S4-02-01: Caloric restriction

Abstract

Excessive caloric intake, diabetes and a sedentary lifestyle may be risk factors for AD. We designed experiments aimed at elucidating the effects of dietary energy intake, diabetes and exercise on hippocampal neuroplasticity and AD pathogenesis. An AD animal model (3xTgAD mice) and diabetic (db/db) mice were used for these studies. 3xTgAD mice were maintained on an ad libitum control diet, a 40% calorie restriction diet (CR) or an intermittent fasting (IF) diet beginning at 3 months of age. Mice were tested in the water maze, and brains examined, at 10 and 17 months of age. In a second study, cognitive function and hippocampal plasticity were evaluated in diabetic mice on CR diet or exercise, compared with control, regimens. Ten month-old 3xTgAD mice in all diet groups performed normally in the water maze. Seventeen month-old 3xTgAD mice fed ad libitum were impaired in both the acquisition and retention trials of the water maze, and both the CR and IF diets ameliorated the deficits. 3xTgAD mice in the CR group showed lower levels of Aβ1–40, Aβ1–42 and phospho-tau in the hippocampus compared to the control diet group, whereas Aβ and phospho-tau levels were not decreased in 3xTgAD mice in the IF group. Data from the second study showed that diabetes impairs cognitive function, and dentate gyrus neurogenesis and synaptic plasticity in mice, by a mechanism involving the adrenal stress hormone corticosterone. Running exercise and CR can counteract the adverse effects of diabetes on hippocampal plasticity and cognitive function by a mechanism associated with increased levels of hippocampal brain-derived neurotrophic factor. Dietary energy restriction can ameliorate age-related deficits in cognitive function by mechanisms that may or may not be related to Aβ and tau pathologies. Moderation in dietary energy intake and regular exercise may protect the brain against AD by suppressing AD pathogenic processes and increasing cellular stress resistance.