Faster ticking rate of the epigenetic clock is associated with faster pubertal development in girls

Abstract

Epigenetic age is an indicator of biological aging, capturing the impact of environmental and behavioral influences across time on cellular function. Deviance between epigenetic age and chronological age (AgeAccel) is a predictor of health. Pubertal timing has similarly been associated with cancer risk and mortality rate among females. We examined the association between AgeAccel and pubertal timing and adolescent breast composition in the longitudinal Growth and Obesity Cohort Study. AgeAccel was estimated in whole blood using the Horvath method at breast Tanner 2 (B2) and 4 (B4). Total breast volume, absolute fibro-glandular volume (FGV), and %FGV were evaluated at B4 using dual X-ray absorptiometry. The impact of AgeAccel (mean: 0; SD: 3.78) across puberty on the time to breast development (thelarche), menarche, and pubertal tempo (thelarche to menarche) was estimated using accelerated failure time models; generalized estimating equations were used to evaluate associations with breast density. A five-year increase in average adolescent AgeAccel was associated with a significant decrease in time to menarche [hazard ratio (HR): 1.37; 95% confidence interval (CI): 1.04, 1.80] adjusting for birth weight, maternal pre-pregnancy body mass index, maternal height, maternal education, B2 height, fat percentage, and cell composition. AgeAccel displayed a stronger inverse association with pubertal tempo (HR: 1.48; 95% CI: 1.10, 1.99). A five-year increase in AgeAccel was associated with 5% greater %FGV, adjusting for B4 percent body fat, and maternal traits (95% CI: 1.01, 1.10). Our study provides unique insight into the influence of AgeAccel on pubertal development in girls, which may have implications for adult health.

Keywords: DNA methylation; Puberty; breast density; epigenetic clock; menarche; thelarche.

Figure 1.

Timing of menarche between categories of average pubertal AgeAccel. Plotting a.) the Kaplain Meier cumulative incidence curve for categories of average pubertal AgeAccel; b.) the Kaplain Meier cumulative incidence curve for categories of cell-type adjusted average pubertal AgeAccel; c.) the predicted cumulative incidence curves for categories of cell-type adjusted AgeAccel from accelerated failure time models adjusting for birth weight, maternal pre-pregnancy BMI, maternal height, and maternal education; and d.) the predicted cumulative incidence curves for categories of cell-type adjusted AgeAccel from accelerated failure time models further adjusting for child height Z-score and fat percentage at B2. Color corresponds to AgeAccel category: Red = (−10, −2]; Blue: (−2, 2], and Green = (2, 10]. Dotted lines indicate the median time to menarche for each category.

Figure 2.

Timing between thelarche and menarche (pubertal tempo) across categories of average pubertal AgeAccel. Plotting a.) the Turnbull estimated cumulative incidence curve for categories of average pubertal AgeAccel; b.) the Turnbull estimated cumulative incidence curve for categories of cell-type adjusted average pubertal AgeAccel; c.) the predicted cumulative incidence curves for categories of cell-type adjusted AgeAccel from accelerated failure time models adjusting for birth weight, maternal pre-pregnancy BMI, maternal height, and maternal education; and d.) the predicted cumulative incidence curves for categories of cell-type adjusted AgeAccel from accelerated failure time models further adjusting for child height Z-score and fat percentage at B2. Color corresponds to AgeAccel category: Red = (−10, −2]; Blue: (−2, 2], and Green = (2, 10]. Dotted lines indicate the median pubertal tempo for each category.