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Science 317 (5839): 803-806

Copyright © 2007 by the American Association for the Advancement of Science

Augmented Wnt Signaling in a Mammalian Model of Accelerated Aging

Hongjun Liu,1 Maria M Fergusson,1* Rogerio M. Castilho,2* Jie Liu,1 Liu Cao,1 Jichun Chen,3 Daniela Malide,4 Ilsa I. Rovira,1 Daniel Schimel,5 Calvin J. Kuo,6 J. Silvio Gutkind,2 Paul M. Hwang,1 Toren Finkel1{dagger}

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.

1 Cardiology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA.
2 Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD 20892, USA.
3 Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA.
4 Light Microscopy Core Facility, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA.
5 Mouse Imaging Facility, NIH, Bethesda, MD 20892, USA.
6 Division of Hematology, Stanford University School of Medicine, Stanford, CA 94305, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: finkelt{at}nih.gov

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