Investigating the role of calorie restriction-induced blood factors in rejuvenating the aged hippocampus - PROJECT SUMMARY Aging leads to cognitive decline and increased risk for age-related neurodegenerative diseases such as Alzheimer’s disease. The increasing rate of population aging places a larger number of people at risk for such cognitive dysfunction. This highlights the need for therapeutic approaches that maintain cognitive integrity in the aging brain. Calorie restriction (CR) is one of the most effective and well-studied non-genetic, rejuvenating systemic interventions—reversing hallmarks of brain aging and improving cognitive function in aged animals. CR is a form of dietary restriction that requires a moderate reduction (10-40% without malnutrition) in overall daily calorie intake compared to ad libitum (AL) feeding. CR has been shown to be particularly beneficial to the hippocampus—a brain region regulating learning and memory processes, and which is highly vulnerable to aging. Indeed, in mice, CR prevents age-related decline in synaptic plasticity and cognition, and rescues these facets of aging when initiated late in life in aged mice. Importantly, these beneficial effects are also seen in humans, where CR in aged individuals is correlated with improved cognitive performance. CR also ameliorates the severity of pathology in models of neurodegenerative diseases such as Alzheimer’s disease. Specifically, CR has been shown to reduce beta-amyloid load and improve cognitive function in several mouse models of Alzheimer’s disease pathology. Despite these promising results, adherence to dietary interventions is especially difficult in the elderly. Therefore, identifying methods to confer the cognitive benefits of CR without its limitations can improve translational applications. Recent work by our lab and others has shown that blood factors induced by other systemic interventions such as exercise can reverse signs of aging in the brain; therefore, this raises the possibility that the benefits of CR can be conferred through circulating factors. In support, my preliminary data demonstrate that aged mice administered CR blood plasma exhibit significant improvements in hippocampal-dependent learning and memory compared to aged mice receiving AL blood plasma, and identify Glutathione Peroxidase 3 (GPX3) as a promising candidate CR-induced pro-youthful circulating blood factor. The goal of this proposal is to determine the mechanisms by which CR blood plasma rejuvenates the aged brain. I hypothesize that CR-induced blood factors reverse age-related neuronal changes and rejuvenate cognitive function in the aged hippocampus. This will be investigated with two Specific Aims: 1. Determine the potential of CR blood plasma administration to reverse age-related cognitive dysfunction and promote neuronal rejuvenation in the aged hippocampus. 2: Investigate the role of CR-induced circulating GPX3 in rejuvenating the aged hippocampus. Ultimately, these studies will have significant translational potential, identifying a potential blood- based therapeutic approach to confer the cognitive benefits of CR, which will increase the translational potential of CR to counter age-related cognitive decline and aging-associated neurodegenerative diseases including Alzheimer’s disease.
