DNA methylation-based measures of biological age: meta-analysis predicting time to death.
Estimates of biological age based on DNA methylation patterns, often referred to as "epigenetic age", "DNAm age", have been shown to be robust biomarkers of age in humans. We previously demonstrated that independent of chronological age, epigenetic age assessed in blood predicted all-cause mortality in four human cohorts. Here, we expanded our original observation to 13 different cohorts for a total sample size of 13,089 individuals, including three racial/ethnic groups. In addition, we examined whether incorporating information on blood cell composition into the epigenetic age metrics improves their predictive power for mortality. All considered measures of epigenetic age acceleration were predictive of mortality (p≤8.2x10-9), independent of chronological age, even after adjusting for additional risk factors (p<5.4x10-4), and within the racial/ethnic groups that we examined (non-Hispanic whites, Hispanics, African Americans). Epigenetic age estimates that incorporated information on blood cell composition led to the smallest p-values for time to death (p=7.5x10-43). Overall, this study a) strengthens the evidence that epigenetic age predicts all-cause mortality above and beyond chronological age and traditional risk factors, and b) demonstrates that epigenetic age estimates that incorporate information on blood cell counts lead to highly significant associations with all-cause mortality.
Longitudinal Studies Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.|The NHLBI's Framingham Heart Study, Framingham, MA 01702, USA.|Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 01702, USA.
Brian H
BH
Chen
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK.|Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.|Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia.
Riccardo E
RE
Marioni
Laboratory of Environmental Epigenetics, Departments of Environmental Health Sciences and Epidemiology, Columbia University Mailman School of Public Health, New York, NY 10032, USA.
Elena
E
Colicino
Department of Internal Medicine, Erasmus University Medical Centre, Rotterdam, 3000 CA, The Netherlands.
Marjolein J
MJ
Peters
Institute of Epidemiology II, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Cavin K
CK
Ward-Caviness
Department of Twin Research and Genetic Epidemiology, Kings College London, London SE1 7EH, UK.
Pei-Chien
PC
Tsai
Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN 55455, USA.
Nicholas S
NS
Roetker
Laboratory of Environmental Epigenetics, Departments of Environmental Health Sciences and Epidemiology, Columbia University Mailman School of Public Health, New York, NY 10032, USA.
Allan C
AC
Just
Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN 55455, USA.
Ellen W
EW
Demerath
Division of Biostatistics, University of Minnesota School of Public Health, Minneapolis, MN, 55455, ; USA.
Weihua
W
Guan
Human Genetics Center, School of Public Health, University of Texas Health Sciences Center at Houston, Houston, TX, ; USA.
Jan
J
Bressler
Human Genetics Center, School of Public Health, University of Texas Health Sciences Center at Houston, Houston, TX, ; USA.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, ; USA.
Myriam
M
Fornage
Longitudinal Studies Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
Stephanie
S
Studenski
Center for Epigenetics, Johns Hopkins University, Baltimore, MD 21205, ; USA.
Amy R
AR
Vandiver
Longitudinal Studies Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
Ann Zenobia
AZ
Moore
Longitudinal Studies Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
Toshiko
T
Tanaka
Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, ; USA.|Institute for Aging Research, Hebrew Senior Life, Boston, MA 02215, USA.
Douglas P
DP
Kiel
Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.|Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, USA.
Liming
L
Liang
Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
Pantel
P
Vokonas
Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
Joel
J
Schwartz
The NHLBI's Framingham Heart Study, Framingham, MA 01702, USA.|Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
Kathryn L
KL
Lunetta
The NHLBI's Framingham Heart Study, Framingham, MA 01702, USA.|Section of General Internal Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
Joanne M
JM
Murabito
Geriatric Unit, Usl Centro Toscana Florence, Italy.
Stefania
S
Bandinelli
Laboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, MD 20814, USA.
Dena G
DG
Hernandez
Epidemiology and Public Health, Medical School, University of Exeter, RILD, Exeter EX2 5DW, ; UK.
David
D
Melzer
Laboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, MD 20814, USA.
Michael
M
Nalls
Epidemiology and Public Health, Medical School, University of Exeter, RILD, Exeter EX2 5DW, ; UK.
Luke C
LC
Pilling
Laboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, MD 20814, USA.
Timothy R
TR
Price
Laboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, MD 20814, USA.
Andrew B
AB
Singleton
Institute of Epidemiology II, Helmholtz Zentrum München, 85764 Neuherberg, Germany.|Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Christian
C
Gieger
Institute of Health Economics and Health Care Management, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Rolf
R
Holle
Institute of Epidemiology II, Helmholtz Zentrum München, 85764 Neuherberg, Germany.|Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Anja
A
Kretschmer
Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck 6020, Austria.
