Theme 2 – Ageing and the Progression to Disease and Frailty

This new theme in CMAR focuses on identifying processes driving the progression of musculoskeletal (MSK) decline with age towards clinical frailty, Rheumatoid Arthritis (RA) and Osteoarthritis (OA). Work within this theme is also trying to identify drivers of the MSK decline in other age-related diseases where frailty, sarcopenia and weakness prevail (such as Chronic Obstructive Pulmonary Disease, Inflammatory Bowel Disease and Trauma). This theme integrates 29 CMAR Principal Investigators who are actively researching various aspects of MSK disease pathogenesis and is supported by substantial funding. Theme two sub-themes include:

How the microbiome influences systemic inflammation and disease pathogenesis

  • We are characterising the microbiota in healthy young and older adults and very early arthritis patients (BEACON cohort) to establish its function in disease development, progression and response to therapy and allowing us to study the very earliest stages of disease with a valid control group

Genomic, proteomic and metabolomic changes influencing progression to disease

This includes:

  • Looking for accelerated immune and epigenetic ageing as causes of RA by measuring specific epigenetic marks that correlate with biological age
  • Investigating epigenetic mechanisms in pathogenesis, by studying the role of long non-coding RNAs in driving the increased risk of OA with obesity and assessing their potential as therapeutic targets
  • Using metabolomics approaches to elucidate the role of metabolic dysregulation in very early RA, using the data to identify prognostic biomarkers and indicators of individual responses to therapy
  • Determining how ageing processes in fibroblasts affect this switch and offer a new therapeutic target
  • Investigating the interaction between inflammation and glucocorticoid metabolism (11βHSD1 activity) as a driver of muscle and bone degradation with ageing and in RA, working with BEACON samples as well as animal models of RA on a 11βHSD1-/- background

The impact of chronic inflammatory disease and trauma on musculoskeletal decline

This sub-theme is supported by collaborations with other Arthritis Research UK and NIHR centres. In this theme our research focuses on the following:

  • The determination of the contribution of physical inactivity to muscle dysfunction in OA and Chronic Obstructive Pulmonary Disease (COPD), and the mechanistic basis of trauma and infection-related sarcopaenia and metabolic dysregulation
  • The role of innate immunity and systemic inflammation in muscle wasting in COPD
  • Testing the hypothesis that trauma accelerates ageing by measuring DNA methylation marks that correlate with biological age using stored samples and clinical data in a trauma cohort in the NIHR trauma centre (SRMRC)
  • Determining the processes driving sarcopaenia in RA, chronic liver disease and Inflammatory Bowel Disease using extensive clinical cohorts with support from the Birmingham Inflammation Biomedical Research Centre (BRC)
  • Understanding dysregulation of anti-inflammatory mechanisms in ageing and RA pathogenesis, looking at the regulation of the master inflammatory gene regulator tristetraprolin by DUSP phosphatases
  • Assessing a novel anti-inflammatory adipokine signalling mechanism

Theme 2 Leads

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Paul Greenhaff, University of Nottingham

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Chris Buckley, University of Birmingham