Epigenetic responses to social and environmental cues in early life and over the life course: impact on healthy ageing in UK population-based cohorts

Epigenetic mechanisms such as DNA methylation are key regulators of gene function. Epigenetic signals are malleable and can change in response to internal and external stimuli. The epigenome thereby provides a mechanism of interaction between the genome with the environment, and we hypothesize that early life stimuli and exposures over the life course leave an epigenetic mark.

The proposal will explore DNA methylation in 4,024 samples from four British cohort studies (the MRC National Survey for Health and Development (NSHD) or 1946 birth cohort, the National Child Development Study (NCDS) or 1958 birth cohort, the 1970 British Cohort Study (BCS70), and the TwinsUK cohort (TwinsUK)) in order to identify epigenetic signatures of early life experience and exposure to social, environmental, and biological stimuli over the life course, linking findings to changes in physical and cognitive function during ageing. Each study captures a range of early life experiences, longitudinal health measures and lifestyle questionnaire data from adult life, DNA samples collected at single or multiple time-points, and in a sample subset, multiple genomic data for follow-up analyses.

The primary research design is a prospective analysis of longitudinal data across 2,336 blood and 1,688 buccal samples from the four cohorts. The first aim of the research will be to establish whether biological, environmental, and social stimuli in early life and over the life course result in detectable differences in DNA methylation profiles in adults. We will consider whether there are epigenetic associations with a number of factors including biological, environmental and social factors in utero and in early childhood (e.g. birthweight, childhood growth, maternal smoking during pregnancy, nutrition, parental socioeconomic position), and in later life: (e.g. smoking, alcohol consumption, physical activity, diet, stressful events, adult socioeconomic position). The second aim is to assess whether there are differences between cohorts in DNA methylation patterns, comparing samples containing individuals born in different years (1946, 1958 and 1970), accounting for age, since these may reflect differences between cohorts in environmental and social influences in early life.

Our third aim is to explore the role of epigenetics in healthy functional ageing by applying a two-fold approach. First, we will compare epigenetic signatures to longitudinal functional health trajectories throughout life across cohorts, across cell types (blood and buccal), and across different age categories. We will explore whether DNA methylation signatures of early life experiences can mediate functional ageing trajectories (such as cardiovascular, lung and cognitive function), and whether they can be reversed in response to social and environmental exposures in later life. Our fourth aim is to apply a new approach to estimate biological age, the epigenetic clock, to assess the rate of epigenetic ageing and relate it to early life stimuli and longitudinal biomedical, social, and environmental trajectories.

Additional analyses in subsamples will include DNA methylation profiling at multiple time-points to estimate reversibility of DNA methylation, cross-tissue comparison across blood, buccal, and additional tissues, and gene expression analysis for functional interpretation. Replication will be pursued in 3,970 samples from four independent UK-population-based cohorts.

The findings will establish the feasibility of our approach by combining modest samples of participants across each of the four cohorts into a large sample well powered to determine the influence of early life factors on epigenetic signatures throughout the life course. The proof of concept approach will allow such analyses to be extended to larger samples within cohorts by forming the basis for further funding applications and establishing an epigenetic research network across UK population-based cohorts.

Human epigenetics is a relatively recent research field and its potential for understanding the pathways linking early experience and later life health, and its clinical, public health and societal relevance is yet to be fully understood. Given this context, impacts are expected on a diverse range of major beneficiaries:

1. Academics from the wider research community, as described in the Academic Beneficiaries section will benefit from:
- The generation of new knowledge related to early life impacts on epigenetics and functional ageing trajectories
- The generation of new datasets to enhance these unique cohorts and integrate with available 'omic data for further exploration by other researchers
- The aggregation through collaboration of additional expertise in this area
- Training of early career researchers in the specific areas, and development of cross-disciplinary expertise.

2. The public sector.
The results of the research will be useful to practitioners working in health education and public health, their regulators, and professional associations. The research also has translational potential of the findings to health management. Translatable findings will include results on reversibility, which will highlight modifiable pathways to stop or reverse degenerative ageing processes by implementing lifestyle changes and more effective strategies for health management. For example, identification of specific methylation changes may help identify new underlying biological mechanisms that link early life exposures to later ageing phenotypes and hence inform new preventative and treatment strategies.

3. The general public.
Findings from the research will be relevant to issues in everyday life, such as parenting, physical and mental health. Translatable findings may include results on reversibility, which may highlight modifiable pathways to stop or reverse degenerative ageing processes by implementing lifestyle changes and more effective strategies for health management.

4. Industry.
Biotechnology companies may be able to exploit the improved biological knowledge that will be generated to develop novel products and services.

Economic and social benefits will be manifest through:
- Improved effectiveness of public services if the new biological insights result in better ways of predicting, treating and preventing functional decline with ageing (by implementing lifestyle changes and more effective strategies for health management, novel treatments, better diagnostics);
- Economic benefits to biotechnology companies able to exploit actionable translational opportunities with respect to the development of novel prognostic and therapeutic approaches that build on the associations we detect;
- Benefits to those developing and marketing omics assays, in terms of defining additional content, and expanding markets;
- Maximising value of omics data collected within systems such as the NHS for other purposes, by augmenting the value of such data for healthy ageing;
- Improved health outcomes if the work leads to potential clinical translation, resulting in further personal, social and economic benefits.

All of the cohorts have an excellent track record in raising awareness of cohort study findings among the public and policy makers (including central, local, and devolved administrations), primarily through media and targeted events, and findings from this work will be communicated to these audience through non-technical briefings and accompanying press releases. The resources for dissemination being developed by the CLOSER project (www.closer.ac.uk) will be used to improve the dissemination of findings to a wide range of beneficiaries