Aging is one of the most important unsolved problems in biomedical science. My laboratory is focused on understanding various functional aspects of the klotho gene, which is involved in the regulation of aging processes in mammals. A defect in klotho gene expression in the mouse results in a syndrome resembling human aging, including a shortened life span, infertility, arteriosclerosis, skin atrophy, muscle atrophy, premature thymic involution, osteoporosis, and pulmonary emphysema. In contrast, Klotho-overexpressing transgenic mice enjoy longer life span than wild-type mice. Thus, the klotho gene may function as an aging suppressor gene. The klotho gene encodes either a single-pass transmembrane protein or a secreted protein that shares sequence similarity with beta-glucosidase enzymes.
Our recent studies have provided evidence that Klotho regulates fibroblast growth factor (FGF) signaling. The transmembrane form of Klotho binds to FGF receptors and is required for FGF23 to bind and activate FGF receptors. FGF23 is a bone-derived hormone that acts on the kidney to inhibit phosphate reabsorption and vitamin D biosynthesis. Interestingly, FGF23-deficient mice exhibit aging-like phenotypes identical with those observed in Klotho-deficient mice, suggesting that abnormal mineral metabolism may accelerate aging processes in mammals.
We have demonstrated that beta-Klotho, a protein homologous to Klotho, also binds to FGF receptors and is required for metabolic activity of FGF19 and FGF21. FGF19 is secreted from intestine upon feeding and acts on liver to suppress bile acid synthesis and secretion. FGF21 is secreted from liver upon fasting and acts on adipocytes to promote lypolysis. Thus, the klotho gene family has evolved in the regulation of metabolic activity of these endocrine FGFs.
Klotho is a multi-functional protein. In addition to its involvement in FGF signaling, Klotho also participates in the regulation of insulin/IGF-1 signaling, resistance to oxidative stress, and ion channel activity in the kidney. Studies on Klotho and beta-Klotho are thus expected to provide new mechanistic insights into the regulation of metabolism, human aging, and age-related diseases.
RESEARCH INTERESTS
Molecular Biology of Aging
RECENT PUBLICATIONS
Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima Y, "Mutation of the mouse klotho gene leads to a syndrome resembling ageing." Nature, 390:45-51, November 1997
Kurosu H, et al., "Suppression of Aging in Mice by the Hormone Klotho" Science, 309:1829-1833, August 2005
Yamamoto M, et al., "Regulation of oxidative stress by the anti-aging hormone Klotho" J Biol Chem, 280:38029-38034, September 2005
Kurosu H et al., "Regulation of fibroblast growth factor-23 signaling by Klotho" J Biol Chem, 281:6120-6123, March 2006
Ogawa, Y., Kurosu, H., Yamamoto, M., Nandi, A., Rosenblatt, K. P., Goetz, R., Eliseenkova, A. V., Mohammadi, M., Kuro-o, M., "Beta-Klotho is required for metabolic activity of fibroblast growth factor 21" Proc Natl Acad Sci U S A, 104:7432-7437, May 2007
SIGNIFICANT PUBLICATIONS
Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima Y, "Mutation of the mouse klotho gene leads to a syndrome resembling ageing." Nature, 390:45-51, November 1997
Kurosu H, et al., "Suppression of Aging in Mice by the Hormone Klotho" Science, 309:1829-1833, August 2005
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