. 2015 Jan 30;16(1):25.

doi: 10.1186/s13059-015-0584-6.

DNA methylation age of blood predicts all-cause mortality in later life

Riccardo E Marioni^{1

2

3}, Sonia Shah^{4

5}, Allan F McRae^{6

7}, Brian H Chen^{8

9}, Elena Colicino¹⁰, Sarah E Harris^{11

12}, Jude Gibson¹³, Anjali K Henders¹⁴, Paul Redmond¹⁵, Simon R Cox^{16

17}, Alison Pattie¹⁸, Janie Corley¹⁹, Lee Murphy²⁰, Nicholas G Martin²¹, Grant W Montgomery²², Andrew P Feinberg^{23

24}, M Daniele Fallin^{25

26}, Michael L Multhaup²⁷, Andrew E Jaffe^{28

29}, Roby Joehanes^{30

31

32}, Joel Schwartz^{33

34}, Allan C Just³⁵, Kathryn L Lunetta^{36

37}, Joanne M Murabito^{38

39}, John M Starr^{40

41}, Steve Horvath^{42

43}, Andrea A Baccarelli^{44

45}, Daniel Levy^{46

47}, Peter M Visscher^{48

49

50}, Naomi R Wray⁵¹, Ian J Deary^{52

53}

Affiliations

¹ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK. riccardo.marioni@ed.ac.uk.
² Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK. riccardo.marioni@ed.ac.uk.
³ Queensland Brain Institute, The University of Queensland, Brisbane, 4072, QLD, Australia. riccardo.marioni@ed.ac.uk.
⁴ Queensland Brain Institute, The University of Queensland, Brisbane, 4072, QLD, Australia. s.shah1@uq.edu.au.
⁵ University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, 4072, QLD, Australia. s.shah1@uq.edu.au.
⁶ Queensland Brain Institute, The University of Queensland, Brisbane, 4072, QLD, Australia. a.mcrae@uq.edu.au.
⁷ University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, 4072, QLD, Australia. a.mcrae@uq.edu.au.
⁸ The NHLBI's Framingham Heart Study, Framingham, MA, 01702, USA. brian.chen@nih.gov.
⁹ Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD, 01702, USA. brian.chen@nih.gov.
¹⁰ Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA. ecolicin@hsph.harvard.edu.
¹¹ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK. Sarah.Harris@igmm.ed.ac.uk.
¹² Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK. Sarah.Harris@igmm.ed.ac.uk.
¹³ Wellcome Trust Clinical Research Facility, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK. jgibson6@staffmail.ed.ac.uk.
¹⁴ Queensland Institute of Medical Research Berghofer Medical Research Institute, Brisbane, 4029, QLD, Australia. Anjali.Henders@qimrberghofer.edu.au.
¹⁵ Department of Psychology, University of Edinburgh, Edinburgh, EH8 9JZ, UK. paul.redmond@ed.ac.uk.
¹⁶ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK. simon.cox@ed.ac.uk.
¹⁷ Department of Psychology, University of Edinburgh, Edinburgh, EH8 9JZ, UK. simon.cox@ed.ac.uk.
¹⁸ Department of Psychology, University of Edinburgh, Edinburgh, EH8 9JZ, UK. Alison.Pattie@ed.ac.uk.
¹⁹ Department of Psychology, University of Edinburgh, Edinburgh, EH8 9JZ, UK. janie.corley@ed.ac.uk.
²⁰ Wellcome Trust Clinical Research Facility, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK. Lee.Murphy@ed.ac.uk.
²¹ Queensland Institute of Medical Research Berghofer Medical Research Institute, Brisbane, 4029, QLD, Australia. Nick.Martin@qimrberghofer.edu.au.
²² Queensland Institute of Medical Research Berghofer Medical Research Institute, Brisbane, 4029, QLD, Australia. Grant.Montgomery@qimrberghofer.edu.au.
