Augmented Wnt Signaling in a Mammalian Model of Accelerated Aging

Abstract

The contribution of stem and progenitor cell dysfunction and depletion in normal aging remains incompletely understood. We explored this concept in the Klotho mouse model of accelerated aging. Analysis of various tissues and organs from young Klotho mice revealed a decrease in stem cell number and an increase in progenitor cell senescence. Because klotho is a secreted protein, we postulated that klotho might interact with other soluble mediators of stem cells. We found that klotho bound to various Wnt family members. In a cell culture model, the Wnt-klotho interaction resulted in the suppression of Wnt biological activity. Tissues and organs from klotho-deficient animals showed evidence of increased Wnt signaling, and ectopic expression of klotho antagonized the activity of endogenous and exogenous Wnt. Both in vitro and in vivo, continuous Wnt exposure triggered accelerated cellular senescence. Thus, klotho appears to be a secreted Wnt antagonist and Wnt proteins have an unexpected role in mammalian aging.

Tumor Suppressor Activity of Klotho in Breast Cancer Is Revealed by Structure–Function Analysis

“…Several studies demonstrated a critical role for residues within klotho's putative active site in mediating some of the activities of klotho. Thus, mutations of these residues abolished its effect on TRPV5 and on the renal phosphate transporter NaPi-2a (11,32,33), but did not affect its ability to inhibit Wnt signaling (34). Our studies indicate that these amino acids are not required for klotho tumor suppressor activity.…”

“…Thus, it was demonstrated that KL1 is essential and sufficient to mediate the antiinflammatory activity of klotho in senescent cells, whereas KL2 did not show any such activity (35). Similarly, KL1 is mandatory and sufficient to inhibit Wnt signaling by klotho, whereas KL2 is devoid of this activity (34). Our data suggest that klotho tumor suppressor activities are KL1 dependent and that KL2 by itself cannot significantly inhibit proliferation of breast cancer cells.…”

“…These data provide an indirect support to the hypothesis that inhibition of the IGF-1 pathway is a major mediator of klotho activities in breast cancer. Interestingly, the same klotho region required for tumor suppression is the one required for the inhibition of the IGF-1 pathway and of Wnt signaling (10,34). Thus, it is possible that a common mechanism that involves inhibition of the Wnt and IGF-1 signaling pathways is responsible to klotho tumor suppressor activities.…”

“…Mutations of klotho putative active sites abolished its effect on TRPV5 and on the renal phosphate transporter NaPi-2a (11,32,33), but did not affect its ability to inhibit Wnt signaling (34). To our knowledge, the role of these residues in mediating klotho tumor suppressor activities has not been studied yet.…”

Xeno-Klotho Inhibits Parathyroid Hormone Signaling

“…Parathyroid hormone (PTH) induces 25-hydroxyvitamin D 3 1a-hydroxylase (1-OH) to generate 1,25VD. (7) Klotho binds to various proteins, including TRPCs, WNT, and receptors for VEGF, FGF, TGF-b, and IGF, (8)(9)(10)(11)(12)(13)(14) to elicit a wide variety of biological responses, including inhibition of fibrosis, epithelial-mesenchymal transition and cancer metastasis, and modulation of endothelial function and insulin action, as well as calcium-phosphate metabolism.…”