Deciphering the molecular basis of accelerated biological aging in substance use disorder: Integrative transcriptomic analysis

Substance use disorders (SUDs) contribute to early-onset age-related diseases and represent a major global health burden. Accelerated biological aging (AA) has been proposed as a key factor behind SUD-related morbidity and mortality. This study aimed to elucidate the molecular basis of AA in SUD by analyzing transcriptomic profiles in postmortem dorsolateral prefrontal cortex tissue from individuals with SUD, including alcohol (AUD), opioid (OUD), and stimulant use disorders (StUD). We examined brain tissue from 58 donors to assess differential aging patterns and AA across SUD using epigenetic clocks specifically designed for brain tissues (DNAmClock Cortical , CerebralCortexClock common , and PCBrainAge). Samples were then stratified into those with and without AA to perform differential expression analyses across groups and to identify biological pathways potentially related to AA. Analyses identified multiple differentially expressed genes linked to AA, revealing unique and overlapping biological pathways within SUD subtypes. Further, our analysis highlighted shared aging mechanisms across SUD subtypes, particularly mitochondrial signaling and metabolic processes. While insightful, these subtype-specific findings remain exploratory due to limited statistical power. Most biological pathways underlying AA in SUD appear to be subtype-specific, with distinct molecular signatures influenced by substance type. Given the cross-sectional design, causal interpretations are limited. Further research may support targeted interventions for aging-related risks in SUD populations.