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 disease and decline is a low-grade, chronic inflammation without overt infection known as “inflammaging”. Among the various organ systems that undergo inflammaging, periodontal disease involves most, if not all, 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 treat periodontal disease is expected to establish the first medical, non-surgical treatment for an age-related oral disease. Moreover, this approach to treat 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, but 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. This provides a geroscience strategy to potentially rejuvenate oral health and reverse periodontal disease in the elderly.
Studies from the field of Geroscience have demonstrated that modulating specific pathways regulating biological aging can positively impact the onset and progression of multiple age-related functional declines and diseases. A pervasive component in most age-related disease and decline is a low-grade, chronic inflammation without overt infection called “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 undergoing “inflammaging”, periodontal disease exemplifies most, if not all, the sources and outcomes of inflammaging. Hence, reversing periodontal disease with geroscience strategies may positively impact aging globally. 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 (PLX3397, BYL719, IPI549, amlexanox, and Rapalink-1) administered orally in the chow in an 8-week study, using rapamycin as a positive control. The drugs have well established pharmacokinetics and pharmacology since they have been investigated for other indications. These compounds have never been before tested in the context of periodontal disease, thus there is high potential for IP surrounding this domain. If this first study demonstrates that any of the small molecules is 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. We envision improvement of the periodontal disease phenotype after 8-week treatment with the candidate compounds maybe a result of (1) an improvement of systemic “inflammaging” to impact periodontal disease that will be tested with the first study, or (2) a direct improvement of periodontal disease, which will be tested with the second study. Either result could be the base for novel IP regarding formulation and/or delivery methods to improve aging, inflammation, and periodontal disease. 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 effects on cognitive function and lifespan. Commercial Viability I am currently a practicing dentist in my community and there is a significant gap in our understanding as dentists why older adults are more susceptible to oral disease and oral health decline. Among the various oral diseases, periodontal disease is a worldwide burden, reduces oral health-related quality of life, impacts systemic health, and an often-neglected age-related disease for which there is no cure. 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 treat 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, which the investigator intend to spin out. If any of the locally administered treatments reverses periodontal disease, we envision the following path towards IP: Localized Delivery of Compound X to Oral Cavity - To treat (indications): a) Age-related periodontal disease in older adults b)Peri-implantitis (periodontal disease of implants) in older adults - 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) Example : Local delivery of antimicrobial compounds - Method 3: Compund X trays Example: Whitening trays If we observe an effect in lifespan and healthspan, additional test of feasibility and safety in other mammalian models (i.e., non-human primates) will begin for application in clinic to target aging.