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Science 309 (5742): 1829-1833

Copyright © 2005 by the American Association for the Advancement of Science

Suppression of Aging in Mice by the Hormone Klotho

Hiroshi Kurosu,1 Masaya Yamamoto,1 Jeremy D. Clark,1 Johanne V. Pastor,1 Animesh Nandi,1 Prem Gurnani,1 Owen P. McGuinness,3 Hirotaka Chikuda,4 Masayuki Yamaguchi,4 Hiroshi Kawaguchi,4 Iichiro Shimomura,5 Yoshiharu Takayama,2 Joachim Herz,2 C. Ronald Kahn,6 Kevin P. Rosenblatt,1 Makoto Kuro-o1*

Abstract: A defect in Klotho gene expression in mice accelerates the degeneration of multiple age-sensitive traits. Here, we show that overexpression of Klotho in mice extends life span. Klotho protein functions as a circulating hormone that binds to a cell-surface receptor and represses intracellular signals of insulin and insulin-like growth factor 1 (IGF1), an evolutionarily conserved mechanism for extending life span. Alleviation of aging-like phenotypes in Klotho-deficient mice was observed by perturbing insulin and IGF1 signaling, suggesting that Klotho-mediated inhibition of insulin and IGF1 signaling contributes to its anti-aging properties. Klotho protein may function as an anti-aging hormone in mammals.

1 Department of Pathology, University of Texas (UT) Southwestern Medical Center at Dallas, 5323 Harry Hines Bouleuvard, Dallas, TX 75390-9072, USA.
2 Department of Molecular Genetics, University of Texas (UT) Southwestern Medical Center at Dallas, 5323 Harry Hines Bouleuvard, Dallas, TX 75390-9072, USA.
3 Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, 702 Light Hall, Nashville, Tennessee 37232-0615, USA.
4 Department of Sensory and Motor System Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-8655, Japan.
5 Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
6 Research Division, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA.

Published online 25 August 2005;

Include this information when citing this paper.

* To whom correspondence should be addressed. E-mail: makoto.kuro-o{at}

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Longitudinal Evaluation of Retinal Ganglion Cell Function and IOP in the DBA/2J Mouse Model of Glaucoma.
M. Saleh, M. Nagaraju, and V. Porciatti (2007)
Invest. Ophthalmol. Vis. Sci. 48, 4564-4572
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Tissue-specific Expression of betaKlotho and Fibroblast Growth Factor (FGF) Receptor Isoforms Determines Metabolic Activity of FGF19 and FGF21.
H. Kurosu, M. Choi, Y. Ogawa, A. S. Dickson, R. Goetz, A. V. Eliseenkova, M. Mohammadi, K. P. Rosenblatt, S. A. Kliewer, and M. Kuro-o (2007)
J. Biol. Chem. 282, 26687-26695
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