To escape aging and aging-related disorders has been one of mankind's biggest dreams from the beginning of history. However, our knowledge regarding the molecular mechanisms of aging has been limited. We recently developed a unique short lifespan mouse strain in which a single gene mutation caused multiple aging-related disorders and identified the responsible gene as klotho. The most characteristic phenotypes seem to be caused by abnormalities in calcium metabolism. Furthermore, the klotho gene is expressed principally in the important tissues for calcium homeostasis such as distal tubule cells of the kidney, choroid plexus in the brain, and the main cells of the parathyroid gland. Klotho plays a critical role for the regulation of calcium and phosphorus homeostasis by negatively regulating the synthesis of active Vitamin D. The deficiency of the klotho gene results in degradation of cells by the activation of calcium-dependent proteolysis in kidney, lung and heart. Importantly, the increased activation of calcium-dependent proteolysis occurs in the tissues of old mice together with the down regulation of klotho gene expression. What is Klotho protein required for and how does it act? In this review, I will discuss our working hypotheses on the biological roles and molecular functions of Klotho protein.

中文翻译：

---

Klotho：衰老的根本调节剂。

从历史开始，摆脱衰老和与衰老相关的疾病一直是人类最大的梦想之一。但是，我们对衰老的分子机制的认识是有限的。我们最近开发了一种独特的短寿命小鼠品系，其中单个基因突变引起多种衰老相关疾病，并将负责的基因鉴定为klotho。最典型的表型似乎是由钙代谢异常引起的。此外，klotho基因主要在钙稳态的重要组织中表达，例如肾脏的远端小管细胞，脑中的脉络丛和甲状旁腺的主要细胞。Klotho通过负调节活性维生素D的合成，在调节钙和磷稳态中起着关键作用。klotho基因的缺陷导致肾，肺和心脏中钙依赖性蛋白水解的激活，导致细胞降解。重要的是，钙依赖性蛋白水解的激活增加在老小鼠的组织中发生，同时下调klotho基因表达。Klotho蛋白需要什么以及它如何起作用？在这篇综述中，我将讨论关于Klotho蛋白的生物学作用和分子功能的工作假设。