Posttraumatic Stress Disorder (PTSD) NAD/Sirtuin Deficiency and SARM1-Mediated Synaptic Vulnerability: Evidence for Accelerated Brain Aging Subtypes

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.