Project Summary Brain imaging research has revealed accelerated age-related white matter, neurochemical and perhaps cortical changes in patients with schizophrenia spectrum disorders. However, imaging studies are typically brain-focused without system-level investigations on the risk factors. Patients with schizophrenia spectrum disorders also have a much shorter lifespan and high morbidity and mortality. However, medical comorbidity studies typically do not include brain-based investigations. It remains unclear why schizophrenia spectrum disorders have high age-related medical burden. Cumulative stress effects are predictive of successful aging in healthy older adults. In patients with schizophrenia spectrum disorders, cumulative stress may disrupt brain structure and function, and/or impaired brain structure and function may distort normal responses to stress leading to increased cumulative stress effects. The proposal research will study cumulative stress and brain imaging age-progression in an age span of 45 years, using a combined longitudinal and age-cohort cross- sectional design. The study proposes to track the progression of stress-related risk factors in the periphery, and the age-related changes in the brain, and to determine whether they will independently or interactively contribute to age-related medical health and functional outcomes in patients with schizophrenia spectrum disorders. These findings may guide the development of clinically actionable strategies to intercept abnormal aging and promote successful aging in patients with this devastating illness.