title: 1,25-Dihydroxyvitamin D and Klotho: A Tale of Two Renal Hormones Coming of Age.
abstract: 1,25-Dihydroxyvitamin D3 (1,25D) is the renal metabolite of vitamin D that signals through binding to the nuclear vitamin D receptor (VDR). The ligand-receptor complex transcriptionally regulates genes encoding factors stimulating calcium and phosphate absorption plus bone remodeling, maintaining a skeleton with reduced risk of age-related osteoporotic fractures. 1,25D/VDR signaling exerts feedback control of Ca/PO4 via regulation of FGF23, klotho, and CYP24A1 to prevent age-related, ectopic calcification, fibrosis, and associated pathologies. Vitamin D also elicits xenobiotic detoxification, oxidative stress reduction, neuroprotective functions, antimicrobial defense, immunoregulation, anti-inflammatory/anticancer actions, and cardiovascular benefits. Many of the healthspan advantages conferred by 1,25D are promulgated by its induction of klotho, a renal hormone that is an anti-aging enzyme/coreceptor that protects against skin atrophy, osteopenia, hyperphosphatemia, endothelial dysfunction, cognitive defects, neurodegenerative disorders, and impaired hearing. In addition to the high-affinity 1,25D hormone, low-affinity nutritional VDR ligands including curcumin, polyunsaturated fatty acids, and anthocyanidins initiate VDR signaling, whereas the longevity principles resveratrol and SIRT1 potentiate VDR signaling. 1,25D exerts actions against neural excitotoxicity and induces serotonin mood elevation to support cognitive function and prosocial behavior. Together, 1,25D and klotho maintain the molecular signaling systems that promote growth (p21), development (Wnt), antioxidation (Nrf2/FOXO), and homeostasis (FGF23) in tissues crucial for normal physiology, while simultaneously guarding against malignancy and degeneration. Therefore, liganded-VDR modulates the expression of a "fountain of youth" array of genes, with the klotho target emerging as a major player in the facilitation of health span by delaying the chronic diseases of aging.
authors.affiliation: Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, Arizona, USA. Electronic address: haussler@email.arizona.edu.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Haussler
authors.affiliation: Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, Arizona, USA.
authors.forename: G Kerr
authors.initials: GK
authors.lastname: Whitfield
authors.affiliation: Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, Arizona, USA.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Haussler
authors.affiliation: School of Mathematical and Natural Sciences, Arizona State University, Glendale, Arizona, USA.
authors.forename: Marya S
authors.initials: MS
authors.lastname: Sabir
authors.affiliation: School of Mathematical and Natural Sciences, Arizona State University, Glendale, Arizona, USA.
authors.forename: Zainab
authors.initials: Z
authors.lastname: Khan
authors.affiliation: School of Mathematical and Natural Sciences, Arizona State University, Glendale, Arizona, USA.
authors.forename: Ruby
authors.initials: R
authors.lastname: Sandoval
authors.affiliation: Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, Arizona, USA; School of Mathematical and Natural Sciences, Arizona State University, Glendale, Arizona, USA.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Jurutka
mesh_terms: D000818:Animals; D000089703:Fibroblast Growth Factor-23; D005786:Gene Expression Regulation / Q000502:physiology; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000090265:Klotho Proteins; D015398:Signal Transduction / Q000502:physiology; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C000717427:FGF23 protein, human; D014807:Vitamin D; C097949:1,25-dihydroxyvitamin D; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: Antifibrosis; Calcium; Detoxification; Ectopic calcification; Fibroblast growth factor-23; Neuroprotection; Phosphate; Prosocial behavior; Transcriptional regulation; Vitamin D receptor