²³ Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. afeinberg@jhu.edu.
²⁴ Departments of Medicine, Molecular Biology/Genetics, Oncology, and Biostatistics, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA. afeinberg@jhu.edu.
²⁵ Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. dfallin@jhu.edu.
²⁶ Department of Mental Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, 21205, USA. dfallin@jhu.edu.
²⁷ Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. mmulthaup@gmail.com.
²⁸ Department of Mental Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, 21205, USA. andrew.jaffe@libd.org.
²⁹ Lieber Institute for Brain Development, Baltimore, MD, 21205, USA. andrew.jaffe@libd.org.
³⁰ The NHLBI's Framingham Heart Study, Framingham, MA, 01702, USA. robyjoehanes@hsl.harvard.edu.
³¹ Harvard Medical School, Boston, MA, 02115, USA. robyjoehanes@hsl.harvard.edu.
³² Hebrew Senior Life, Boston, MA, 02131, USA. robyjoehanes@hsl.harvard.edu.
³³ Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA. jschwrtz@hsph.harvard.edu.
³⁴ Department of Epidemiology, Harvard T.H. Chan School of Public Health, 665 Huntington Ave, Boston, MA, 02115, USA. jschwrtz@hsph.harvard.edu.
³⁵ Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA. acjust@hsph.harvard.edu.
³⁶ The NHLBI's Framingham Heart Study, Framingham, MA, 01702, USA. klunetta@bu.edu.
³⁷ Department of Biostatistics, Boston University School of Public Health, Boston, MA, 02118, USA. klunetta@bu.edu.
³⁸ The NHLBI's Framingham Heart Study, Framingham, MA, 01702, USA. murabito@bu.edu.
³⁹ Section of General Internal Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, 02118, USA. murabito@bu.edu.
⁴⁰ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK. jstarr@staffmail.ed.ac.uk.
⁴¹ Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, EH8 9JZ, UK. jstarr@staffmail.ed.ac.uk.
⁴² Human Genetics, Gonda Research Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095-7088, USA. shorvath@mednet.ucla.edu.
⁴³ Biostatistics, School of Public Health, University of California Los Angeles, Los Angeles, CA, 90095, USA. shorvath@mednet.ucla.edu.
⁴⁴ Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA. abaccare@hsph.harvard.edu.
⁴⁵ Department of Epidemiology, Harvard T.H. Chan School of Public Health, 665 Huntington Ave, Boston, MA, 02115, USA. abaccare@hsph.harvard.edu.
⁴⁶ The NHLBI's Framingham Heart Study, Framingham, MA, 01702, USA. levyd@nhlbi.nih.gov.
⁴⁷ Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD, 01702, USA. levyd@nhlbi.nih.gov.
⁴⁸ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK. peter.visscher@uq.edu.au.
⁴⁹ Queensland Brain Institute, The University of Queensland, Brisbane, 4072, QLD, Australia. peter.visscher@uq.edu.au.
⁵⁰ University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, 4072, QLD, Australia. peter.visscher@uq.edu.au.
⁵¹ Queensland Brain Institute, The University of Queensland, Brisbane, 4072, QLD, Australia. naomi.wray@uq.edu.au.
⁵² Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK. i.deary@ed.ac.uk.
⁵³ Department of Psychology, University of Edinburgh, Edinburgh, EH8 9JZ, UK. i.deary@ed.ac.uk.

