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.