Epigenetic Aging in Monozygotic Twins Exposed to Psychosocial Adversity Suggests Sex-Specific, Contextual Outcomes

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Abstract
Background: Psychosocial adversity (PSA) contributes to long-term health disparities and increased risk for non-communicable diseases. The effects of PSA arise through complex interactions between genes and the environment, which involve immune, endocrine, and epigenetic dysregulation. Methods: To examine how adversity affects mental and physical health via epigenetic alterations in a more controlled way, we examined the relationship between PSA and epigenetic aging in 28 monozygotic (MZ) twin pairs discordant for negative life experiences. Whole-blood DNA methylation (DNAm) profiling was performed using the Illumina Infinium EPIC v2 BeadChip array. Epigenetic age acceleration (EAA) was calculated using a panel of first to third-generation clocks, namely, Horvath, Hannum, PhenoAge (Levine), GrimAge (v2.0), Elastic Net and DunedinPACE. Results: Though we did not observe any significant group-level differences in epigenetic age acceleration between PSA and control at large, sex-stratified analyses revealed that PSA exposed males exhibited significant reductions in EAA compared to their co-twins when assessed using the Hannum, PhenoAge, and DunedinPACE clocks. In females, regression analyses showed significant positive associations between EAA and both negative life events and shame perception. Application of the dimensional model of adversity further revealed that psychosocial threat was strongly associated with increased EAA in females, whereas deprivation showed a weaker but significant association with EAA in males. These findings suggest a sex-specific and context-dependent biological response to PSA, potentially reflecting either adaptive or maladaptive epigenetic remodelling. Conclusion: The observed epigenetic age deceleration in PSA-exposed males, together with the associations between EAA and threat, shame perception, and life events in females, highlight the importance of context and perception in shaping sex-specific responses to adversity. Our results underscore the utility of MZ twin study designs in isolating psychosocial stress driven epigenetic effects and support DNAm clocks as biomarkers of stress-related biological aging. Overall, this study advances our understanding of the molecular underpinnings of social health inequalities and may inform future interventions aimed at promoting resilience and stress adaptation.

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