Cuicui Wang1, Wenli Ni2, Yueli Yao2, Allan Just3, Jonathan Heiss3, Yaguang Wei4, Xu Gao5, Brent A Coull6, Anna Kosheleva4, Andrea A Baccarelli5, Annette Peters7, Joel D Schwartz4. 1. Department of Environmental Health, Harvard T.H. Chan School of Public Health, 401 Park Drive, West of Landmark Center, Boston, MA 02215, United States. Electronic address: cuicuiwang@hsph.harvard.edu. 2. Institute of Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany. 3. Department of Environmental Medicine, and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, United States. 4. Department of Environmental Health, Harvard T.H. Chan School of Public Health, 401 Park Drive, West of Landmark Center, Boston, MA 02215, United States. 5. Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, United States. 6. Department of Environmental Health, Harvard T.H. Chan School of Public Health, 401 Park Drive, West of Landmark Center, Boston, MA 02215, United States; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, United States. 7. Institute of Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany; Institute of Medical Information Science, Biometry, and Epidemiology, Ludwig Maximilians University, Munich, Germany.
Abstract
BACKGROUND: DNA methylation (DNAm) may play a role in age-related outcomes. It is not yet known which DNAm-based biomarkers of age acceleration (BoAA) has the strongest association with age-related endpoints. METHODS: We collected the blood samples from two independent cohorts: the Normative Ageing Study, and the Cooperative Health Research in the Region of Augsburg cohort. We measured epigenome-wide DNAm level, and generated five DNAm BoAA at baseline. We used Cox proportional hazards model to analyze the relationships between BoAA and all-cause death. We applied the Fine and Gray competing risk model to estimate the risk of BoAA on myocardial infarction (MI), stroke, and cancer, accounting for death of other reasons as the competing risks. We used random-effects meta-analyses to pool the individual results, with adjustment for multiple testing. FINDINGS: The mean chronological ages in the two cohorts were 74, and 61, respectively. Baseline GrimAgeAccel, and DNAm-related mortality risk score (DNAmRS) both had strong associations with all-cause death, MI, and stroke, independent from chronological age. For example, a one standard deviation (SD) increment in GrimAgeAccel was significantly associated with increased risk of all-cause death [hazard ratio (HR): 2.01; 95% confidence interval (CI), 1.15, 3.50], higher risk of MI (HR: 1.44; 95% CI, 1.16, 1.79), and elevated risk of stroke (HR: 1.42; 95% CI, 1.06, 1.91). There were no associations between any BoAA and cancer. INTERPRETATION: From the public health perspective, GrimAgeAccel is the most useful tool for identifying at-risk elderly, and evaluating the efficacy of anti-aging interventions. FUNDING: National Institute of Environmental Health Sciences of U.S., Harvard Chan-NIEHS Center for Environmental Health, German Federal Ministry of Education and Research, and the State of Bavaria in Germany.
BACKGROUND: DNA methylation (DNAm) may play a role in age-related outcomes. It is not yet known which DNAm-based biomarkers of age acceleration (BoAA) has the strongest association with age-related endpoints. METHODS: We collected the blood samples from two independent cohorts: the Normative Ageing Study, and the Cooperative Health Research in the Region of Augsburg cohort. We measured epigenome-wide DNAm level, and generated five DNAm BoAA at baseline. We used Cox proportional hazards model to analyze the relationships between BoAA and all-cause death. We applied the Fine and Gray competing risk model to estimate the risk of BoAA on myocardial infarction (MI), stroke, and cancer, accounting for death of other reasons as the competing risks. We used random-effects meta-analyses to pool the individual results, with adjustment for multiple testing. FINDINGS: The mean chronological ages in the two cohorts were 74, and 61, respectively. Baseline GrimAgeAccel, and DNAm-related mortality risk score (DNAmRS) both had strong associations with all-cause death, MI, and stroke, independent from chronological age. For example, a one standard deviation (SD) increment in GrimAgeAccel was significantly associated with increased risk of all-cause death [hazard ratio (HR): 2.01; 95% confidence interval (CI), 1.15, 3.50], higher risk of MI (HR: 1.44; 95% CI, 1.16, 1.79), and elevated risk of stroke (HR: 1.42; 95% CI, 1.06, 1.91). There were no associations between any BoAA and cancer. INTERPRETATION: From the public health perspective, GrimAgeAccel is the most useful tool for identifying at-risk elderly, and evaluating the efficacy of anti-aging interventions. FUNDING: National Institute of Environmental Health Sciences of U.S., Harvard Chan-NIEHS Center for Environmental Health, German Federal Ministry of Education and Research, and the State of Bavaria in Germany.
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