ObjectiveThoracic aortic aneurysm and dissection (TAAD) is a cardiovascular disease with a high mortality rate. Aging is an important risk factor for TAAD. This study explored the relationship between aging and TAAD and investigated the underlying mechanisms, which may contribute to the diagnosis and treatment of TAAD.MethodsHuman aging genes were obtained from the Aging Atlas official website. Various datasets were downloaded from the GEO database:the human TAAD dataset GSE52093 were used for screening differentially expressed genes (DEGs); GSE137869, GSE102397 and GSE153434 were used as validation sets, and GSE9106 was used for diagnostic prediction of receiver operating characteristic (ROC) curves. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA), and protein–protein interaction (PPI) network analysis were used to screen differentially co-expressed genes from human aging genes and TAAD. Using five methods of the cytoHubba plugin in Cytoscape software (Degree, Closeness, EPC, MNC, Radiality), hub genes were identified from the differentially co-expressed genes. Single-cell RNA sequencing was used to verify the expression levels of hubgenes in different cell types of aortic tissue. ROC curves were used to further screen for diagnostic genes.ResultsA total of 70 differentially co-expressed genes were screened from human aging genes and DEGs in human TAAD dataset GSE52093. GO enrichment analysis revealed that the DEGs played a major role in regulating DNA metabolism and damaged DNA binding. KEGG enrichment analysis revealed enrichment in the longevity regulating pathway, cellular senescence, and HIF-1 signaling pathway. GSEA indicated that the DEGs were concentrated in the cell cycle and aging-related p53 signaling pathway. The five identified hubgenes wereMYC,IL6,HIF1A,ESR1, andPTGS2. Single-cell sequencing of the aging rat aorta showed that hubgenes were expressed differently in different types of cells in aortic tissue. Among these five hubgenes,HIF1AandPTGS2were validated in the aging dataset GSE102397;MYC,HIF1AandESR1were validated in the TAAD dataset GSE153434. The combined area under the diagnostic ROC curve (AUC) values for the five hub genes were >0.7 in the testing and training sets of the dataset GSE9106. The combined AUC values ofMYCandESR1were equal to the combin ed AUC values of the five hub genes.ConclusionThe HIF-1 signaling pathway may play an important role in TAAD and aging.MYCandESR1may have diagnostic value for aging-related TAAD.