Title: Dunhill Medical Trust Healthy Lifespan Institute Doctoral Training Programme
Funder: Dunhill Medical Trust

Abstract: Over 60% of those aged over 65 have multimorbidity and 25-50% of those 80+ have frailty. Currently, each disease is treated individually with problems of reduced efficacy and increased side effects due to polypharmacy. Frailty and multimorbidity are responsible for approximately 70% of health and social care costs. Recent research suggests that mechanisms of ageing such as senescence are causal to multiple diseases (eg. cardiovascular, cancer, musculoskeletal, neurodegenerative) and to frailty. Ageing and senescence can be halted in several ways: improving diet and physical activity, reducing deprivation or by the use of drugs (geroprotectors) - offering an opportunity for a more holistic approach to the treatment of multimorbidity and frailty. However, more in depth knowledge is required to understand the relationship between mechanisms driving ageing and multimorbidity, how multimorbidity develops and how socio-economic policies and public health approaches can effectively prevent multimorbidity and frailty, and when a drug approach is more cost-effective. To achieve this, HELSI has brought together a multidisciplinary group of researchers and launched an innovative programme of work which maps closely to Dunhill’s strategic priorities on understanding the mechanisms of ageing and helping to treat age-related diseases, disability and frailty and find new effective ways to improve the life of older people. The students’ projects will be central to the delivery of the following HELSI aims: 1) Understanding the common molecular mechanisms driving ageing (e.g. DNA damage, inflammation, senescence) and underpinning clusters of multimorbidity and frailty. This theme will focus on the common biological pathways of ageing underpinning cancer, cardiovascular, musculoskeletal and neurodegenerative diseases. These discoveries provide targets for the development of new drugs to prevent multimorbidity and biomarkers to monitor public health and socio-economic policy interventions. Project examples: identification of molecular pathways driving chronic macrophage dysfunction and inflammation with ageing in cardiovascular and neurodegenerative diseases; Identification of DNA damage/repair pathways conferring resistance to cardiovascular and neurodegenerative disease with age in the naked mole rat. 2) Identifying clusters and longitudinal patterns of multimorbidity, early determinants and biomarkers, using innovative machine learning and statistical approaches and understanding how these patterns change with deprivation. Sheffield Teaching Hospital NHS Trust gives HELSI investigators access to anonymised patient-level HES data from over 500 million records of patient visits over 25 years. These enable us to track how multimorbidity clusters develop over time, linked to NHS Sheffield CCG, covering the entire Sheffield GP-registered population with demographics, diagnostic records for long-term conditions and tests. Selected clusters can then be used to determine biomarkers, determinants and common molecular pathways underpinning clusters in follow-up studies. Project examples: Identification of co-morbidity clusters and determinants in patients affected by osteoarthritis using machine learning; Understanding the effect of health inequalities in multimorbidity, identifying clusters, trajectories and risk factors in the most and least deprived areas in Sheffield. 3) Devising new interventions to reduce the impact of ageing on the development of multimorbidity and frailty. We will use knowledge developed above to identify new targets for the development of geroprotectors (drugs targeting specific mechanisms of ageing, such as senescence) for the prevention of multimorbidity and frailty. We have a unique drug discovery pipeline with novel in vivo non-mammalian models for the screening of new senolytics. This is used in combination with exclusive pre-clinical in vivo animal models of age-related diseases and comorbidity (e.g. dementia and atherosclerosis) to support clinical trial data. We have an established protocol for the longitudinal testing of healthspan in mice. Biomarkers identified above, together with new tracking technologies developed by HELSI (Active10) will be used to monitor the efficacy of public health interventions (eg. exercise, diet) and improve compliance. Project examples: Acquisition and analysis of real-world sensing data to aid prediction, diagnosis and monitoring of cardiovascular and musculoskeletal disease; Screening of a library of molecules targeting mitochondrial dysfunction to prevent senescence and improve healthspan. 4. Delivering impacts from our work through knowledge exchange. Co-production with service users, patients and carers is pivotal in the development of effective products and services. HELSI has expertise in co-production with a wide range of patient groups. Our students will have the opportunity to work closely with primary care, nursing, public health agencies and service user communities to co-produce and translate knowledge to make a difference to people’s lives. Project examples: Co-production of research instruments with groups of employers and employees to investigate the impact of multimorbidity on later working life; Co-production of research instruments and knowledge exchange with nurses and patients suffering from severe multimorbidity.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE