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Research Paper|Volume 18|pp 466—512

The mediating role of DNA methylation clocks in associations of race, ethnicity, education, income, and occupation with mortality: findings from NHANES 1999-2002

Hanyang Shen1, Nicole Gladish1, Tiffany Fan2, Andres Cardenas1,3, Belinda L. Needham4, David H. Rehkopf1,3,5,6,7
  • 1Department of Epidemiology and Population Health, Stanford University, Palo Alto, CA 94305, USA
  • 2Institute for Computational and Mathematical Engineering, Stanford University, Palo Alto, CA 94305, USA
  • 3Department of Pediatrics, Stanford University, Palo Alto, CA 94305, USA
  • 4Department of Epidemiology, University of Michigan, Ann Arbor, MI 48109, USA
  • 5Department of Health Policy, Stanford University, Palo Alto, CA 94305, USA
  • 6Department of Medicine (Primary Care and Population Health), Stanford University, Palo Alto, CA 94305, USA
  • 7Department of Sociology, Stanford University, Palo Alto, CA 94305, USA
Received: October 24, 2025Accepted: March 24, 2026Published: May 8, 2026
https://doi.org/10.18632/aging.206377

Copyright: © 2026 Shen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Race, ethnicity, education, income, and occupation are important social factors affecting health and longevity. DNA methylation aging biomarkers may mediate the effects of these social factors on mortality, but so far, no studies have investigated the extent of this mediation systematically in a nationally represents samples of the U.S. population. This study aims to provide systematic evidence on the mediating proportion of DNA methylation clocks between these social factors and mortality using the US National Health and Nutrition Examination Survey (NHANES) 1999-2002 (N=2,402) linked with National Death Index mortality data through 2019. After adjusting for gender, age, age2, and nativity, multiple DNA methylation clocks significantly mediated the pathways between social factors and all-cause mortality. Among all the 13 DNA methylation biomarkers available in NHANES, GrimAge2 consistently exhibited the strongest positive mediation capturing the social disparities on mortality up to 52% (95%CI: 26%-128%), followed by the DunedinPoAm. These effects generally exceeded the mediation proportion of traditional clinical risk factors collected in our study (such as C-reactive protein). This study suggested that DNA methylation epigenetic biomarkers may have utility as clinical aging indicators of the biological embedding of social disadvantage.