Epigenetic responses to dietary change across organismal lifespan

Lead Research Organisation: Babraham Institute
Department Name: UNLISTED

Abstract

The epigenome is susceptible to changes during organismal lifespan. Some of these accumulate in a linear manner and appear to be intrinsically programmed (see Obj. 5), but additionally the epigenome responds to extrinsic and environmental factors amongst which diet has emerged as a key component. This objective focuses on epigenetic change as a function of age and diet during lifespan and at the interface between generations in a range of model organisms. Dietary restriction (DR) without malnutrition has beneficial health effects for model organisms as well as for humans, raising the prospect of preventative medicine against age-related disease. Understanding which aspects of normal metabolism are detrimental to health is key to the development of therapeutics that capture the beneficial effects of DR, in itself an unrealistic treatment. Various signalling pathways mediate the effects of DR on health, however, DR-associated epigenetic changes that likely mediate long-term consequences are largely unexplored. The effects of DR on lifespan are similar across disparate eukaryotes diverged by millions of years, allowing the use of genetically powerful model organisms including C. elegans and S. cerevisiae to elucidate underlying mechanisms. This allows us to approach the transcriptomic and metabolic consequences of DR in a systematic manner, and to probe the modulation of these effects by epigenetic states that change throughout life. A few histone modifiers have begun to emerge as conserved contributors to ageing, for example the histone acetyltransferase CBP-1/p300. In worms, CBP-1 mutants are short lived and gain no lifespan extension from DR; CBP expression is also predictive of lifespan in mice, and the closest functional CBP ortholog in yeast, Rtt109, is a critical regulator of lifespan30,31. H3K4 and H3K36 methylation have been similarly implicated in lifespan in multiple organisms32,33 but epigenetic changes linked to ageing in normal conditions and under DR largely remain unknown. In humans, the dramatic rise in average maternal age and BMI at pregnancy are both linked to an increased frequency of pregnancy complications as well as higher rates of developmental abnormalities and long-term disease predisposition even in the absence of chromosomal abnormalities34-36. The degree to which epigenetic deregulation contributes to these effects is not understood. Using the mouse as a model, we and others have demonstrated particularly tight control of epigenetic marks during reproduction and embryogenesis, including how gamete-derived DNA methylation persists through epigenetic reprogramming into the cleavage-stage embryo and has differential effects in the first lineages37. We can use this extensive knowledge to reference any maternal age-related changes and evaluate their likely functional outcomes. Although oocyte defects are a major component of the maternal age-associated reproductive decline, we also have strong evidence for an important contribution from the ageing maternal environment, through impacts on placentation and altered endometrial signals. In this Objective we will characterise age-linked epigenetic changes in a range of model systems, determine how these are modulated by diet and study downstream consequences for gene expression, lifespan, and reproductive health.
 
