The effect of inter-individual variability in stress responses during ageing

Lead Research Organisation: Babraham Institute
Department Name: UNLISTED

Abstract

Ageing was once regarded as a random and progressive decline, until ground-breaking work in the nematode Caenorhabditis elegans demonstrated that a number of pathways control longevity, including insulin signaling pathway. Despite been genetically controlled, life expectancy is variable in many organisms, including laboratory strains of C. elegans, that lack genetic variability. The ageing process is exquisitely sensitive to protein folding homeostasis in the cell and molecular chaperones, key targets of insulin signaling pathway, are pivotal to this process by refolding proteins misfolded by genetic and/or environmental stressors. Despite its essentiality, it has been shown that chaperone’s transcription is highly stochastic across species. Moreover, we have previously demonstrated that inter-individual variation in chaperone expression in C. elegans is a good predictor of both stress resistance and mutation penetrance. We think that part of the mechanism that leads to lifespan variability is related to the inter-individual variability of chaperones and other genes that modulate longevity. We are interested in understanding what are the causes underlying inter-individual variability in the longevity pathways. A clue comes from the observation that the level of chaperone expression is passed through at least one generation. Because trans-generational memory in adaptation is usually associated with epigenetic mechanisms, these new findings suggest that at least part of the variability is related to chromatin modifications. In addition, we are interested in using sophisticated statistical tools to develop early biomarkers that can perform as predictors of lifespan as well as health-span. We think that the questions that we are addressing will get us closer to understanding what makes us different as individuals and how these differences influence the way we age.

Publications

10 25 50
 
Description My laboratory is interested in understanding the non-genetic contributions to that affect ageing. This is, how environmental factors, such as diet and stress, can affect how long we live. We use the nematode C.elegans to address the question of why there is so much variability in lifespan? This is obvious for identical twins, and can be well studied in laboratory model organisms such as the worm, where colonies are resemble identical twins because they are genetically homogeneous. We have discovered that many of the genes that respond to the environment are variably expressed among individual worms. We have also discovered that there is a coupling between transcription and translation among these variable genes. We have also found that this coupling is influenced by signals from the germline, at the commence of reproduction, that coincides with the beginning of the ageing process. We are currently studying how coupling of transcription and translation can influence the variability of the ageing process and the environmental and physiological inputs that can prolong life by preserving such coupling.
Exploitation Route Once our research is published, our work will conceptually influence the field of ageing and gene expression. We have also pioneered novel single-animals technologies in C.elegans, that can be used by anyone interested in monitoring transcriptional variability. Finally, we have advanced the field of genetics by inferring genetic interactions without using genetic mutations. This model of thinking could be extended to other model organisms and humans.
Sectors Education,Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description My research has contributed to knowledge exchange through a variety of venues including high school education, general public education, training of doctoral and post-doctoral students, international collaborations through pan-european networks and with Chile in South-America. Also the launching of an international workshop to be held at Babraham Institute in 2017.
First Year Of Impact 2015
Sector Healthcare
Impact Types Societal,Economic

 
Description BBSRC Global Challenge Research Fund
Amount £5,000 (GBP)
Funding ID BB/GCRF-IAA/02 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 12/2016 
End 03/2017
 
Description European Research Council Starting grant
Amount € 1,500,000 (EUR)
Organisation European Research Council (ERC) 
Sector Public
Country Belgium
Start 05/2015 
End 05/2020
 
Description GENIE COST
Amount € 7,000 (EUR)
Organisation European Cooperation in Science and Technology (COST) 
Department COST Action
Sector Public
Country Belgium
Start 08/2015 
End 09/2018
 
Description Royal society Partnership award
Amount £2,000 (GBP)
Organisation The Royal Society 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2016 
End 12/2017
 
Title A protocol for high-throughput quantitative RT-qPCR in single C. elegans using nanofluidic technology 
Description high throughput protocol for fast and reliable determination of gene expression levels in single or pooled C. elegans samples utilizing nanofluidics real time polymerase chain reaction. 
Type Of Material Biological samples 
Year Produced 2020 
Provided To Others? Yes  
Impact Help other C elegans reserachers with the measurement of rare transcripts from single worm samples. 
 
Title Novel method to study metabolic fluxes during ageing 
Description The novel method has been christened "Metab_FBA" and it is a novel flux balance analysis method to study ageing samples 
Type Of Material Technology assay or reagent 
Year Produced 2019 
Provided To Others? Yes  
Impact This development is a step forward for the field of metabolism and ageing in multicellular model organisms 
 
Title Worm-Align and Worm_CP 
Description Worm-align/Worm_CP is a simple FIJI/CellProfiler workflow that can be used to straighten and align Caenorhabditis elegans samples and to score whole-worm image-based assays without the need for prior training steps. We have applied Worm-align/Worm_CP to the quantification of heat-shock induced expression in live animals or lipid droplets in fixed samples. 
Type Of Material Biological samples 
Year Produced 2020 
Provided To Others? Yes  
Impact Publication of the method in JOVE journal 
 
