To study and manipulate heterogeneous epigenetic states that operate during ageing
Lead Research Organisation:
Babraham Institute
Department Name: UNLISTED
Abstract
A central debate in ageing research is whether ageing is simply due to wear and tear, or to a hard coded ageing programme in our genes. While a decline in cellular and organismal functions with age might suggest the former, the large variability observed in the lifespans of closely related species may support the hypothesis that ageing is a regulated process. A number of biomarkers of ageing have been identified, such as telomere erosion and p16 expression. In mammals, ageing is accompanied by global changes in DNA methylation, characterised by global hypomethylation and focal hypermethylation (mainly of CpG islands). Recently, a “clock” was described that can predict human chronological age based on specific changes at a discrete set of CpG sites throughout the genome65. This (DNAm) clock has since been shown not only to predict chronological age ±3.6 years but also biological age, providing a potential measure of an organism’s health in the context of its chronological age. For example, the clock of the liver “ticks” faster in individuals with fatty liver disease. Some organs however such as the cerebellum and potentially the placenta show a different methylation age trajectory.
Organisations
- Babraham Institute, United Kingdom (Lead Research Organisation)
- University of Edinburgh, United Kingdom (Collaboration)
- Max Planck Society (Collaboration)
- Stuttgart University, Germany (Collaboration)
- The Wellcome Trust Sanger Institute (Collaboration)
- University of Cambridge, United Kingdom (Collaboration)
- Broad Institute (Collaboration)
- National Institute of Environmental Health Sciences (Collaboration)
- Stanford University, United States (Collaboration)
- Imperial College London (Collaboration)
- Pasteur Institute, Paris (Collaboration)
- University of Nottingham (Collaboration)
- EMBL - European Bioinformatics Institute, United Kingdom (Collaboration)
Publications
Aarts M
(2017)
Coupling shRNA screens with single-cell RNA-seq identifies a dual role for mTOR in reprogramming-induced senescence.
in Genes & development
Bell CG
(2019)
DNA methylation aging clocks: challenges and recommendations.
in Genome biology
Brighton PJ
(2017)
Clearance of senescent decidual cells by uterine natural killer cells in cycling human endometrium.
in eLife
Cruz C
(2018)
Tri-methylation of histone H3 lysine 4 facilitates gene expression in ageing cells.
in eLife
Hahn O
(2017)
Dietary restriction protects from age-associated DNA methylation and induces epigenetic reprogramming of lipid metabolism.
in Genome biology
Hahn O
(2018)
Hepatic gene body hypermethylation is a shared epigenetic signature of murine longevity.
in PLoS genetics
Hastings J
(2019)
Flow with the flux: Systems biology tools predict metabolic drivers of ageing in C. elegans
in Current Opinion in Systems Biology
Hastings J
(2019)
Multi-Omics and Genome-Scale Modeling Reveal a Metabolic Shift During Aging.
in Frontiers in molecular biosciences
Hastings J
(2017)
WormJam: A consensus C. elegans Metabolic Reconstruction and Metabolomics Community and Workshop Series
in Worm
Hernando-Herraez I
(2019)
Ageing affects DNA methylation drift and transcriptional cell-to-cell variability in mouse muscle stem cells.
in Nature communications
| Description | We have discovered the first non-human epigenetic ageing clock in the mouse, based on sequencing the methylome in many tissues and at many age-stages. From this we derived a tissue-independent age-predictor. This can predict chronological age +/- 3.3 weeks and also records biological interventions that shorten lifespan, such as for example ovariectomy or high fat diet (PMID 28399939). We have identified ageing related DNA methylation signatures in mouse liver that are characteristic of lifespan-extending interventions, particularly dietary restriction and reduced TOR signalling (rapamycin treatment) (PMID 30462643). |
| Exploitation Route | We have filed a patent application on the mouse epigenetic clock. This clock could be useful for others who are using mouse models to look for nutritional influences on life expectancy or who are looking to develop life-extending or rejuvenating drugs, especially as the results of certain treatments may already be recorded in the ageing clock at a relatively young age, thus saving time and cost. This patent application has led to a collaboration with a small company, Shift Bioscience, who were partially embedded in our lab in 2018. |
| Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |
| URL | https://www.babraham.ac.uk/our-research/epigenetics |
| Description | We contributed to a parliamentary POSTNOTE on the ageing process and health. We have successfully applied for a Royal Society science exhibit Race Against the Ageing Clock 2018, and organised this very successful Royal Society exhibit which involved 42 staff members from our Epigenetics ISPG and an audience of 8400 general educated members of the public. We applied for a patent on the mouse epigenetic ageing clock, and embedded a small company who work on the epigenetics of ageing, Shift Bioscience, in our ISPG. Finally, our former PhD student Tom Stubbs established in 2018 the company Chronomics who work on using DNA methylation profiling for health assessment and lifestyle choices. |
| First Year Of Impact | 2018 |
| Sector | Healthcare |
| Impact Types | Societal,Policy & public services |
| Description | Member SAB Max Planck Institute for Ageing Cologne |
| Geographic Reach | Local/Municipal/Regional |
| Policy Influence Type | Participation in a advisory committee |
| Description | Postnote to Parliament on ageing |
| Geographic Reach | National |
| Policy Influence Type | Gave evidence to a government review |
| Description | Steering board Human Cell Atlas |
