High fat diet increases hippocampal oxidative stress and cognitive impairment in aged mice: implications for decreased Nrf2 signaling

J Neurochem. 2010 Sep;114(6):1581-9. doi: 10.1111/j.1471-4159.2010.06865.x. Epub 2010 Jul 27.


Long term consumption of a high fat diet (HFD) contributes to increased morbidity and mortality. Yet the specific effects of HFD consumption on brain aging are poorly understood. In the present study 20-month old male C57Bl/6 mice were fed either 'western diet' (41% fat), very high fat lard diet (60% fat), or corresponding control diets for 16 weeks and then assessed for changes in metabolism and brain homeostasis. Although both HFDs increased adiposity and fasting blood glucose, only the high fat lard diet increased age-related oxidative damage (protein carbonyls) and impaired retention in the behavioral test. This selective increase in oxidative damage and cognitive decline was also associated with a decline in NF-E2-related factor 2 (Nrf2) levels and Nrf2 activity, suggesting a potential role for decreased antioxidant response. Taken together, these data suggest that while adiposity and insulin resistance following HFD consumption are linked to increased morbidity, the relationship between these factors and brain homeostasis during aging is not a linear relationship. More specifically, these data implicate impaired Nrf2 signaling and increased cerebral oxidative stress as mechanisms underlying HFD-induced declines in cognitive performance in the aged brain.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adiposity
  • Aging / metabolism*
  • Aging / psychology
  • Animals
  • Blood Glucose / metabolism
  • Body Weight
  • Cognition Disorders / etiology
  • Cognition Disorders / metabolism*
  • Cognition Disorders / psychology
  • Dietary Fats / administration & dosage*
  • Hippocampus / metabolism*
  • Insulin / blood
  • Leptin / blood
  • Male
  • Maze Learning
  • Mice
  • Mice, Inbred C57BL
  • NF-E2-Related Factor 2 / physiology*
  • Oxidative Stress*
  • Protein Carbonylation
  • Signal Transduction


  • Blood Glucose
  • Dietary Fats
  • Insulin
  • Leptin
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse