Comparing the Effects of Low-Protein and High-Carbohydrate Diets and Caloric Restriction on Brain Aging in Mice

Cell Rep. 2018 Nov 20;25(8):2234-2243.e6. doi: 10.1016/j.celrep.2018.10.070.


Calorie restriction (CR) increases lifespan and improves brain health in mice. Ad libitum low-protein, high-carbohydrate (LPHC) diets also extend lifespan, but it is not known whether they are beneficial for brain health. We compared hippocampus biology and memory in mice subjected to 20% CR or provided ad libitum access to one of three LPHC diets or to a control diet. Patterns of RNA expression in the hippocampus of 15-month-old mice were similar between mice fed CR and LPHC diets when we looked at genes associated with longevity, cytokines, and dendrite morphogenesis. Nutrient-sensing proteins, including SIRT1, mTOR, and PGC1α, were also influenced by diet; however, the effects varied by sex. CR and LPHC diets were associated with increased dendritic spines in dentate gyrus neurons. Mice fed CR and LPHC diets had modest improvements in the Barnes maze and novel object recognition. LPHC diets recapitulate some of the benefits of CR on brain aging.

Keywords: brain aging; calorie restriction; cardiometabolic health; cognitive function; hippocampus; protein restriction.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / drug effects
  • Aging / physiology*
  • Animals
  • Behavior, Animal / drug effects
  • Biomarkers / metabolism
  • Body Composition / drug effects
  • Brain / drug effects
  • Brain / pathology
  • Brain / physiology*
  • Caloric Restriction
  • Cognition / drug effects
  • Dendritic Spines / drug effects
  • Dendritic Spines / metabolism
  • Diet, Protein-Restricted*
  • Dietary Carbohydrates / pharmacology*
  • Female
  • Gene Expression Regulation / drug effects
  • Heart / drug effects
  • Heart / physiology
  • Inflammation / pathology
  • Male
  • Memory / drug effects
  • Mice


  • Biomarkers
  • Dietary Carbohydrates