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Oxidative stress and epigenetic mortality risk score: associations with all-cause mortality among elderly people

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Abstract

Oxidative stress (OS) has been found to be related to accelerated aging and many aging-related health outcomes. Recently, an epigenetic “mortality risk score” (MS) based on whole blood DNA methylation at 10 mortality-related CpG sites has been demonstrated to be associated with all-cause mortality. This study aimed to address the association between OS and MS, and to assess and compare their performance in the prediction of all-cause mortality. For 1448 participants aged 50–75 of the German ESTHER cohort study, the MS was derived from the DNA methylation profiles measured by Illumina HumanMethylation450K Beadchip and the levels of two urinary OS markers, 8-isoprostane (8-iso) and oxidized guanine/guanosine [including 8-hydroxy-2′-deoxyguanosine (8-oxo)], were measured by ELISA kits. Associations between OS markers and the MS were evaluated by linear and ordinal logistic regression models, and their associations with all-cause mortality were examined by Cox regression models. Both OS markers were associated with the MS at baseline. The 8-iso levels and MS, but not 8-oxo levels, were associated with all-cause mortality during a median follow-up of 15.1 years. Fully-adjusted hazard ratios (95% CI) were 1.56 (1.13–2.16) for the 4th quartile of 8-iso levels compared with the 1st, 1.71 (1.27–2.29) and 2.92 (2.03–4.18) for the moderate and high MS defined by 2–5 and > 5 CpG sites with aberrant methylation compared with a MS of 0–1, respectively. After controlling for 8-iso levels, the hazard ratios of MS remained essentially unchanged while the association of 8-iso levels with mortality was attenuated. This study demonstrates that OS is highly associated with the epigenetic MS, and the latter at the same time has a higher predictive value for all-cause mortality.

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Acknowledgements

The ESTHER study was supported by the Baden-Württemberg state Ministry of Science, Research and Arts (Stuttgart, Germany), the Federal Ministry of Education and Research (Berlin, Germany), and the Federal Ministry of Family Affairs, Senior Citizens, Women and Youth (Berlin, Germany). Measurements of the oxidative stress markers were partly funded by the German Research Foundation (DFG, Grant No.: SCHO 1545/3-1). Xu Gao and Xīn Gào are supported by the grant from the China Scholarship Council (CSC). The authors gratefully acknowledge contributions of DKFZ Genomics and Proteomics Core Facility, especially Melanie Bewerunge-Hudler and Matthias Schick, in the processing of DNA samples and performing the laboratory work, Dr. Jonathan Heiss for providing the estimation of leukocyte distribution and Ms. Chen Chen for the language assistance.

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  1. Xu Gao

    Present address: Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA

Authors and Affiliations

  1. Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120, Heidelberg, Germany

    Xu Gao, Xīn Gào, Yan Zhang, Ben Schöttker & Hermann Brenner

  2. Medical Faculty Heidelberg, University of Heidelberg, Im Neuenheimer Feld 672, 69120, Heidelberg, Germany

    Xu Gao & Xīn Gào

  3. Network Aging Research, University of Heidelberg, Bergheimer Straße 20, 69115, Heidelberg, Germany

    Xīn Gào, Ben Schöttker & Hermann Brenner

  4. Saarland Cancer Registry, Präsident Baltz Strasse 5, 66119, Saarbrücken, Germany

    Bernd Holleczek

  5. Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, 69120, Heidelberg, Germany

    Hermann Brenner

  6. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Hermann Brenner

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Gao, X., Gào, X., Zhang, Y. et al. Oxidative stress and epigenetic mortality risk score: associations with all-cause mortality among elderly people. Eur J Epidemiol 34, 451–462 (2019). https://doi.org/10.1007/s10654-019-00493-7

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