Type 5 adenylyl cyclase disruption increases longevity and protects against stress

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenylyl Cyclases / 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


  • Isoenzymes
  • Growth Hormone
  • Superoxide Dismutase
  • Mitogen-Activated Protein Kinase 1
  • Adenylyl Cyclases
  • adenylyl cyclase type V