AimIn clinical practice, cardiologists frequently note substantial differences in coronary artery health among patients of the same age bracket. This observation led to our investigation into identifying genes that are shared between atherosclerosis and aging, as well as those that are specifically amplified in atherosclerosis alone.MethodsOur study leveraged existing gene expression datasets from the Gene Expression Omnibus (GEO), avoiding the need for new experimental research involving human or animal subjects. We focused on analyzing two specific datasets: one comprising artery samples from individuals with and without atherosclerosis, and the other featuring samples from people in middle age versus those in older age groups. To identify significant genes, we applied a technique known as the weighted average difference (WAD).ResultsOur analysis identified 14 genes that were upregulated in both aging and atherosclerosis, hinting at the involvement of the type I interferon response in both conditions. Conversely, 408 genes that exhibited heightened activity within atherosclerotic lesions indicated an augmentation in lysosome‐related processes. While aging might create a groundwork that predisposes individuals to atherosclerosis, the progression of atherosclerosis also involves distinct factors such as type I interferon response and an increase in lysosomal activity.ConclusionsAging encompasses more than just the senescence of vascular cells; it is significantly affected by extracellular factors such as type I interferon. The onset of atherosclerosis, therefore, cannot be attributed solely to aging. Instead, it likely involves enhanced mechanisms such as phagocytosis and heighted lysosomal activity. Geriatr Gerontol Int 2024; ••: ••–••.