Thursday, April 10, 2025
4/10/2025
Molecular Mechanisms of Aging in Schizophrenia: Implications of Bioenergetic Metabolism and Redox Biology - Project Summary Schizophrenia (SZ) is a devastating psychiatric disorder that brings heavy burden to health care systems. A large literature indicates that individuals with SZ show markers of early aging, such as faster decline in cognitive functioning, increased risk for dementia, and significantly shorter life expectancies. Interestingly, the increased rate of dementia in SZ cannot be fully accounted for by the established dementia risk factors or the pathology of neurodegenerative disorders, suggesting additional pathological causes of cognitive impairment and increased mortality in older SZ patients. Additionally, many SZ patients develop medical conditions such as diabetes, metabolic syndrome, and cardiovascular disease, conditions often exacerbated by side effects of antipsychotic medications. However, it is unclear whether these phenomena reflect premature aging early in life, accelerated pace of aging later, toxic effects of chronic psychosis with antipsychotic therapy, or a mixture of all three. Recent advances in the field of early psychosis including our own work suggest that an “immuno-oxidative” pathway, including NMDA receptor hypofunction/glutamatergic dysfunction, bioenergetic impairment/redox dysregulation, and neuroinflammation, form a “central hub” of brain pathology in SZ. These biochemical abnormalities result in neuronal dysfunction that eventually might disrupt the long distance and large-scale neuronal communication, thereby leading to cognitive dysfunction. To study these phenomena, we have developed novel neuroimaging approaches to measure the redox ratio (NAD+/NADH) in vivo, as well as other markers of mitochondrial function, including creatine kinase (CK)/ATPase activity and the antioxidant glutathione (GSH)—a molecule essential for cellular repair that has functional ties to NAD. Research has shed some light on these mechanisms in early phases of SZ and transition to chronic illness. However, little progress has been made in understanding their role across the lifespan in SZ, despite the fact that these abnormalities are closely linked with the diverse early aging phenomena seen in SZ. In this application, we propose to extend our previous research on the early stage of SZ to older populations to examine the trajectory of biochemical abnormalities in SZ. Our overarching hypothesis is that metabolic and redox abnormalities continue to unfold over the lifespan and are associated with additional sequelae for impaired brain function in SZ. To capture the full aging trajectory, we propose an accelerated longitudinal design where we recruit patients with SZ and age/sex-matched healthy controls (HC) between the ages of 40-70. We will collect a broad neurochemical profile as described above, but also structural, functional, and vascular neuroimaging, as well as comprehensive cognitive and clinical assessments. This rich dataset will enable us to explore dynamic mental illness trajectories. It may provide targets for future interventions to slow down abnormal aging, reduce risk of dementia, and delay mortality among people with SZ.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).