DNA methylation-based measures of biological age: meta-analysis predicting time to death
Brian H Chen, Riccardo E Marioni, Elena Colicino, Marjolein J Peters, Cavin K Ward-Caviness, Pei-Chien Tsai, Nicholas S Roetker, Allan C Just, Ellen W Demerath, Weihua Guan, Jan Bressler, Myriam Fornage, Stephanie Studenski, Amy R Vandiver, Ann Zenobia Moore, Toshiko Tanaka, Douglas P Kiel, Liming Liang, Pantel Vokonas, Joel Schwartz, Kathryn L Lunetta, Joanne M Murabito, Stefania Bandinelli, Dena G Hernandez, David Melzer, Michael Nalls, Luke C Pilling, Timothy R Price, Andrew B Singleton, Christian Gieger, Rolf Holle, Anja Kretschmer, Florian Kronenberg, Sonja Kunze, Jakob Linseisen, Christine Meisinger, Wolfgang Rathmann, Melanie Waldenberger, Peter M Visscher, Sonia Shah, Naomi R Wray, Allan F McRae, Oscar H Franco, Albert Hofman, André G Uitterlinden, Devin Absher, Themistocles Assimes, Morgan E Levine, Ake T Lu, Philip S Tsao, Lifang Hou, JoAnn E Manson, Cara L Carty, Andrea Z LaCroix, Alexander P Reiner, Tim D Spector, Andrew P Feinberg, Daniel Levy, Andrea Baccarelli, Joyce van Meurs, Jordana T Bell, Annette Peters, Ian J Deary, James S Pankow, Luigi Ferrucci, Steve Horvath, Brian H Chen, Riccardo E Marioni, Elena Colicino, Marjolein J Peters, Cavin K Ward-Caviness, Pei-Chien Tsai, Nicholas S Roetker, Allan C Just, Ellen W Demerath, Weihua Guan, Jan Bressler, Myriam Fornage, Stephanie Studenski, Amy R Vandiver, Ann Zenobia Moore, Toshiko Tanaka, Douglas P Kiel, Liming Liang, Pantel Vokonas, Joel Schwartz, Kathryn L Lunetta, Joanne M Murabito, Stefania Bandinelli, Dena G Hernandez, David Melzer, Michael Nalls, Luke C Pilling, Timothy R Price, Andrew B Singleton, Christian Gieger, Rolf Holle, Anja Kretschmer, Florian Kronenberg, Sonja Kunze, Jakob Linseisen, Christine Meisinger, Wolfgang Rathmann, Melanie Waldenberger, Peter M Visscher, Sonia Shah, Naomi R Wray, Allan F McRae, Oscar H Franco, Albert Hofman, André G Uitterlinden, Devin Absher, Themistocles Assimes, Morgan E Levine, Ake T Lu, Philip S Tsao, Lifang Hou, JoAnn E Manson, Cara L Carty, Andrea Z LaCroix, Alexander P Reiner, Tim D Spector, Andrew P Feinberg, Daniel Levy, Andrea Baccarelli, Joyce van Meurs, Jordana T Bell, Annette Peters, Ian J Deary, James S Pankow, Luigi Ferrucci, Steve Horvath
Abstract
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.
Keywords: DNA methylation; all-cause mortality; epigenetic clock; epigenetics; lifespan; mortality.
Conflict of interest statement
The Regents of the University of California is the sole owner of a provisional patent application directed at the invention of measures of epigenetic age acceleration for which SH is a named inventor. The other authors declare no conflicts of interest.
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