Description In Objective 3.1 Epigenetic impacts of diet across lifespan, we have optimised low-cell number yeast ChIPseq assays suitable for elucidating histone modifications genome wide in ageing cells. Using these methods, we have obtained ChIPseq data for histone modification H3K4me3 across age, along with RNAseq profiles of H3K4me-deficient mutants. This has identified previously unknown roles for H3K4me3 in facilitating gene expression, and revealed that the known coupling of transcription to H3K4me3 is progressively lost with age (PMID: 30274593). In terms of responses to dietary change, we have discovered a critical role for diet in defining the health of aged yeast, and observe major differences in transcriptome dynamics during ageing in different carbon sources. To study metabolic fluxes that occur during ageing we generated high temporal resolution transcriptomic and metabolomic datasets in normal or long lived worms, and performed a detailed study of age-associated changes in the Citric Acid cycle (PMID: 30788345). This revealed a large efflux of acetyl-CoA molecules from excess fat metabolism in long lived animals, and we are studying how this metabolite affects the levels of acetylation in histones with knock on effects on transcriptional outputs. In mouse, we found in the liver that dietary restriction protects from age-associated DNA methylation changes (consistent with the ageing retarding role of dietary restriction), and induces epigenetic reprogramming of lipid metabolism, with methylation changes at loci involved in lipid metabolism affecting gene expression and the resulting lipid profile (PMID: 28351387). We have further identified age-related methylation signatures for interventions including DR and rapamycin (PMID: 30462643). In Objective 3.2 Epigenetic effects of diet at the interface between generations, we have transcriptionally profiled E11.5 trophoblast and decidual components from pregnancies developed in young and aged females, and found key differences that relate to the activation status of genes controlled by pregnancy hormones. We have also assessed uNK cell numbers and maturation state in these pregnancies and found no difference, pointing to the decidual stromal cell compartment that is most impacted by age. We have also profiled for DNA methylation changes in uteri of young and aged females, as well as placentas developed in these mothers, and are currently investigating if age manifests in epigenetic differences with functional consequences in these reproductive tissues.
Exploitation Route These findings are beneficial to the knowledge economy, relating as they do to the impact of diet on ageing, which is a major focus area for both academics and industry. Our findings regarding the impact of maternal age on the placenta have implications for healthcare professionals in terms of advice, guidelines and policies. Observations of the effect of dietary restriction on lipid metabolism should be helpful in optimizing diets to maximize health-span benefits, and similarly tools such as the worm metabolic network are of general use to the academic community and to specific companies in understanding metabolic impacts of specific dietary changes. We have further used our findings to engage with social scientists focused on the practice of ageing research itself. We continue to pursue public engagement activities relevant to the ageing process, and these are informed by our latest findings
Sectors Education,Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description We were approached by the Physiological Society for input to their Growing Older, Better project. The purpose of the report is to identify key policy areas within lifelong health that The Physiological Society can focus on over the next 3-5 years to improve the landscape for research into healthy ageing and shape the wider policy environment. After an initial scoping meeting, the epigenetics of ageing was selected as a topic of special interest for the Physiological Society. A further one-to-one meeting with JH clarified focus areas for the report and JH has been requested to write a section of the report on Epigenetics of Ageing.
First Year Of Impact 2018
Sector Healthcare,Government, Democracy and Justice,Pharmaceuticals and Medical Biotechnology
Impact Types Policy & public services

 
Description Chair of SAB Centre for Trophoblast Research University of Cambridge
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
Impact Has changed the perception of placenta and trophoblast in reproduction
 
Description European Research Council Starting grant
Amount € 1,500,000 (EUR)
Organisation European Research Council (ERC) 
Sector Public
Country European Union (EU)
Start 06/2015 
End 05/2020
 
Description Flagship
Amount € 1,000,000 (EUR)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 02/2019 
End 03/2020
 
Description GENIE COST
Amount € 7,000 (EUR)
Organisation European Cooperation in Science and Technology (COST) 
Department COST Action
Sector Public
Country Belgium
Start 09/2015 
End 09/2018
 
Title C elegans Metabolic Reconstruction Model 
Description Merged and re-annotated C elegans Metabolic Reconstruction Model 
Type Of Material Technology assay or reagent 
Year Produced 2018 
Provided To Others? Yes  
Impact This is a great improvement to the C elegans research community 
 
Title PCR Bayes 
Description Novel algorithm to quantify expression and biological variability of steady state transcripts 
Type Of Material Technology assay or reagent 
Year Produced 2017 
Provided To Others? No  
Impact This is a novel tool which extends the capabilities of C elegans researchers to quantitate biological noise in single worms 
 
Title copper response in yeast 
Description Response of yeast to copper treatment by RNAseq and replication fork stalling 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Impact data re-use 
URL https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE86283
 
Description Frenk for Biogerontology review 
Organisation University of North Carolina at Chapel Hill
Country United States 
Sector Academic/University 
PI Contribution Writing
Collaborator Contribution Writing
Impact publication pmid 29492790
Start Year 2017
 
