Augmented Wnt signaling in a mammalian model of accelerated aging

Hongjun Liu; Maria M. Fergusson; Rogerio M. Castilho; Jie Liu; Liu Cao; Jichun Chen; Daniela Malide; Ilsa I. Rovira; Daniel Schimel; Calvin J. Kuo; J. Silvio Gutkind; Paul M. Hwang; Toren Finkel

doi:10.1126/science.1143578

Augmented Wnt signaling in a mammalian model of accelerated aging

Hongjun Liu, Maria M. Fergusson, Rogerio M. Castilho, Jie Liu, Liu Cao, Jichun Chen, Daniela Malide, Ilsa I. Rovira, Daniel Schimel, Calvin J. Kuo, J. Silvio Gutkind, Paul M. Hwang, Toren Finkel

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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.

Original language	English (US)
Pages (from-to)	803-806
Number of pages	4
Journal	Science
Volume	317
Issue number	5839
DOIs	https://doi.org/10.1126/science.1143578
State	Published - Aug 10 2007
Externally published	Yes

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title = "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.",

author = "Hongjun Liu and Fergusson, {Maria M.} and Castilho, {Rogerio M.} and Jie Liu and Liu Cao and Jichun Chen and Daniela Malide and Rovira, {Ilsa I.} and Daniel Schimel and Kuo, {Calvin J.} and Gutkind, {J. Silvio} and Hwang, {Paul M.} and Toren Finkel",

year = "2007",

month = aug,

day = "10",

doi = "10.1126/science.1143578",

language = "English (US)",

volume = "317",

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T1 - Augmented Wnt signaling in a mammalian model of accelerated aging

AU - Liu, Hongjun

AU - Fergusson, Maria M.

AU - Castilho, Rogerio M.

AU - Liu, Jie

AU - Cao, Liu

AU - Chen, Jichun

AU - Malide, Daniela

AU - Rovira, Ilsa I.

AU - Schimel, Daniel

AU - Kuo, Calvin J.

AU - Gutkind, J. Silvio

AU - Hwang, Paul M.

AU - Finkel, Toren

PY - 2007/8/10

Y1 - 2007/8/10

N2 - 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.

AB - 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.

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JO - Science

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Augmented Wnt signaling in a mammalian model of accelerated aging

Abstract

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