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Schizophrenia and Epigenetic Aging Biomarkers: Increased Mortality, Reduced Cancer Risk, and Unique Clozapine Effects

Published:February 07, 2020DOI:https://doi.org/10.1016/j.biopsych.2020.01.025

      Abstract

      Background

      Schizophrenia (SZ) is associated with increased all-cause mortality, smoking, and age-associated proteins, yet multiple previous studies found no association between SZ and biological age using Horvath’s epigenetic clock, a well-established aging biomarker based on DNA methylation. However, numerous epigenetic clocks that may capture distinct aspects of aging have been developed. This study tested the hypothesis that altered aging in SZ manifests in these other clocks.

      Methods

      We performed a comprehensive analysis of 14 epigenetic clocks categorized according to what they were trained to predict: chronological age, mortality, mitotic divisions, or telomere length. To understand the etiology of biological age differences, we also examined DNA methylation predictors of smoking, alcohol, body mass index, serum proteins, and cell proportions. We independently analyzed 3 publicly available multiethnic DNA methylation data sets from whole blood, a total of 567 SZ cases and 594 nonpsychiatric controls.

      Results

      All data sets showed accelerations in SZ for the 3 mortality clocks up to 5 years, driven by smoking and elevated levels of 6 age-associated proteins. The 2 mitotic clocks were decelerated in SZ related to antitumor natural killer and CD8T cells, which may help explain conflicting reports about low cancer rates in epidemiological studies of SZ. One cohort with available medication data showed that clozapine is associated with male-specific decelerations up to 7 years in multiple chronological age clocks.

      Conclusions

      Our study demonstrates the utility of studying the various epigenetic clocks in tandem and highlights potential mechanisms by which mental illness influences long-term outcomes, including cancer and early mortality.

      Keywords

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      Linked Article

      • Epigenetic Clocks in Schizophrenia: Promising Biomarkers, Foggy Clockwork
        Biological PsychiatryVol. 88Issue 3
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          Increased mortality in schizophrenia runs through all age groups, resulting in a 10- to 20-year shortening of life expectancy compared with the general population. This “mortality gap” may have grown wider over the course of the last several decades (1), mandating renewed efforts by academia and the public health sector to mitigate the current situation. Importantly, two thirds of the excess mortality in schizophrenia is driven by chronic metabolic diseases, including type II diabetes and dyslipidemia, and cardiovascular disease with a multitude of contributing factors, such as unhealthy lifestyles, poor diet, smoking, and excess alcohol consumption (1).
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