Causal and Systems-Based Epigenetic Clocks Demonstrate Accelerated Aging in Patients with Schizophrenia

Abstract:
Background/Significance: Schizophrenia is a severe, chronic psychiatric disorder associated with numerous physiological and behavioral changes. Schizophrenia is associated premature death, in some studies up to 20 years earlier than age-matched controls, which is not entirely explained by behavioral factors. Prior epigenetic studies have suggested there are accelerated aging phenotypes associated with schizophrenia, but these have depended on the specific epigenetic clock used1. New, more advanced epigenetic clocks may allow insight into the potential mechanistic relationships between schizophrenia, epigenetic changes associated with aging, and premature morbidity and mortality.

Methods: In this study, we analyzed causality-enriched epigenetic clocks2 as well as systems-based epigenetic clocks3 in publicly available datasets of patients with Schizophrenia and controls. Seven cross-sectional datasets containing DNA methylation data were available for this study, with a total samples size of 4,146 individuals, including 2,210 patients with schizophrenia and 1,936 controls. Meta-analyses utilized fixed effects models and accounted for age and reported sex.

Results: Meta-analyses demonstrated broad evidence of accelerated epigenetic aging in the tested epigenetic clocks in patients with schizophrenia compared to healthy controls. Across all three causality-enriched clocks (CausAge, DamAge, and AdaptAge), patients with schizophrenia had accelerated epigenetic aging compared to controls (all p < 0.001). SystemsAge also demonstrated accelerated epigenetic aging in patients with schizophrenia (p < 1e-117). This age acceleration was seen in ten of the eleven individual system clocks, with the most prominent acceleration in the Heart, Lung, and Inflammation clocks. Further analyses assessed for associations with these clocks and exposure to psychiatric medications, which identified an association between Clozapine use and age acceleration in the Heart, Metabolic, Inflammation, and Lung clocks. Further sub-analyses assessed potential differences in first-episode psychosis. Age-by-disease interactions were seen in the causality-enriched clocks, but generally absent from the systems-based clocks.

Discussion: These are the first analyses of causality- and systems-based clocks in patients with schizophrenia. They demonstrate broad evidence of accelerated aging, including in both harmful (e.g., DamAge) and adaptive (e.g., AdaptAge) methylation sites, and across a wide range of physiological systems. These data support recent findings in 2nd generation epigenetic clocks of accelerated epigenetic aging in patients with Schizophrenia, and suggests a broad premature aging process that invokes both protective and damaging changes with aging1. Future work may examine whether specific subtypes/symptom patterns are related to age acceleration, and whether other medications may blunt or enhance these effects.

Conclusions/Implications: Patients with schizophrenia show broad age acceleration across multiple clocks and biological systems. Further age acceleration is seen in individuals treated with Clozapine, particularly in cardiometabolic clocks, supporting that there are physical health consequences to both the disease and treatment of schizophrenia.