Obesity increases vascular senescence and susceptibility to ischemic injury through chronic activation of Akt and mTOR

Sci Signal. 2009 Mar 17;2(62):ra11. doi: 10.1126/scisignal.2000143.

Abstract

Obesity and age are important risk factors for cardiovascular disease. However, the signaling mechanism linking obesity with age-related vascular senescence is unknown. Here we show that mice fed a high-fat diet show increased vascular senescence and vascular dysfunction compared to mice fed standard chow and are more prone to peripheral and cerebral ischemia. All of these changes involve long-term activation of the protein kinase Akt. In contrast, mice with diet-induced obesity that lack Akt1 are resistant to vascular senescence. Rapamycin treatment of diet-induced obese mice or of transgenic mice with long-term activation of endothelial Akt inhibits activation of mammalian target of rapamycin (mTOR)-rictor complex 2 and Akt, prevents vascular senescence without altering body weight, and reduces the severity of limb necrosis and ischemic stroke. These findings indicate that long-term activation of Akt-mTOR signaling links diet-induced obesity with vascular senescence and cardiovascular disease.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Cardiovascular Diseases / etiology*
  • Carrier Proteins / metabolism*
  • Cellular Senescence / drug effects
  • Cellular Senescence / physiology*
  • Disease Susceptibility / etiology
  • Eating
  • Enzyme Activation / drug effects
  • Ischemia / etiology*
  • Mice
  • Mice, Transgenic
  • Obesity / complications*
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction / drug effects
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases

Substances

  • Carrier Proteins
  • Phosphotransferases (Alcohol Group Acceptor)
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Sirolimus