The Role of Epigenetic Clocks in Explaining Educational Inequalities in Mortality: A Multicohort Study and Meta-analysis

Giovanni Fiorito, Sara Pedron, Lifepath consortium, Carolina Ochoa-Rosales, Cathal McCrory, Silvia Polidoro, Yan Zhang, Pierre Antoine Dugué, Scott Ratliff, Wei N. Zhao, Gareth J. McKay, Giuseppe Costa, Maria Giuliana Solinas, Kathleen Mullan Harris, Rosario Tumino, Sara Grioni, Fulvio Ricceri, Salvatore Panico, Hermann Brenner, Lars SchwettmannMelanie Waldenberger, Pamela R. Matias-Garcia, Annette Peters, Allison Hodge, Graham G. Giles, Lauren L. Schmitz, Morgan Levine, Jennifer A. Smith, Yongmei Liu, Frank Kee, Ian S. Young, Bernadette McGuinness, Amy Jayne McKnight, Joyce van Meurs, Trudy Voortman, Rose A. Kenny, Paolo Vineis, Cristian Carmeli*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

11 Citations (Scopus)


Educational inequalities in all-cause mortality have been observed for decades. However, the underlying biological mechanisms are not well known. We aimed to assess the role of DNA methylation changes in blood captured by epigenetic clocks in explaining these inequalities. Data were from 8 prospective population-based cohort studies, representing 13 021 participants. First, educational inequalities and their portion explained by Horvath DNAmAge, Hannum DNAmAge, DNAmPhenoAge, and DNAmGrimAge epigenetic clocks were assessed in each cohort via counterfactual-based mediation models, on both absolute (hazard difference) and relative (hazard ratio) scales, and by sex. Second, estimates from each cohort were pooled through a random effect meta-analysis model. Men with low education had excess mortality from all causes of 57 deaths per 10 000 person-years (95% confidence interval [CI]: 38, 76) compared with their more advantaged counterparts. For women, the excess mortality was 4 deaths per 10 000 person-years (95% CI: -11, 19). On the relative scale, educational inequalities corresponded to hazard ratios of 1.33 (95% CI: 1.12, 1.57) for men and 1.15 (95% CI: 0.96, 1.37) for women. DNAmGrimAge accounted for the largest proportion, approximately 50%, of the educational inequalities for men, while the proportion was negligible for women. Most of this mediation was explained by differential effects of unhealthy lifestyles and morbidities of the World Health Organization (WHO) risk factors for premature mortality. These results support DNA methylation-based epigenetic aging as a signature of educational inequalities in life expectancy emphasizing the need for policies to address the unequal social distribution of these WHO risk factors.

Original languageEnglish
Pages (from-to)1750-1759
Number of pages10
JournalThe journals of gerontology. Series A, Biological sciences and medical sciences
Issue number9
Publication statusPublished - Sept 2022

Bibliographical note

This work was supported by the European Commission [Grant Horizon
2020 number 633666]. G.F. is supported by Programma Operativo
Nazionale (PON), Ricerca e Innovazione 2014-2020, Attrazione e Mobilità
Internazionale (AIM) code AIM1874325-2. M.G.S. is supported by ‘Fondo di
Ateneo per la ricerca 2019’, University of Sassari, Italy.

Publisher Copyright:
© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: [email protected].


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