Towards Developing Biomarkers for Premature Aging in Schizophrenia

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Project Summary / Abstract Cumulative evidence from large-clinical and neuroimaging studies suggests that the pathophysiology of schizophrenia involves an increased vulnerability to premature aging. However, this knowledge has not been translated into clinical practice due to the lack of understanding of the biological underpinnings of premature aging in schizophrenia. Additionally, there remains a current lack of diagnostic tools for detecting and monitoring individuals who experience premature aging in a clinical setting. This lack establishes the critical need to develop in vivo biomarkers of premature aging in schizophrenia to provide a novel avenue toward diagnosis and neuroprotective treatment. The current proposal provides a step to tackling this challenge through a large, multimodal study of schizophrenia. The central hypotheses state that individuals with schizophrenia are more vulnerable to premature aging, as indicated by an increased expression of senescence-associated secretory phenotype (SASP) proteins, and that the increased expression of SASP proteins explains abnormalities in physical health, cognition, and brain structure in schizophrenia. The applicant, Dr. Johanna Seitz-Holland, has access to several cross-sectional datasets, including clinical, cognitive, blood, structural, and diffusion data, spanning the schizophrenia lifespan. In the K99 phase, she will utilize data from 80 individuals with early schizophrenia and 80 matched healthy individuals to establish the increased expression of SASP proteins as a biomarker for increased vulnerability to premature aging in early course schizophrenia. In the R00 phase, Dr. Seitz-Holland will include data from over 700 individuals (18-85 years) and characterize the role of the increased expression of SASP proteins as a mediator between schizophrenia, physical health, cognition, and structural brain abnormalities across the lifespan. Successful completion of these aims will yield several impactful outcomes. The findings will inform the development of a clinically feasible, minimally invasive, and low-risk biomarker for premature aging. In addition, the findings will allow the development of a parsimonious hypothesis that accounts for aspects of brain and physical health deficits. Lastly, they will provide a scientific basis for developing novel neuroprotective treatments. Dr. Seitz-Holland’s long-term goal is to conduct translational research to increase the life quality of those with psychotic disorders. This application builds on her postdoctoral training in multimodal trajectory schizophrenia studies and complements it with training from world-class experts in the use and analysis of blood biomarker data and geriatric science. This award will thus provide her with a unique opportunity to develop into an independent researcher who can effectively conduct multimodal psychiatric studies and translate findings into the evidence-based diagnosis and treatment strategies needed in clinical science.