EAA and the Developmental Origins of Health and Disease
Development is a highly complex essential process (Fig. 1A ). Factors such as environmental exposures may perturb DNAm during development, and thereby lead to long-term changes that influence susceptibility to disease. In early life, the majority of CpG sites across the genome are hypomethylated, leaving them vulnerable to aberrant methylation caused by environmental factors (Fig. 1A ). Subsequent DNAm patterns may reflect exposures during these stages of life and influence the epigenetic clock and EAA. Previous studies on development have primarily focused on the pre-natal and early life periods, but development also encompasses other life stages of rapid change such as puberty and even menopause. Studies have shown that exposures such as smoking in adolescence can alter DNAm during adolescence89. Whether this leads to impacts on epigenetic aging which continue in later life remains under-explored.
It has been suggested that an individual’s EAA trajectory is established in childhood and continues at the same rate throughout adulthood90. However, more work examining this question is needed. In addition, it is necessary to study whether the rate of EAA is influenced by environmental exposures during critical developmental periods such as puberty, pregnancy, and menopause. Most current epigenetic clocks, except the PedBE clock and gestational age clocks, were developed using mainly adult samples. This means that CpG sites involved in early growth and developmental processes may not be captured in these clocks.