Oxidative stress and epigenetic mortality risk score: associations with all-cause mortality among elderly people
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.
KeywordsOxidative stress DNA methylation Mortality risk score Epigenetic epidemiology Aging All-cause mortality
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.
Compliance with ethical standards
Conflict of interests
The authors declare that they have no competing interests.
- 1.Salmon AB, Richardson A, Perez VI. Update on the oxidative stress theory of aging: does oxidative stress play a role in aging or healthy aging? Free Radic Biol Med. 2010;48(5):642–55. https://doi.org/10.1016/j.freeradbiomed.2009.12.015.CrossRefGoogle Scholar
- 4.Schöttker B, Brenner H, Jansen EH, Gardiner J, Peasey A, Kubinova R, et al. Evidence for the free radical/oxidative stress theory of ageing from the CHANCES consortium: a meta-analysis of individual participant data. BMC Med. 2015;13(1):300. https://doi.org/10.1186/s12916-015-0537-7.CrossRefGoogle Scholar
- 5.Stephens JW, Khanolkar MP, Bain SC. The biological relevance and measurement of plasma markers of oxidative stress in diabetes and cardiovascular disease. Atherosclerosis. 2009;202(2):321–9. https://doi.org/10.1016/j.atherosclerosis.2008.06.006.CrossRefGoogle Scholar
- 6.Montuschi P, Collins JV, Ciabattoni G, Lazzeri N, Corradi M, Kharitonov SA, et al. Exhaled 8-isoprostane as an in vivo biomarker of lung oxidative stress in patients with COPD and healthy smokers. Am J Respir Crit Care Med. 2000;162(3 Pt 1):1175–7. https://doi.org/10.1164/ajrccm.162.3.2001063.CrossRefGoogle Scholar
- 9.Gao X, Gào X, Zhang Y, Breitling LP, Schöttker B, Brenner H. Associations of self-reported smoking, cotinine levels and epigenetic smoking indicators with oxidative stress among older adults: a population-based study. Eur J Epidemiol. 2017;32(5):443–56. https://doi.org/10.1007/s10654-017-0248-9.CrossRefGoogle Scholar
- 11.Hedman AK, Mendelson MM, Marioni RE, Gustafsson S, Joehanes R, Irvin MR et al. Epigenetic patterns in blood associated with lipid traits predict incident coronary heart disease events and are enriched for results from genome-wide association studies. Circ Cardiovasc Genet 2017;10(1). https://doi.org/10.1161/circgenetics.116.001487.
- 15.Zhang Y, Saum KU, Schöttker B, Holleczek B, Brenner H. Methylomic survival predictors, frailty, and mortality. Aging (Albany NY) 2018. https://doi.org/10.18632/aging.101392.
- 20.Harrell FE Jr, Lee KL, Mark DB. Multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Stat Med. 1996;15(4):361–87. https://doi.org/10.1002/(SICI)1097-0258(19960229)15:4%3c361:AID-SIM168%3e3.0.CO;2-4.CrossRefGoogle Scholar
- 21.Schöttker B, Brenner H, Jansen EH, Gardiner J, Peasey A, Kubinova R, et al. Evidence for the free radical/oxidative stress theory of ageing from the CHANCES consortium: a meta-analysis of individual participant data. BMC Med. 2015;13(1):300. https://doi.org/10.1186/s12916-015-0537-7.CrossRefGoogle Scholar
- 22.Kjaer LK, Cejvanovic V, Henriksen T, Petersen KM, Hansen T, Pedersen O, et al. Cardiovascular and all-cause mortality risk associated with urinary excretion of 8-oxoguo, a biomarker for rna oxidation, in patients with type 2 diabetes: a prospective cohort study. Diabetes Care. 2017;40(12):1771–8. https://doi.org/10.2337/dc17-1150.CrossRefGoogle Scholar
- 24.Centers for Disease C, Prevention. Smoking-attributable mortality, years of potential life lost, and productivity losses–United States, 2000–2004. MMWR Morb Mortal Wkly Rep 2008;57(45):1226–8.Google Scholar
- 26.Dalaveris E, Kerenidi T, Katsabeki-Katsafli A, Kiropoulos T, Tanou K, Gourgoulianis KI, et al. VEGF, TNF-alpha and 8-isoprostane levels in exhaled breath condensate and serum of patients with lung cancer. Lung Cancer. 2009;64(2):219–25. https://doi.org/10.1016/j.lungcan.2008.08.015.CrossRefGoogle Scholar
- 28.Murtas D, Piras F, Minerba L, Ugalde J, Floris C, Maxia C, et al. Nuclear 8-hydroxy-2′-deoxyguanosine as survival biomarker in patients with cutaneous melanoma. Oncol Rep. 2010;23(2):329–35.Google Scholar