EcMagine': Extracellular Matrix ageing across the life course interdisciplinary research network

Lead Research Organisation: University of Liverpool
Department Name: Musculoskeletal & Ageing Science

Abstract

Advances in science, medicine and living conditions mean that people are living longer. Whilst a longer life brings exciting opportunities, ageing is too often associated with ill health and frailty. The ageing demographic brings with it a steep increase in the public burden of health and social care as well as financial challenges for pension funds. Across the UK, and globally, there are inequalities in the lived experience of ageing, with social demographics, life course experiences and genetic factors influencing stark disparities between chronological and biological age in different populations.

Our application focusses on the ageing of extracellular matrix (ECM), the main structural component of tissues and organs. The ECM is a three-dimensional network of molecules which not only provides resilience to all tissues in the body, but also controls key biophysical signals to support vital cell functions. The ECM makes up a large fraction of many tissues; for example, in the bone, the ECM is mineralised providing essential strength, whilst in the lung, it provides elasticity necessary for normal function. The ECM in each organ is very distinct and very dynamic, responding to various external factors such as day/night cycles, highlighting its malleability.

With age, ECM deteriorates through a process influenced by an imbalance between its production and turnover, chemical changes to molecules as well as changes in its relationship with our cells. Importantly, ECM deterioration with age directly influences key functions of cells and tissues in our body leading to abnormal communication between our cells and loss of vital functions, which contributes to many age-related diseases.

Studying ECM ageing across the life course poses particular challenges due to differences between model organisms and humans, the limitations of using standard 2-dimensional culturing of isolated cells and difficulties in accessing healthy human tissues. Fortunately, using approaches in material science and tissue engineering to develop humanised cell models with organ-specific ECM scaffolds has enormous potential for high-throughput mechanistic and drug screening studies to target age-related ECM degradation and combat hallmarks of cellular ageing, thus offering novel, more effective and safer solutions.

We propose a new interdisciplinary ageing network bringing together biologists, chemists, geneticists, ageing scientists, engineers, mathematicians, health and social scientists and clinicians. The network will be led by investigators at the Universities of Liverpool, Glasgow, Manchester, Nottingham and Newcastle but will operate across the whole of UK. We will engage industry stakeholders and technology providers in the network events and liaise with the public and local charities through to research experts on the external advisory panel. A key focus of the network will be increasing the knowledge of this new interdisciplinary field, facilitating sharing of technologies for rapid discoveries and pioneering new models to study ageing. Our network will provide informed recommendations for future research to address inequalities influencing ECM ageing.

The network will act to increase capacity and diversity in the field through pump-priming activities, network events and incorporating diversity and inclusivity in network activities. The network will operate via a website interface facilitating member registration and communication. Communications will be supported by newsletters, social media and network events. More broadly, the network will interface with relevant research societies, related networks, doctoral training partnerships and technician development centres.

Working together, sharing models, technologies, knowledge and expertise, our unique approach will generate paradigm-shifting discoveries with long-term benefits for discovery science, industry and medicine to improve lives of older people.

Technical Summary

Ageing leads to progressive decline in metabolic/behavioural/physiological functions, leading to reduced healthspan. Across the world, numbers of people >65 are increasing 3 times faster than those <15. >65s will make up >25% of UK population in 50 years, with regional health inequalities exacerbating disparities in healthspan.
Our network focusses on the ageing of extracellular matrix (ECM), a major structural & functional determinant of tissue resilience with remarkable tissue specificity. Our tissues comprise of cells and >1000 ECM proteins. The ECM facilitates cell-matrix and cell-cell communication, and exchange of nutrients and growth factors. The ECM undergoes structural changes with age, leading to accumulation of fragmented, cross-linked ECM proteins and loss of ECM ligands. Alterations to ECM underpin many age-related tissue changes, such as loss of elasticity, poor healing, scarring, abnormal growths and entry into senescence, a hallmark of ageing. Remarkably, ECM is a target of daily changes governed by our ~24h (circadian) time-keeping mechanisms, highlighting ECM as a malleable driver of tissue ageing. However, there is a critical need to understand how ageing alters the ECM of specific organ/tissue systems, how age-associated ECM impacts tissue-specific deterioration and the roles of specific cell sub-types involved.
The EcMagine Northern-led Ageing Network brings together complementary expertise in key aspects of ageing, matrix biology, chronobiology, AI/computational modelling and tissue engineering across UK to develop novel models to study ECM ageing, particularly 3D biological models, new biomaterials to mimic tissue-specific ECM and in silico models to predict novel anti-ageing therapies. Working together, sharing models, technologies, knowledge and expertise, we will strategically address challenges in ageing research and generate paradigm-shifting discoveries with long-term benefit of improving lives and outcomes for older people.

