Concurrent multi-organ responses to chronic physical activity and inactivity intervention to increase research discovery in human health and wellbeing

The UK population is getting older, with those aged 65 years and over set to increase to 1 in 4 of the population by 2039. However in the last 30 years the maintenance of good health has not kept pace with this increased lifespan. It follows, that on average, adults in the UK typically spend the last decade of their life in poor-health, which poses major consequences to health and social care services, employment, the individual and their family. The COVID-19 pandemic has further exposed our unhealthy nation, and raised government and public health awareness around the associations between physical inactivity, sedentarism and poor health, which is now a major public health priority. To address this, the UK Government has set a target of "at least five extra healthy, independent years of life by 2035". Furthermore, number of recent high-level reports have highlighted that the UK must maximise strengths in research, technology, innovation, and data analysis to improve the state of the nation's health. It is vital for individual wellbeing and the UK economy that more adults reach old age in better health and maintain a good quality of life for a greater proportion of their older age. Key to achieving this is a requirement to understand the mechanisms underpinning the trajectory of health progression as we age.

On this basis, this application sets out to provide ground-breaking whole body and multi-organ insights into physiological and metabolic responses to 6 months of highly controlled physical activity and inactivity intervention in people at key risk of inactivity induced decline (overweight, 55-65 year old men and women). This will be realised through a programme four integrated work packages (WPs):
WP 1: Longitudinal physical activity and inactivity interventions that will form the bedrock of the programme of research into which new tools, technologies and multivalent, trans-organ approaches (work packages 2 - 4) will be incorporated at multiple time points.
WP 2: involves participants undergoing comprehensive multi-organ magnetic resonance imaging and spectroscopy measurements in the resting state and during within-bore exercise to manifest metabolic and physiological adaptations to the physical activity interventions.
WP 3: involves administration of oral stable isotope tracers to provide insight of the impact of the study physical activity interventions on skeletal muscle protein synthesis and muscle protein degradation under "free-living" conditions.
WP 4: involves measuring changes in the plasma metabolome (all metabolite levels) in response to physical activity interventions which will represent the culmination of all biological processes within the cell, tissue or whole system.
The analytical outputs from WPs 2 to 4 will be deployed alongside the physiological measurements of WP 1 to provide an unprecedented rich multi-dimensional view of human adaptation to altered physical activity. It will ultimately aim to identify measures that indicate organ level adaptation and hence can be deployed as biomarkers in the future.

This programme of research will dovetail world-leading magnetic resonance technology, biotechnology and human biology expertise to permit a comprehensive array of non- and minimally invasive structural, metabolic and physiological endpoints to be quantified in the same individuals and monitored over the course of 6 months physical activity interventions. This will deliver unprecedented mechanistic insight of physiological adaptations where and when they happen in the human body and will push the boundary of bioscience discovery. Ultimately it will enable recommendations to be made which will maximise increases in functional capacity in adults at risk of decline, thereby helping adults reach old age in good health. Furthermore, we will make this unprecedented data set and sample/tissue archive available to future researchers to address novel questions/hypotheses.

Robust evidence of the biological mechanisms responsible for the positive health effects of chronic physical activity, and negative health effects of inactivity, in overweight adults is lacking, particularly at a multi-organ level. This is especially important given that multimorbidity from middle-age onwards is associated with poor health outcomes, and government and public health bodies recognise that it is imperative to address this. Through four integrated work packages (WP1, highly controlled 6-month longitudinal physical activity and inactivity interventions; WP2, multi-organ magnetic resonance imaging and spectroscopy; WP3, oral stable isotope tracer determination of muscle proteostasis in free-living people; WP4, plasma metabolome (the culmination of all cellular biological processes); we will deliver (in middle-aged, overweight adults), i) a within participant multi-faceted study with both longitudinal, and short to longer term insights; ii) an investigation of controlled physical activity and inactivity impacts in core organs regulating health; iii) an allied investigation of activity and inactivity within the same experimental paradigm; iv) use of cutting-edge technologies; v) establishment of a rich data and tissue/sample archive for future research. This project offers unique opportunity to dovetail world-leading MR technology, biotechnology and human biology expertise that will permit a comprehensive array of structural, metabolic, molecular and physiological endpoints to be quantified in the same individuals and monitored over the course of chronic physical activity interventions. The proposed state-of-the-art techniques are non- or minimally invasive, allowing measurements to be repeated in a given individual. Independent projects using different volunteer cohorts and shorter interventions would be grossly inferior from a number of perspectives. This research will allow recommendations to be made that will help adults reach old age in better health.