Structural Disadvantage in Adolescence and Biological Aging in Early Midlife.

Abstract

Upstream social determinants, including structural disadvantages, are critical drivers of health and aging. While structural disadvantages shape biological aging and inflammatory processes among older adults, it is less clear how this association emerges and endures over the life course. To assess whether adolescent exposure to structural disadvantage is associated with epigenetic aging and inflammation-related DNA methylation (DNAm) in early midlife and to evaluate whether associations differ by race. This prospective cohort study used data from non-Hispanic Black and White respondents in the National Longitudinal Study of Adolescent to Adult Health (Add Health). Add Health comprises a nationally representative cohort of US adolescents in grades 7 to 12 in 1994 (wave I) followed for over 20 years across 6 waves of data. Venous blood samples were collected (2016-2018) and analyzed for DNAm (2021-2024) among Add Health respondents in early midlife (ages 33-43 years at blood collections). Data were analyzed from September 2024 to February 2026. The main exposure was structural disadvantage in adolescence, assessed as 5 county-level economic, education, and segregation indicators from the 1990 decennial US Census. The main outcomes included 3 epigenetic clocks (PhenoAge, GrimAge2, and DunedinPACE) and 2 measures of inflammation-related DNAm (C-reactive protein [CRP] and tumor necrosis factor-α). Confirmatory factor analysis was used to derive a latent factor of structural disadvantage in adolescence, and multivariate regression models assessed the association between the structural disadvantage latent measure and each outcome. Data from 3788 participants (mean [SD] age at wave V, 38.4 [0.01] years; 50.9% [SE, 1.1%] female and 49.1% [SE, 1.1%] male; and 19.7% [SE, 0.9%] Black and 80.3% [SE, 0.9%] White) were analyzed. Considering average associations across the sample, exposure to higher vs lower levels of structural disadvantage in adolescence was associated with accelerated epigenetic aging (GrimAge2: β, 0.35 [95% CI, 0.09-0.61]; DunedinPACE: β, 0.08 [95% CI, 0.03-0.13]) and greater CRP-related DNAm (β, 0.07 [95% CI, 0.02-0.12]), even after adjusting for self-reported race and family socioeconomic status. Findings from an interaction model suggested that while Black respondents experienced faster epigenetic aging and greater CRP-related DNAm overall, the association between adolescent structural disadvantage and these outcomes was slightly negative for Black respondents, yet positive for White respondents. In this prospective cohort study of adults in early midlife, the results suggest that early-life contexts were important factors for accelerated epigenetic aging and CRP-related DNAm. These findings enhance understanding of when and how disparities in aging-related diseases may emerge, informing effective solutions for addressing the rising burden of aging-related diseases.