Publications

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publication icon
Dalby MJ (2024) Strengths and opportunities in research into extracellular matrix ageing: A consultation with the ECMage research community. in BioEssays : news and reviews in molecular, cellular and developmental biology

 
Description Significant achievements
We have so far met award objectives in:
i) Capacity building by supporting post-doctoral research associates, PhD students and technical staff to develop knowledge and expertise in state-of-the-art technologies to study ECM ageing and to develop careers in this interdisciplinary area: 'Advanced Technologies' is one of the network's 4 themes. An in-person and hybrid event including sandpit was held in September 2022 with excellent attendance at the 'Advanced Technologies' round table discussion. Our network has been awarded a further £60k (£50k plus 20% uplift) in open competition for FTMA4 funding entitled "Enhancing staff mobility to build capacity in extracellular matrix ageing research and development". Our first Exchange and Mobility call has incorporated our original laboratory exchange funding opportunity and the additional FTMA4 funding, 11 awards have been made. A second round of Exchange funding resulted in 3 exchanges of awards to ECRs/technicians. Capacity building was further developed by holding joint network conferences, encouraging interdisciplinarity, firstly as a hybrid satellite meeting at the British Society for Matrix Biology Autumn Meeting in September 2022 where we hosted talks by members and a sandpit to encourage partnerships in research projects. We joined the MRC Versus Arthritis Centre for Integrated Research into Musculoskeletal Ageing (CIMA) in January 2023 for a hybrid conference with a sandpit focusing on the gaps in research and developing joint applications to pump priming funding. Our symposium at TERMIS EU 2023 "TE & RM approaches in extracellular matrix ageing" was well attended, by our own membership as well as other TERMIS EU delegates. Our joint network meeting in January 2024 with BLAST network and the Glasgow CDT "Young Leaders in interdisciplinary Ageing Science" encouraged a wide range of delegates and talks, and our sandpit focusing on EDI in research was well-received and informative for all involved. A Webinar hosted by The Biochemical Society organised by and presented by ECMage Co-I and ECR members 'Biochemistry Focus ECR webinar - ECM/Redox Signalling Axis: From Cancer to Tissue Repair and Smarter Regenerative Therapies', with the aim to encourage wider dialogue and working collaboratively across and beyond our community, was attended by over 60 ECMage members.
ii) Preliminary data derived from pump-priming activities that will support future work in the area, especially by supporting career-development fellowship applications from early career researchers: Award of 4 high-quality pump-priming applications totalling £18,489. These were either awarded (3 projects) or co-awarded (1 project) to early career researchers. The second round of pump priming resulted in a further £11,897 as three awards to early career researchers.
iii) A position paper summarising the state-of-the-art, key questions and aspects requiring further investigation in the ECM ageing field; covering ECM alterations over life course, diversity and inequalities between populations, alternative in vitro biological and computational models and appropriate direction in biomaterials and tissue engineering research has been accepted. Our in person event with CIMA 27/1/23 focused on discussion to form the basis of a this paper. Data was collated and the position paper has been accepted for open access publication (Bioessays).
iv) A database of models (encompassing in vitro, in vivo, populations and computational models) that can recapitulate ECM ageing or life course events, with information about the limitations and appropriate applications of each: Excellent discussion around the theme 'Tissue Engineering and Novel in Vitro Models' at both network meetings. These considered the requirement for appropriate models and the models database is in progress and is in the process of being populated.
v) Facilitating new joint grant applications including those from interdisciplinary, cross-institutional and inclusive coinvestigator teams: In person and hybrid network meetings totalling 205 attendees, including 94 ECRs resulted in 23 Pump priming applications to two rounds totalling £30 of funding. Exchange and mobility funding of £3K supplemented by success in BBSRC FTMA funding of £60k received 15 applications, 13 successful. All were cross institutional and inclusive of ECRs.
Exploitation Route The award is ongoing, but is on-target to achieve its objectives including the creation of a database of models (encompassing in vitro, in vivo, populations and computational models) that can recapitulate ECM ageing or life course events, with information about the limitations and appropriate applications of each.
Cross-institutional and interdisciplinary collaborations resulting from network events have led to pump priming and exchange and mobility applications, with the expectation that this will lead to larger grant applications.
Sectors Education

Healthcare

Manufacturing

including Industrial Biotechology

Pharmaceuticals and Medical Biotechnology

URL https://www.ukanet.org.uk/ecmage/
 
Description Ageing Research Networks Global Partnering Awards UK, Singapore, and Australia
Amount £187,581 (GBP)
Funding ID BB/Y006976/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 07/2023 
End 04/2025
 
Description Anglo Japanese Global Partnering Award
Amount £132,215 (GBP)
Funding ID BB/Y006984/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 07/2023 
End 04/2025
 
Description EuroAgeNet: European Partnerships in Ageing Science
Amount £206,587 (GBP)
Funding ID BB/Y00695X/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 07/2023 
End 04/2025
 
Description FTMA4 Enhancing staff mobility to build capacity in extracellular matrix ageing research and development
Amount £60,000 (GBP)
Funding ID BB/X01780X/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 01/2023 
End 03/2023
 
Description UK Ageing Research Networks Partnership with the USA and Canada
Amount £173,533 (GBP)
Funding ID BB/Y006968/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 07/2023 
End 04/2025