Lanske Beate, Razzaque M Shawkat
Department of Developmental Biology, Harvard School of Dental Medicine, Research and Educational Building, 190 Longwood Avenue, Boston, MA 02115, USA.
Ageing Res Rev. 2007 May;6(1):73-9. doi: 10.1016/j.arr.2007.02.002. Epub 2007 Feb 20.
Suitable mammalian models for aging with a wide range of age-associated pathology are desirable to study molecular mechanisms of human aging. Recent studies have identified that fibroblast growth factor 23 (Fgf-23) null mice and klotho hypomorphs could generate multiple premature aging-like features, including shortened lifespan, infertility, kyphosis, atherosclerosis, extensive soft tissue calcifications, skin atrophy, muscle wasting, T cell dysregulation, pulmonary emphysema, osteoporosis/osteopenia, abnormal mineral ion metabolism, and impaired vitamin-D homeostasis. The strikingly similar in vivo phenotypes of two separate genetically altered mouse lines implicate that the premature aging-like features may be partly regulated through a common signaling pathway involving both Fgf-23 and klotho; such speculation is experimentally supported by the observation that Fgf-23 requires klotho as a cofactor to exert its functions. Despite about 2000-fold higher serum levels of Fgf-23 in klotho mutants (compared to wild-type animals), these mice show physical, biochemical and morphological features similar to Fgf-23 null mice, but not as Fgf-23 transgenic mice; these observations suggest that widely encountered premature aging-like features in klotho mutant mice are due to the inability of Fgf-23 to exert its bioactivities in absence of klotho. The results of recent studies showing klotho as a cofactor in Fgf-23 signaling consequently explains that the premature aging-like features in klotho-deficient mice is not a primary cause, rather a consequence of lacking Fgf-23 activity. These understandings will help us to redefine the role of klotho as an aging factor.
为了研究人类衰老的分子机制，需要合适的哺乳动物衰老模型，这些模型具有广泛的与年龄相关的病理学特征。最近的研究发现，成纤维细胞生长因子23（Fgf - 23）基因敲除小鼠和klotho低表达小鼠可产生多种早衰样特征，包括寿命缩短、不育、脊柱后凸、动脉粥样硬化、广泛的软组织钙化、皮肤萎缩、肌肉萎缩、T细胞失调、肺气肿、骨质疏松/骨质减少、矿物质离子代谢异常以及维生素D稳态受损。两个独立的基因改变小鼠品系在体内表现出惊人的相似表型，这表明早衰样特征可能部分通过涉及Fgf - 23和klotho的共同信号通路进行调节；Fgf - 23需要klotho作为辅助因子来发挥其功能这一观察结果为这种推测提供了实验支持。尽管与野生型动物相比，klotho突变体小鼠血清中Fgf - 23水平高约2000倍，但这些小鼠表现出与Fgf - 23基因敲除小鼠相似的生理、生化和形态学特征，而与Fgf - 23转基因小鼠不同；这些观察结果表明，klotho突变体小鼠中广泛出现的早衰样特征是由于在缺乏klotho的情况下Fgf - 23无法发挥其生物活性所致。最近的研究结果表明klotho是Fgf - 23信号传导中的辅助因子，因此解释了klotho缺陷小鼠中的早衰样特征不是主要原因，而是缺乏Fgf - 23活性的结果。这些认识将有助于我们重新定义klotho作为衰老因子的作用。
