HDHL EpiBrain: Epigenetic effects of B-vitamins on brain health throughout life

What's already known in this research area: Folic acid and closely related vitamins (vitamin B12, vitamins B6 and riboflavin) are critical for brain health throughout life. Low intakes of these nutrients may impact adversely on brain development in early life and brain function in later life. In early life, folic acid supplements are recommended for women who are trying to become pregnant and during the first 12 weeks of pregnancy in order to reduce the risk of neural tube defects (NTDs) including spina bifida. Apart from preventing NTDs, however, folic acid intake of mums during pregnancy appears to be associated with better cognitive performance in the child, but this aspect is still under investigation by scientists worldwide. The link between nutritional factors such as folic acid in mums during pregnancy and brain health in the child may be explained by 'Epigenetics'. This is the study of processes (such as DNA methylation) that alter our genes by switching them on and off, and we now know that diet can have a major influence on these genetic processes. These changes to our genes happen throughout the lifecycle, from the time of conception, through pregnancy, childhood, middle age and old age.

What EpiBrain will address: In order to support health improvement strategies, both for mothers during pregnancy and their babies on one hand, and for adults as they age on the other, we need a better understanding of how folic acid and related B vitamins influence specific genes related to brain development in the child and cognitive function in older adults. This is the overall purpose of the EpiBrain project.

How this will be achieved: The EpiBrain project will bring together research teams from the UK Canada and Spain who have strong expertise in nutrition and epigenetics and a track record of working successfully together. Our work will use 'epigenome-wide association studies' or EWAS, an approach that involves rapidly scanning complete sets of DNA to find epigenetic marks linked with health. This approach is necessary to more fully explore the biological basis explaining the impacts of maternal folic acid supplementation in pregnancy on brain development in the child, and interventions with B vitamins to improve cognitive function in later life. We will conduct new epigenetics analysis on stored samples from studies previously conducted by our research teams in pregnancy and older age. Dietary, nutritional and epigenetic data will be linked with cognitive function measurements in children and older adults. Brain function assessment will also include neuroimaging data using state-of-art magnetoencephalography (MEG) conducted in early and late life on our study participants, providing a direct measure of brain activity.

Why the results of the EpiBrain project are important: The EpiBrain project will lead to improved understanding of the role of folic acid and other B vitamins, their epigenetic effects and brain function in childhood and older age, with expected results anticipated to provide scientific substantiation to support nutritional strategies for sustaining better brain health through the lifespan. This project is very timely because of potential imminent changes in fortification and supplementation policies. The implementation of mandatory food fortification for NTD prevention is currently being debated at national levels in the UK and Ireland, while the team in Canada is working on challenges and solutions for the generating guidelines in relation to the amount of folic acid to incorporate into folic acid supplements for pregnant women. The EpiBrain project provides a unique opportunity for a truly transnational collaboration to study the potential effects of folic acid (that may be mediated by Epigenetics) on brain health throughout the lifecycle.

Low dietary and biomarker status of folate and interrelated B vitamins (methyl donor nutrients) are known to lead to perturbations in one carbon (1C) metabolism that can impact adversely on brain development in early life and brain function in later life. Better maternal folate status in pregnancy is however associated with improved cognition in the offspring, whilst optimal folate and related B vitamin status may prevent cognitive decline in later life. The biological mechanisms explaining these relationships may involve DNA methylation of epigenetically-controlled genes related to brain development and function. A better understanding of the mechanisms linking relevant B vitamins and the epigenome with brain health at critical stages of the lifecycle is necessary to support evidence-based health improvement strategies. The EpiBrain project aims to investigate the nutrition-epigenome-brain relationship through the lifespan with a focus on methyl donor nutrients and their related epigenetic effects in relation to brain outcomes. We will conduct new epigenetics analysis on stored samples and access data from existing well characterised cohorts, both prospective studies (maternal-offspring pairs) and randomised controlled trials in pregnancy and older age. Genomic DNA extracted from maternal, child and older adult blood samples will be analysed for differentially methylated regions by genome-wide methylation analysis (850k microarray). Dietary, nutrient biomarker and epigenetic data will be linked with cognition in children and older adults. Brain function assessment will also include neuroimaging data using state-of-art magnetoencephalography (MEG) conducted in early and late life on B-vitamin trial participants to study the effects of methyl donor nutrients on neurological functioning. The EpiBrain project will provide scientific substantiation to support nutritional strategies for sustaining better brain health through the lifespan.

Our proposal aligns closely with the JPI HDHL vision to support high-quality, translational, collaborative research and addresses the specific aim of this call, to further understanding of diet-epigenome relationships and their effect on human health across the lifespan. The proposed research focuses on methyl donor nutrients and their related epigenetic effects in relation to brain outcomes. We anticipate that results will contribute valuable data to help develop effective targeted nutritional strategies to promote better brain health throughout the lifespan and that the project overall will result in important societal impacts.

Health Impacts
The proposed research is well aligned with the goal of promoting health and wellness across the life span in global populations. The benefits of folic acid fortification in relation to the prevention of neural tube defects are well established however the role of folate and related B-vitamins on other key health outcomes, particularly neurodevelopment and brain function are less well understood but are suggested to be mediated by 1-carbon related epigenetic mechanisms. We plan to investigate these associations and in particular whether the epigenetics related to brain function in early life are also related to cognitive function in later life, and how these relationships are impacted by dietary intake and biochemical B-vitamin status. The current proposal thus offers a unique opportunity to investigate these associations in populations (Canadian, British and Spanish) with very different exposures to folate and related methyl nutrients thus providing novel data to help advance our understanding in this important research area across the global intake range. The findings will provide scientific substantiation to support intervention strategies for sustaining better health and preventing disease across the lifespan and align with a recent call from the European Food Safety Authority (EFSA) that prioritised the need for interdisciplinary collaboration and a targeted exploitation of available human epidemiological and clinical data to investigate the association between epigenetic changes and health effects. In their report outlining a 'A Cross-Council vision for Food, Nutrition and Health research' the Research Councils in the UK reported that many of the mechanisms underpinning the effects of food and nutrition on long-term health were under-investigated and called for multidisciplinary partnerships to deliver a robust and authoritative evidence base crucial to the development of healthier food products, optimisation and stratification of dietary guidelines, and determination of effective intervention strategies. https://mrc.ukri.org/documents/ pdf/cross-council-fnh-bk-26-march-2015/. It is envisaged the proposal will make a significant contribution to the evidence base for the European commission framework programme for research and innovation (Horizon 2020) 'Societal Challenges' relating to: 'Improving understanding of the determinants of health and disease prevention' and the European Innovation Partnership Strategic Implementation Plan on active and healthy ageing for: 'Prevention of functional decline, both physical and cognitive, in older people.

Societal and other impacts
EpiBrain brings together researchers with expertise in nutrition, epigenetics and neurodevelopment to engage in diet and health research at an international level.
It will establish a critical mass of expertise in this research area, allowing for excellent science and sharing of innovative approaches and infrastructures, and the data gathered will be made available to the wider research community.
A highly relevant aspect of EpiBrain will be to provide stakeholders, policy-makers, influencers and healthcare regulatory bodies at national and international levels with up-to-date and easily adaptable scientifically robust. recommendations for evidence-based action.