PR000355 (Project)

Description:Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that robs people of their memory and cognitive function. Currently, no successful treatment or preventative measure exists for AD. Calorie restriction (CR) is a dietary regimen posited to suppress genetic programs of aging and reduce AD-related pathology. CR is known to enhance longevity and mitigate aging phenotypes in multiple model species. Mechanisms underlying the benefits of CR remain unknown, particularly in areas of the brain selectively vulnerable to age-related AD pathology such as the hippocampus, a region crucial for learning and memory. Moreover, AD pathology can be influenced by changes in diet, metabolism, and immunity, indicating that factors distant from the brain may play a role in pathogenesis. The intestinal microbiota, composed of trillions of microbial cells, influences host metabolism, immunity, and cognitive function, and is posited to be linked mechanistically to AD pathobiology, but a specific role remains to be adequately tested. We hypothesize that mechanisms underlying the benefits of CR are cell-type and organ specific, involving the gut-brain microbiome throughout the lifespan, this requiring subregional analysis in the brain as well as coordinated assessments of key peripheral targets including the liver, fecal pellets , and plasma. Thus, CR is proposed to be a viable treatment option that may ameliorate the development of AD-related pathology, and importantly, reveal mechanisms that attenuate age-related expression changes in vulnerable cells.