Accelerated Pace of Aging in Schizophrenia: Five Case-Control Studies

Objectives Schizophrenia is associated with increased risk of developing multiple aging-related diseases, including metabolic, respiratory, and cardiovascular diseases, and Alzheimer's and related dementias, leading to the hypothesis that schizophrenia is accompanied by accelerated biological aging. This has been difficult to test because there is no widely accepted measure of biological aging. Epigenetic clocks are promising algorithms that are used to calculate biological age on the basis of information from combined cytosine-phosphate-guanine sites (CpGs) across the genome, but they have yielded inconsistent and often negative results about the association between schizophrenia and accelerated aging. Here we test the schizophrenia-aging hypothesis using a DNA methylation measure that is uniquely designed to predict an individual's rate of aging. Methods We brought together 5 case-control datasets to calculate DunedinPACE (Pace of Aging Calculated from the Epigenome), a new measure trained on longitudinal data to detect differences between people in their pace of aging over time. Data were available from 1812 psychosis cases (schizophrenia or first-episode psychosis) and 1753 controls. Mean chronological age was 38.9 (SD=13.6) years. Results We observed consistent associations across datasets between schizophrenia and accelerated aging as measured by DunedinPACE. These associations were not attributable to tobacco smoking or clozapine medication. Conclusion Schizophrenia is accompanied by accelerated biological aging, already by midlilfe. This may explain schizophrenia's wide-ranging risk for developing multiple different age-related physical diseases: metabolic, respiratory, cardiovascular, dementia. Measures of biological aging could prove valuable for assessing patients' risk for physical and cognitive decline and for evaluating intervention effectiveness.