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Evaluation of the relationship between senescence, frailty and deprivation; a biomarker study


Department of Oncology and Metabolism

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Prof Lynda Wyld , Prof I Bellantuono , Dr M Tomlinson , Prof Janet Brown No more applications being accepted Funded PhD Project (European/UK Students Only)
Sheffield United Kingdom Cell Biology Developmental Biology Epidemiology Pathology

About the Project

This three and a half (3.5) year studentship is part of the newly formed Dunhill Medical Trust and Healthy Lifespan Institute Doctoral Training Programme at The University of Sheffield. We aim to train the next generation of researchers to advance the understanding of the mechanisms of ageing, and to find new effective ways to improve the lives of older people living with the multiple age-related diseases that adversely impact quality of life as we age, cause disability and frailty, and result in significant costs to health and social care services. See here to see more about being part of our PGR network. 

Ageing and frailty represent a major global challenge for health care due to the significant expansion of older aged populations in the developed world. A key consequence of frailty is loss of resilience, i.e. the ability to respond to adverse events such as infections (e.g. flu, COVID19), surgery or fractures. Frail patients often do not survive such events or fail to recover fully, suffering long-term loss of independence. 

The identification of new methods to identify patients with frailty and new treatments to prevent the development or worsening of frailty, are an urgent health care priority.

Evidence suggests that a key driver of frailty is senescence. Senescent cells are characterised by irreversible proliferative arrest, and the release of damaging, pro-inflammatory and tissue remodelling factors.  A new class of drugs, senolytics, reduce senescent cells in animal models, resulting in reduced frailty and extended lifespan.  However, it is unknown whether senescence is a driver of frailty in humans and whether senescence can be used as a marker to identify those at risk of developing frailty and benefiting of senolytic therapies. In our previous work, in older women undergoing surgery, we have shown that inability to function normally doubles after surgery and 30% do not recover fully even after 2 years, suggesting loss of resilience and onset of frailty following surgery. In addition, there is evidence that frailty is increased with socio-economic factors such as poverty and neighbourhood characteristics such as deprivation. 

We hypothesize that there is a correlation between functional impairment, both before and after surgery, and senescence levels, and that deprivation is associated with higher levels of senescence.  

We will access our existing database from a completed large multicentre cohort of over 3400 women over age 70 with extensive data including baseline health, post treatment outcomes, postal addresses that can be used to determine deprivation levels based on English Indices of Deprivation. 

Aims

1.  Determine whether senescence levels in normal tissues correlate with age, frailty, and deprivation in a large cohort of older women.

2.  Determine whether levels of cellular senescence in normal tissue (adipose and skin) have prognostic significance for survival, pre-treatment frailty and post-treatment resilience. 

To achieve these objectives, sections from fat, skin tissues of older women before and at the time of surgery will be stained for a panel of senescence biomarkers, (γH2AX, 53BP1, telomere associated foci, Ki67, p16, p21) with methods available in our laboratory and scored using a variety of methodologies. Senescence levels will be correlated with age, fitness, frailty, survival, deprivation index and functional impairment after treatment. A multivariate Cox proportional hazards model will optimise a final panel of 3-5 markers, using bootstrap methods to validate the multivariate model, and choice of biomarkers in the final panel. We will undertake latent growth modelling and other structural equation modelling techniques to analyse the impact of deprivation on health, frailty, survival and QoL trajectories.

Entry Requirements:

Candidates must have:

  • Upper second class honours degree (2.1) or above in a biological science, an interest in the biology of ageing. 
  • Candidates will be expected to provide a convincing justification as to why they would like to undertake the project in their application statement, demonstrating any research knowledge and, if applicable, any experience relevant to the project. 
  • Candidates must be home based/EU students

To apply:

Complete a Postgraduate Research application form here. Please state the title of the studentship, the main supervisor and select Oncology & Metabolism as the department. 

We encourage applicants to make informal enquiries to Lynda Wyld or Ilaria Bellantuono ([Email Address Removed], [Email Address Removed])


Funding Notes

Each studentship will be supported for 3.5 years with the student expected to submit their thesis by the end of this funding period, receiving:
stipend and fees funded at UKRI levels
- a £5000 Research Training Support Grant per year
- £300 travel budget per year
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