May have weak glycosidase activity towards glucuronylated steroids. However, it lacks essential active site Glu residues at positions 241 and 874, suggesting it may be inactive as a glycosidase in vivo. May be involved in the regulation of calcium and phosphorus homeostasis by inhibiting the synthesis of active vitamin D. Essential factor for the specific interaction between FGF23 and FGFR1. The Klotho peptide generated by cleavage of the membrane-bound isoform may be an anti-aging circulating hormone which would extend life span by inhibiting insulin/IGF1 signaling. a beta-D-glucuronoside + H2O = an alcohol + D-glucuronate Inhibited by D-saccharic acid 1,4-lactone and taurocholic acid. Optimum pH is 5.5. Homodimer. Interacts with FGF23 and FGFR1. Isoform 1 shedding leads to a soluble peptide. Membrane-bound protein is present in distal renal tubules, inner ear, ependymal cells of brain choroid plexus, elongating spermatids and mature oocytes (at protein level). Soluble peptide is present in serum (100 pM) and cerebrospinal fluid. Expressed strongly in kidney, moderately in brain choroid plexus, and at low levels in pituitary, placenta, skeletal muscle, urinary bladder, aorta, pancreas, testis, ovary, colon, thyroid gland and adipocytes. Not expressed in the embryo. Expressed in the kidney of newborns. Induced by 1,25-dihydroxyvitamin D(3) in kidney. Down-regulated by angiotensin II and up-regulated by statins through modulation of the RhoA pathway in epithelial cells (in vitro). Isoform 1 (but not isoform 2) is up-regulated by thyroid hormone in adipocytes. Contains 2 glycosyl hydrolase 1 regions. However, the first region lacks the essential Glu active site residue at position 241, and the second one lacks the essential Glu active site residue at position 874. N-glycosylated. Mice display a syndrome resembling to human aging, with short lifespan, infertility, atherosclerosis, skin atrophy, osteoporosis and emphysema. They have various metabolic abnormalities, including increased insulin sensitivity and decreased insulin production. Mice overexpressing Kl have increased resistance to insulin and IGF1, a lifespan extended of more than 20%, and generate fewer offspring. Predominates over the secreted form by more than 10 times in all tissues examined. Belongs to the glycosyl hydrolase 1 family. Klotho subfamily. The thread of life - Issue 65 of December 2005