Editors' ChoiceAging

Complement Is Bad for Aging

See allHide authors and affiliations

Science Signaling  12 Jun 2012:
Vol. 5, Issue 228, pp. ec162
DOI: 10.1126/scisignal.2003300

The transcriptional regulator β-catenin, which is stabilized by activation of the Wnt pathway, functions in development and adult tissue homeostasis, as well as contributes to various diseases and aging-related conditions. Noting that human serum can activate Wnt signaling, Naito et al. isolated the complement component C1q as an activator of the β-catenin reporter (TOPFLASH) and as a molecule that stabilized β-catenin when applied to cultured cells. C1q was more abundant in serum and tissues from aged mice. Binding assays with the cysteine-rich domain of the Wnt receptor Frizzled showed that C1q bound to this receptor. Activation of the β-catenin pathway was reduced in cultured cells exposed to serum depleted of C1q or in tissues from mice deficient for C1q. Furthermore, the aging-associated increase in Wnt signaling was absent in C1q-deficient mice. C1q associates with and activates two proenzymes: C1r and C1s. C1r and C1s were not present in the purified C1q that was added exogenously to cultured cells but were produced by HepG2 cells and released into the culture medium. Knockdown of these two enzymes or addition of inhibitors of C1s blocked activation of Wnt signaling by exogenously applied C1q. Because deletion of the extracellular domain of the Wnt co-receptor LRP6 constitutively activates the Wnt pathway, Naito et al. tested whether LRP6 was a target for C1s-mediated cleavage and found that C1s cleaved the LRP6 extracellular domain in vitro and when C1q was added to cultured cells. The cleavage fragment was detected in mouse serum and was increased in the serum of aged mice. Addition of C1q, Wnt, or serum from aged mice inhibited satellite muscle cell proliferation and promoted fibroblast proliferation and production of collagen. Treating injured skeletal muscle in young mice with C1q impaired tissue repair and promoted fibrosis. Inhibition of C1s or deficiency of C1q promoted tissue regeneration after muscle injury in aged mice. Thus, binding of C1q to Frizzled activates C1s, which cleaves and activates the co-receptor LRP6, resulting in activation of the Wnt pathway. Increased abundance of C1q in circulation leading to activation of the Wnt pathway may contribute to the aging-related decline in tissue regenerative capacity.

A. T. Naito, T. Sumida, S. Nomura, M.-L. Liu, T. Higo, A. Nakagawa, K. Okada, T. Sakai, A. Hashimoto, Y. Hara, I. Shimizu, W. Zhu, H. Toko, A. Katada, H. Akazawa, T. Oka, J.-K. Lee, T. Minamino, T. Nagai, K. Walsh, A. Kikuchi, M. Matsumoto, M. Botto, I. Shiojima, I. Komuro, Complement C1q activates canonical Wnt signaling and promotes aging-related phenotypes. Cell 149, 1298–1313 (2012). [Online Journal]

Stay Connected to Science Signaling