The PedBE clock accurately estimates DNA methylation age in pediatric buccal cells

Abstract

The development of biological markers of aging has primarily focused on adult samples. Epigenetic clocks are a promising tool for measuring biological age that show impressive accuracy across most tissues and age ranges. In adults, deviations from the DNA methylation (DNAm) age prediction are correlated with several age-related phenotypes, such as mortality and frailty. In children, however, fewer such associations have been made, possibly because DNAm changes are more dynamic in pediatric populations as compared to adults. To address this gap, we aimed to develop a highly accurate, noninvasive, biological measure of age specific to pediatric samples using buccal epithelial cell DNAm. We gathered 1,721 genome-wide DNAm profiles from 11 different cohorts of typically developing individuals aged 0 to 20 y old. Elastic net penalized regression was used to select 94 CpG sites from a training dataset (n = 1,032), with performance assessed in a separate test dataset (n = 689). DNAm at these 94 CpG sites was highly predictive of age in the test cohort (median absolute error = 0.35 y). The Pediatric-Buccal-Epigenetic (PedBE) clock was characterized in additional cohorts, showcasing the accuracy in longitudinal data, the performance in nonbuccal tissues and adult age ranges, and the association with obstetric outcomes. The PedBE tool for measuring biological age in children might help in understanding the environmental and contextual factors that shape the DNA methylome during child development, and how it, in turn, might relate to child health and disease.

Genes and environments, development and time

“…Mood disorders, for example, may be traceable in part to misalignments between external temporal patterning (e.g., shift work) and internal rhythms (e.g., temperature, circadian gene expression, and sleep). Recent work by Horvath and Raj on an "epigenetic clock" (51) has demonstrated how the passage of time is linked to aging-related shifts in epigenetic marks, and in the present volume a pediatric "clock" that accurately estimates DNA methylation age is described (52).…”

“…The aging or cellular weathering associated with the passage of time in individual lives is not absolute but dependent upon cumulative exposures to adversity, and perhaps other factors. McEwen et al (52) develop a pediatric-buccal-epigenetic (PedBE) clock tool by using the DNA methylome to measure the biological age of children ages 0 to 20 y taken from 11 distinct cohorts. They find an array of methylation scores at 94 CpG dinucleotide sites highly predictive of chronological age.…”

The influences of DNA methylation and epigenetic clocks, on metabolic disease, in middle-aged Koreans

“…DNA methylation age, in blood, can predict the age of onset of chronic diseases [18]. Similarly, the change of DNAm age is faster in children, due to developmental growth [8,19], and degenerative phenotypes, such as [20]. Research is now increasingly showing that the origins of risk for chronic conditions, such as diabetes and heart disease, begin in early childhood, or even earlier [21,22].…”

Recalibrating the Epigenetic Clock: Implications for Assessing Biological Age in the Human Cortex

“…Resolution of these biases requires the construction of specific DNAm clocks developed using data generated on the relevant tissue-type and including broad representation of the age spectrum they will be used to interrogate. Recently, a number of tissue-specific DNA methylation clocks have been described, including clocks designed for whole blood (Hannum et al, 2013;Zhang et al, 2019), muscle (Voisin et al, 2019), bone (Gopalan et al, 2019) and paediatric buccal cells (McEwen et al, 2019). Importantly, although these DNAm age estimators have increased predictive accuracy within the specific tissues in which they were built, they lose this precision when applied to other tissues (El Khoury et al, 2019).…”