The Relationship between Inflammation and Cognition in a Monkey Model of Human Aging

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ABSTRACT This application is for a supplement to the P51 Primate Research Center Grant that supports the Washington National Primate Research Center. This supplement will be used to conduct a 1-year pilot study towards establishing a new research program to characterize the association between inflammation and age-related changes in cognitive performance and oral health in monkeys (rhesus macaques). Monkeys provide a strong model for advancing our understanding of the neurobiology of human memory and executive function due to robust cross-species similarities in the anatomy and connectivity of the medial temporal lobe and prefrontal cortex. Accumulating evidence has suggested an association between cognitive impairment and systemic immune activation. Elevated serum levels of pro-inflammatory cytokines have been shown to be related to cognitive impairment, and this inflammation-cognition association has been demonstrated in otherwise healthy older individuals. Along with inflammation-cognition, inflammation-oral health association is also demonstrated in older individuals in the form of periodontal disease (PD), a chronic inflammatory oral disease affecting nearly 70% of U.S. adults over the age of 65 which leads to a dysbiotic oral microbiome, destruction of the gingival epithelium and periodontal bone with ultimately tooth loss. PD is also a major risk factor for several other age-related disorders, including heart disease and diabetes, and patients with chronic periodontal disease have a higher risk of developing dementia. We recently discovered that the specific mTOR inhibitor rapamycin caused a revertive shift of the old oral microbiome to be more similar to the young oral microbiome in mice, attenuated gingival and periodontal tissue inflammation, and reversed periodontal bone loss in old animals. Thus, the overarching goals of this proposal are to (1) determine whether elevated levels of pro-inflammatory cytokines are associated with cognitive decline, (2) establish the aged rhesus monkey as a model for naturally occurring periodontal disease, and (3) analyze the direct impact of mTOR inhibition on age-related oral and cognitive decline.