Liu Hongjun, Fergusson Maria M, Castilho Rogerio M, Liu Jie, Cao Liu, Chen Jichun, Malide Daniela, Rovira Ilsa I, Schimel Daniel, Kuo Calvin J, Gutkind J Silvio, Hwang Paul M, Finkel Toren
Cardiology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA.
Science. 2007 Aug 10;317(5839):803-6. doi: 10.1126/science.1143578.
The contribution of stem and progenitor cell dysfunction and depletion in normal aging remains incompletely understood. We explored this concept in the Klotho mouse model of accelerated aging. Analysis of various tissues and organs from young Klotho mice revealed a decrease in stem cell number and an increase in progenitor cell senescence. Because klotho is a secreted protein, we postulated that klotho might interact with other soluble mediators of stem cells. We found that klotho bound to various Wnt family members. In a cell culture model, the Wnt-klotho interaction resulted in the suppression of Wnt biological activity. Tissues and organs from klotho-deficient animals showed evidence of increased Wnt signaling, and ectopic expression of klotho antagonized the activity of endogenous and exogenous Wnt. Both in vitro and in vivo, continuous Wnt exposure triggered accelerated cellular senescence. Thus, klotho appears to be a secreted Wnt antagonist and Wnt proteins have an unexpected role in mammalian aging.
在正常衰老过程中，干细胞和祖细胞功能障碍及耗竭的作用仍未完全明确。我们在加速衰老的Klotho小鼠模型中探究了这一概念。对年轻Klotho小鼠的各种组织和器官进行分析发现，干细胞数量减少，祖细胞衰老增加。由于klotho是一种分泌蛋白，我们推测klotho可能与干细胞的其他可溶性介质相互作用。我们发现klotho与多种Wnt家族成员结合。在细胞培养模型中，Wnt-klotho相互作用导致Wnt生物活性受到抑制。来自klotho缺陷动物的组织和器官显示出Wnt信号增强的迹象，klotho的异位表达拮抗内源性和外源性Wnt的活性。在体外和体内，持续暴露于Wnt均会引发细胞加速衰老。因此，klotho似乎是一种分泌型Wnt拮抗剂，而Wnt蛋白在哺乳动物衰老过程中具有意想不到的作用。
