αKlotho Regulates Age-Associated Vascular Calcification and Lifespan in Zebrafish

Abstract

Summary: The hormone αKlotho regulates lifespan in mice, as knockouts die early of what appears to be accelerated aging due to hyperphosphatemia and soft tissue calcification. In contrast, the overexpression of αKlotho increases lifespan. Given the severe mouse phenotype, we generated zebrafish mutants for αklotho as well as its binding partner fibroblast growth factor-23 (fgf23). Both mutations cause shortened lifespan in zebrafish, with abrupt onset of behavioral and degenerative physical changes at around 5 months of age. There is a calcification of vessels throughout the body, most dramatically in the outflow tract of the heart, the bulbus arteriosus (BA). This calcification is associated with an ectopic activation of osteoclast differentiation pathways. These findings suggest that the gradual loss of αKlotho found in normal aging might give rise to ectopic calcification. : αKlotho regulates mineral homeostasis and affects lifespans in mammals. Singh et al. show that a loss of αklotho in zebrafish results in reduced lifespans and vascular calcification in the outflow tract of the heart. Vascular calcification is associated with an upregulation of bone remodeling pathways and osteoclast differentiation. Keywords: αKlotho, Klotho, FGF23, aging, calcification, cardiovascular system, zebrafish