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

Mech Ageing Dev. 2005 Dec;126(12):1274-83. doi: 10.1016/j.mad.2005.07.007. Epub 2005 Sep 6.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging*
  • Animals
  • Arteriosclerosis / genetics
  • Bone Diseases, Metabolic / genetics
  • Crosses, Genetic
  • Female
  • Gene Expression
  • Genetic Techniques
  • Glucuronidase
  • Hypogonadism / genetics
  • Immunohistochemistry
  • 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

Substances

  • Membrane Proteins
  • Testosterone
  • Ribonucleases
  • Glucuronidase
  • klotho protein