Theme 1 – Mechanisms of Musculoskeletal Ageing

Theme 1 sub-themes:

The mechanisms underlying anabolic resistance

The mechanisms underlying anabolic resistance with age continues to be a major research interest for CMAR. We are:

  • Using stable isotope tracers and deuterated water to quantify protein and substrate turnover in acute and chronic intervention studies in older people to understand better the aetiology and drivers of anabolic resistance, including a focus on insulin resistance
  • Employing tracer approaches combined with metabolomics to generate non-invasive biomarkers of muscle protein synthesis and breakdown in humans, which can then be used in large-scale intervention studies in theme 3
  • Using our access to spaceflight research facilities to study the effects of immobilisation on insulin resistance and muscle anabolic responses
  • Determining alterations in skeletal muscle intermediary metabolism and associated molecular regulation of anabolic responses
  • Determine the impact of Vitamin D bioavailability on muscle anabolic responses and bone biology
  • Using a model system based approach, examining mechanisms of sarcopaenia in C. elegans
  • Examining the impact of sedentary behaviour and obesity on muscle metabolic quality and the mechanistic determinants

The role played by cell senescence and autophagy in musculoskeletal decline

This is a new topic area for CMAR. Research in this sub-theme will investigate:

  • The role of declining NAD+ supply in muscle mitochondrial function with age in humans as supplementation with nicotinamide riboside has been shown to restore NAD+ levels and reduce functional senescence in muscle cells in mice
  • The processes driving the accumulation of senescent cells with age, specifically the involvement of reduced NK cell cytotoxicity towards senescent cells
  • Whether down-regulation of autophagy with age predisposes mesenchymal stem cells towards the adipocyte lineage resulting in osteoporosis and infiltration of adipocytes into muscle
  • The impact on the bone health of age-dependent changes in the vasculature and bone marrow microenvironment

The impact of age on motor control and neuromuscular function

This sub-theme is a continuation of work started in phase 1 and includes:

  • Investigation of the impact of behavioural training on neural control of movement with age
  • Characterisation of neural mechanisms that mediate age-related changes in multisensory integration and how they relate to motor function
  • The impact of age and disease on motor control and movement learning
  • The central mechanisms involved in compensation for age-related vestibular loss and the variability that increases fall risk
  • The impact of ageing and physical inactivity on neuromuscular junction integrity

Factors affecting the musculoskeletal ageing trajectory

This area of interest has expanded since the first phase and includes:

  • Using 2.5 million data points for muscle function generated in the Guangzhou Biobank Cohort Study (GBCS) (30,000 adults aged 55-80 at inception 10 years ago) which we are analysing to understand the ageing trajectory in a large and stable population.
  • Phenotyping the Guangzhou Biobank Cohort Study this includes muscle biopsies, which we are using to study MSK ageing mechanisms and determinants (genetic and environmental) of the ageing trajectory.
  • The impact of age and disease on motor control and movement learning
  • We are also developing projects using existing resources such as UK Biobank, online data and tissue banks in CMAR to identify lifestyle factors and molecular mechanisms influencing the trajectory of disease and frailty

Theme 1 Leads

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Phil Atherton, University of Nottingham

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Martin Hewison, University of Birmingham