Cellular Senescence in Periodontitis: From Pathogenesis to Therapeutics

Over 70% of the elderly population exhibits some forms of periodontal diseases, imposing a significant global health burden. Cellular senescence is a hallmark of aging, which can be triggered by various extrinsic and intrinsic stressors. Senescent cells maintain metabolic activity and display a senescence-associated secretory phenotype (SASP). The accumulation of senescent cells within tissues can have detrimental effects, fostering further senescence in neighboring cells, and ultimately leading to numerous chronic conditions. Senotherapeutics, such as dasatinib and quercetin (DQ), are being used as safe and effective strategies to alleviate senescent cell burden and SASP in multiple chronic inflammatory conditions. Our hypothesis posits that cellular senescence serves as a driver of periodontitis, and targeting senescent cells could enhance disease outcomes. This study entails investigating senescence signatures such as p16, lipofuscin and β- galactosidase and SASP in gingival tissues from both periodontitis and healthy subjects, as well as examining the effects of pharmacological and genetic senescent cell targeting in preclinical disease models. We demonstrated significantly increased levels of senescence markers within periodontitis lesions compared to periodontally healthy sites, with specific patterns based on tissue localizations. P16 levels were predominantly upregulated in the epithelial layers, whereas lipofuscin and β-galactosidase were abundant in the connective tissue region, colocalizing with fibroblasts and macrophages. In vivo observations aligned with the clinical data, showcasing increased senescence in the course of periodontitis. Intriguingly, DQ treatment reduced senescent cell burden and mitigated alveolar bone loss in both young and aged mice. Additionally, we demonstrated the therapeutic effects of DQ on gingival keratinocytes in response to chronic exposure to F. nucleatum. Specifically, DQ exerts its mitigating effect on senescence through multiple cellular pathways, such as cell cycle arrest, metabolic dysfunction, and cellular morphology. Furthermore, we employed a mouse model for genetically targeting senescent cells, yielding improved periodontitis phenotypes. In summary, our study underscores the role of cellular senescence in periodontitis, suggesting that targeting senescence holds promise as an innovative approach to enhance periodontal health among susceptible individuals.