To escape aging and aging-related disorders has been one of mankind's biggest 
dreams from the beginning of history. However, our knowledge regarding the 
molecular mechanisms of aging has been limited. 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 and heart. Importantly, the 
increased activation of calcium-dependent proteolysis occurs in the tissues of 
old mice together with the down regulation of klotho gene expression. What is 
Klotho protein required for and how does it act? In this review, I will discuss 
our working hypotheses on the biological roles and molecular functions of Klotho 
protein.