1,25-Dihydroxyvitamin D and Klotho: A Tale of Two Renal Hormones Coming of Age

Mark R. Haussler, G. Kerr Whitfield, Carol A. Haussler, Marya S. Sabir, Zainab Khan, Ruby Sandoval, Peter W. Jurutka

Research output: Chapter in Book/Report/Conference proceedingConference contribution

41 Scopus citations


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.

Original languageEnglish (US)
Title of host publicationVitamin D Hormone, 2016
EditorsGerald Litwack
PublisherAcademic Press Inc.
Number of pages66
ISBN (Print)9780128048245
StatePublished - 2016

Publication series

NameVitamins and Hormones
ISSN (Print)0083-6729


  • Antifibrosis
  • Calcium
  • Detoxification
  • Ectopic calcification
  • Fibroblast growth factor-23
  • Neuroprotection
  • Phosphate
  • Prosocial behavior
  • Transcriptional regulation
  • Vitamin D receptor

ASJC Scopus subject areas

  • Physiology
  • Endocrinology


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