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bioRxiv · 10.1101/2025.09.25.678652

Early-life nutrition supplementation and epigenetic age in middle-adulthood among Guatemalan adults

Chapnick, M.·Yu, E. A.·Smith, A. K.·Conneely, K. N.·Ramirez-Zea, M.·Qin, Z. S.·Staimez, L. R.·Vaccarino, V.·Stein, A. D.
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Abstract

ObjectivesEpigenetic clocks are biomarkers of aging. Epigenetic clocks are associated with early-life famine exposure. We investigated the impact of a cluster-randomized early-life nutrition intervention on epigenetic age. MethodsWe analyzed follow-up data from participants in the INCAP Nutrition Supplementation Trial, conducted in 4 villages in eastern Guatemala. DNA methylation was measured in buffy coat samples using the Illumina InfiniumTM MethylationEPICv2.0 array and standard quality control procedures. Epigenetic age was quantified using DunedinPACE, PhenoAge, and GrimAge. PhenoAge and GrimAge acceleration were calculated as residuals by regressing epigenetic age on chronological age. We used intent-to-treat difference-in-difference modeling to assess the impact of a protein-energy supplement provided during the first 1,000 days of life (conception to age 2y) on epigenetic age in middle adulthood. Covariates included sex, birth year, the trial supplement type (atole [intervention] vs. fresco [control]), exposure period of supplement (any of the first 1,000 days, other), and a random effect to account for sibships. The primary coefficient of interest was represented by the interaction between supplement type and exposure period. ResultsThe analysis included 1095 participants (mean age 45.0 y (SD 4.3); 60.3 % female, 40.3 % exposed to any atole during the first 1,000 days, mean DunedinPACE 1.2 (SD 0.1), Phenoage 46.7 y (SD 6.7), and GrimAge 56.3 y (SD 4.1). In difference-in-difference analyses, exposure to atole during any of the first 1,000-day period was associated with lower DunedinPACE (- 0.03, 95% CI -0.06, -0.004), PhenoAge acceleration (- 1.91 y, 95% CI -3.43, -0.39), and GrimAge acceleration (-0.85 y, 95% CI -1.53, -0.11) compared to other exposures. Following additional adjustment for cell type proportions, the direction of the coefficients remained the same but were no longer statistically significant. ConclusionsExposure to atole during the first 1,000 days was associated with modest reductions in epigenetic age as measured by DunedinPACE, PhenoAge, and GrimAge. These findings complement prior evidence of epigenetic age acceleration among individuals with early-life famine exposure.

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Chapnick, M., Yu, E. A., Smith, A. K., Conneely, K. N., Ramirez-Zea, M., Qin, Z. S., Staimez, L. R., Vaccarino, V., Stein, A. D.. 2025-09-29. Early-life nutrition supplementation and epigenetic age in middle-adulthood among Guatemalan adults. https://doi.org/10.1101/2025.09.25.678652

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