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.