Florian
F
Kronenberg
Institute of Epidemiology II, Helmholtz Zentrum München, 85764 Neuherberg, Germany.|Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Sonja
S
Kunze
Institute of Epidemiology II, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Jakob
J
Linseisen
Institute of Epidemiology II, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Christine
C
Meisinger
Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, 40225 Düsseldorf, Germany.
Wolfgang
W
Rathmann
Institute of Epidemiology II, Helmholtz Zentrum München, 85764 Neuherberg, Germany.|Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Melanie
M
Waldenberger
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK.|Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia.|University of Queensland Diamantina Institute, University of Queensland, Brisbane, Queensland, Australia.
Peter M
PM
Visscher
Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia.|University of Queensland Diamantina Institute, University of Queensland, Brisbane, Queensland, Australia.
Sonia
S
Shah
Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia.
Naomi R
NR
Wray
Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia.|University of Queensland Diamantina Institute, University of Queensland, Brisbane, Queensland, Australia.
Allan F
AF
McRae
Department of Epidemiology, Erasmus University Medical Centre, Rotterdam, 3015 CN, The Netherlands.
Oscar H
OH
Franco
Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.|Department of Epidemiology, Erasmus University Medical Centre, Rotterdam, 3015 CN, The Netherlands.
Albert
A
Hofman
Department of Internal Medicine, Erasmus University Medical Centre, Rotterdam, 3000 CA, The Netherlands.|Department of Epidemiology, Erasmus University Medical Centre, Rotterdam, 3015 CN, The Netherlands.
André G
AG
Uitterlinden
HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
Devin
D
Absher
Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, ; Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
Themistocles
T
Assimes
VA Palo Alto Health Care System, Palo Alto CA 94304, USA.
Morgan E
ME
Levine
VA Palo Alto Health Care System, Palo Alto CA 94304, USA.
Ake T
AT
Lu
Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, ; Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.|Department of Preventive Medicine, Feinberg School of Medicine, Northwestern UniversityChicago, IL 60611, USA.
Philip S
PS
Tsao
Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern UniversityChicago, IL 60611, USA.|Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, and the Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02215, USA.
Lifang
L
Hou
Center for Translational Science Children's National Medical Center, George Washington University, Washington, DC 20010, USA.
JoAnn E
JE
Manson
Department of Family Medicine and Public Health, University of California-San Diego, La Jolla, CA 92093-0725, ; USA.
Cara L
CL
Carty
Department of Epidemiology, University of Washington School of Public Health, Seattle, WA 98195, USA.
Andrea Z
AZ
LaCroix
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, ; USA.|Departments of Medicine, Molecular Biology/Genetics, Oncology, and Biostatistics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Alexander P
AP
Reiner
Department of Twin Research and Genetic Epidemiology, Kings College London, London SE1 7EH, UK.
Tim D
TD
Spector
Center for Epigenetics, Johns Hopkins University, Baltimore, MD 21205, ; USA.|Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 01702, USA.
Andrew P
AP
Feinberg
The NHLBI's Framingham Heart Study, Framingham, MA 01702, USA.|Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
Daniel
D
Levy
Laboratory of Environmental Epigenetics, Departments of Environmental Health Sciences and Epidemiology, Columbia University Mailman School of Public Health, New York, NY 10032, USA.|Department of Psychology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK.
Andrea
A
Baccarelli
Department of Internal Medicine, Erasmus University Medical Centre, Rotterdam, 3000 CA, The Netherlands.
Joyce
J
van Meurs
Department of Twin Research and Genetic Epidemiology, Kings College London, London SE1 7EH, UK.
Jordana T
JT
Bell
Institute of Epidemiology II, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Annette
A
Peters
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK.|Department of Biostatistics, School of Public Health, University of California Los Angeles, Los Angeles, CA 90095, USA.
Ian J
IJ
Deary
Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN 55455, USA.
James S
JS
Pankow
Longitudinal Studies Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
Luigi
L
Ferrucci
VA Palo Alto Health Care System, Palo Alto CA 94304, USA.|Department of Biostatistics, School of Public Health, University of California Los Angeles, Los Angeles, CA 90095, USA.
Steve
S
Horvath
D000375:Aging / Q000235:genetics / Q000502:physiology*; D019175:DNA Methylation / Q000502:physiology*; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D016015:Logistic Models; D008297:Male; D009026:Mortality; D044469:Racial Groups; D012307:Risk Factors; D016019:Survival Analysis; D016176:T-Lymphocyte Subsets
DNA methylation; all-cause mortality; epigenetic clock; epigenetics; lifespan; mortality
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