Understanding and enhancing the physiological resilience of older adults to improve health-span: a focus on skeletal muscle

‘Loss of resilience’ describes enhanced vulnerability to, and impaired recovery from stress events when compared to a robust [youthful/healthy] state; and is commonly encountered with advancing age-(1).

With ageing populations around the world, and the associated rise in years spent in ill-health-(2), there is an urgent need to understand this loss of physiological resilience and potential strategies to mitigate these declines.

Researchers generally focus on static measures of ageing phenomena; here, we propose to focus on dynamic, temporal measures of resilience.

Although a recent national GIRFT (Getting It Right First Time) report-(3) suggests that improving frailty management could save the NHS >£600-million/year, furthering understanding of the biological mechanisms driving reduced resilience to inform on PRECISION mitigation strategies (i.e., for the right people at the right time) could have a much bigger impact on the total cost of frailty to UK health systems (~£5.8-billion/year).

Considering the bodies major organ systems, it is skeletal muscle deterioration, including the associated metabolic and functional declines, that is postulated to be a core driver of reduced resilience in older adults with and without disease-(4).

Indeed, skeletal muscle weakness is at the fore of both frailty (the clinical term encompassing loss of resilience)-(5) and sarcopenia definitions-(6).

A consequence of reduced resilience is that the time people spend in good health (their health-span) is now much shorter than overall lifespan-(7), with resultant unsustainable impacts on individuals (including quality of life and mental well-being) and healthcare systems-(8).

With ~50% of adults >65y suffering from multimorbidity, and this number increasing to ~80% of those >80y, it is clear biological maintenance systems diminish with advancing age-(9).

Reduced muscle mass is associated with reduced physical function, but is also associated with all-cause hospitalisation, multi-morbidity, and all-cause mortality-(10).

In addition, poor muscle ‘health’ (mass and function) is also associated with an up to 10-fold increase in the probability of dying after emergency admission to hospital, and for surgical patients is associated with increased length of hospital stay, clinical complications, and loss of independence-(11,12).

To contextualise the magnitude of this issue, frail adults >75y account for >4,000 UK hospital admissions each day and one-fifth of hospital bed occupancy-(13).

In youth and health, muscle maintenance is achieved via a dynamic equilibrium between muscle protein synthesis (MPS) and muscle protein breakdown (MPB), paired with neuromuscular interaction-(14). This equilibrium is driven by nutritional influences on MPS and MPB, but also preservation of muscle-nerve connections.

To exemplify: 1) protein containing nutrition and resulting pancreatic insulin secretion increase MPS and supress MPB-(15), and 2) muscle contraction stimulates MPS and preserves muscle-nerve connections-(16).

Both these facets are subject to dysregulation in ageing-(17,18), with our research group unique in the ability to assess these in tandem.

Our approach is to address the loss of physiological resilience with ageing and future proof this direction of travel in bioscience by hosting three PhDs in this space: PhD 1- Supported by the Nottingham NIHR BRC, a human-volunteer study of older adults exploring the impact of an already-licensed mechanistic target of rapamycin (mTOR) inhibitor (which has been shown to attenuate sarcopenia in pre-clinical models of ageing-(19)) on muscle growth and function will inform on the potential of this inhibition to enhance the resilience of older adults.

Based on the observation that control of mTOR (a protein kinase and key component of muscle mechanical and nutrient sensing) is lost with advancing age such that it is chronically and constitutively activated and fails to respond to normal anabolic cues-(20), biological samples from this study will also allow future exploration of the impact of this intervention on other organ systems for which favourable pre-clinical data is emerging (i.e., the immune system).

PhD 2- Supported by SoLS, including a £2M UKRI grant awarded to Co-I Greenhaff, this project will address the long-standing debate surrounding the role of physical activity in ageing processes and to what extent, in relation to muscle mass and function, the observed physiology of ageing is largely the physiology of inactivity-(21).

To better understand the biological mechanisms that underpin associations between physical activity levels and muscle health, a human-volunteer study of older adults exploring the pattern and magnitude of change in metabolic, molecular, and morphological parameters in response to chronic changes in physical activity will be conducted.

The results of this study will provide ground-breaking insights into physiological adaptations that occur over the course of 6-months physical (in)activity in people at risk of inactivity-induced declines in resilience and generate a rich and unique legacy data set for future research exploitation.

PhD 3- Supported by SoM, including an £800K MRC grant to PI Phillips, this project will consider the importance of muscle mass and function for older patient cohorts.

With elective surgery a clear and common example of a stress event encountered by older adults-(22), and recognising that physiological resilience is not just preparedness for stress events but also the ability to recover from them, this project will focus on practicable neuromuscular electrical simulation (NMES) as a rehabilitation strategy in older surgical patients.

After delivery protocol optimisation, NMES (both with and without enhanced nutritional intake-(23)) will be employed in both the initial post-operative period when ‘regular’ physical activity (i.e., voluntary contractions) is simply not feasible, and as a longer term-strategy adjuvant to standard care.

To ensure that all students develop a comprehensive toolkit of experience-based research skills, in addition to the interdisciplinary human studies outlined above (each of which require aspects of human measurement, laboratory/image analysis, complex data-handling, and tasks related to research governance and management), each student will also engage with PPI-E (see Section 5) and a relevant qualitative research exercise (e.g., Delphi or Systematic Review).

In addition, the precise plans for the human studies will be made with the students considering their experience and interests, emerging literature, and newly available technologies/methods.

The research we propose is at the critical interface of clinical and basic-sciences and represents interventional, translational science with embedded mechanistic science.

Few other groups, if any, are as rich in clinical-mechanistic research in the UK and the exceptional training it can offer.