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The Klotho protein is known to be involved in premature aging as an aging suppressor. Overexpression of the Klotho gene extends lifespan in mice and defective Klotho results in rapid aging and early death. Both the membrane and secreted forms of Klotho have biological activity. Klotho serves as a co-receptor for fibroblast growth factor (FGF), but it also functions as a humoral factor that regulates cell survival and proliferation, vitamin D metabolism, cardiac remodeling progresses to heart failure, and calcium and phosphate homeostasis that correlates with its affect on aging and may serve as a key factor in cancer development with potential tumor suppressor effect. Moreover, Klotho protects against several pathogenic processes in a FGF23-independent manner. These processes include cancer metastasis, vascular calcification, and renal fibrosis. This book covers the recent advances in Klotho research and discusses novel klotho-dependent mechanisms that are clinically relevant in aging and age-related diseases as well as the particular role of Klotho as a target for potential therapeutics.