Zebrafish Group, Chemical Biology and Therapeutics, Novartis Institutes for Biomedical Research, 181 Massachusetts Avenue, Cambridge, MA 02139, USA.
Preclinical Safety, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
Cell Rep. 2019 Sep 10;28(11):2767-2776.e5. doi: 10.1016/j.celrep.2019.08.013.
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 激素调节小鼠的寿命，敲除小鼠由于高磷血症和软组织钙化而早期死亡，似乎是由于加速衰老。相比之下，αKlotho 的过表达会延长寿命。鉴于严重的小鼠表型，我们还生成了 αklotho 及其结合伴侣成纤维细胞生长因子 23（fgf23）的斑马鱼突变体。这两种突变都会导致斑马鱼寿命缩短，大约在 5 个月大时，行为和退行性身体变化突然出现。全身的血管发生钙化，在心脏的流出道、动脉球（BA）中最为明显。这种钙化与破骨细胞分化途径的异位激活有关。这些发现表明，正常衰老过程中逐渐丧失 αKlotho 可能导致异位钙化。
