{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Albuquerque-Souza E"],"funding":["NIDCR NIH HHS","National Institute of Dental and Craniofacial Research"],"pagination":["1628-1636"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9703528"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["101(13)"],"pubmed_abstract":["TLR9 is a critical nucleic acid sensing receptor in mediating periodontitis and periodontitis-associated comorbidities. Emerging evidence implicates TLR9 as a key sensor during aging, although its participation in periodontal aging is unexplored. Here, we investigated whether TLR9-mediated host responses can promote key hallmarks of aging, inflammaging, and senescence, in the course of periodontitis using a multipronged approach comprising clinical and preclinical studies. In a case-control model, we found increased TLR9 gene expression in gingival tissues of older (≥55 y) subjects with periodontitis compared to older healthy subjects as well as those who are younger (<55 y old) with and without the disease. Mechanistically, this finding was supported by an in vivo model in which wild-type (WT) and TLR9<sup>-/-</sup> mice were followed for 8 to 10 wk (young) and 18 to 22 mo (aged). In this longitudinal model, aged WT mice developed severe alveolar bone resorption when compared to their younger counterpart, whereas aged TLR9<sup>-/-</sup> animals presented insignificant bone loss when compared to the younger groups. In parallel, a boosted inflammaging milieu exhibiting higher expression of inflammatory/osteoclast mediators (<i>Il-6</i>, <i>Rankl</i>, <i>Cxcl8</i>) and danger signals (<i>S100A8</i>, <i>S100A9</i>) was noted in gingival tissues of aged WT mice compared to the those of aged TLR9<sup>-/-</sup> mice. Consistently, WT aged mice displayed an increase in prosenescence balance as measured by p16<i><sup>INK4a</sup></i>/p19<i><sup>ARF</sup></i> ratio compared to the younger groups and aged TLR9<sup>-/-</sup> animals. Ex vivo experiments with bone marrow-derived macrophages primed by TLR9 ligand (ODN 1668) further corroborated in vivo and clinical data and showed enhanced inflammatory-senescence circuit followed by increased osteoclast differentiation. Together, these findings reveal first systematic evidence implicating TLR9 as one of the drivers of periodontitis during aging and functioning by boosting a deleterious inflammaging/senescence environment. This finding calls for further investigations to determine whether targeting TLR9 will improve periodontal health in an aging population."],"journal":["Journal of dental research"],"pubmed_title":["TLR9 Mediates Periodontal Aging by Fostering Senescence and Inflammaging."],"pmcid":["PMC9703528"],"funding_grant_id":["R01DE025037","R01 DE025037","R01 DE027374","R01DE027374"],"pubmed_authors":["Li Y","Xia-Juan X","Rattanaprukskul K","Sahingur SE","Jiang M","Albuquerque-Souza E","Crump KE","Shelling B"],"additional_accession":[]},"is_claimable":false,"name":"TLR9 Mediates Periodontal Aging by Fostering Senescence and Inflammaging.","description":"TLR9 is a critical nucleic acid sensing receptor in mediating periodontitis and periodontitis-associated comorbidities. Emerging evidence implicates TLR9 as a key sensor during aging, although its participation in periodontal aging is unexplored. Here, we investigated whether TLR9-mediated host responses can promote key hallmarks of aging, inflammaging, and senescence, in the course of periodontitis using a multipronged approach comprising clinical and preclinical studies. In a case-control model, we found increased TLR9 gene expression in gingival tissues of older (≥55 y) subjects with periodontitis compared to older healthy subjects as well as those who are younger (<55 y old) with and without the disease. Mechanistically, this finding was supported by an in vivo model in which wild-type (WT) and TLR9<sup>-/-</sup> mice were followed for 8 to 10 wk (young) and 18 to 22 mo (aged). In this longitudinal model, aged WT mice developed severe alveolar bone resorption when compared to their younger counterpart, whereas aged TLR9<sup>-/-</sup> animals presented insignificant bone loss when compared to the younger groups. In parallel, a boosted inflammaging milieu exhibiting higher expression of inflammatory/osteoclast mediators (<i>Il-6</i>, <i>Rankl</i>, <i>Cxcl8</i>) and danger signals (<i>S100A8</i>, <i>S100A9</i>) was noted in gingival tissues of aged WT mice compared to the those of aged TLR9<sup>-/-</sup> mice. Consistently, WT aged mice displayed an increase in prosenescence balance as measured by p16<i><sup>INK4a</sup></i>/p19<i><sup>ARF</sup></i> ratio compared to the younger groups and aged TLR9<sup>-/-</sup> animals. Ex vivo experiments with bone marrow-derived macrophages primed by TLR9 ligand (ODN 1668) further corroborated in vivo and clinical data and showed enhanced inflammatory-senescence circuit followed by increased osteoclast differentiation. Together, these findings reveal first systematic evidence implicating TLR9 as one of the drivers of periodontitis during aging and functioning by boosting a deleterious inflammaging/senescence environment. This finding calls for further investigations to determine whether targeting TLR9 will improve periodontal health in an aging population.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Dec","modification":"2026-06-03T09:29:37.661Z","creation":"2025-04-06T00:32:58.415Z"},"accession":"S-EPMC9703528","cross_references":{"pubmed":["35918888"],"doi":["10.1177/00220345221110108"]}}