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Aging (Albany NY). 2019 Jan 21;11(2):303-327. doi: 10.18632/aging.101684.

DNA methylation GrimAge strongly predicts lifespan and healthspan.

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Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Center of Development and Aging, New Jersey Medical School, Rutgers State University of New Jersey, Newark, NJ 07103, USA.
Radiation Effects Department, Centre for Radiation, Chemical and Environmental Hazards, Public Health England, Chilton, Didcot, Oxfordshire OX11 0RQ, United Kingdom.
Center for Population Epigenetics, Robert H. Lurie Comprehensive Cancer Center and Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Laboratory of Environmental Epigenetics, Departments of Environmental Health Sciences Epidemiology, Columbia University Mailman School of Public Health, New York, NY 10032, USA.
Departments of Genetics, Biostatistics, Computer Science, University of North Carolina, Chapel Hill, NC 27599, USA.
Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC 27599, USA.
Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC 27516, USA.
Department of Medicine (Division of Cardiovascular Medicine), Stanford University School of Medicine, Stanford, CA 94305, USA.
VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.
Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, USA, Baltimore, MD 21224, USA.
Department of Biostatistics, Fielding School of Public Health, University of California Los Angeles, Los Angeles, CA 90095, USA.


It was unknown whether plasma protein levels can be estimated based on DNA methylation (DNAm) levels, and if so, how the resulting surrogates can be consolidated into a powerful predictor of lifespan. We present here, seven DNAm-based estimators of plasma proteins including those of plasminogen activator inhibitor 1 (PAI-1) and growth differentiation factor 15. The resulting predictor of lifespan, DNAm GrimAge (in units of years), is a composite biomarker based on the seven DNAm surrogates and a DNAm-based estimator of smoking pack-years. Adjusting DNAm GrimAge for chronological age generated novel measure of epigenetic age acceleration, AgeAccelGrim.Using large scale validation data from thousands of individuals, we demonstrate that DNAm GrimAge stands out among existing epigenetic clocks in terms of its predictive ability for time-to-death (Cox regression P=2.0E-75), time-to-coronary heart disease (Cox P=6.2E-24), time-to-cancer (P= 1.3E-12), its strong relationship with computed tomography data for fatty liver/excess visceral fat, and age-at-menopause (P=1.6E-12). AgeAccelGrim is strongly associated with a host of age-related conditions including comorbidity count (P=3.45E-17). Similarly, age-adjusted DNAm PAI-1 levels are associated with lifespan (P=5.4E-28), comorbidity count (P= 7.3E-56) and type 2 diabetes (P=2.0E-26). These DNAm-based biomarkers show the expected relationship with lifestyle factors including healthy diet and educational attainment.Overall, these epigenetic biomarkers are expected to find many applications including human anti-aging studies.


DNA methylation; epigenetics; mortality; proteomics

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