Masuda Hiroaki, Chikuda Hirotaka, Suga Tatsuo, Kawaguchi Hiroshi, Kuro-o Makoto
Department of Pathology, The University of Texas Southwestern Medical Center at Dallas, 6000 Harry Hines Blvd., Dallas, TX 75390-9072, USA.
Mech Ageing Dev. 2005 Dec;126(12):1274-83. doi: 10.1016/j.mad.2005.07.007. Epub 2005 Sep 6.
Mice carrying a loss-of-function mutation in the klotho gene (KL(-/-) mice) develop ageing-like symptoms around 4 weeks after birth and suffer from multiple age-related disorders observed in humans, including osteoporosis, arteriosclerosis, and pulmonary emphysema. The klotho gene encodes a single-pass transmembrane protein that may function in signaling pathways that suppress ageing. To investigate the ability of Klotho to regulate the development of ageing-related disorders, we established an inducible Klotho expression system using KL(-/-) mice carrying an exogenous klotho gene fused to the mouse metallothionein-I promoter, in which Klotho expression was dependent on zinc water feeding. We demonstrate that many advanced ageing-like KL(-/-) phenotypes were restored to normal whenever Klotho expression was induced. Conversely, decreasing Klotho expression in these rescued KL(-/-) mice induced several ageing-like KL(-/-) phenotypes. Our data indicate that Klotho may be effective in the treatment of multiple age-related disorders and is essential for maintaining animals free of these disorders.
携带klotho基因功能丧失突变的小鼠（KL(-/-)小鼠）在出生后约4周出现类似衰老的症状，并患有多种在人类中观察到的与年龄相关的疾病，包括骨质疏松症、动脉硬化和肺气肿。klotho基因编码一种单次跨膜蛋白，可能在抑制衰老的信号通路中发挥作用。为了研究Klotho调节与衰老相关疾病发展的能力，我们利用携带与小鼠金属硫蛋白-I启动子融合的外源klotho基因的KL(-/-)小鼠建立了一个可诱导的Klotho表达系统，其中Klotho的表达依赖于锌水喂养。我们证明，只要诱导Klotho表达，许多晚期类似衰老的KL(-/-)表型就会恢复正常。相反，在这些获救的KL(-/-)小鼠中降低Klotho表达会诱导出几种类似衰老的KL(-/-)表型。我们的数据表明，Klotho可能对治疗多种与年龄相关的疾病有效，并且对于维持动物免受这些疾病的影响至关重要。
