Integrated Multiomics Analysis and Mendelian Randomization Identify SIRT1 as a Pivotal Aging-Associated Gene in...

Meningiomas (MGMs) are the most prevalent benign intracranial tumors in adults, with incidence markedly increasing with age, underscoring the need to explore aging-associated molecular mechanisms. In this study, we integrated transcriptomic datasets (GSE43290, GSE54934, GSE77259, and GSE183655) from the GEO database and aging-related genes (ARGs) from the Human Aging Genomic Resources to identify key genes implicated in MGM. We screened differentially expressed ARGs (ARG-DEGs) and conducted GO and KEGG pathway enrichment analyses, revealing significant involvement in cancer-related processes, viral infection pathways, and the FoxO signaling pathway. Using LASSO, SVM, CytoHubba-MCC, and MCODE algorithms, we identified two hub ARGs, SIRT1 and CEBPB. Immune infiltration analysis via ssGSEA indicated notable alterations in B cells, neutrophils, helper T cells, and regulatory T cells between MGM and healthy tissues, all closely associated with the hub genes. Furthermore, construction of a miRNA-TF-mRNA regulatory network highlighted the complex upstream regulation of these genes. Mendelian randomization analysis supported a potential causal relationship between SIRT1 and MGM development. Single-cell RNA sequencing data further confirmed heterogeneous expression of SIRT1 across key cell populations within MGM, brain-tumor interface, and dura mater tissues. These findings were validated through qRT-PCR and Western blot analyses, which demonstrated significant differences in SIRT1 expression at both the transcript and protein levels. Collectively, our study reveals that aging and immune dysregulation contribute to MGM pathogenesis and highlights SIRT1, in particular, as a potential diagnostic biomarker and therapeutic target, offering new insights into age-related mechanisms underlying MGM.