aKlotho regulates age-associated vascular calcification and lifespan in zebrafish

The hormone aKlotho regulates lifespan in mice as knockouts die early of what appears to be accelerated aging due to hyperphosphatemia and soft tissue calcification. In contrast, its overexpression increases lifespan. Given the severe mouse phenotype, we generated zebrafish mutants for aklotho 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 five months of age. There is calcification of vessels throughout the body, most dramatically in the outflow tract of the heart, the bulbus arteriosus (BA). This calcification is associated with ectopic activation of osteoclast differentiation pathways. These findings suggest that the gradual loss of aKlotho found in normal aging might give rise to ectopic calcification.