Genetics of the Leading Causes of Death in Human Aging

Abstract The relationship between age-related genetic factors and health conditions has become a pivotal focus in aging research, particularly as the World Health Organization (WHO) delineates the leading global causes of mortality. However, the direct impact of age-related genes on the leading cause of death remains poorly understood. To investigate this gene-aging relationship, we analyzed protein-protein interactions using gene set enrichment analysis (GSEA) of a set of 307 age-related genes previously curated. The results indicated significant associations with 113 diverse disease categories, while adhering to a stringent false discovery rate (FDR) threshold of less than 1 x 10 -5 . Due to the difficulties in aligning the disease categories with WHO’s leading causes of death, we reclassified the WHO categories using the more precise nomenclature specified in the 11 th Revision of the International Classification of Diseases (ICD-11). The age-related genes account for the leading causes of death, with the exceptions being two infectious communicable diseases, tuberculosis and COVID-19. They impact the cardiovascular system, brain, lungs, and the whole body, while this study could not identify death by aging, which is not a well-defined medical cause of death. Furthermore, we identified a set of 15 recurring genes shared among multiple diseases, including TNF, AKT1, IL6, CDK2A, APOE, and TP53. This gene set was enriched for several disease categories, including cancer, inflammatory diseases, metabolic disorders, and neurodegenerative diseases. Additionally, it shows significant enrichment in various biological categories, with the regulation of nitric oxide activity being the most prominent; other enriched categories include the regulation of microRNA, lipid and carbohydrate metabolism, smooth muscle cell proliferation, insulin signaling, and phosphatidylinositol-3 kinase (PI3K) signaling. The findings suggest that the recurring genes act as pleiotropic hubs, influencing multiple leading causes of death, while other genes are more specific to each disease category.