期刊
CELL
卷 130, 期 2, 页码 247-258出版社
CELL PRESS
DOI: 10.1016/j.cell.2007.05.038
关键词
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资金
- NHLBI NIH HHS [HL033107, HL059139, HL65183, HL069752, HL069020] Funding Source: Medline
- NIA NIH HHS [AG023137, AG014121, AG028854] Funding Source: Medline
- NICHD NIH HHS [HD01457] Funding Source: Medline
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 similar to 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.
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