Description Human Cell Atlas 
Organisation Broad Institute
Country United States 
Sector Charity/Non Profit 
PI Contribution Contributed to formulating the white paper of the Human Cell Atlas.
Collaborator Contribution Conceived the project and brought the international consortium together.
Impact The white paper was published Regev et al 2017. It involves single cell biologists and computational and modelling scientists.
Start Year 2016
 
Description Ageing workshop - DH 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Involvement in a workshop to explore the ethics behind healthy ageing research at Long Road Sixth Form College. Gave a 10-minute lay talk on my work related to healthy ageing, followed by a facilitated discussion about what could lie in the future if we achieve our research goals, based on some pre-prepared question cards.
Year(s) Of Engagement Activity 2018
 
Description Ageing workshop for visiting students - DH 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact Workshop to explore the ethics behind healthy ageing research for French students visiting the Babraham Institute.
Year(s) Of Engagement Activity 2018
 
Description An invited talk at conference "Networks Of Cellular Surveillance Mechanisms" 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact International conference in Heidelberg, Germany
Year(s) Of Engagement Activity 2018
 
Description Article on JH lab Ageing Research in Cambridge Independent 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Media (as a channel to the public)
Results and Impact An article on our yeast research was published following an in depth interview with me (JH).
Year(s) Of Engagement Activity 2017
 
Description Article on JH lab research on WIRED website and in Quanta magazine 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Article on JH lab research following in-depth interview
Year(s) Of Engagement Activity 2017
URL https://www.wired.com/story/bacteria-may-rig-their-dna-to-speed-up-evolution/
 
Description Babraham Schools day 2018 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Experiments on epigenetics for local 6th form schools
Year(s) Of Engagement Activity 2018
 
Description Babraham Schools' Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Hands-on demonstration to secondary school children, most of whom interested in pursuing biomedical sciences as undergraduates.
Year(s) Of Engagement Activity 2018
 
Description British Yeast Group meeting 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Talk to scientists in this and other areas focused on yeast research
Year(s) Of Engagement Activity 2017
URL https://microbiologysociety.org/event/society-events-and-meetings/focused-meeting-2017-british-yeast...
 
Description Cambridge Science Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Babraham Institute exhibit on the Epigenetic Ageing Clock presented at the Cambridge Science Festival, involving activities and question/answer interactions with members of the public
Year(s) Of Engagement Activity 2018
 
Description Expert group on epigenetics in ageing for the Shysiological Society 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact The Physiological Society is undergoing a review of its future strategy. As part of this, various expert groups were convened, and the importance of Epigenetics in the Ageing process was found to be of particular interest.
Year(s) Of Engagement Activity 2018
 
Description Follow-up meeting with Physiological Society representatives to discuss Epigenetics in Ageing 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Following the previous meeting, the policy manager for the Physiological Society requested a further one-to-one meeting to discuss the importance of epigenetics in ageing research.
Year(s) Of Engagement Activity 2019
 
Description GENIE network of C elegans researchers 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Joining this pan european network has allowed us to attend conferences, network with other C elegans labs across Europe and obtaining funding to organise a workshop on C elegans metabolic reconstruction.
Year(s) Of Engagement Activity 2015,2016,2017,2018
 
Description GENiE workshop "Extending the consensus representation of C. elegans metabolism" 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Study participants or study members
Results and Impact https://www.helmholtz-muenchen.de/genie-workshop-2017/program/index.html
Year(s) Of Engagement Activity 2018
URL https://www.helmholtz-muenchen.de/genie-workshop-2017/program/index.html
 
Description Host lab for BI Schools Day 2017 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact School visit to institute, children performed some experiments for a day
Year(s) Of Engagement Activity 2017
 
Description Host lab for BI Schools Day 2018 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Groups of schoolchildren and teachers were hosted in my lab for a day to perform experiments and learn about research careers.
Year(s) Of Engagement Activity 2018
 
