Rattanaprukskul K, Xia X-J, Hysa M, Jiang M, Hung M, Suslavich S F, Sahingur S E
Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Periodontology, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand.
J Dent Res. 2025 Apr;104(4):419-427. doi: 10.1177/00220345241299789. Epub 2025 Jan 10.
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, , 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.
细胞衰老已成为衰老的核心标志之一，也是包括牙周疾病在内的慢性合并症的驱动因素。衰老也可发生在较年轻的组织中，并引发代谢改变和功能障碍，最终导致加速衰老和病理后果。衰老疗法，如达沙替尼和槲皮素（DQ）的联合使用，正越来越多地用于改善慢性疾病的临床结局，并通过减少衰老细胞负担和衰老相关分泌表型（SASP）来促进健康寿命。最近的证据表明，衰老细胞和SASP也可能促成牙周疾病的发病机制。在本研究中，我们使用衰老的临床前模型研究了DQ干预对牙周组织健康的影响。在体外，持续暴露于牙周细菌后，DQ通过调节关键衰老标志物如p16、SA-β-半乳糖苷酶和层粘连蛋白B1的水平以及与SASP相关的炎症介质（包括白细胞介素-8、基质金属蛋白酶（MMP）-1和MMP-3）来改善人牙龈角质形成细胞衰老的生物学特征。在体内，口服DQ可减轻牙龈组织中的衰老细胞负担和SASP，并减少老年小鼠自然进展的牙周骨丢失。总的来说，我们的研究结果为转化研究提供了概念验证证据，并表明靶向牙龈衰老和衰老相关分泌组可能是改善牙周健康的有效策略，特别是在易感人群中。
