Yan Lin, Vatner Dorothy E, O'Connor J Patrick, Ivessa Andreas, Ge Hui, Chen Wei, Hirotani Shinichi, Ishikawa Yoshihiro, Sadoshima Junichi, Vatner Stephen F
Department of Cell Biology and Molecular Medicine and Cardiovascular Research Institute, UMDNJ-New Jersey Medical School, Newark, NJ 07103, USA.
Cell. 2007 Jul 27;130(2):247-58. doi: 10.1016/j.cell.2007.05.038.
Mammalian models of longevity are related primarily to caloric restriction and alterations in metabolism. We examined mice in which type 5 adenylyl cyclase (AC5) is knocked out (AC5 KO) and which are resistant to cardiac stress and have increased median lifespan of approximately 30%. AC5 KO mice are protected from reduced bone density and susceptibility to fractures of aging. Old AC5 KO mice are also protected from aging-induced cardiomyopathy, e.g., hypertrophy, apoptosis, fibrosis, and reduced cardiac function. Using a proteomic-based approach, we demonstrate a significant activation of the Raf/MEK/ERK signaling pathway and upregulation of cell protective molecules, including superoxide dismutase. Fibroblasts isolated from AC5 KO mice exhibited ERK-dependent resistance to oxidative stress. These results suggest that AC is a fundamentally important mechanism regulating lifespan and stress resistance.
长寿的哺乳动物模型主要与热量限制和新陈代谢的改变有关。我们研究了5型腺苷酸环化酶（AC5）基因敲除（AC5 KO）的小鼠，这些小鼠对心脏应激具有抗性，且平均寿命延长了约30%。AC5 KO小鼠可防止骨密度降低和衰老引起的骨折易感性。年老的AC5 KO小鼠还可免受衰老诱导的心肌病影响，如肥大、凋亡、纤维化和心脏功能降低。通过基于蛋白质组学的方法，我们证明了Raf/MEK/ERK信号通路的显著激活以及细胞保护分子（包括超氧化物歧化酶）的上调。从AC5 KO小鼠分离的成纤维细胞表现出对氧化应激的ERK依赖性抗性。这些结果表明，腺苷酸环化酶是调节寿命和抗应激能力的一个至关重要的机制。
