The Effect of Calorie Restriction on Brain Structure and Function in Aging Rhesus Monkeys

Calorie restriction (CR) without malnutrition has been consistently shown to be effective in slowing aging and prolonging lifespan in lower animal models; similar evidence is still emerging in nonhuman primate models. This intervention thus provides a powerful model for studying the processes underlying aging and aging retardation. In this thesis, we examined the effect of CR on brain health in the rhesus macaque model using imaging, behavioral, and histopathologic techniques. The primary hypothesis of this project was that CR decelerates the rate of age-related changes in the brain in rhesus monkeys. In the first study, we investigated the association between cognitive and motor performance and anatomic and microstructural brain integrity measured with magnetic resonance imaging in aged monkeys. We showed that performance on a cognitive conceptual shift task was significantly associated with higher gray matter volume in frontal and parietal cortices, and decreased microstructural health in major association fiber bundles. Slower performance on the motor task was significantly correlated with low volumetric measures in cortical, subcortical, and cerebellar areas and low microstructural integrity in several major association fiber bundles. Differences in brain-behavior correlations between control and CR animals indicated a protective effect of the dietary intervention. In the second study, we used tractography to study changes in white matter integrity within the corpus callosum. Our findings indicated that there is an age-related loss of white matter integrity in the genu, that there is a posterior to anterior decline in white matter integrity within the corpus callosum, and that CR results in the preservation of white matter integrity in the splenium. In the final study, we investigated differences in gliosis and amyloid plaque load in the hippocampus and the adjacent cortical areas of control and CR male rhesus macaques using immunostaining methods. Our results demonstrated that CR significantly reduces the age-associated gliosis in the hippocampus and entorhinal cortex of rhesus macaques. However, we did not find a regulatory effect of CR on amyloid plaque deposition in the aged monkey hippocampus and adjacent cortex. Collectively, these results suggest that CR has a salubrious effect on brain aging.