X-ray Research Irradiation System

Lead Research Organisation: Newcastle University
Department Name: Institute for Ageing and Health

Abstract

Aging of cells and organisms is largely determined by damage to cellular molecules, the efficiency of damage repair and the cellular mechanisms of response and adaptation to the remaining damage. We are primarily interested in the mechanisms and the importance of cellular senescence, which is the permanent loss of the ability of cells to divide and growth. Damage to DNA, either in the form of loss of telomeres (the very ends of all chromosomes), or of DNA breaks, is a major trigger of cellular senescence. Thus, senescence prevents the growth of cells with damaged, mutated DNA, which means that it protects organisms against tumour growth. However, senescent cells are not only proliferation-inhibited, they also show very different gene expression pattern and functionalities from their young, proliferating counterparts. In other words, the presence of even few senescent cells impacts on the surrounding tissue and these cells can change function of the organ they reside in, thus contributing to ageing. While the signals connecting DNA damage or telomere loss with proliferation arrest have been reasonably well characterized in recent years (and we have contributed to this), the whole network of signalling processes generating the complete senescent phenotype is still very much unclear, despite its obvious importance for the ageing process as a whole. We are convinced that a thorough characterisation of this network of signalling and response processes will not only provide ample clues to understand why old cells and organs are more frail and vulnerable to disease. It might also indicate possible targets for intervention, at the molecular level, in the cellular ageing process and thus contribute to postponing age-related disease. To study DNA damage responses and repair, we need technologies to measure accurately the timing of changes in a great number of factors possibly involved in the response, and of the interactions between them. This generates a vast number of data, and we need mathematical and statistical methods to integrate and evaluate these data and to draw conclusions from them. All such technologies have been established on-site over a number of years and are now ready to use. However, we also need a means to inflict DNA damage in a well-controlled fashion and at a defined point in time. Ionizing radiation is a well-accepted generator of DNA damage, and an X-ray irradiator is both most versatile (the characteristics of the radiation can easily be modified using different filters) and least hazardous (no permanently radioactive material involved). So far, the necessary equipment is only available off-site. This seriously compromises our ability to perform exact time-course analyses, as our results may become dependent on traffic conditions in town. Moreover, valuable research time is wasted on travel and logistics is complex. It is envisaged that a growing number of research groups on the Campus will become engaged in similar research projects within the next few years. An X-ray irradiator will thus remain an essential part of the research infrastructure on the Campus for the years to come.

Technical Summary

A major focus of research at the growing Campus for Ageing and Vitality is on mechanisms and signalling pathway networks in stress-induced cellular ageing. This research is at the core of all main programmes within the BBSRC-funded Centre for Systems Biology of Ageing and Nutrition (CISBAN), and is essential for MRC-funded biomarker studies in human populations. It involves generation of DNA damage in a highly reproducible fashion and at a well-defined point in time followed by kinetic measurements of repair activities or response signalling pathway activation. For this work, a reliable source of ionizing radiation immediately adjacent to the tissue culture laboratories is essential. An X-ray irradiator combines low hazard, ease of use and high versatility. It will form an essential part of research infrastructure on the Campus, as this type of research is planned to grow vigorously over the next few years. Moreover, it will support groups working in the vicinity of the Campus that are engaged in ageing and stem cell research.

Publications

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Basterfield L (2010) Intestinal tumours, colonic butyrate and sleep in exercised Min mice. in The British journal of nutrition

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Brain JG (2013) Biliary epithelial senescence and plasticity in acute cellular rejection. in American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

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Cameron KM (2011) Gross energy metabolism in mice under late onset, short term caloric restriction. in Mechanisms of ageing and development

 
Description The equipment provided by this award has helped us to better define the mechanisms that contribute to the process of cell senescence. This has helped to understand why and how senescent cells accumulate with age in mammals including humans and how they contribute to chronic inflammation and aggravated oxidative stress. Based on these results, we were able to identify chronic inflammation as a cause of accelerated ageing in mammals due to its impact on cell senescence.
Exploitation Route Our results provide a basis for the development/re-use of drugs to slow down the ageing process and postpone the onset of age-related diseases and disabilities
Sectors Healthcare

 
Description Pioneer Award
Amount £195,251 (GBP)
Funding ID C12161/A24009 
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2017 
End 01/2019
 
Description Validation of Senolytics as treatment for Sarcopenia and Frailty
Amount £86,352 (GBP)
Organisation Versus Arthritis 
Department Arthritis Research UK Centre for Musculoskeletal Ageing Research
Sector Academic/University
Country United Kingdom
Start 05/2019 
End 04/2021
 
Description Newspaper interviews 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Interviews for various print media

some interviews (e.g. Financial Times 2010) led to widespread international media interest
Year(s) Of Engagement Activity 2007,2008,2009,2010
 
Description radio interviews 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Media (as a channel to the public)
Results and Impact explained results to a wide audience

none known
Year(s) Of Engagement Activity 2010,2014