PMID: 25633388
PMCID: PMC4350614
DOI: 10.1186/s13059-015-0584-6

DNA methylation age of blood predicts all-cause mortality in later life

Riccardo E Marioni et al. Genome Biol. 2015.

. 2015 Jan 30;16(1):25.

doi: 10.1186/s13059-015-0584-6.

Authors

Affiliations

¹ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK. riccardo.marioni@ed.ac.uk.
² Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK. riccardo.marioni@ed.ac.uk.
³ Queensland Brain Institute, The University of Queensland, Brisbane, 4072, QLD, Australia. riccardo.marioni@ed.ac.uk.
⁴ Queensland Brain Institute, The University of Queensland, Brisbane, 4072, QLD, Australia. s.shah1@uq.edu.au.
⁵ University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, 4072, QLD, Australia. s.shah1@uq.edu.au.
⁶ Queensland Brain Institute, The University of Queensland, Brisbane, 4072, QLD, Australia. a.mcrae@uq.edu.au.
⁷ University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, 4072, QLD, Australia. a.mcrae@uq.edu.au.
⁸ The NHLBI's Framingham Heart Study, Framingham, MA, 01702, USA. brian.chen@nih.gov.
⁹ Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD, 01702, USA. brian.chen@nih.gov.
¹⁰ Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA. ecolicin@hsph.harvard.edu.
¹¹ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK. Sarah.Harris@igmm.ed.ac.uk.
¹² Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK. Sarah.Harris@igmm.ed.ac.uk.
¹³ Wellcome Trust Clinical Research Facility, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK. jgibson6@staffmail.ed.ac.uk.
¹⁴ Queensland Institute of Medical Research Berghofer Medical Research Institute, Brisbane, 4029, QLD, Australia. Anjali.Henders@qimrberghofer.edu.au.
¹⁵ Department of Psychology, University of Edinburgh, Edinburgh, EH8 9JZ, UK. paul.redmond@ed.ac.uk.
¹⁶ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK. simon.cox@ed.ac.uk.
¹⁷ Department of Psychology, University of Edinburgh, Edinburgh, EH8 9JZ, UK. simon.cox@ed.ac.uk.
¹⁸ Department of Psychology, University of Edinburgh, Edinburgh, EH8 9JZ, UK. Alison.Pattie@ed.ac.uk.
¹⁹ Department of Psychology, University of Edinburgh, Edinburgh, EH8 9JZ, UK. janie.corley@ed.ac.uk.
²⁰ Wellcome Trust Clinical Research Facility, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK. Lee.Murphy@ed.ac.uk.
²¹ Queensland Institute of Medical Research Berghofer Medical Research Institute, Brisbane, 4029, QLD, Australia. Nick.Martin@qimrberghofer.edu.au.
²² Queensland Institute of Medical Research Berghofer Medical Research Institute, Brisbane, 4029, QLD, Australia. Grant.Montgomery@qimrberghofer.edu.au.
²³ Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. afeinberg@jhu.edu.
²⁴ Departments of Medicine, Molecular Biology/Genetics, Oncology, and Biostatistics, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA. afeinberg@jhu.edu.
²⁵ Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. dfallin@jhu.edu.
²⁶ Department of Mental Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, 21205, USA. dfallin@jhu.edu.
²⁷ Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. mmulthaup@gmail.com.
²⁸ Department of Mental Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, 21205, USA. andrew.jaffe@libd.org.
²⁹ Lieber Institute for Brain Development, Baltimore, MD, 21205, USA. andrew.jaffe@libd.org.
³⁰ The NHLBI's Framingham Heart Study, Framingham, MA, 01702, USA. robyjoehanes@hsl.harvard.edu.
³¹ Harvard Medical School, Boston, MA, 02115, USA. robyjoehanes@hsl.harvard.edu.
³² Hebrew Senior Life, Boston, MA, 02131, USA. robyjoehanes@hsl.harvard.edu.
³³ Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA. jschwrtz@hsph.harvard.edu.
³⁴ Department of Epidemiology, Harvard T.H. Chan School of Public Health, 665 Huntington Ave, Boston, MA, 02115, USA. jschwrtz@hsph.harvard.edu.
³⁵ Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA. acjust@hsph.harvard.edu.
³⁶ The NHLBI's Framingham Heart Study, Framingham, MA, 01702, USA. klunetta@bu.edu.
³⁷ Department of Biostatistics, Boston University School of Public Health, Boston, MA, 02118, USA. klunetta@bu.edu.
³⁸ The NHLBI's Framingham Heart Study, Framingham, MA, 01702, USA. murabito@bu.edu.
³⁹ Section of General Internal Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, 02118, USA. murabito@bu.edu.
⁴⁰ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK. jstarr@staffmail.ed.ac.uk.
⁴¹ Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, EH8 9JZ, UK. jstarr@staffmail.ed.ac.uk.
⁴² Human Genetics, Gonda Research Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095-7088, USA. shorvath@mednet.ucla.edu.
⁴³ Biostatistics, School of Public Health, University of California Los Angeles, Los Angeles, CA, 90095, USA. shorvath@mednet.ucla.edu.
⁴⁴ Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA. abaccare@hsph.harvard.edu.
⁴⁵ Department of Epidemiology, Harvard T.H. Chan School of Public Health, 665 Huntington Ave, Boston, MA, 02115, USA. abaccare@hsph.harvard.edu.
⁴⁶ The NHLBI's Framingham Heart Study, Framingham, MA, 01702, USA. levyd@nhlbi.nih.gov.
⁴⁷ Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD, 01702, USA. levyd@nhlbi.nih.gov.
⁴⁸ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK. peter.visscher@uq.edu.au.
⁴⁹ Queensland Brain Institute, The University of Queensland, Brisbane, 4072, QLD, Australia. peter.visscher@uq.edu.au.
⁵⁰ University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, 4072, QLD, Australia. peter.visscher@uq.edu.au.
⁵¹ Queensland Brain Institute, The University of Queensland, Brisbane, 4072, QLD, Australia. naomi.wray@uq.edu.au.
⁵² Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK. i.deary@ed.ac.uk.
⁵³ Department of Psychology, University of Edinburgh, Edinburgh, EH8 9JZ, UK. i.deary@ed.ac.uk.

