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

Abstract Genetic background is a major confound in studies linking psychosocial adversity (PSA) to biological ageing, and few designs can fully control for it. We used the ImmunoTwin cohort of monozygotic (MZ) twin pairs discordant for PSA to hold genetic background constant and isolate its epigenetic signature directly. Epigenetic age acceleration (EAA) was measured across six clocks (Horvath, Hannum, Elastic Net, Levine, GrimAge v2, DunedinPACE) in 28 PSA-discordant MZ pairs (18 female, 10 male), with within-pair PSA differences derived from six questionnaires and further resolved into threat and deprivation domains using the dimensional model of adversity and psychopathology (DMAP). No group-level EAA differences emerged across the full sample, but sex-stratified analysis told a different story. PSA-exposed males showed reduced EAA relative to their genetically identical co-twin on the Hannum, Levine and DunedinPACE clocks; females showed no such shift. Within pairs, however, greater PSA discordance tracked with higher EAA in females, driven by shame perception, negative life events and threat, and with deprivation-linked EAA change in males. Because co-twins share genotype, developmental timing and much of their early environment, these within-pair effects cannot be explained by heritable variation, and instead point to a genuinely sex-specific, context-dependent biological embedding of adversity. The findings are preliminary given modest stratum sizes, but they offer some of the cleanest evidence yet that the epigenetic footprint left by PSA diverges by sex once genetic background is held constant. Highlights Monozygotic twins isolate the epigenetic signature of PSA from genetic background PSA-exposed males show reduced epigenetic age acceleration versus their co-twin In females, shame, life events and threat drive greater epigenetic ageing In males, deprivation rather than threat drives epigenetic ageing differences Adversity’s epigenetic footprint diverges sharply by sex, twin design confirms