Aging of the gut involves progressive changes in structure, function, and microbial composition, which impact overall health. The vermiform appendix extends from the apex of the cecum; it contains gut-associated lymphoid tissue and serves as a reservoir of gut microbiota. This study investigates histologic and gene expression changes in 20 morphologically normal appendiceal samples obtained from pediatric (n = 5), adult (n = 8), and geriatric (n = 7) patients. Histologic analysis revealed a higher prevalence of lymphoid follicles reduction and the presence of fibrous obliteration of the appendiceal tip in aged samples. RNA sequencing identified 1004 differentially expressed genes (385 upregulated and 619 downregulated; p < 0.05) between the adult and geriatric population. Upregulated pathways were enriched for oxidative stress response, cholesterol metabolism, and mucosal barrier maintenance, including NRF2 targets (NQO1, MGST1), suggesting enhanced antioxidant activity. Downregulated genes were associated with synaptic signaling, ion channel regulation, and neuronal adhesion (e.g., GRIA2, RET, NOS1, NCAM2, CNTN1), reflecting age-related decline in enteric neuronal integrity. Across all age groups, 25 protein-coding genes showed progressive expression shifts with aging, including upregulation of CLDN2, MUC2, and GDF15, and downregulation of NOG and NELL2, indicating barrier loosening, chronic inflammation, and reduced regenerative potential. These findings suggest that aging of the vermiform appendix recapitulates key processes of intestinal aging, including oxidative stress, inflammaging, and neuronal loss, supporting its potential use as a model tissue for studying gut aging mechanisms.