Late Breaking Abstract - Epigenetic reprogramming via HDAC9 in premature aging-associated inflammation

<bold>Introduction:</bold> Premature aging involves accelerated manifestation of age-related features, influenced by epigenetic modifications. HDAC9, a class IIa histone deacetylase, is implicated in various physiological processes. <bold>Aims and objectives:</bold> The aim of the study is to unveil the role of HDAC9 deficiency in the premature aging phenotype leading to chronic inflammation. <bold>Methods:</bold> Two age groups of mice was used and we investigated lung structural changes using hematoxylin and eosin staining and FACS analysis. Alveolar epithelial type II cells (AT2) were isolated to examine HDAC9 deficiency by utilizing senescence markers (beta-galactosidase, p16, and p21), and ATAC- and RNA-sequencing, and metabolome profiling. Finally, senolytic drug treatment was employed. <bold>Results:</bold> HDAC9 knockout (KO) mice had reduced lung alveolarization. Young HDAC9 KO-AT2 cells showed increased expression of p16 and p21, and higher release of pro-inflammatory cytokines. Pulmonary inflammation led to the formation of inducible Bronchus-Associated Lymphoid Tissue (iBALT) near remodeled pulmonary vasculature. FACS analysis revealed changes in cell composition in aged HDAC9 KO lungs, with an elevated CD8+/CD4+ T-cell ratio indicating a chronic adaptive immune response. ATAC and RNA sequencing showed alterations related to senescence and metabolism. Metabolomic profiling indicated a shift in metabolites. Senolytic cell therapy mitigated the SAS phenotype in HDAC9-deficient lungs by targeting senescent cells. <bold>Conclusion:</bold> The targeting of HDAC9 and its downstream signaling is crucial to comprehend the regulation of premature aging-related lung remodeling and inflammation.