Dasatinib and Quercetin Limit Gingival Senescence, Inflammation, and Bone Loss

Cellular senescence has emerged as one of the central hallmarks of aging and drivers of chronic comorbidities, including periodontal diseases. Senescence can also occur in younger tissues and instigate metabolic alterations and dysfunction, culminating in accelerated aging and pathological consequences. Senotherapeutics, such as the combination of dasatinib and quercetin (DQ), are being increasingly used to improve the clinical outcomes of chronic disorders and promote a healthy life span through the reduction of senescent cell burden and senescence-associated secretory phenotype (SASP). Recent evidence suggests that senescent cells and SASP can contribute to the pathogenesis of periodontal diseases as well. In this study, we investigated the effect of DQ interventions on periodontal tissue health using preclinical models of aging. In vitro, DQ ameliorated biological signatures of senescence in human gingival keratinocytes upon persistent exposure to periodontal bacteria, <i>Fusobacterium nucleatum</i>, by modulating the levels of key senescence markers such as p16, SA-β-galactosidase, and lamin-B1 and inflammatory mediators associated with SASP including interleukin-8, matrix metalloproteinase (MMP)-1, and MMP-3. In vivo, the oral administration of DQ mitigated senescent cell burden and SASP in gingival tissues and reduced naturally progressing periodontal bone loss in aged mice. Collectively, our findings provide proof-of-concept evidence for translational studies and reveal that targeting gingival senescence and the senescence-associated secretome can be an effective strategy to improve periodontal health, particularly in vulnerable populations.