DNAm-based signatures of accelerated aging and mortality in blood are associated with low renal function

Pamela R. Matías-García*, Cavin K. Ward-Caviness, Laura M. Raffield, Xu Gao, Yan Zhang, Rory Wilson, Xīn Gào, Jana Nano, Andrew Bostom, Elena Colicino, Adolfo Correa, Brent Coull, Charles Eaton, Lifang Hou, Allan C. Just, Sonja Kunze, Leslie Lange, Ethan Lange, Xihong Lin, Simin LiuJamaji C. Nwanaji-Enwerem, Alex Reiner, Jincheng Shen, Ben Schöttker, Pantel Vokonas, Yinan Zheng, Bessie Young, Joel Schwartz, Steve Horvath, Ake Lu, Eric A. Whitsel, Wolfgang Koenig, Jerzy Adamski, Juliane Winkelmann, Hermann Brenner, Andrea A. Baccarelli, Christian Gieger, Annette Peters, Nora Franceschini, Melanie Waldenberger*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


Background: The difference between an individual's chronological and DNA methylation predicted age (DNAmAge), termed DNAmAge acceleration (DNAmAA), can capture life-long environmental exposures and age-related physiological changes reflected in methylation status. Several studies have linked DNAmAA to morbidity and mortality, yet its relationship with kidney function has not been assessed. We evaluated the associations between seven DNAm aging and lifespan predictors (as well as GrimAge components) and five kidney traits (estimated glomerular filtration rate [eGFR], urine albumin-to-creatinine ratio [uACR], serum urate, microalbuminuria and chronic kidney disease [CKD]) in up to 9688 European, African American and Hispanic/Latino individuals from seven population-based studies. Results: We identified 23 significant associations in our large trans-ethnic meta-analysis (p < 1.43E−03 and consistent direction of effect across studies). Age acceleration measured by the Extrinsic and PhenoAge estimators, as well as Zhang’s 10-CpG epigenetic mortality risk score (MRS), were associated with all parameters of poor kidney health (lower eGFR, prevalent CKD, higher uACR, microalbuminuria and higher serum urate). Six of these associations were independently observed in European and African American populations. MRS in particular was consistently associated with eGFR (β = − 0.12, 95% CI = [− 0.16, − 0.08] change in log-transformed eGFR per unit increase in MRS, p = 4.39E−08), prevalent CKD (odds ratio (OR) = 1.78 [1.47, 2.16], p = 2.71E-09) and higher serum urate levels (β = 0.12 [0.07, 0.16], p = 2.08E−06). The “first-generation” clocks (Hannum, Horvath) and GrimAge showed different patterns of association with the kidney traits. Three of the DNAm-estimated components of GrimAge, namely adrenomedullin, plasminogen-activation inhibition 1 and pack years, were positively associated with higher uACR, serum urate and microalbuminuria. Conclusion: DNAmAge acceleration and DNAm mortality predictors estimated in whole blood were associated with multiple kidney traits, including eGFR and CKD, in this multi-ethnic study. Epigenetic biomarkers which reflect the systemic effects of age-related mechanisms such as immunosenescence, inflammaging and oxidative stress may have important mechanistic or prognostic roles in kidney disease. Our study highlights new findings linking kidney disease to biological aging, and opportunities warranting future investigation into DNA methylation biomarkers for prognostic or risk stratification in kidney disease.

Original languageEnglish (US)
Article number121
JournalClinical Epigenetics
Issue number1
StatePublished - Dec 2021


  • Aging
  • DNAm age
  • Epigenetic age acceleration
  • Glomerular filtration rate
  • Kidney function
  • Serum urate
  • UACR

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Developmental Biology
  • Genetics(clinical)


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