Singh, Ajeet, Sosa, Maria, Fang, Jian, Shanmukhappa, Shiva, Hubaud, Alexis, Fawcett, Caroline, Molind, Gregory, Tsai, Ting, Capodieci, Paola, Wetzel, Kristie, Sanchez, Ellen, Wang, Guangliang, Coble, Matthew, Tang, Wenlong, Cadena, Samuel, Fishman, Mark and Glass, David (2019) α-Klotho regulates age-associated vascular mineralization and lifespan in zebrafish. Cell reports, 28 (11). pp. 2767-2776. ISSN 22111247

Abstract

α-Klotho is an anti-aging hormone regulating mineral homeostasis together with Fibroblast Growth Factor-23 (FGF23) in mammals. Cellular and molecular mechanisms through which these signals regulate age-related conditions, such as vascular mineralization remain intriguing. It is not known if aging mechanisms controlled by α-Klotho/FGF23 signaling are evolutionarily conserved. To this end, we generated knockouts carrying homozygous mutations in α-klotho and fgf23 in zebrafish. Both knockouts display an adult-onset decline in body condition and behavior, and an early-onset morbidity. Bulbus arteriosus, the outflow tract of zebrafish heart shows extensive mineralization in the mutants. RNA-seq analysis of kidney, heart and gills shows an ectopic activation of bone-remodeling pathway, extracellular matrix remodeling factors osteoclast differentiation and inflammation in the vasculature. Taken together, these findings indicate a conserved role of α-Klotho/FGF23 signaling in regulating vertebrate life span and identify molecular mechanisms underlying vascular mineralization.

Item Type:	Article
Date Deposited:	25 Sep 2019 00:45
Last Modified:	25 Sep 2019 00:45
URI:	https://oak.novartis.com/id/eprint/39169