Authors: Yan L; Vatner DE; O'Connor JP; Ivessa A; Ge H; Chen W; Hirotani S; Ishikawa Y; Sadoshima J; Vatner SF
Abstract: 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.Keywords: Adenylate Cyclase/*metabolism; Animals; Body Weight; Bone and Bones/enzymology; Cardiomyopathies/enzymology; Cells, Cultured; Gene Expression; Growth Hormone/metabolism; Heat-Shock Response; Isoenzymes/*metabolism; Longevity/*physiology; MAP Kinase Signaling System; Mice; Mice, Knockout; Mitogen-Activated Protein Kinase 1/metabolism; Models, Biological; *Oxidative Stress; Saccharomycetales; Superoxide Dismutase/genetics; Up-Regulation/genetics
Date: July 31, 2007
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Yan L, Vatner DE, O'Connor JP, Ivessa A, Ge H, Chen W, Hirotani S, Ishikawa Y, Sadoshima J, Vatner SF (2007) Type 5 adenylyl cyclase disruption increases longevity and protects against stress. Cell 130: 247-58.