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. 2016 Nov 8;8(11):2814-2826.
doi: 10.18632/aging.101094.

Caloric Restriction Preserves Memory and Reduces Anxiety of Aging Mice With Early Enhancement of Neurovascular Functions

Free PMC article

Caloric Restriction Preserves Memory and Reduces Anxiety of Aging Mice With Early Enhancement of Neurovascular Functions

Ishita Parikh et al. Aging (Albany NY). .
Free PMC article


Neurovascular integrity plays an important role in protecting cognitive and mental health in aging. Lifestyle interventions that sustain neurovascular integrity may thus be critical on preserving brain functions in aging and reducing the risk for age-related neurodegenerative disorders. Here we show that caloric restriction (CR) had an early effect on neurovascular enhancements, and played a critical role in preserving vascular, cognitive and mental health in aging. In particular, we found that CR significantly enhanced cerebral blood flow (CBF) and blood-brain barrier function in young mice at 5-6 months of age. The neurovascular enhancements were associated with reduced mammalian target of rapamycin expression, elevated endothelial nitric oxide synthase signaling, and increased ketone bodies utilization. With age, CR decelerated the rate of decline in CBF. The preserved CBF in hippocampus and frontal cortex were highly correlated with preserved memory and learning, and reduced anxiety, of the aging mice treated with CR (18-20 months of age). Our results suggest that dietary intervention started in the early stage (e.g., young adults) may benefit cognitive and mental reserve in aging. Understanding nutritional effects on neurovascular functions may have profound implications in human brain aging and age-related neurodegenerative disorders.

Keywords: anxiety; blood-brain barrier; caloric restriction; cerebral blood flow; cognition; magnetic resonance imaging (MRI); mammalian target of rapamcyin (mTOR).

Conflict of interest statement

The authors of this manuscript have no conflict of interests to declare.


Figure 1
Figure 1. Caloric restriction enhances neurovascular functions in young mice
(A) CBF maps superimposed on structural brain images; the color code indicates the level of CBF in a linear scale. Quantitative CBF (ml/g/min) obtained from (B) Frontal Cortex and (C) Hippocampus. (D) Representative confocal images showing increased luminal accumulation of NBD-CSA fluorescence (green) in brain capillaries isolated from young CR mice; shown in arbitrary fluorescence units (scale 0-255). (E) Corresponding quantitative fluorescence data. Data are mean ± SEM. **p < 0.01; ***p < 0.001; n.s.: non-significant; AL: ad libitum; CR: caloric restriction.
Figure 2
Figure 2. Caloric restriction enriches vascular signaling markers and shifts metabolism in young mice
(A) Western blotting (WB) of mTOR, eNOS, P-gp and GLUT1 from the cortical vasculature, β-Actin was used as loading control; corresponding values of (B) mTOR, (C) eNOS, (D) P-gp, and (E) GLUT1 between the young AL and CR mice. All the WB data were normalized to β-Actin and compared to young AL (100%). (F) Blood glucose and (G) Blood Ketone levels of the mice. *p < 0.05; **p < 0.01; ***p < 0.001; AL: ad libitum; CR: caloric restriction.
Figure 3
Figure 3. Caloric restriction decelerates the rate of decline of cerebral blood flow in aging mice
Old CR mice had significantly higher CBF in (A) Frontal cortex and (B) Hippocampus; however (C) P-gp activity did not show significance when compared with old AL mice. The age-dependent changes between AL and CR mice in (D) CBF within frontal cortex, and (E) hippocampus, and (F) Difference in cortical P-gp activity, between AL and CR mice. Data are mean ± SEM. **p < 0.01; n.s.: non-significant; AL: ad libitum; CR: caloric restriction.
Figure 4
Figure 4. Caloric restriction preserves learning and long-term memory of aging mice
(A) An illustration of the Radial Arm Water Maze. Mice were trained to locate the hidden platform through a 2-day, 30 trials testing (3 blocks each day, 5 trials each block). Wrong entries were recorded as errors. (B) Young AL and CR mice did not have significantly different performances across the 6 blocks. (C) Old AL mice performed worse in Block 1 (initial learning phase) and Block 4 (initial recall phase) compared to the old CR mice. The comparison among the four groups for (D) Block 1 and (E) Block 4. Significant inverse correlation between errors made in Blocks 1 and 4 and CBF in (F) hippocampus (r2 = 0.29, p < 0.001) and (G) frontal cortex (r2 = 0.27, p < 0.001). Color codes indicate the four groups of mice. Data are mean ± SEM. **p < 0.01; AL: ad libitum; CR: caloric restriction.
Figure 5
Figure 5. Caloric restriction reduces anxiety of aging mice
(A) An illustration of the Elevated Plus Maze. The maze consists of four arms (two enclosed arms and two open arms) elevated 100 cm above the floor. Anxiety level was determined the time spent in the closed arms (conceived as a safe place) over a 5 minutes testing session. Closed arm duration (in seconds) of (B) Young AL and CR mice, and (C) Old AL and CR mice. (D) The age-dependent changes of anxiety level between AL and CR mice. Significant inverse correlation between closed arm duration and CBF in (E) hippocampus (r2 = 0.40, p < 0.0001) and (F) frontal cortex (r2 = 0.39, p < 0.0001). Color codes indicate the four groups of mice. Data are mean ± SEM. **p < 0.01; AL: ad libitum; CR: caloric restriction.

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