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Cell. 2007 Jul 27;130(2):247-58.

Type 5 adenylyl cyclase disruption increases longevity and protects against stress.

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1
Department of Cell Biology and Molecular Medicine and Cardiovascular Research Institute, UMDNJ-New Jersey Medical School, Newark, NJ 07103, USA.

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.

PMID:
17662940
DOI:
10.1016/j.cell.2007.05.038
[Indexed for MEDLINE]
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