Augmented Wnt Signaling in a Mammalian Model of Accelerated Aging

作者：Hongjun Liu, Marı́a M. Fergusson, ROGERIO MORAES CASTILHO, Jie Liu, Liu Cao, Jichun Chen, Daniela A. Malide, Ilsa I. Rovira, Daniel M. Schimel, Calvin Jay Kuo, Jorge Silvio Gutkind, Paul M. Hwang, Toren Finkel · 发表于：Science · 年份：2007 · DOI：10.1126/science.1143578 · 被引用次数：756 · 研究领域：Genetic Syndromes and Imprinting、Hair Growth and Disorders、Parathyroid Disorders and Treatments

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.