotypes

SummaryWnt 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. We here report that complement C1q activates canonical Wnt signaling and promotes aging-associated decline in tissue regeneration. Serum C1q concentration is increased with aging, and Wnt signaling activity is augmented during aging in the serum and in multiple tissues of wild-type mice, but not in those of C1qa-deficient mice. C1q activates canonical Wnt signaling by binding to Frizzled receptors and subsequently inducing C1s-dependent cleavage of the ectodomain of Wnt coreceptor low-density lipoprotein receptor-related protein 6. Skeletal muscle regeneration in young mice is inhibited by exogenous C1q treatment, whereas aging-associated impairment of muscle regeneration is restored by C1s inhibition or C1qa gene disruption. Our findings therefore suggest the unexpected role of complement C1q in Wnt signal transduction and modulation of mammalian aging.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (227 K)Download as PowerPoint slideHighlights► The C1q complement protein is an activator of canonical Wnt signaling ► C1q activates canonical Wnt signaling by inducing cleavage of LRP6, a Wnt coreceptor ► Serum C1q levels increase with aging ► C1q-dependent Wnt signaling impairs the regenerative capacity of skeletal muscles