Molecular Basis of Klotho: From Gene to Function in Aging

The discovery of the Klotho (KL) gene, which was originally identified as a putative aging-suppressor gene, has generated tremendous interest and has advanced understanding of the aging process. In mice, the overexpression of the KL gene extends the life span, whereas mutations to the KL gene shorten the life span. The human KL gene encodes the alpha-Klotho protein, which is a multifunctional protein that regulates the metabolism of phosphate, calcium, and vitamin D. alpha-Klotho also may function as a hormone, although the alpha-Klotho receptor(s) has not been found. Point mutations of the KL gene in humans are associated with hypertension and kidney disease, which suggests that alpha-Klotho may be essential to the maintenance of normal renal function. Three alpha-Klotho protein types with potentially different functions have been identified: a full-length transmembrane alpha-Klotho, a truncated soluble alpha-Klotho, and a secreted alpha-Klotho. Recent evidence suggests that alpha-Klotho suppresses the insulin and Wnt signaling pathways, inhibits oxidative stress, and regulates phosphatase and calcium absorption. In this review, we provide an update on recent advances in the understanding of the molecular, genetic, biochemical, and physiological properties of the KL gene. Specifically, this review focuses on the structure of the KL gene and the factors that regulate KL gene transcription, the key sites in the regulation of alpha-Klotho enzyme activity, the alpha-Klotho signaling pathways, and the molecular mechanisms that underlie alpha-Klotho function. This current understanding of the molecular biology of the alpha-Klotho protein may offer new insights into its function and role in aging.