Description Invited speaker in a conference:"Advances at the interface between metabolism and epigenetics" 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited speaker in the conference: "Advances at the interface between metabolism and epigenetics", held in Cambridge, UK
Year(s) Of Engagement Activity 2018
 
Description Invited speaker to a conference: "Systems biology of model organisms" 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited speaker at workshop "Systems biology of model organisms" held in Bordeaux, France.
Year(s) Of Engagement Activity 2019
 
Description Invited talk at British Society for Research on Ageing 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Supporters
Results and Impact Invited talk to other ageing researchers
Year(s) Of Engagement Activity 2017
URL http://bsra.org.uk/bsra-2017-university-exeter/
 
Description Lifelab - DH and AW 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Together with the Wellcome Genome Campus, European Molecular Biology Laboratory European Bioinformatics Institute, the University of Cambridge and the Medical Research Council Laboratory for Molecular Biology, the Institute organised 'LifeLab' as part of European Researchers Night 2018. Took part in the event presenting different exhibits to public audience, presenting the flow-sorting model and a Chip-seq model in the form of interactive games.
Year(s) Of Engagement Activity 2018
 
Description Organisation of C.elegans Cambridge local area meetings 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact An audience of about 10-15 science labs from around the Cambridge area attend these events, including many PhD students and postdocs. The aim of these meetings is dissemination of techniques and science as well as networking.
Year(s) Of Engagement Activity 2015,2017,2018
 
Description Partcipation in The Future of Ageing 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact A representative of the Casanueva lab attended a debate on the future of gein at London School of Economics geared towards general public.
Year(s) Of Engagement Activity 2018
 
Description Partnership Award from Royal Society 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact My lab obtained funding to organise a short course for about 50 students in local high-schools to teach them how to work with the nematode C elegans.
Year(s) Of Engagement Activity 2016
 
Description Pilot Collaborative Ethnography with Bioscientists at BI Engaged in Modelling Ageing 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Working Paper Presentations & Articles in Process:
Based on this initial research, Joanna and Carrie have an article in preparation for Medical Anthropology Quarterly. The article is entitled: "Working with models of ageing: Entanglements of human and animal health and wellbeing." This paper was presented at the Life Sciences & Society Lab, Centre of Sociological Research (CeSO), KU Leuven, Parkstraat 45, 3000 Leuven, Belgium 24th- 25th October.
In addition, Carrie will draw upon her research in writing one chapter of her book on Care as Science, which she plans to start writing in 2018.
Joanna is also drawing on her research at BI in two further papers.
The first, a methodological exploration, draws together the pilot study work at BI with her earlier work on the NDA project with David Kipling: Latimer, J. (forthcoming) Knowledge, life & intimacy: being alongside the life sciences of ageing. For publication in: Latimer, J. & Lopez, D. (eds.) Intimate Entanglements. The Sociological Review Special Issue/Monograph Series. London: Sage. This paper has been presented at Disrupting the Human. Science in Public Annual Conference, iHuman, Sheffield Universiy, 13-15th July, and at a recent workshop Intimate Entanglements, York Medical Society, 19-20 February 2018.
The second draws together the work at BI with Gould's PhD study (funded by the ESRC) An ethnographic study of anti-ageing science: Gould, S. and Latimer, J. Giving Life Time: Reimagined Futures and Interrupted Becoming/s at the Frontiers of the Life Science of Ageing. For submission to Ageing & Society. This paper was presented at the Anthropological Association Gerontology Group Annual Conference. Oxford Brookes University, June, 2017.
Year(s) Of Engagement Activity 2017,2018
 
Description Presenter and organising committee for RSSE exhibit "Race Against the Ageing Clock" 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Major exhibit at the Royal Society Summer Exhibition, also at Cambridge Science Fare and other events. Based on research from Reik lab and Babraham scientists on the discovery of mouse ageing clock. Involved scientists at all levels from Babraham discussing ageing research with scientifically engaged public. RSSE was attended by ~8000 people, and the Babraham Exhibit was popular and busy, resulting in numerous discussions of the ageing process and the potential for therapeutic approaches to ageing at all levels with members of the public.
Year(s) Of Engagement Activity 2018
URL https://royalsociety.org/science-events-and-lectures/2018/summer-science-exhibition/exhibits/ageing-...
 