PMID: 25633388
PMCID: PMC4350614
DOI: 10.1186/s13059-015-0584-6

Abstract

Background: DNA methylation levels change with age. Recent studies have identified biomarkers of chronological age based on DNA methylation levels. It is not yet known whether DNA methylation age captures aspects of biological age.

Results: Here we test whether differences between people's chronological ages and estimated ages, DNA methylation age, predict all-cause mortality in later life. The difference between DNA methylation age and chronological age (Δage) was calculated in four longitudinal cohorts of older people. Meta-analysis of proportional hazards models from the four cohorts was used to determine the association between Δage and mortality. A 5-year higher Δage is associated with a 21% higher mortality risk, adjusting for age and sex. After further adjustments for childhood IQ, education, social class, hypertension, diabetes, cardiovascular disease, and APOE e4 status, there is a 16% increased mortality risk for those with a 5-year higher Δage. A pedigree-based heritability analysis of Δage was conducted in a separate cohort. The heritability of Δage was 0.43.

Conclusions: DNA methylation-derived measures of accelerated aging are heritable traits that predict mortality independently of health status, lifestyle factors, and known genetic factors.

PubMed Disclaimer

Figures

**Figure 1**
**Plot of predicted methylation age against chronological age and plot of Hannum versus Horvath predicted methylation age.** *To prevent the potential identification of individual participants, only FHS data points with chronological ages between 45 and 85, and NAS data points between ages 56 and 100 are displayed. r = Pearson correlation coefficient. FHS: Framingham Heart Study, LBC: Lothian Birth Cohort, NAS: Normative Aging Study.

**Figure 2**
**Meta-analysis results of Δ** _age **versus mortality.** The basic adjusted models controlled for chronological age, sex (NAS had only male participants), and laboratory batch (FHS only). The fully adjusted models controlled for chronological age, sex, smoking, education, childhood IQ (LBC1921 and LBC1936 only), social class (LBC1921 and LBC1936 only), *APOE* (LBC1921, LBC1936, and NAS only), cardiovascular disease, high blood pressure, and diabetes. CI: confidence interval, FHS: Framingham Heart Study, HR: hazard ratio, LBC: Lothian Birth Cohort, NAS: Normative Aging Study, W: fixed effect weight.

**Figure 3**
**Survival probability by quartiles of Δ** _age **in LBC1921 adjusted for sex, and chronological age.** LBC: Lothian Birth Cohort.

**Figure 4**
**Heritability of methylation Δ** _age **. (A)** Intra-class correlation of Hannum and Horvath Δ_age across relationship class. **(B)** Heritability of Hannum and Horvath Δ_age in BSGS data. Both plots show estimates with standard errors. *Pseudo-independent pairs. r represents the degree of relatedness.

See this image and copyright information in PMC

References

1. Thornburg KL, Shannon J, Thuillier P, Turker MS. In utero life and epigenetic predisposition for disease. Adv Genet. 2010;71:57–78. doi: 10.1016/B978-0-12-380864-6.00003-1. - DOI - PMC - PubMed
1. Bell JT, Tsai PC, Yang TP, Pidsley R, Nisbet J, Glass D, et al. Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population. PLoS Genet. 2012;8:e1002629. doi: 10.1371/journal.pgen.1002629. - DOI - PMC - PubMed
1. Bollati V, Schwartz J, Wright R, Litonjua A, Tarantini L, Suh H, et al. Decline in genomic DNA methylation through aging in a cohort of elderly subjects. Mech Ageing Dev. 2009;130:234–9. doi: 10.1016/j.mad.2008.12.003. - DOI - PMC - PubMed
1. Christensen BC, Houseman EA, Marsit CJ, Zheng S, Wrensch MR, Wiemels JL, et al. Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CpG island context. PLoS Genet. 2009;5:e1000602. doi: 10.1371/journal.pgen.1000602. - DOI - PMC - PubMed
1. Fraga MF, Esteller M. Epigenetics and aging: the targets and the marks. Trends Genet. 2007;23:413–8. doi: 10.1016/j.tig.2007.05.008. - DOI - PubMed

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DNA methylation age of blood predicts all-cause mortality in later life

Affiliations

DNA methylation age of blood predicts all-cause mortality in later life

Authors

Affiliations

Abstract

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References

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LinkOut - more resources

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