We recently developed a unique short lifespan mouse strain in which a single gene mutation caused multiple aging-related disorders and identified the responsible gene as klotho. The most characteristic phenotypes seem to be caused by abnormalities in calcium metabolism. Furthermore the klotho gene is expressed principally in the important tissues for calcium homeostasis such as distal tubule cells of the kidney, choroid plexus in the brain, and the main cells of the parathyroid gland. Klotho plays a critical role for the regulation of calcium and phosphorus homeostasis by negatively regulating the synthesis of active vitamin D. The deficiency of the klotho gene results in degradation of cells by the activation of calcium dependent proteolysis in kidney, lung, heart and other tissues. Importantly, the increased activation of calcium- dependent proteolysis occurs in tissues of old mice together with the down regulation of klotho gene expression.