Pathophysiological Role of Chronic Inflammation in Ageing-Associated Diseases

Abstract

Chronic low-grade systemic inflammation in the absence of overt infection is a hallmark of aged tissues and age-related disorders. Although chronic inflammation is primarily mediated by the local production of inflammatory mediators, recent studies suggest that blood-borne factors may also directly regulate the ageing process. In this chapter, we describe an unexpected role of complement C1q in canonical Wnt signalling and age-related phenotypes. Consistent with a previous report demonstrating that canonical Wnt signalling is augmented in various aged tissues, serum and tissue levels of C1q increase with age. C1q directly binds to Frizzled with high affinity and recruits C1r and C1s to form the C1 complex. Activated C1s in the C1 complex cleave the extracellular domain of LRP6, resulting in constitutive activation of canonical Wnt signalling. This newly identified C1q-canonical Wnt pathway promotes ageing-associated impairment of skeletal muscle regeneration and hypertensive arterial remodeling. These findings demonstrate that C1q promotes age-related phenotypes in a complement pathway-independent manner. The results also provide a molecular link between age-related disorders and a critical component of the classical complement pathway involved in chronic inflammation.