The role of DNA methylation in the life course and age acceleration

Worldwide, ageing represents a major concern. Indeed, ageing is not only characterized by
the accumulation of cellular or molecular damage over time and the decrease of physiological
capacities, but it induces a higher health care burden, putting considerable pressure on public
finances. Early life adversity (ELA) regroups different types of exposure all influencing individual
ageing. The ELA label refers to socio-economic status, emotional and environmental exposures. As
demonstrated in the Developmental Origins of Health and Diseases (DOHaD) concept, the most
sensitive period of life covers the time between conception and age 2 where ELA is mainly
occurring. Nonetheless, from conception to adulthood remains a period when ELA can occur. As life
circumstances directly interact with biological processes, in this thesis I considered how socioeconomic
stress as well as early maternal experience can be perceived by their offspring and how
this may have epigenomic effects. Following the DOHaD concept, we used the Avon Longitudinal
Parents and Children (ALSPAC) cohort to investigate how maternal trauma can affect their child’s
epigenomes as well as the epigenetic ageing process. Here, we used different approaches to
investigate this mother-child association. Firstly, the use of epigenetic clocks (EC) using DNA
methylation pattern and considered as an accurate age biomarker, allowed us to demonstrate that
child ageing is not associated with maternal trauma exposure. Secondly, the epigenome wide
association study (EWAS) approach investigated whether the ageing process is associated to
underlying biological mechanisms. Our EWAS models highlighted that maternal experience induces
epigenetic imprints, for example in DNA methylation (DNAm), in their children remaining over
years. Additionally, we demonstrated that those imprinted marks are associated with biological
pathways such as Parkinson disease or oxidative phosphorylation pathways. Within those pathways
of interest, we also observed that associated genes such as COX7C known to be associated with
ageing were up regulated. On the contrary other genes were down regulated. Finally, we shed into
light that mothers possess “directing CpGs” mainly associated with imprinted child’s DNAm,
suggesting that an epigenetic transmission mechanism took place. Here, in the ALAC project, we
answered to three key points of maternal-child association: 1) the in-utero transmission from the
individual’s mother, 2) the effects of individual life events and statuses prior to the measurement
of the epigenetic clock, and 3) changes evaluation in the EC within the same individual as well as
the association between levels and changes in the clock between mother and child.