Posttraumatic Stress Disorder (PTSD) NAD/Sirtuin Deficiency and SARM1-Mediated Synaptic Vulnerability: Evidence for...

Anxiety disorders and posttraumatic stress disorder (PTSD) often occur alongside signs of accelerated biological aging, yet the molecular pathways that connect genetic liability to synaptic and circuit-level dysfunction remain unclear. We performed a multi-gene-set transcriptome-wide association study using large-scale genome-wide association study (GWAS) summary statistics for anxiety disorders and PTSD, with a focus on curated aging-related pathways across brain regions involved in fear, reward, memory, and stress regulation. The analysis identified 185 significant enrichments, with strong cross-disorder concordance in senescence, telomere maintenance, and mitochondrial modules. PTSD showed a distinctive negative signature in nicotinamide adenine dinucleotide (NAD) metabolism and sirtuin-related pathways, most prominently driven by sirtuin 3 (SIRT3), together with evidence of sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1)-linked axonal and synaptic vulnerability. Anxiety disorders showed stronger enrichment in mitochondrial intrinsic apoptosis and inflammatory-redox signaling, alongside glutamatergic and astrocytic plasticity changes. Both conditions shared senescence and deoxyribonucleic acid (DNA)-damage programs, with NIMA-related kinase 4 (NEK4) emerging as a common driver. These pathways converged on complement-mediated pruning and presynaptic remodeling, suggesting a mechanistic bridge from cellular aging to fear and reward circuit dysfunction. Together, the findings support an association-based model in which genetic liability for anxiety disorders and PTSD converges on stress-aging biology at the synapse, while diverging by disorder. This framework points to candidate biologically distinct subtypes and offers practical opportunities for biomarker development, patient stratification, and subtype-guided therapeutic strategies. These subtype labels are proposed biological hypotheses rather than validated clinical categories.