T1. EPIGENETIC AGEING IN CHILDREN AND ADOLESCENTS AND ITS ASSOCIATION WITH ENVIRONMENTAL STRESS AND PERIPHERAL INFLAMMATORY BIOMARKERS

Background Early-life stressors have been consistently associated with an increased risk for physical and mental health conditions and are believed to be biologically embedded through epigenetic mechanisms, including a global acceleration of the epigenetic pace of ageing (EPA). Recent literature also describes stress-related alterations in immune and neuroendocrine responses among exposed youth, suggesting that the EPA may be possibly driven by a biological dysregulation of the organism. Among early-life stressors, lower socioeconomic status (SES), childhood maltreatment (CM) and psychiatric disorders seem to play a crucial role. Thus, the aims of this study were: i) to identify environmental stressors and profiles of immune/neuroendocrine biomarkers that are associated with EPA; 3) to explore if immune/neuroendocrine biomarkers mediate the association between early life stress and EPA. Methods 203 children and adolescents (7-17 years) from the Epi_Young_Stress project were included. DNA methylation in PBMCs was quantified with Illumina EPIC array v1 and EPA was estimated using DunedinPACE clock. Biomarkers comprised blood IL-6, IL-10, IL-1β, MCP1, and cortisol and were collected after the Trier-Social-Stress administration. Information regarding SES, CM and current psychiatric status was retrieved during a face-to-face interview. Linear regression and mediation models were conducted controlling for possible confounders. Moreover, a principal component analysis of the immune biomarkers was conducted to capture latent biological profiles. Results Our results indicate that sex (β=.023*), SES (β=-.001***), IL-1β (β=-.026*), and IL-6 (β=.07***) were significantly associated with DunedinPACE. Since IL-6 levels were also related to current psychiatric status, a mediation model was built. Mediation analysis revealed a significant indirect effect of psychiatric status on EPA through IL-6 (β = −0.008*), highlighting the role of altered inflammatory stress reactivity. Notably, this indirect pathway showed an opposite direction to the direct effect (β = 0.028*), suggesting a complex and potentially compensatory biological mechanism. Moreover, PCA of immune markers identified a latent inflammatory dimension characterized by elevated levels of the four biomarkers. This component was negatively associated with psychiatric status and positively with EPA, although no mediation effects were observed for this latent factor. Discussion In conclusion, SES emerges as a strong predictor of higher EPA, while no direct associations with other environmental stressors were found. In addition, psychiatric status appears to be associated with altered inflammatory stress responsivity, particularly involving IL-6 signaling, which may partially contribute to epigenetic ageing. Overall, these findings suggest that reduced plasticity of the immune system constitutes a potential biological pathway linking early adversity, ageing and disease in children and adolescents.