Description BBSRC Global Challenge Research Fund BBSRC Impact Acceleration Account Award made to the Babraham Institute (Award Ref: BB/GCRF-IAA/02). 
Organisation Pontifical Catholic University of Chile
Country Chile 
Sector Academic/University 
PI Contribution We have established a collaboration with chilean researchers. It has resulted in hosting a visitor to the Institute and the plan is to further expand the collaboration by applying to additional funds.
Collaborator Contribution My partners have sent a PDRA to work in our laboratory an obtain preliminary results that can be used for follow up funding requests.
Impact -Generation of RNA libraries for early ageing points in C. elegans -Visit to Chilean Institutions for networking purposes -Hosting visitors for data acquisition and networking purposes.
Start Year 2017
 
Description COST Action_Worm Genie (COST BM1408) 
Organisation European Union
Country European Union (EU) 
Sector Public 
PI Contribution Financing for traveling and collaborations around europe for other labs in the EU
Collaborator Contribution Financing for traveling and collaborations around europe for my lab members
Impact -knoweldge exchange -conferences -bringing new technologies to the lab -using infrastructure that was not present in house
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 Development of Computational methods for network analysis during ageing 
Organisation Rovira i Virgili University
Country Spain 
Sector Academic/University 
PI Contribution We design a "wisdom-of-the-crowds" GRN inference pipeline, and couple it to network analyses, to understand the organisational principles governing gene regulation in long-lived glp-1/Notch C. elegans. The GRN has three layers (input, core, output) and is topologically equivalent to bow-tie/hourglass structures prevalent among metabolic networks. To assess functional importance of structural layers, we screened 80% of the regulators and discovered 50 new ageing genes, 86% with human orthologues and 56% further extending the long life of glp-1. Genes essential for longevity-including ones involved in insulin-like signalling (ILS)-are at the core, indicating that GRN's structure is predictive of functionality. Using in vivo reporters, we found an intricate relationship between fat accumulation, SOD enzymes, and lifespan. We queried 5,497 genetic interactions (https://s-andrews.github.io/wormgrn/qpcr/), and identified modulators that phenocopy ILS genes and share identical targets. We present a framework with predictive power that can accelerate discovery in C. elegans and potentially humans.
Collaborator Contribution We design a "wisdom-of-the-crowds" GRN inference pipeline, and couple it to network analyses, to understand the organisational principles governing gene regulation in long-lived glp-1/Notch C. elegans. The GRN has three layers (input, core, output) and is topologically equivalent to bow-tie/hourglass structures prevalent among metabolic networks. To assess functional importance of structural layers, we screened 80% of the regulators and discovered 50 new ageing genes, 86% with human orthologues and 56% further extending the long life of glp-1. Genes essential for longevity-including ones involved in insulin-like signalling (ILS)-are at the core, indicating that GRN's structure is predictive of functionality. Using in vivo reporters, we found an intricate relationship between fat accumulation, SOD enzymes, and lifespan. We queried 5,497 genetic interactions (https://s-andrews.github.io/wormgrn/qpcr/), and identified modulators that phenocopy ILS genes and share identical targets. We present a framework with predictive power that can accelerate discovery in C. elegans and potentially humans.
Impact This is multidisciplinary partnership that successfully developed a predictive tool to study ageing in C elegans. It also developed searchable a tool for the community: https://s-andrews.github.io/wormgrn/qpcr/
Start Year 2018
 
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 A talk at "Networks of Cellular Surveillance Mechanisms" Conference 
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 An invited talk at an Interational Conference in Heidelberg
Year(s) Of Engagement Activity 2018
 
Description A talk at the Longevity leaders workshop in Oxford, UK 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact I gave an invited talk at this foru organised by the companu Juvenescence
Year(s) Of Engagement Activity 2019
 
Description An invited talk at "Advances in metabolic communication" conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The conference was organised by Nature Metabolism in Brazil
Year(s) Of Engagement Activity 2019
 
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 Cambridge Science Festival 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Media (as a channel to the public)
Results and Impact This was a presentation for wider audience by laetitia Chauve
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 General public workshop "Cambridge Climate and sustainability festival" 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Invited speaker at "Cambridge Climate and sustainability festival" at St John's college February 16th, 2019
Year(s) Of Engagement Activity 2019
 
Description Institute for Continuing Learning 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Laetitia Chauve participated in a program designed to show Epigenetics in live nematodes
Year(s) Of Engagement Activity 2019
 
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 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 Organisation of an International Conference 
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 European C.elegans Conference, Marseille, France.
Year(s) Of Engagement Activity 2020
 
Description Organisation of an International Conference 
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 TAGC Allied Genetics conference in Washington, DC, USA.
Year(s) Of Engagement Activity 2020
 
Description Organisation on International Conference 
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 Organisation of european C.elegans conference
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 Presentation at Universidad Andres Bello, Chile 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Presentation to a wide audience of students from Universidad Andres Bello, Chile, about current research.
Year(s) Of Engagement Activity 2014
 
Description 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 We invited students to our lab to show them C elegans
Year(s) Of Engagement Activity 2018,2019,2020
 
Description Senior citizen visit to BI 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Gave a talk about ageing to senior citizens that visited campus
Year(s) Of Engagement Activity 2015
 
Description Single cell workshop Heidelberg 
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 Presentation and attendance to a workshop hosted at EMBL in Heidelberg on Single cell technologies
Year(s) Of Engagement Activity 2015
 
Description Talk for senior citizens at Rotary Club Cambridge 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact I gave a talk about ageing for a broad audience of senior citizens.
Year(s) Of Engagement Activity 2015