Regulation of multiple ageing-like phenotypes by inducible klotho gene expression in klotho mutant mice.
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.
Masuda
Hiroaki
H
Department of Pathology, The University of Texas Southwestern Medical Center at Dallas, 6000 Harry Hines Blvd., Dallas, TX 75390-9072, USA.
Chikuda
Hirotaka
H
Suga
Tatsuo
T
Kawaguchi
Hiroshi
H
Kuro-o
Makoto
M
D000375:Aging; D000818:Animals; D001161:Arteriosclerosis / Q000235:genetics; D001851:Bone Diseases, Metabolic / Q000235:genetics; D003433:Crosses, Genetic; D005260:Female; D015870:Gene Expression; D005821:Genetic Techniques; D005966:Glucuronidase; D007006:Hypogonadism / Q000235:genetics; D007150:Immunohistochemistry; D000090265:Klotho Proteins; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008957:Models, Genetic; D009154:Mutation; D010641:Phenotype; D012260:Ribonucleases / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution
D008565:Membrane Proteins; D013739:Testosterone; D012260:Ribonucleases; D005966:Glucuronidase; D000090265:Klotho Proteins