Early life adversity and trajectories of cardiometabolic health, cognitive function and physical function: improving understanding of the mechanisms a

Lead Research Organisation: University of Bristol
Department Name: Social Medicine

Abstract

Good health starts in early life. In early childhood, children in 'healthy' families learn that they can rely on their carers for their physical and emotional wellbeing. This allows the child to develop behaviours and other assets that will enable them to maintain their own wellbeing in later life. When the family safety net is compromised in one or more ways, the emotional and physical development of young children is vulnerable. Early life adversity is a risk factor for adverse cardiometabolic health, and poorer cognitive and physical function - three aspects of healthy aging essential for longevity and the maintenance of independence in old age. Questions remain, however, about the pathways and mechanisms through which the adverse health consequences of early life adversity arise. Most research on this topic comes from studies with health measured at a single age in adulthood. Such studies cannot explore the dynamic relationships between early life adversity and changes in health across the life course. We will investigate this in longitudinal studies with repeated measures of health in 3 cohorts. Using repeated measures of health will enable us to assess whether some people remain resilient to the health effects of early adversity, whether some people with favourable health profiles at earlier ages experience deterioration in mid-life health, and the potential for reversibility, i.e. an improvement in health during mid-life. The role of adversity (e.g. abusive or dysfunctional relationships) and resources (e.g. social support) experienced in adulthood also remains uncertain. In all 3 cohorts, we will examine whether adversity and resources in adulthood explain or alter the relationship between early adversity and trajectories of health. Risk factors such as smoking and obesity play a role in the generation of health inequalities, and interventions that reduce these risk factors would reduce the adverse health consequences of early life adversity. However, most of this evidence comes from studies with single measurements of smoking, obesity, etc. In all 3 cohorts, we will use repeated measurements of smoking, alcohol use, physical activity, mental health and personality traits, and explore their role in the relationship between early life adversity and later health. Our approach will enable us to identify detrimental or health-promoting behavioural or psychological trajectories. Finally, insufficient attention has been given in the literature to the the biological mechanisms through which early life adversity affects later health. We will estimate the role of two biological processes, DNA methylation and cortisol, in the associations between early life adversity and trajectories of health.

Planned Impact

The main beneficiaries of this research will be:
1. those responsible for designing interventions that seek to alleviate the adverse consequences of early life adversity; our results will shed light on the potential impact of such interventions
2. national and international guideline writers, who will make use of the interventions detailed above

Publications

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Houtepen LC (2018) Childhood adversity and DNA methylation in two population-based cohorts. in Translational psychiatry

 
Description 1. Methods for characterising early life adversity
We evaluated three approaches to defining exposure to multiple childhood social risk factors: cumulative risk, factor analysis, and latent class analysis. We used data from the National Survey of Health and Development cohort (NSHD) to compare the utility of the three approaches when examining associations with physical capability and common affective symptoms in adults aged 60 to 64 years. Examining cumulative risk on the basis of exposure to the sum of individual childhood social risk factors acknowledges that childhood social risk factors tend to accumulate and increases the statistical power when some exposures to specific childhood social risk factors are not common. Formulating metrics of multiple childhood social risk factor exposures into a composite metric may also reduce measurement error. The total cumulative risk approach assumes that different types of social risk exposures have an equivalent impact on the risk of physical or mental capability. This misses the opportunity to examine what happens when children are exposed to social risk factors in different domains of risk within the family environment. Factor analysis partly addresses this issue by allowing the identification of a smaller number of empirically derived, grouped social risk factors thus helping to understand the separate or unique contributions of different kinds of social risk factors on different aging outcomes. In our data, latent class analysis models did not fit well and so did not provide a suitable approach for categorising exposure to early life adversity. Both socioeconomic and psychosocial exposures are relevant for physical capability, though with larger effect sizes for socioeconomic exposures. Greater exposure to psychosocial risk factors in childhood was associated with common affective symptoms in older age, and this was not explained by childhood socioeconomic risk factors. (Reference: Caleyachetty et al. J Aging Health 2016 doi: 10.1177/0898264316680434. [Epub ahead of print])

