Epigenetic age acceleration mediates the association between low-grade systemic inflammation and cardiovascular diseases: insight from the NHANES 1999-2002.

Background: Currently, with the global aging of the population, inflammation, recognized as a hallmark in age-related diseases, has been studied and linked to cardiovascular diseases (CVD). However, limited evidence on whether inflammation modifies epigenetic aging and affects CVD risk.

Methods: This study included 404 CVD patients and 1941 non-CVD individuals from the 1999-2002 National Health and Nutrition Examination Survey cross-sectional data. Low-grade systemic inflammation was assessed using C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), and systemic inflammation response index (SIRI). Epigenetic age accelerations (EAAs) were calculated as the residuals between chronological and epigenetic ages: Horvath age acceleration (AgeAccel), AgeAccelHannum, and AgeAccelPheno. Weighted linear and logistic regression analyzed the associations between exposures and outcomes, with mediating effects assessed using the Sobel test.

Results: After adjusting confoundings, the log-transformed NLR and SIRI were positively associated with CVD risk, and the odds ratio (OR) ranges from 1.260 to 1.354 (all P < 0.05). Furthermore, the ln-transformed CRP was positively associated with AgeAccelHannum and AgeAccelPheno, and the coefficient (β) ranges from 0.505 to 1.304 (all P < 0.05); the ln-transformed NLR and SIRI were positively associated with all three EAAs, and the β ranges from 0.392 to 2.212 (all P < 0.005). Additionally, 1-unit increase in AgeAccelHannum and AgeAccelPheno was associated with 2.8% (OR: 1.028, 95% CI 1.007-1.049, P = 0.011) and 3.5% (OR: 1.035, 95% CI 1.014-1.056, P = 0.002) increase in CVD risk, respectively. After adjusting confoundings, mediation analysis showed that AgeAccelHannum mediates 10.44% (P = 0.046) of the association between NLR and CVD risk; and AgeAccelPheno mediates 24.03% (P = 0.009) and 18.16% (P = 0.015) of the NLR-CVD and SIRI-CVD risk associations, respectively.

Conclusion: Our results demonstrate that EAAs mediate the association between systemic inflammation and CVD risk, highlighting the potential of a multi-target approach to inflammation and epigenetic modifications for personalized management to reduce CVD risk.