Introduction:
DNA methylation (DNAm) is a dynamic epigenetic modification that refers to the bonding of a methyl (CH3) group to the 5th carbon of a Cytosine base to form 5-methyl-Cytosine (5mC)1. This process primarily occurs at Cytosine-phosphate-Guanine (CpG) dinucleotides2. DNAm is altered by factors such as environmental exposures (e.g. smoking3, pesticide exposures4), disease (including asthma5), cell type6, sex7 and age2. As such, the study of DNAm has great potential to help characterize the impact of gene-environment interactions on the development of disease.
There is growing interest in considering aging as more than just the passing of calendar years but, rather, as a life-long process beginning at birth and influenced by an accumulation of environmental exposures and disease. Consistent patterns of age-associated DNAm changes have been identified2,8-11, resulting in the development of epigenetic clocks12 that reflect biological aging (e.g. susceptibility to disease, fragility and early mortality). These ’clocks’ refer to mathematical algorithms that use DNAm levels at select CpG sites to calculate epigenetic age (EA)13. A variety of disease phenotypes14-18, including asthma and allergy19,20, have demonstrated associations with epigenetic age acceleration (EAA), where epigenetic age is different than chronological, or actual, age (CA).
EAA captures biological aging which may be faster or slower than calendar time. A key question is whether EAA is established during childhood and impacts disease risk in later life. This aligns with the Developmental Origins of Health and Disease (DOHaD)21 hypothesis that prenatal and early life exposures during the first 1000 days cause DNAm changes that influence the likelihood of disease in later life. This premise has led to a focus on the study of epigenetic aging in relation to prenatal and childhood exposures (Fig.1A ). There is evidence of differential methylation in cord blood due to in utero exposures, including elevated maternal BMI22, air pollution23, and the widely reported and replicated effects of maternal smoking24(Table 1 ). In addition, maternal smoking has been linked to increased EAA well into childhood (years 6-11)4.
Asthma is a complex phenotype influenced by genetic and environmental factors, that demonstrates age and sex specific prevalence patterns25. Childhood asthmatics are predominately male (65%), while 65% of adult asthmatics are female (Fig.1B )25. There are two main asthma subtypes – allergic and non-allergic. Allergic asthmatics have an additional allergic disease (e.g., atopy or eczema), whereas non-allergic asthmatics have asthma without additional allergic disease. Understanding the relationship between EAA and asthma26 may clarify the mechanisms whereby early life exposures affect methylation and disease susceptibility.