DNAm and Aging
Consistent changes in DNAm over the lifespan across individuals have been identified by multiple studies9,34-37. Cord blood tends to show low levels of DNAm10,38followed by a rapid increase in the early years of life38,39, and then a gradual loss of methylation with aging2. In particular, CpG sites linked to embryonic developmental genes gain methylation during childhood, while regions related to immune processes lose methylation40. Genes located in the Major Histocompatibility Complex (MHC) class I and II40 – in particularHLA-B , HLA-C , HLA-DMA , HLA-DPB1 – become demethylated with age. This is significant as MHC I and II genes have previously been associated with asthma and allergic disease41-44,40,45,46.
The immune system has two key mechanisms: innate immunity and adaptive immunity. MHC complexes are part of the adaptive immune system and are involved in recognizing and destroying pathogens47. The innate system is present in the fetus and at birth, but is subdued to tolerate the stress of fetal development48. The adaptive immune response develops throughout the lifespan, with T cells playing a key role; the helper T cells can be further divided into Th1 and Th2 cells. Th2 cells stimulate the production of antibodies and have been linked to increased IgE response in atopy49, and to asthma and other allergic diseases50. Fetal and neonatal T cells differ significantly from adult cells. Environmental exposures may activate fetal/neonatal T-cells, resulting in a Th2 immune response48. For example, Zhang et al . found that changes in DNAm within Th2 pathway genes between the ages of 10 and 18 increase the risk for acquisition of asthma in girls51.
The rate of DNAm fluctuation during childhood is three to four times greater than in adulthood52. Studies have suggested that early life changes might follow a logarithmic, rather than linear, pattern52-54. In older age, there is a pattern of increased DNAm discordance across individuals (the so-called “epigenetic drift” phenomenon). Epigenetic drift2 is defined by the accumulation of random changes in DNAm over time, leading to increased inter-individual variance in methylation patterns with age36,37,55-57, a difference that is more pronounced in later life36,37,55. The increase in epigenetic drift in older age has led researchers to postulate that aging may be a process of ‘memorizing’ life-time environmental exposures58. Understanding the effect of these exposures on DNAm is essential to the study of differential rates of aging.