Research Paper Volume 17, Issue 7 pp 1702—1720
Second generation DNA methylation age predicts cognitive change in midlife: the moderating role of childhood socioeconomic status
- 1 Department of Psychology, University of Virginia, Charlottesville, VA 22904, USA
- 2 Department of Psychology, University of Southern California, Los Angeles, CA 90089, USA
- 3 Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA
- 4 Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
- 5 Department of Family and Geriatric Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA
- 6 Institute for Gerontology, Jönköping University, Jönköping, Sweden
- 7 Center for Economic and Social Research, University of Southern California, Los Angeles, CA 90089, USA
- 8 Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY 40202, USA
- 9 Norton Children’s Research Institute Affiliated with The University of Louisville School of Medicine, Louisville, KY 40202, USA
Received: April 14, 2025 Accepted: July 8, 2025 Published: July 23, 2025
https://doi.org/10.18632/aging.206284How to Cite
Copyright: © 2025 Bell 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
DNA methylation age (DNAmAge) surpasses chronological age in its ability to predict age-related morbidities and mortality. This study analyzed data from 287 middle-aged twins in the Louisville Twin Study (mean age 51.9 years ± 7.03) to investigate the effect of DNAmAge acceleration on change in IQ (ΔIQ) between childhood and midlife, while testing childhood socioeconomic status (SES) as a moderator of the relationship. DNAmAge was estimated with five commonly used algorithms, or epigenetic clocks (Horvath, Horvath Skin and Blood, GrimAge, and PhenoAge). A factor analysis of these measures produced a two-factor structure which we identified as first generation and second generation measures. Results of genetically informed, quasi-causal regression models indicated that accelerated second generation DNAmAge predicted more negative ΔIQ from childhood to midlife, after accounting for genetic and environmental confounds shared by twins. The relationship between DNAmAge and ΔIQ was moderated by childhood SES, with a stronger effect observed among twins from low SES backgrounds. Second generation DNAmAge measures trained to estimate phenotypic biological age show promise in their predictive value for cognitive decline in midlife. Our genetically informed twin design suggested that epigenetic aging may represent a pathway through which early-life socioeconomic disadvantage impacts midlife cognitive health.