2. Methods for assessing the association of early life adversity with later outcomes
Many questions in life course epidemiology involve mediation and/or interaction because of the long latency period between exposures and outcomes. We explored how mediation analysis (based on counterfactual theory and implemented using conventional regression approaches) links with a structured approach to selecting life course hypotheses. Using theory and simulated data, we showed how the alternative life course hypotheses assessed in the structured life course approach correspond to different combinations of mediation and interaction parameters. For example, an early life critical period model corresponds to a direct effect of the early life exposure, but no indirect effect via the mediator and no interaction between the early life exposure and the mediator. We also compared these methods using data from the mothers of the Avon Longitudinal Study of Parents and Children (ALSPAC), focusing on the association of parental occupational social class (early life exposure) and own adult occupational social class (mediator) with physical capability (outcome). In the ALSPAC data, part of the association between parental social class and mid-life physical capability is mediated by own adult social class, but there is also an interaction such that there was a negative effect of low social class in childhood on physical capability in those who had high social class in adulthood, but no effect of low social class in childhood on physical capability in those who also had low social class in adulthood. (Reference: Howe LD et al., Int J Epidemiol (2016) 45 (4): 1280-1294. DOI: https://doi.org/10.1093/ije/dyw254)

3. Associations of early life adversity with cardiometabolic health, cognitive function and physical capability
In analyses of the association between early life adversity and BMI trajectories in the NSHD cohort, we demonstrated that mean BMI increased linearly with increasing exposure to childhood socioeconomic risk factors for both sexes (p for trend= <0.001) . Exposure to a higher number of childhood socioeconomic risk factors among women but not men, was associated with a faster increase in BMI from 20 to 64 years, even after adjustment for adult socioeconomic position. There was no evidence of an association between exposure to childhood psychosocial risk factors and mean BMI in either sex. (Reference: Caleyachetty et al. In preparation)
In the mothers of the ALSPAC study, we used factor analysis to define exposure to multiple types of early life adversity (lack of maternal care, maternal overprotection, parental mental illness, household dysfunction, sexual abuse, physical and emotional abuse, and neglect in childhood). These factor scores were then combined into a second order factor model to represent total early life adversity exposure. We investigated associations of these early life adversity factor scores, and childhood SEP, with composite measures of cognitive and physical capability at mean age 51 years. There was evidence that, compared to participants whose fathers had 'professional' occupations, participants whose father's had 'managerial/technical', 'skilled non-manual', 'skilled manual' and 'partly or unskilled manual' occupations had, on average, lower physical and cognitive capability. There was a clear trend for increasing magnitudes of association with lowering childhood SEP. There was also evidence that greater total psychosocial adversity in childhood was associated with lower physical capability. Total psychosocial adversity in childhood was not associated with cognitive capability. (Reference: Anderson EL et al. Psychology & Aging. In Press)
In the mothers of the ALSPAC study, no specific form of psychosocial adversity (lack of maternal care, maternal overprotection, parental mental illness, household dysfunction, sexual abuse, physical and emotional abuse, and neglect in childhood) was consistently associated with cardiovascular risk factors (body mass index (BMI), waist circumference, systolic and diastolic blood pressure, plasma glucose, insulin, triglycerides, low and high density lipoprotein cholesterol, C-reactive protein, carotid intima-media thickness (cIMT) and arterial distensibility, assessed at mean age 51 years). There was evidence that a one standard deviation greater cumulative psychosocial adversity was associated with 0.51cm greater waist circumference (95% confidence interval [CI]: 0.02cm, 1.00cm, p=0.04) and a lower arterial distensibility, even after adjustment for age, ethnicity, childhood SEP and adult SEP. (Reference: Anderson EL et al. Revise and Resubmit with Int J Equity and Health). Similar analysis in the NSHD participants showed no consistent evidence to suggest that cumulative psychosocial adversity (as measured by a summary score), or any specific form of psychosocial adversity, was associated with CVD risk factors. There was some evidence that parental death was associated with higher systolic and diastolic blood pressure, but given the lack of association with any of the other ten CVD risk factors, this finding needs further replication in other large, well characterised studies. (Reference: Anderson EL et al. In preparation)
Within the Caerphilly Prospective Cohort Study, we have examined associations of life course socioeconomic position with trajectories of cognitive function from mid to late life. In this sample, SEP in childhood and adulthood were related to cognitive capability at age 53 years childhood; but the magnitude of association and strength of evidence was much greater for adulthood SEP, and associations of adulthood SEP were independent of childhood SEP. Consistent with these findings, we also provide evidence of a critical period in adulthood for associations of SEP and cognitive capability in mid-life, using the structured life course approach. We found no evidence that childhood SEP nor adulthood SEP is related to the rate of cognitive decline over time. Our findings are consistent with the cognitive reserve hypothesis; whereby individuals with higher adult SEP continue to have greater cognitive capability compared with similarly-aged individuals with lower adult SEP, but both have a similar rate of decline. (Reference: Anderson EL et al. In Preparation)

