DNA methylation GrimAge version 2

Ake T Lu, Alexandra M. Binder, Joshua Zhang, Qi Yan, Alex P Reiner, Simon R. Cox, Janie Corley, Sarah Harris, Pei-Lun Kuo, Ann Zenobia Moore, Stefania Bandinelli, James Stewart, Cuicui Wang, Elissa J Hamlat, Elissa S. Epel, Joel Schwartz, Eric A Whitsel, Adolfo Correa, Luigi Ferrucci, Riccardo E MarioniSteve Horvath

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

We previously described a DNA methylation (DNAm) based biomarker of human mortality risk DNAm GrimAge. Here we describe version 2 of GrimAge (trained on individuals aged between 40 and 92) which leverages two new DNAm based estimators of (log transformed) plasma proteins: high sensitivity C-reactive protein (logCRP) and hemoglobin A1C (logA1C). We evaluate GrimAge2 in 13,399 blood samples across nine study cohorts. After adjustment for age and sex, GrimAge2 outperforms GrimAge in predicting mortality across multiple racial/ethnic groups (meta P=3.6x10-167 versus P=2.6x10-144) and in terms of associations with age related conditions such as coronary heart disease, lung function measurement FEV1 (correlation= -0.31, P=1.1x10-136), computed tomography based measurements of fatty liver disease. We present evidence that GrimAge version 2 also applies to younger individuals and to saliva samples where it tracks markers of metabolic syndrome.
DNAm logCRP is positively correlated with morbidity count (P=1.3x10-54). DNAm logA1C is highly associated with type 2 diabetes (P=5.8x10-155). DNAm PAI-1 outperforms the other age-adjusted DNAm biomarkers including GrimAge2 in correlating with triglyceride (cor=0.34, P=9.6x10-267) and visceral fat (cor=0.41, P=4.7x10-41).
Overall, we demonstrate that GrimAge version 2 is an attractive epigenetic biomarker of human mortality and morbidity risk.
Original languageEnglish
Pages (from-to)9484—9549
Issue number23
Early online date14 Dec 2022
Publication statusE-pub ahead of print - 14 Dec 2022

Keywords / Materials (for Non-textual outputs)

  • DNA methylation
  • epigenetic clock
  • healthspan
  • mortality


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