Integrated proteomic and metabolomic analyses implicate redox-metabolic pathways in PTSD-associated multisystem disease and accelerated aging

Posttraumatic stress disorder (PTSD) is associated with increased risk of chronic disease and premature aging, yet underlying molecular mechanisms remain unclear. We performed plasma proteomics (SomaScan; 9404 proteins) and targeted metabolomics (145 metabolites) in 393 World Trade Center responders (232 with PTSD, 161 trauma-exposed controls). A total of 114 proteins and seven metabolites were differentially expressed in PTSD. Top proteins included NCAN, BCAN, NCAM1, and GDF15. Top metabolites included serotonin, lactate, glutamic acid, and cystathionine. Integrative analyses showed coordinated proteomic-metabolomic alterations, with widespread correlations linking metabolites involved in redox and amino acid metabolism to synaptic and oxidative stress-related proteins. Gene ontology enrichment identified neuronal plasticity, immune activation, extracellular matrix remodeling, and oxidative stress. Proteomic organ aging analyses revealed accelerated aging in the pancreas, lung, and at the organismal level in PTSD. These results reveal a redox-metabolic mechanism through which PTSD may drive multisystem aging and elevate disease risk. PTSD is associated with increased risk of chronic disease and accelerated aging, but the underlying biological mechanisms remain poorly understood. Here, authors integrated proteomic and metabolomic profiling of World Trade Center responders identified coordinated molecular alterations linked to neuronal signaling, oxidative stress, and accelerated organ aging in PTSD.