Description Royal Society Summer Exhibition 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Babraham Institute exhibit on the Epigenetic Ageing Clock as invited entry presented at the Royal Society Summer Exhibition, involving activities and question/answer interactions with members of the public, fellows of the Royal Society, policymakers
Year(s) Of Engagement Activity 2018
 
Description Savile Club epigenetics talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Presentation about epigenetics at the London Savile Club
Year(s) Of Engagement Activity 2018
 
Description Sophianum School collaboration - Technasium 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Schools
Results and Impact The Babraham Institute is continuing to coordinate activities supporting its commitment as a signatory of the Concordat on Openness on Animal Research. Institute staff, including animal unit managers, have been working closely with a school in the Netherlands to prepare and launch the Institute's contribution to the national 'Technasium' education programme, which aims to draw together students and industry.

Two projects, developed in collaboration with the Institute's Public Engagement team and teachers from the Sophianum School in Gulpen, will challenge students to research and design systems to improve the efficiency and safety of animal care systems. A third project will require the students to research how legislation regulating the use of animals in science, as well as public opinion, can vary throughout Europe and the world.

A two-day visit on 19th & 20th May will kick-start a 10-week programme for the 15-year old students, who will work in teams and compete to design the best solutions to the challenges. The Institute's animal technicians will monitor student progress by commenting on YouTube videos posted fortnightly by the teams. Regular video calls into the animal unit and the Institute's laboratories will allow live discussion between the students, the animal technicians and the scientists who use animals as part of their research.

The challenge projects will finish in July, with the winning Sophianum team coming to the Babraham Institute as part of their prize. The students will visit Institute animal facilities and will get a chance to see the award-winning camera system which displays live feeds from the facility - allowing groups to appreciate first-hand both the animal care environment and the nature of working within an animal research unit.

This pilot project will also involve sixth-form students at the school who will learn about the Institute's research and take part in workshops to discuss the ethics of the use of animals in science. The Institute has been running ethics workshops for secondary and sixth form students since 2005, with contributions from Understanding Animal Research, the European Animal Research Association and the Institute of Animal Technology.

The success of the Technasium project will be evaluated by both the Institute and Sophianum School, with a view to developing future challenges.
Year(s) Of Engagement Activity 2017,2018
 
Description Talk at British Yeast Group by Lab member Ryan Hull 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Conference presentation at the British Yeast Group meeting
Year(s) Of Engagement Activity 2018
 
Description Talk at Cambourne Library 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact 15 general audience attended an Epigenetics presentation and discussion
Year(s) Of Engagement Activity 2018
 
Description Talk at DNA Replication as a Source of DNA Damage Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk to other members of research community.
Year(s) Of Engagement Activity 2017
URL https://www.fusion-conferences.com/conference67.php
 
Description Talk at EMBO Evolution and Ecology meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk and poster presentation at EMBO meeting
Year(s) Of Engagement Activity 2018
URL https://www.embl.de/training/events/2018/EAE18-01/
 
Description Talk at EpiChrom 2019 by lab member Ryan Hull 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Talk at EpiChrom 2019 meeting
Year(s) Of Engagement Activity 2019
URL https://www.scilifelab.se/epichrom-2019/
 
Description Technasium Project - DH 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Schools
Results and Impact Event at Sophianum School in the Netherlands, involving their secondary and sixth form students. We delivered workshops exploring the ethics of the use of animals in science, explained the research carried out at the Babraham Institute and described our careers in science.
Year(s) Of Engagement Activity 2018
URL https://www.babraham.ac.uk/news/2016/05/technasium-project-launch
 
Description UKRI launch 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Policymakers/politicians
Results and Impact UKRI launch event 2018
Year(s) Of Engagement Activity 2018