Regulation of multiple ageing-like phenotypes by inducible klotho gene expression in klotho mutant mice

• Published in: Mechanisms of ageing and development 2005-12, Vol.126 (12), p.1274-1283
• Main Authors: Masuda, Hiroaki, Chikuda, Hirotaka, Suga, Tatsuo, Kawaguchi, Hiroshi, Kuro-o, Makoto
• Format: Article
• Language: English
• Subjects: Ageing; Aging; Animals; Arteriosclerosis - genetics; Biological and medical sciences; Bone Diseases, Metabolic - genetics; Crosses, Genetic; Development. Metamorphosis. Moult. Ageing; Female; Fundamental and applied biological sciences. Psychology; Gene Expression; Genetic Techniques; Glucuronidase; Hypogonadism - genetics; Immunohistochemistry; Klotho; Male; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Knockout; Mice, Mutant Strains; Mice, Transgenic; Models, Genetic; Mutation; Phenotype; Ribonucleases - metabolism; Testosterone - metabolism; Time Factors; Tissue Distribution; Transgenic mice; Vertebrates: anatomy and physiology, studies on body, several organs or systems
• ISSN: 0047-6374; 0304-3940; 1872-6216
• DOI: 10.1016/j.mad.2005.07.007

Mice carrying a loss-of-function mutation in the klotho gene ( KL −/− mice) develop ageing-like symptoms around 4 weeks after birth and suffer from multiple age-related disorders observed in humans, including osteoporosis, arteriosclerosis, and pulmonary emphysema. The klotho gene encodes a single-pass transmembrane protein that may function in signaling pathways that suppress ageing. To investigate the ability of Klotho to regulate the development of ageing-related disorders, we established an inducible Klotho expression system using KL −/− mice carrying an exogenous klotho gene fused to the mouse metallothionein-I promoter, in which Klotho expression was dependent on zinc water feeding. We demonstrate that many advanced ageing-like KL −/− phenotypes were restored to normal whenever Klotho expression was induced. Conversely, decreasing Klotho expression in these rescued KL −/− mice induced several ageing-like KL −/− phenotypes. Our data indicate that Klotho may be effective in the treatment of multiple age-related disorders and is essential for maintaining animals free of these disorders.