Klotho.
The klotho gene was identified as an "aging-suppressor" gene in mice that accelerates aging when disrupted and extends life span when overexpressed. It encodes a single-pass transmembrane protein and is expressed primarily in renal tubules. The extracellular domain of Klotho protein is secreted into blood and urine by ectodomain shedding. The two forms of Klotho protein, membrane Klotho and secreted Klotho, exert distinct functions. Membrane Klotho forms a complex with fibroblast growth factor (FGF) receptors and functions as an obligate co-receptor for FGF23, a bone-derived hormone that induces phosphate excretion into urine. Mice lacking Klotho or FGF23 not only exhibit phosphate retention but also display a premature-aging syndrome, revealing an unexpected link between phosphate metabolism and aging. Secreted Klotho functions as a humoral factor that regulates activity of multiple glycoproteins on the cell surface, including ion channels and growth factor receptors such as insulin/insulin-like growth factor-1 receptors. Potential contribution of these multiple activities of Klotho protein to aging processes is discussed.
Kuro-o
Makoto
M
Department of Pathology, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9072, USA. makoto.kuro-o@utsouthwestern.edu
D000375:Aging / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001842:Bone and Bones / Q000502:physiology; D015220:Calcium Channels / Q000502:physiology; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000172:deficiency / Q000502:physiology; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D007668:Kidney / Q000502:physiology; D000090265:Klotho Proteins; D008136:Longevity / Q000502:physiology*; D051379:Mice; D018384:Oxidative Stress; D010710:Phosphates / Q000502:physiology / Q000652:urine; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D050916:TRPV Cation Channels / Q000502:physiology; D014807:Vitamin D / Q000502:physiology
D015220:Calcium Channels; C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D010710:Phosphates; D017468:Receptors, Fibroblast Growth Factor; D050916:TRPV Cation Channels; C492240:Trpv5 protein, mouse; D014807:Vitamin D; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins