Introduction: Cardiovascular diseases (CVDs) continue to be the leading cause of morbidity and mortality among older adults, largely driven by ageing-related processes, including cellular senescence. Senescent cells develop a senescence-associated secretory phenotype (SASP), characterized by the release of pro- and anti-inflammatory proteins. The SASP alters the tissue microenvironment and promotes chronic inflammation and endothelial dysfunction. Previous studies have identified a robust SASP core proteome, suggesting that circulating SASP proteins may serve as biomarkers of biological ageing and predictors of age-related diseases.
Methods: In this study, we examined associations between circulating SASP proteins and cardiovascular health outcomes, including myocardial infarction, stroke, congestive heart failure, and hypertension. We measured a SASP panel of eleven proteins (CCL3, TNFRSF6, IGFBP-1, Total Inhibin, MMP-1, FABP4, GDF-15, IL-15, IL-6, Leptin, and Osteopontin), in plasma samples from 1,779 participants of the CARLA study aged 45–83 years at baseline. Up to 20 years of follow-up data were available. All analyses were adjusted for age and sex.
Results: Multivariate logistic regression revealed significant and biologically relevant associations between circulating SASP proteins and cardiovascular outcomes. Higher GDF-15 levels were positively associated with myocardial infarction (OR 1.72, 95% CI 1.28–1.28, p = 0.052) and stroke (OR 1.90, 95% CI 1.02–3.55, p = 0.047). Elevated levels of IGFBP-1 (OR 1.41, 95% CI 0.49–3.71, p = 2.0×10-4) and GDF-15 (OR 2.23, 95% CI 1.16–4.68, p = 2.1×10-5) were positively associated with congestive heart failure. For hypertension, FABP4, IL-15, and Leptin showed positive associations (OR 1.34, 2.42, 1.44; p < 0.027), whereas IGFBP-1 and Total Inhibin were inversely associated (OR 0.79, 0.45; p < 0.0055). TNFRSF6, MMP-1, IL-6, and Osteopontin were not significantly associated.
Spearman correlations were used to examine associations of circulating SASP proteins with cardiac autonomic function and left ventricular structure, with p-values adjusted for multiple testing using the false discovery rate (FDR) method. IGFBP-1 was positively correlated with HRV indices SDNN (r = 0.072, FDR p = 0.013) and RMSSD (r = 0.094, FDR p = 0.00077), whereas FABP4 (r = -0.083, FDR p = 0.0034; r = -0.060, FDR p = 0.049) and Leptin (r = -0.110, FDR p = 8.86×10-5; r = -0.088, FDR p = 0.00194) were inversely correlated. GDF-15 (r = -0.068, FDR p = 0.022) and IL-6 (r = -0.083, FDR p = 0.0047) showed additional inverse associations with SDNN. Echocardiographic analyses indicated that higher Leptin (r = -0.270, FDR p = 1.24×10-27) and FABP4 (r = -0.179, FDR p = 5.75×10-12) levels were associated with increased left ventricular end-diastolic diameter, while TNFRSF6 displayed a modest inverse correlation (r = -0.077, FDR p = 0.0068).
Conclusion: These findings highlight the interplay between circulating SASP proteins and cardiovascular outcomes in an ageing cohort. GDF-15, IGFBP-1, Leptin, FABP4, and IL-15 were associated with myocardial infarction, stroke, congestive heart failure, and hypertension, as well as with cardiac autonomic function and structural parameters. Overall, these results underscore the potential of SASP proteins as biomarkers for cardiovascular risk stratification in epidemiological studies.
