RNA-based Indicators of Cellular Senescence Predict Aging Health Outcomes in the Health and Retirement Study

Abstract Cellular senescence, a hallmark of aging, can be quantified through the expression levels of genes related to cell cycle arrest (CCA), macromolecular damage (MD), and the senescence-associated secretory phenotype (SASP). How cellular senescence links to sociodemographic characteristics, behavioral factors, and age-related health outcomes in representative populations remains unknown. Using a nationally representative subsample from the U.S. Health and Retirement Study with RNA sequencing data, we calculated five RNA-based cellular senescence scores: CCA, MD, SASP, a summary senescence score, and SenMayo. Linear regression models assessed their associations with sociodemographic and behavioral factors (N=3,580), as well as age-related health outcomes, including mortality (N=3,554), multimorbidity (N=3,580), biological age acceleration (N=2,660), and epigenetic age acceleration (N=3,580). Senescence scores increased with age (β=0.04–0.13, all p<0.043), except for CCA, which decreased (β=-0.05 to -0.09, all p<0.019). Women (β=0.04, p=0.021) and individuals with class II obesity (β=0.08, p<0.001) exhibited higher senescence levels. All senescence scores, except CCA, were significantly associated with epigenetic aging, accelerated biological age, multimorbidity, and 6-year mortality (all p<0.001). These associations remained significant after adjusting for GrimAge indicating that cell senescence adds to the explanation of health outcomes by epigenetic mechanisms . RNA-based senescence scores enhance our understanding of aging mechanisms related to physiological decline and health outcomes.