4. Early life adversity and DNA methylation
DNA methylation-based biomarkers are highly correlated with chronological age; departures of methylation-predicted age from chronological age can be used to define a measure of age acceleration, which may represent a potential biological mechanism linking environmental exposures to later health outcomes. Using data from two cohorts of women (mothers from the Avon Longitudinal Study of Parents and Children, ALSPAC, N=989 and MRC National Survey of Health and Development, NSHD, N=773), we assessed associations of SEP, psychosocial adversity in childhood (parental physical or mental illness or death, parental separation, parental absence, sub-optimal maternal bonding, abuse and neglect) and a cumulative score of these psychosocial adversity measures, with DNA methylation age acceleration in adulthood (measured in peripheral blood at mean chronological ages 29 and 47 years (ALSPAC) and buccal cells at age 53 years (NSHD)). We also assessed whether associations differed according to adult SEP. No associations were observed between low SEP, any of the measures of psychosocial adversity or the cumulative psychosocial adversity score and age acceleration. For example, manual childhood SEP (compared to non-manual) was associated with age deceleration by 0.10 years (95% CI -0.66 to 0.46) in meta-analysed 47-year ALSPAC and NSHD results. Results were similar when stratified by adult SEP. (Reference: Lawn R et al. In preparation). To extend this analysis, we are also carrying out epigenome wide association analysis of each individual form of early life adversity and the score of cumulative exposure. Results will be available imminently (Houtepen et al. In preparation).

5. DNA methylation and measures of physical capability
We investigated the association of epigenetic age with physical capability in later life. Having a higher epigenetic than chronological age (known as age acceleration, AA) has been found to be associated with an increased rate of mortality. Similarly, physical capability has been proposed as a marker of ageing due to its consistent associations with mortality. We used data from 790 women from the NSHD who had DNA methylation data available. AA from blood was associated with a greater decrease in grip strength from age 53 to 60-64 (0.42kg decrease per year of AA, 95% confidence interval 0.03, 0.82kg; p=0.03, n=152), but no associations were observed with standing balance time or chair rise speed. Current smoking and lower BMI were associated with lower epigenetic age from buccal cells. We found evidence that AA in blood is associated with a greater decrease in grip strength in British females between 53 and 60-64, but no association with standing balance time or chair rise speed was found. (Reference: Simpkin AJ et al. BMJ Open 2017. In Press)
Exploitation Route Replication in other cohorts; more detailed examination of mediation pathways and resilience; extension to further ageing outcomes
Sectors Education,Healthcare

 
Description We submitted a summary of our findings to a parliamentary Science and Technology committee on Evidence-based early-years intervention.
First Year Of Impact 2018
Sector Government, Democracy and Justice
Impact Types Societal

 
Description Submission to science and technology select committee
Geographic Reach National 
Policy Influence Type Gave evidence to a government review
 
Description Interstela
Amount £249,391 (GBP)
Funding ID ES/N000382/1 
Organisation Economic and Social Research Council 
Sector Public
Country United Kingdom
Start 12/2015 
End 06/2018
 
Description Medical Research Council Career Development Award
Amount £783,730 (GBP)
Funding ID MR/M020894/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2015 
End 06/2022
 
Description MRC LHA 
Organisation University College London
Department MRC Unit for Lifelong Health and Ageing
Country United Kingdom 
Sector Academic/University 
PI Contribution I have been working on, supervising and collaborating on analyses of the NSHD cohort in relation to pathways from early life exposures to healthy ageing
Collaborator Contribution Data sharing - NSHD data - and collaboration in terms of providing expertise in measures of healthy ageing
Impact PMID:27681097
Start Year 2015
 
Description Oral presentation at CLOSER conference - R Lawn 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact R Lawn presented paper on early life adversity and DNA methylation as an oral presentation at the CLOSER conference, London
Year(s) Of Engagement Activity 2017
 
Description Pint of science - public engagement 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact L Houtepen gave a 'pint of science' talk about epigenetics
Year(s) Of Engagement Activity 2017
 
Description Poster presentation Lawn et al Canada 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Poster presentation at the 2016 Human Behaviour and Evolution Society conference in Canada: 'Associations between psychosocial adversity and epigenetic ageing: Avon Longitudinal Study of Parents and Children' Authors: R Lawn, EL Anderson, M Suderman, AJ Simpkin, C Relton, I Penton-Voak, LD Howe.
Rebecca Lawn represented the Interstela project at the 2016 Human Behaviour and Evolution Society conference in Vancouver, Canada by presenting this poster.
Year(s) Of Engagement Activity 2016
URL http://www.bristol.ac.uk/integrative-epidemiology/epigenetics-social-science-network/research-output...
 
Description Poverty Safari 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Public engagement event to discuss poverty and its consequences
Year(s) Of Engagement Activity 2018
 
Description Workshop: child maltreatment: resilience and embodiment 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Interdisciplinary workshop discussing various perspectives on child maltreatment
Year(s) Of Engagement Activity 2018