| Geographic Reach | Multiple continents/international |
| Policy Influence Type | Participation in a advisory committee |
| Description | Flagship |
| Amount | € 1,000,000 (EUR) |
| Organisation | European Commission |
| Sector | Public |
| Country | European Union (EU) |
| Start | 02/2019 |
| End | 03/2020 |
| 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 | Single cell triple-omics |
| Description | Single cell triple-omics combining transcriptome, methylome, and chromatin accessibility from the same single cell. |
| Type Of Material | Technology assay or reagent |
| Year Produced | 2017 |
| Provided To Others? | Yes |
| Impact | This method was just published. |
| Title | Transcriptome datasets of reproductive tissues in ageing females (GSE98901) |
| Description | RNA-seq datasets of trophoblast, endometrium and deciduae of mouse conceptuses developed in young versus aged females |
| Type Of Material | Database/Collection of data |
| Year Produced | 2017 |
| Provided To Others? | Yes |
| Impact | Significant changes imposed by maternal age on expression profiles of endoemtrial tissue and decidual development. Work shows the impact of the older female on reproductive success, unrelated to oocyte fitness. |
| Description | Collaboration with Linda Partridge and Andreas Beyer |
| Organisation | Max Planck Society |
| Department | Max Planck Institute for the Biology of Ageing |
| Country | Germany |
| Sector | Academic/University |
| PI Contribution | We helped to conceive the study, profiled methylomes and transcriptomes and interpreted data |
| Collaborator Contribution | They helped to conceive the study and provided ageing mouse cohorts with switched dietary restriction |
| Impact | One publication so far (Hahn et al 2017). Multidisciplinary with epigeneticists, ageing researchers, and lipidomics researchers involved. |
| Start Year | 2014 |
| Description | Collaboration with Oliver Stegle |
| Organisation | EMBL European Bioinformatics Institute (EMBL - EBI) |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We conceived the study and provided sequencing datasets and interpretation. |
| Collaborator Contribution | They helped with conceiving the study and provided computational analysis and modelling. |
| Impact | Initial work has been published in Stubbs et al 2017. The work is multidisciplinary involving epigeneticists and computational biologists and modellers. |
| Start Year | 2016 |
| Description | Collaboration with Sharahgim Tajkbash |
| Organisation | Pasteur Institute, Paris |
| Country | France |
| Sector | Academic/University |
| PI Contribution | Help with single cell sequencing and analysis of muscle stem cells |
| Collaborator Contribution | Collected muscle stem cell samples for sequencing |
| Impact | First paper is in revision. Involves cell biology, organismal biology, computation, epigenetics, sequencing. |
| Start Year | 2017 |
| Description | Cornelia De Moor |
| Organisation | University of Nottingham |
| Department | School of Mechanical, Materials and Manufacturing Engineering |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | DeMoor lab has brought to us her expertise on RNA technology |
| Collaborator Contribution | DEMoor lab has optimised an LRPAT technology to measure polyA length to C elegans. |
| Impact | DEMoor lab has optimised an LRPAT technology to measure polyA length to C elegans. |
| Start Year | 2016 |
| Description | Deciduoma |
| Organisation | National Institute of Environmental Health Sciences |
| Department | Reproductive and Developmental Biology Laboratory |
| Country | United States |
| Sector | Public |
| PI Contribution | Characterisation of reproductive defects in older females |
| Collaborator Contribution | Decidualisation model to assess the effect in the absence of an implanting embryo |
| Impact | Collaborative publication (PMID: 28874785) |
| Start Year | 2016 |
| Description | Development of computational methods for the quantification of biological variability |
| Organisation | EMBL European Bioinformatics Institute (EMBL - EBI) |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Development of an algorithm based on Bayesian statistics that quantifies variability in steady state levels of mRNA from nanofluidics-based PCR. |
| Collaborator Contribution | Development of an algorithm based on Bayesian statistics that quantifies variability in steady state levels of mRNA from nanofluidics-based PCR. |
| Impact | It is a multi-disciplinary collaboration involving high end PCR technology and statistical modelling. |
| Start Year | 2015 |
| 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 | Jesus Gil senescence |
| Organisation | Imperial College London |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Contributed single cell sequencing and analysis. |
| Collaborator Contribution | Conceived and conducted the study. |
| Impact | Publication Aarts et al 2017. Involves senescence biologists, single cell biologists, computational biologists. |
| Start Year | 2016 |
| Description | Jurkowski |
| Organisation | University of Stuttgart |
| Country | Germany |
| Sector | Academic/University |
| PI Contribution | Helped with reagents and interpretation. |
| Collaborator Contribution | Conceived and conducted study. |
| Impact | Publication Stepper et al 2017. Involves biochemists, epigeneticists. |
| Start Year | 2016 |
| Description | Kosuke Yusa |
| Organisation | The Wellcome Trust Sanger Institute |
| Country | United Kingdom |
| Sector | Charity/Non Profit |
| PI Contribution | We have together conceived and conducted experiments to identify new regulators of human pluripotency and reprogramming using genome-wide genetic screens. |
| Collaborator Contribution | Our partner provided expertise about the screen design, provided the cell line and lentiviral library, and sequenced the DNA samples. |
