A unique short lifespan mouse strain was developed in which a single gene mutation caused multiple aging-related disorders. The gene responsible has been identified as the klotho gene. The most characteristic phenotypes of klotho mice seem caused by abnormalities in calcium metabolism. Klotho plays a critical role in the regulation of calcium and phosphorus homeostasis by negatively regulating active vitamin D synthesis. A defect in klotho gene expression causes the independent impairment both of osteoblast and osteoclast differentiation, leading to low-turnover osteopenia. In humans, two klotho gene polymorphisms were significantly associated with bone density in aged postmenopausal women, but not in pre-menopausal or younger postmenopausal women in two genetically distinct racial populations. The klotho gene is predominantly expressed in the kidney and the expression level of klotho RNA was shown to be greatly reduced in the kidneys of chronic renal failure (CRF) patients. Angiotensin II induced renal klotho down-regulation through angiotensin type 1 receptor-dependent but pressor-independent events, while dietary P(i) restriction induced klotho expression. The down-regulation of the renal klotho gene could increase renal damage induced by angiotensin II, while klotho gene induction could have therapeutic possibilities in treating angiotensin II-induced kidney damage.