Periodontal disease (periodontitis) is a chronic oral disease impacting over 70% of older adults, where inflammation of the tissues supporting the teeth results in loss of connective tissue attachment, bone, and ultimately the tooth. The greatest underlying risk factor for periodontitis is age, and its association with other age-related diseases, such as heart disease, diabetes, and Alzheimer disease, highlights the importance of incorporating this oral disease in geroscience studies. We propose to test a series of compounds targeting inflammation in a mouse model of age-related periodontitis.
A component in most age-related diseases is the low-grade, chronic inflammation without overt infection known as “inflammaging”.While the sources and causes of “inflammaging” are diverse, such as the accumulation of damaged macromolecules, harmful byproducts from the microbiome, cellular senescence, and immunosenescence, finding suitable models which encompass these various elements to evaluate and target “inflammaging” has been a challenge. Among the various organ systems that undergo inflammaging, periodontal disease involves most sources and outcomes of inflammaging. Thus, evaluating pathways that target “inflammaging” may provide a unique, Geroscience-based treatment modality to reverse periodontal disease. This novel approach to treating periodontal disease is expected to establish the first medical, non-surgical treatment for age-related oral disease. Moreover, this approach to treating periodontal loss is expected to have a positive impact on age-related cognitive decline. Efforts to slow the progression of periodontitis in older adults have been attempted through various therapies, including scaling and root planing (“deep cleanings”) or antibacterial adjuncts to reduce pathogens in the pocket. However, these treatment modalities are invasive, need to be repeated often, and rely on access to such modalities, which may be limited for many older adults. Furthermore, current therapies are limited to treating the symptoms and fail to address the underlying cellular and molecular causes of periodontal disease, which we hypothesize are a direct consequence of biological aging. In a recent study, we demonstrate that short-term treatment with rapamycin, an immunosuppressive and antiproliferative mTOR inhibitor, rejuvenates the aged oral cavity of elderly mice, including regeneration of periodontal bone, attenuation of gingival and periodontal bone inflammation, and revertive shift of the oral microbiome toward a more youthful composition.
Based on our findings with rapamycin, we propose to use small molecule inhibitors of the PI3K/NFkB/mTOR pathway to treat periodontal disease and will test 5 candidates administered orally in the chow in an 8-week study, using rapamycin as a positive control. The drugs have well-established pharmacokinetics and pharmacology. These compounds have never been before tested in the context of periodontal disease, thus there is high potential for IP. If this first study demonstrates that any of the small molecules are effective in reversing periodontal disease when administered systemically, a second sub-study will be carried out to test the effectiveness of their local delivery by brushing the interventions across the gum line, comparing them with locally delivered rapamycin. Our collaborators also have preliminary data showing that a few of the tested interventions have beneficial effects on neurodegeneration and cognitive decline. Therefore, besides periodontal bone loss, the study will address the effects on cognitive function and lifespan. Commercial Viability A major neglect in all current standard therapy and research is the impact of aging biology, such as “inflammaging”, that may contribute to periodontitis in older adults. Our new and substantively different approach to treating periodontal disease is expected to clarify and demonstrate the first medical, non-surgical treatment for an age-related oral disease. Results from the proposed study will provide critical pre-clinical IP data to support a future company targeting periodontal disease through geroscience. Method 1: Compound X Toothpaste a) Prescription (from the dental office or medical office) b) Over-the-counter (in low doses) Method 2: Direct Delivery of Compound X to periodontal pockets with periodontal disease a) IP surrounding both formulation and delivery mode b) Completed in dental offices (medical offices) Method 3: Compound X trays