| Impact | Manuscript in preparation. |
| Start Year | 2017 |
| Description | Ludovic Vallier |
| Organisation | University of Cambridge |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We are working jointly on investigating the role of TGFb signalling in the control of human pluripotent states. |
| Collaborator Contribution | Our partner provided expertise in TGFb signalling, contributions to experimental design, conducted experiments, and were jointly involved in interpreting results. |
| Impact | The major output so far is the collection of data. |
| Start Year | 2018 |
| Description | Sean Bendall |
| Organisation | Stanford University |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | We are working together to devise new ways to measure and understand heterogeneity in human pluripotent cells, including being able to associate protein, epigenetic and signalling variability in the same individual cells. |
| Collaborator Contribution | Our partner is a leader in the field of mass cytometry and is contributing to the experiment design and execution, including data analysis. |
| Impact | This collaboration led to additional funding through the BBSRC UK - USA Partnership Award. |
| Start Year | 2017 |
| Description | Tony Green |
| Organisation | University of Cambridge |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Helped with single cell RNA sequencing and interpretation. |
| Collaborator Contribution | Conceived and conducted the study. |
| Impact | Published Kirschner et al 2017. Haematologists, single cell biologists, ageing biologists. |
| Start Year | 2016 |
| Description | Uterine pathologies and maternal age |
| Organisation | University of Edinburgh |
| Department | MRC Centre for Reproductive Health |
| Country | United Kingdom |
| Sector | Public |
| PI Contribution | Molecular assessment of changes occurring in older females |
| Collaborator Contribution | Pathological characterisation and assessment of uterine pathologies that become more frequent with age |
| Impact | Collaboration established. Application for future funding in progress. |
| Start Year | 2017 |
| Title | Novel Age Calculation Method |
| Description | Method to calculate methylation age |
| IP Reference | WO2018146482 |
| Protection | Patent application published |
| Year Protection Granted | 2017 |
| Licensed | Yes |
| Impact | Too early as this started in 2018 |
| 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 | Cambridge Epigenetics Club |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Professional Practitioners |
| Results and Impact | 150 people attended an evening of scientific presentations and networking as part of the Cambridge Epigenetics Club. This happens ~6 times per year. I organise these events with colleagues at the University of Cambridge, and the Club is sponsored by Abcam. The main outcomes are to bring together people from academia, industry, schools, and the general public to interact and discuss cutting edge epigenetics research. |
| Year(s) Of Engagement Activity | 2018,2019 |
| URL | https://www.abcam.com/events/cambridge-epigenetics-club |
| 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 | Computational Modeling in Biology Network |
| Form Of Engagement Activity | Engagement focused website, blog or social media channel |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | I created COMBINE to coordinate the development of standards in computational systems biology. The initiative includes several workshops a year (discussion of future standards, implementation of current standards, and end-user training), diffusion lists, social media dissemination. |
| Year(s) Of Engagement Activity | 2011,2012,2013,2014,2015 |
| URL | http://co.mbine.org |
| 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 | 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 | Nine invited presentations at international meetings, including EMBO, FASEB, Keystone, American Association for Cancer Research |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Postgraduate students |
| Results and Impact | Conference presentations about our research |
| 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 | 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 | SysMod 2017 |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | I organised the 2nd meeting of the ISCB Community of Special Interest SysMod. Up to 270 people attended depending on the talk. |
| Year(s) Of Engagement Activity | 2017 |
| 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 | 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 |
| Description | WT/EBI course in silico systems biology |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Postgraduate students |
| Results and Impact | I organised this one-week course, and gave presentations entitled: "What is Systems Biology? Where does it come from?", "The many faces of modelling in biology", "Modelling in systems biology, a few challenges", "From art to engineering: two decades of standards and tools towards digital organisms", "Modelling chemical kinetics" plus a tutorial on stochastic simulations of biological systems. |
| Year(s) Of Engagement Activity | 2017 |
| Description | Wellcome Genome Campus Cell Fate Workshop |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Postgraduate students |
| Results and Impact | This was an invitation only workshop organised by us on the Hinxton campus which brought together some of the international leaders working on cell fate biology and pathology. A meeting report was produced subsequently. |
| Year(s) Of Engagement Activity | 2018 |
| Description | eLife Community Webinar - Refreshing approaches to researcher evaluation |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | I animated a webinar discussing various ways to bypass the traditional publication-based evaluation of researchers. |
| Year(s) Of Engagement Activity | 2017 |