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

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.