DOI: 10.1126/science.1143578. Augmented Wnt Signaling in a Mammalian Model of Accelerated Aging

Augmented Wnt Signaling in a Mammalian Model of Accelerated Aging

10.1126/science.1143578

Crossref journal-article

American Association for the Advancement of Science (AAAS)

Science (221)

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.

Bibliography

Liu, H., Fergusson, M. M., Castilho, R. M., Liu, J., Cao, L., Chen, J., Malide, D., Rovira, I. I., Schimel, D., Kuo, C. J., Gutkind, J. S., Hwang, P. M., & Finkel, T. (2007). Augmented Wnt Signaling in a Mammalian Model of Accelerated Aging. Science, 317(5839), 803â806.

Authors 13

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

References 24 Referenced 629

10.1038/nature04958
10.1038/36285
N. M. Xiao, Y. M. Zhang, Q. Zheng, J. Gu, Chin. Med. J. (Engl.)117, 742 (2004). / Chin. Med. J. (Engl.) (2004)
Materials and methods are available as supporting material on Science Online.
10.1111/j.1087-0024.2004.09313.x
10.1126/science.1092436
10.1038/nm1328
10.1146/annurev.cellbio.22.010305.104357
10.1016/j.cell.2005.01.028
10.1242/dev.126.20.4557
10.1172/JCI28551
10.1677/joe.0.1640239
10.1126/science.1114245
10.1074/jbc.C500457200
10.1096/fj.05-5432fje
10.1038/nature05315
10.1038/nature05659
10.1158/0008-5472.CAN-04-2623
10.1101/gad.1051603
10.1038/ni1387
10.1038/ni1381
10.1126/science.1144090
10.1126/science.1112766
We thank R. Moon for the Wnt (TOP/FOP) reporter constructs M. Kuro-o for generating the klotho mice and H. Dietz for providing the klotho mice. The TOPGAL mouse was generated by E. Fuchs and kindly provided by Y. Yang. We also thank J. G. Kang for technical help. This work was supported by Intramural NIH funds (T.F.) a grant from the Ellison Medical Foundation (T.F.) and an NIH 1 R01 DK069989-01 to C.J.K.

Dates

Type	When
Created	18 years ago (Aug. 9, 2007, 4:39 p.m.)
Deposited	1 year, 7 months ago (Jan. 10, 2024, 4:38 a.m.)
Indexed	24 minutes ago (Aug. 30, 2025, 8:40 p.m.)
Issued	18 years ago (Aug. 10, 2007)
Published	18 years ago (Aug. 10, 2007)
Published Print	18 years ago (Aug. 10, 2007)

Funders 0

None

BibTeX

@article{Liu_2007, title={Augmented Wnt Signaling in a Mammalian Model of Accelerated Aging}, volume={317}, ISSN={1095-9203}, url={http://dx.doi.org/10.1126/science.1143578}, DOI={10.1126/science.1143578}, number={5839}, journal={Science}, publisher={American Association for the Advancement of Science (AAAS)}, author={Liu, Hongjun and Fergusson, Maria M and Castilho, Rogerio M. and Liu, Jie and Cao, Liu and Chen, Jichun and Malide, Daniela and Rovira, Ilsa I. and Schimel, Daniel and Kuo, Calvin J. and Gutkind, J. Silvio and Hwang, Paul M. and Finkel, Toren}, year={2007}, month=aug, pages={803–806} }

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