The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies

Brain Res Rev. 2009 Mar;59(2):293-315. doi: 10.1016/j.brainresrev.2008.09.002. Epub 2008 Sep 25.


Both calorie restriction and the ketogenic diet possess broad therapeutic potential in various clinical settings and in various animal models of neurological disease. Following calorie restriction or consumption of a ketogenic diet, there is notable improvement in mitochondrial function, a decrease in the expression of apoptotic and inflammatory mediators and an increase in the activity of neurotrophic factors. However, despite these intriguing observations, it is not yet clear which of these mechanisms account for the observed neuroprotective effects. Furthermore, limited compliance and concern for adverse effects hamper efforts at broader clinical application. Recent research aimed at identifying compounds that can reproduce, at least partially, the neuroprotective effects of the diets with less demanding changes to food intake suggests that ketone bodies might represent an appropriate candidate. Ketone bodies protect neurons against multiple types of neuronal injury and are associated with mitochondrial effects similar to those described during calorie restriction or ketogenic diet treatment. The present review summarizes the neuroprotective effects of calorie restriction, of the ketogenic diet and of ketone bodies, and compares their putative mechanisms of action.

Publication types

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

MeSH terms

  • Animals
  • Brain Diseases / diet therapy*
  • Brain Diseases / metabolism
  • Brain Diseases / physiopathology
  • Caloric Restriction*
  • Cytoprotection / drug effects
  • Cytoprotection / physiology*
  • Diet, Ketogenic*
  • Energy Metabolism / drug effects
  • Energy Metabolism / physiology
  • Food Deprivation / physiology*
  • Humans
  • Ketone Bodies / metabolism
  • Ketone Bodies / pharmacology
  • Ketone Bodies / therapeutic use
  • Mitochondria / metabolism
  • Neuroprotective Agents / metabolism
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use


  • Ketone Bodies
  • Neuroprotective Agents