Gene expression composite scores of cellular senescence predict aging health outcomes in the Health and Retirement Study

Cellular senescence, a hallmark of aging, can be quantified by the gene expression composite scores for the canonical senescence pathway (CSP), senescence initiating pathway (SIP), senescence response pathway (SRP), a summary of the three, and the SenMayo gene list; however, these have not been probed in representative populations. Using RNA sequencing data from the U.S. representative Health and Retirement Study (HRS) sample (N = 3580), we examine how these composite scores relate to sociobehavioral factors and aging-related outcomes. Senescence scores generally increase with age except for CSP. Higher scores are observed in women and individuals with class II obesity. All scores, except for CSP, are associated with accelerated epigenetic aging, physiological dysregulation, multimorbidity, cognitive decline, and 6-year mortality (all p < 0.05). These associations largely persist after adjustment for DunedinPACE. Our findings suggest that cellular senescence gene expression composite scores capture meaningful variation in aging-related health and complement existing epigenetic aging biomarkers.