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Augmented Wnt Signaling in a Mammalian Model of Accelerated Aging
Hongjun Liu,1Maria M Fergusson,1*Rogerio M. Castilho,2*Jie Liu,1Liu Cao,1Jichun Chen,3Daniela Malide,4Ilsa I. Rovira,1Daniel Schimel,5Calvin J. Kuo,6J. Silvio Gutkind,2Paul M. Hwang,1Toren Finkel1
The contribution of stem and progenitor cell dysfunction anddepletion in normal aging remains incompletely understood. Weexplored this concept in the Klotho mouse model of acceleratedaging. Analysis of various tissues and organs from young Klothomice revealed a decrease in stem cell number and an increasein progenitor cell senescence. Because klotho is a secretedprotein, we postulated that klotho might interact with othersoluble mediators of stem cells. We found that klotho boundto various Wnt family members. In a cell culture model, theWnt-klotho interaction resulted in the suppression of Wnt biologicalactivity. Tissues and organs from klotho-deficient animals showedevidence of increased Wnt signaling, and ectopic expressionof klotho antagonized the activity of endogenous and exogenousWnt. Both in vitro and in vivo, continuous Wnt exposure triggeredaccelerated cellular senescence. Thus, klotho appears to bea secreted Wnt antagonist and Wnt proteins have an unexpectedrole 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.
To whom correspondence should be addressed. E-mail: finkelt{at}nih.gov
Nuclear envelope defects cause stem cell dysfunction in premature-aging mice.
J. Espada, I. Varela, I. Flores, A. P. Ugalde, J. Cadinanos, A. M. Pendas, C. L. Stewart, K. Tryggvason, M. A. Blasco, J. M.P. Freije, et al. (2008)
J. Cell Biol.
181, 27-35
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Phosphate Metabolism. Meeting Report from the 29th Annual Meeting of the American Society for Bone and Mineral Research: September 16-19, 2007 in Honolulu, Hawaii, USA.
G. J. Strewler (2007)
IBMS BoneKEy
4, 342-345
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To whom correspondence should be addressed. E-mail: 
