A possible mediating role of SASP in the association between environmental air pollution and incident atherosclerotic cardiovascular disease

Cellular senescence is a state of cell cycle arrest with the loss of capacity for replication. Senescent cells produce molecules called the senescence-associated secretory phenotype (SASP), which mediate the damaging effects of senescent cells, and also signal nearby cells to become senescent. Senescence has been linked to numerous diseases, including atherosclerotic cardiovascular disease (ASCVD). Particulate matter less than 2.5 μm in aerodynamic diameter (PM 2.5 ) has also been associated with ASCVD, as well as cellular senescence. Our aim was to evaluate whether SASP mediated the effect of PM 2.5 exposure on incident ASCVD. Data were from 38,261 participants in the UK Biobank Pharma Proteomics Project (UKB-PPP) who resided within 400 km of Greater London, including air pollution exposure measured in 2010, plasma proteomic measurements collected at baseline, and incident ASCVD ascertained through electronic health records over a mean follow-up of 13.3 years. The SASP index was derived as the first principal component of 94 SASP-related proteins selected a priori. A one–standard deviation (SD) increase in the SASP index was significantly associated with a 12.9% higher risk of incident ASCVD (adjusted hazard ratio [aHR] = 1.129; 95% CI 1.096 to 1.164). PM 2.5 exposure was positively associated with the SASP index (0.026 SD increase per interquartile range [IQR]; 95% CI 0.014 to 0.038) and with incident ASCVD (aHR = 1.059; 95% CI, 1.023 to 1.098 per IQR). The SASP index demonstrated a statistically significant mediation effect in the association between PM 2.5 exposure and incident ASCVD (indirect effect as log(aHR) = 0.0032 mediated through the SASP index, 95% CI 0.0017 to 0.0049), accounting for 5.52% of the total association. The potential mediating role of the SASP index offers insight into a potential mechanism of how senescence may be associated with cardiovascular disease. Further research is warranted to validate our findings and inform the development of targeted public health interventions.