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α-Klotho regulates age-associated vascular mineralization and lifespan in zebrafish

Singh, Ajeet and Sosa, Maria and Fang, Jian and Shanmukhappa, Shiva and Hubaud, Alexis and Fawcett, Caroline and Molind, Gregory and Tsai, Ting and Capodieci, Paola and Wetzel, Kristie and Sanchez, Ellen and Wang, Guangliang and Coble, Matthew and Tang, Wenlong and Cadena, Samuel and 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

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