Epigenetic and biological age acceleration in children with atopic dermatitis

Abstract

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease resulting from the complex interplay of genetic and environmental factors, meriting exploration using temporally dynamic biomarkers. DNA methylation-based algorithms have been trained to accurately estimate biological age, and deviation of predicted age from true age (epigenetic age acceleration) has been implicated in several inflammatory diseases, including asthma.

Objective: We sought to determine the role of epigenetic and biological aging, telomere length, and epigenetically inferred abundance of 7 inflammatory biomarkers in AD.

Methods: We performed DNA methylation-based analyses in a pediatric AD cohort (n = 24, mean ± standard deviation [SD] age 2.56 ± 0.28 years) and age-matched healthy subjects (n = 24, age 2.09 [0.15] years) derived from blood using 5 validated algorithms that assess epigenetic age (Horvath, Skin&Blood) and biological age (PhenoAge, GrimAge), telomere length (TelomereLength), and inflammatory biomarker levels.

Results: Epigenetic and biological age, but not telomere length, were accelerated in AD patients for 4 algorithms: Horvath (+0.88 years; 95% confidence interval [CI], 0.33 to 1.4; P = 2.3 × 10^-3), Skin&Blood (+0.95 years; 95% CI, 0.67 to 1.2; P = 1.8 × 10^-8), PhenoAge (+8.2 years; 95% CI, 3.4 to 13.0; P = 1.3 × 10^-3), and GrimAge (+1.8 years 95% CI, 0.22 to 3.3; P = .026). Moreover, patients had increased levels of β₂ microglobulin (+47,584.4 ng/mL; P = .029), plasminogen activation inhibitor 1 (+3,432.9 ng/mL; P = 1.1 × 10^-5), and cystatin C (+31,691 ng/mL; P = 4.0 × 10^-5), while levels of tissue inhibitor metalloproteinase 1 (-370.7 ng/mL; P = 7.5 × 10^-4) were decreased compared to healthy subjects.

Conclusion: DNA methylation changes associated with epigenetic and biological aging, and inflammatory proteins appear early in life in pediatric AD and may be relevant clinical biomarkers of pathophysiology.

Keywords: Atopic dermatitis; DNA methylation; biological aging; epigenetic aging; inflammatory biomarkers.

Fig 1

Epigenetic age acceleration (EAA) in AD compared to healthy subjects across 5 epigenetic clock algorithms. Y-axes represent age-adjusted measures of epigenetic age acceleration (years) and telomere length (kb). P values reflect 2-tailed groupwise differences in mean acceleration measures between groups by Welch t test; point and whiskers represent mean group value and 95% CI, respectively.

Fig 2

Cross-sectional differences in GrimAge-associated estimated plasma proteins in AD patients. Y-axes represent age-adjusted relative estimated abundance of plasma protein levels (ng/mL) inferred from DNAm state. P values reflect 2-tailed groupwise differences by Welch t test. Notches represent group median values; boxes, interquartile range; and whiskers, range of extreme values.