Genetics of the Leading Causes of Death in Human Aging

The relationship between age-related genetic factors and health conditions is crucial in aging research, particularly with respect to the leading global causes of mortality identified by the World Health Organization (WHO). To investigate the direct impact of these genes, we conducted a disease association analysis that compared 307 age-related genes with multiple control gene sets. Our results showed that the age-related gene set was significantly enriched with 113 disease categories compared to the controls, achieving a stringent false discovery rate (FDR) of less than 1 × 10−5. Interestingly, the disease ontology categories did not align directly with the WHO’s primary causes, leading us to reclassify them using the ICD-11 framework. Our analysis revealed that age-related genes are enriched among leading causes of death, particularly those affecting the cardiovascular system, brain, and lungs. We identified 15 recurring genes, including TNF, AKT1, IL6, and CDKN2A, with no evident publication bias, except for TP53, which may have a modest effect. These genes are associated with cancer, inflammatory diseases, and metabolic disorders, highlighting protein–protein networks in nitric oxide regulation and insulin signaling. This study provides a comprehensive analysis and reclassification of the genetic factors linked to human aging and health outcomes, generating key hypotheses in human aging.