Title: Engineering novel in-vitro Model systems to accelERate aGEing research Dunhill Medical Trust Doctoral Training Programme (EMERGE DMT DTP)
Funder: Dunhill Medical Trust

Abstract: NOVELTY OF RESEARCH Despite the increased need for new strategies to improve the health and quality of older life, we still have limited knowledge of the mechanisms driving ageing and how they can influence/ be influenced by disease development. Existing clinical practice has been guided by evidence derived from in-vitro and in-vivo models based on young or adult human physiology. Such studies do not take into account age-dependent variations thus failing to truly understand the physiological mechanism of ageing. This invariably means that much basic biological evidence is not always suitable to enable understanding and treatment of age-related diseases and frailty. The slow pace in growth and interest in ageing research can be attributed to the lack of mechanistic insights and platforms for research that can reliably replicate the biology of ageing. The Academy of Medical Sciences report “Rejuvenating Ageing Research” identified the need to focus on biomedical research and developing the critical mass of researchers in this field. Specifically, under its recommendation for the prioritisation of ageing research ‘Developing our understanding of the basic biology of healthy ageing’ was listed as the 1st priority. AREAS TO BE INVESTIGATED We are now seeking to establish the Dunhill Medical Trust ‘Engineering novel Model systems to accelERate aGEing research’ doctoral training programme (EMERGE DTP). The proposed five DMT-funded PhD students in EMERGE will work towards understanding the biology of ageing by developing novel in-vitro and in-silico research platforms for the investigation of the physiological mechanism of ageing. This will allow us to define potential common mechanisms that may lead to age-related diseases and/or situations of mutli-morbidity in the older population. We believe that clarifying the underpinning ageing mechanisms and the development of validated platforms will accelerate ageing research. Additionally, powerful in-vitro system will accelerate preclinical validation guiding in vivo experiments and limiting the numbers of animals/in-vivo models required for validation. Previous work by university researchers has led to development of novel in-vitro platforms for osteoarthritis (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3947852/) and gut microbiome (https://www.ncbi.nlm.nih.gov/pubmed/31676474). We will be building on our core expertise but this time with a focus on ageing to develop platforms for in-vitro or in-silico interrogation of cell ageing mechanisms in a physiological system. These are for example (but not limited to) digestion, musculoskeletal, circulatory, epithelial/wound healing and urinary (incontinence). Through a three phased approached over three years we will (Phase 1) establish features of cellular ageing in a particular physiological system using state-of-the-art molecular and/or functional electrophysiological techniques. We will then use this information (Phase 2) to design and validate our in-vitro/in-silico cellular models. In the final phase (Phase 3) we will use these platforms to establish selected mechanisms/biology of ageing. Our work will involve a time dependent series of experimental interrogation in this phase to focus on understanding how cellular ageing process/biological mechanisms in each of these physiological systems differ. This will help us understand how such biological mechanisms drive the ageing process and onset of age-related disease. Some aspects of our work will involve the use of decellularised native and synthetic scaffolds to build ageing cellular models such as spheres (e.g. https://www.ncbi.nlm.nih.gov/pubmed/30176009) that will be amenable to seeding with multicellular components mimicking the three dimensional properties of whole physiological systems. Findings from each distinct project where appropriate can be fed into potential in-silico modelling of these aged physiological systems to help drive more computational biology based ageing research. As per AMRC guidelines, an internal call for potential projects that will meet the above aims and strategic priorities will be held. There will be the stipulation that the project topics have to be for the benefit of older people. Proposals will be scored by a panel of five academics chaired by the lead applicant following internal referee’s comments. The underpinning science for all proposal must embed an interdisciplinary component looking at developing platforms for the study of the biology of ageing in a body/physiological system. WHY IS THIS IMPORTANT We are of the opinion that these platforms will serve as the backbone of future ageing research and help reduce costly experimental interrogations that are limited to the ageing of animal models. Intensification into ageing research facilitated by the use of novel in-vitro/in-silico platforms will lead to opportunities to further our understanding of the biology of ageing, expedite drug development pipelines and improve our ability to risk predict health outcomes in the ageing population. In the long term all these will facilitate research aimed at fulfilling the UK government’s challenge of increasing healthy life expectancy by five or more years by 2035.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE