Life-long dietary restrictions have negligible or damaging effects on late-life cognitive performance: A key role for genetics in outcomes

Abstract

Several studies report that caloric restriction (CR) or intermittent fasting (IF) can improve cognition, while others report limited or no cognitive benefits. Here, we compare the effects of 20% CR, 40% CR, 1-day IF, and 2-day IF feeding paradigms to ad libitum controls on Y-maze working memory (WM) and contextual fear memory (CFM) in a large population of Diversity Outbred mice that model the genetic diversity of humans. While CR and IF interventions improve lifespan, we observed no enhancement of working memory or CFM in mice on these feeding paradigms, and report 40% CR to be damaging to recall of CFM. Using Quantitative Trait Loci mapping, we identified the gene Slc16a7 to be associated with CFM outcomes in aged mice on lifespan promoting feeding paradigms. Limited utility of dieting and fasting on memory in mice that recapitulate genetic diversity in the human population highlights the need for anti-aging therapeutics that promote cognitive function, with the neuronal monocarboxylate transporter MCT2 encoded by Slc16a7 highlighted as novel target.

Keywords: Caloric restriction; Cognition; Genetic diversity; Intermittent fasting; Metabolism.

Fig. 1.

Caloric restriction and intermittent fasting paradigms have no effect on working memory in the Diversity outbred mouse population. (A) Overview of the experimental timeline; mice were longitudinally tested at 10 and 22 months on the Y-maze working memory task. After fear conditioning at 24 months mice were aged out to their maximum lifespan. (B) We observed no significant effects of diet on age related decline of working memory measured by % spontaneous alternations in the Y-maze working memory task from 10 months of age to 22. Each dot represents an individual mouse, yellow lines denote line of best fit between ages. Significance testing was performed using 2-way repeated measures ANOVA.

Fig. 2.

Contextual fear memory is impaired in diversity outbred mice on 40% caloric restriction compared to intermittent fasting and Ad Lib control groups. (A) CFC testing schematic; on day 1 mice were given 4 foot-shocks. Twenty-four hours later mice were placed in the same context without any shocks (B) % Freezing on day 1 of training before receiving shocks (baseline) and during each post-shock (PS) interval. Acquisition of CFC was comparable across all feeding paradigms. Data are expressed as mean ± SEM, significance was determined using 1-way repeated measures ANOVA. (C) Recall of Contextual Fear Memory (CFM) measured by total percent freezing of mice on day 2. Significant effect of diet on % Freezing was determined with a linear mixed model with test batch treated as a random effect. (D) Boxplot of body weights at 24 months of age across all feeding paradigms. A Post-hoc Tukey test was used to determine significant differences between diet groups; p-values were corrected for multiple comparisons using Holm correction (E) Scatter plot correlating CFM percent freezing and 24 month body weight across the entire DO population. ^nsp > 0.05, * p < 0.05, ** p < 0.01 *** p < 0.001, n = 502. Boxplots encompass the 25th to 75th percentile with whiskers indicating 10th and 90th percentiles, median lines are indicated within each box.

Fig. 3.

Slc16a7 is associated with variation long-term memory outcomes. (A) QTL map across the entire genome identifies a locus on chromosome 10 that significantly associates with changes in recall of CFM in aged DO mice. Significance score (LOD) is represented on the y-axis. The dashed red represents significance threshold from permutation testing (1000 permutations, p-value = 0.05) (B) (Top) Area under the significant QTL peak showing genes and gene modules within this region. (Bottom) SNP marker associations of the 8 DO founders labeled above. The x-axis shows the distribution along the chromosome in physical distance, SNPs colored in red fall within a LOD 1.5 drop of the peak marker. Minor allele frequency for SNPs significant SNPs is shown below. The x-axis is physical distance in Mb along the chromosome. (C) Haplotype effects of the 8 founders at the QTL region for CFM. The y-axis for the top panel is the effect coefficient.