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.
Organisations
- Babraham Institute, United Kingdom (Lead Research Organisation)
- Rovira i Virgili University (Collaboration)
- European Union (Collaboration)
- Pontifical Catholic University of Chile (Collaboration)
- University of Nottingham (Collaboration)
- EMBL - European Bioinformatics Institute, United Kingdom (Collaboration)
People |
ORCID iD |
| Maria Olivia Casanueva (Principal Investigator) |
Publications
Chauve L
(2019)
A neuronal thermostat controls membrane fluidity in C. elegans
Chauve L
(2020)
High-Throughput Quantitative RT-PCR in Single and Bulk C. elegans Samples Using Nanofluidic Technology.
in Journal of visualized experiments : JoVE
Haeussler S
(2020)
Autophagy compensates for defects in mitochondrial dynamics.
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
Hattwell
(2020)
"Using genome scale metabolic networks for analysis, visualization, and integration of targeted metabolomics data"
in Methods in molecular biology
Hattwell JPN
(2020)
Using Genome-Scale Metabolic Networks for Analysis, Visualization, and Integration of Targeted Metabolomics Data.
in Methods in molecular biology (Clifton, N.J.)
Li C
(2016)
Epigenetic inheritance of proteostasis and ageing.
in Essays in biochemistry
Okkenhaug H
(2020)
Worm-align and Worm_CP, Two Open-Source Pipelines for Straightening and Quantification of Fluorescence Image Data Obtained from <em>Caenorhabditis elegans</em>
in Journal of Visualized Experiments
Özbey NP
(2020)
Tyramine Acts Downstream of Neuronal XBP-1s to Coordinate Inter-tissue UPRER Activation and Behavior in C. elegans.
in Developmental cell
| 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 |