Abstract
IMPORTANCE: In the US, Black individuals experience higher mortality risk than White individuals. Greater stress exposure and its biological sequelae are theorized to drive this heightened risk. OBJECTIVE: To evaluate whether greater cumulative lifespan stress exposure and elevated inflammation are associated with increased mortality risk among Black compared with White US individuals. DESIGN, SETTING, AND PARTICIPANTS: This longitudinal cohort study (St Louis Personality and Aging Network) recruited participants from 2007 to 2011 from the St Louis, Missouri, metropolitan area. Participants were required to have a mailing address to permit longitudinal follow-up and sixth grade reading level to facilitate understanding of the consent form; active psychosis was excludsionary. Data were analyzed from April to September 2025. EXPOSURE: A latent lifespan cumulative stress factor was derived by applying bifactor confirmatory analysis to assessments of childhood maltreatment, lifetime trauma exposure, research assistant-verified stressful life events, major experiences of discrimination, and indices of socioeconomic status (ie, highest level of self and parental education, and annual household income). MAIN OUTCOMES AND MEASURES: C-reactive protein (CRP) and interleukin-6 (IL-6) were measured from serum collected from 2014 to 2019 following all indices included in the cumulative stress factor. A CRP-IL-6 composite was formed. Mortality and cause of death were obtained from the Centers for Disease Control and Prevention National Death Index queried in December 2023. Linear regression and accelerated failure time models estimated mediational effects (ie, direct and indirect associations). RESULTS: Among 1554 participants (505 Black [32.5%]; 1049 White [67.5%]; 853 [54.9%] female; mean [SD] age at baseline, 58.1 [2.9] years), Black individuals had shorter survival times than White individuals (time ratio, 0.937 [95% CI, 0.918 to 0.957]). Cumulative lifetime stress and the CRP-IL-6 composite, which were each higher among Black compared with White individuals, partially mediated the associations between race and mortality, accounting for 49.3% of racial disparities in mortality (indirect associations: serial, b = -0.006 [95% CI, -0.008 to -0.044]; cumulative stress, b = -0.009 [95% CI, -0.017 to -0.002]; CRP-IL-6, b = -0.016 [95% CI, -0.025 to -0.009]). CONCLUSIONS AND RELEVANCE: In this cohort study of St Louis adults, heightened cumulative lifespan stress and elevated inflammation were associated with shorter survival among Black participants, suggesting these pathways may represent plausible mechanisms mediating racial disparities in mortality among Black and White US individuals. The findings underscore the need for policies that address structural racism, alongside treatments that reduce inflammation and limit stress exposure to reduce mortality disparities.