Type 5 adenylyl cyclase disruption increases longevity and protects against stress.
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.
Department of Cell Biology and Molecular Medicine and Cardiovascular Research Institute, UMDNJ-New Jersey Medical School, Newark, NJ 07103, USA.
Lin
L
Yan
Dorothy E
DE
Vatner
J Patrick
JP
O'Connor
Andreas
A
Ivessa
Hui
H
Ge
Wei
W
Chen
Shinichi
S
Hirotani
Yoshihiro
Y
Ishikawa
Junichi
J
Sadoshima
Stephen F
SF
Vatner
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D001835:Body Weight; D001842:Bone and Bones / Q000201:enzymology; D009202:Cardiomyopathies / Q000201:enzymology; D002478:Cells, Cultured; D015870:Gene Expression; D013006:Growth Hormone / Q000378:metabolism; D018869:Heat-Shock Response; D007527:Isoenzymes / Q000378:metabolism*; D008136:Longevity / Q000502:physiology*; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D008954:Models, Biological; D018384:Oxidative Stress; D004718:Saccharomycetales; D013482:Superoxide Dismutase / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
D007527:Isoenzymes; D013006:Growth Hormone; D013482:Superoxide Dismutase; D019950:Mitogen-Activated Protein Kinase 1; D000262:Adenylyl Cyclases; C419510:adenylyl cyclase type V