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
Arasaradnam RP
(2010)
DNA methylation of ESR-1 and N-33 in colorectal mucosa of patients with ulcerative colitis (UC).
in Epigenetics
Basterfield L
(2010)
Intestinal tumours, colonic butyrate and sleep in exercised Min mice.
in The British journal of nutrition
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
Cameron K
(2011)
Gross energy metabolism in mice under late onset, short term caloric restriction
in Mechanisms of Ageing and Development
Caple F
(2010)
Inter-individual variation in DNA damage and base excision repair in young, healthy non-smokers: effects of dietary supplementation and genotype.
in The British journal of nutrition
Carroll B
(2017)
Persistent mTORC1 signaling in cell senescence results from defects in amino acid and growth factor sensing.
in The Journal of cell biology
Correia-Melo C
(2016)
Mitochondria are required for pro-ageing features of the senescent phenotype.
in The EMBO journal
Da Silva PFL
(2019)
The bystander effect contributes to the accumulation of senescent cells in vivo.
in Aging cell
Dalle Pezze P
(2014)
Dynamic modelling of pathways to cellular senescence reveals strategies for targeted interventions.
in PLoS computational biology
Deelen J
(2014)
Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age.
in Human molecular genetics
Duran AL
(2013)
Shared Ageing Research Models (ShARM): a new facility to support ageing research.
in Biogerontology
Fielder E
(2017)
The DNA Damage Response in Neurons: Die by Apoptosis or Survive in a Senescence-Like State?
in Journal of Alzheimer's disease : JAD
Gavriilidis C
(2013)
Mitochondrial dysfunction in osteoarthritis is associated with down-regulation of superoxide dismutase 2.
in Arthritis and rheumatism
Hewitt G
(2016)
SQSTM1/p62 mediates crosstalk between autophagy and the UPS in DNA repair.
in Autophagy
Holly AC
(2015)
Comparison of senescence-associated miRNAs in primary skin and lung fibroblasts.
in Biogerontology
Ishaq A
(2018)
Metabolic memory of dietary restriction ameliorates DNA damage and adipocyte size in mouse visceral adipose tissue.
in Experimental gerontology
Ishaq A
(2018)
Dietary Restriction Ameliorates Age-Related Increase in DNA Damage, Senescence and Inflammation in Mouse Adipose Tissuey.
in The journal of nutrition, health & aging
Jurk D
(2012)
Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response.
in Aging cell
Jurk D
(2014)
Chronic inflammation induces telomere dysfunction and accelerates ageing in mice.
in Nature communications
Korolchuk VI
(2017)
Mitochondria in Cell Senescence: Is Mitophagy the Weakest Link?
in EBioMedicine
Langie SA
(2017)
The Ageing Brain: Effects on DNA Repair and DNA Methylation in Mice.
in Genes
Lawless C
(2012)
A stochastic step model of replicative senescence explains ROS production rate in ageing cell populations.
in PloS one
Lisanti S
(2012)
Standardization and quality controls for the methylated DNA immunoprecipitation technique.
in Epigenetics
Martin-Ruiz CM
(2015)
Reproducibility of telomere length assessment: an international collaborative study.
in International journal of epidemiology
Mathers JC
(2010)
Induction of epigenetic alterations by dietary and other environmental factors.
in Advances in genetics
Miwa S
(2016)
Carboxylesterase converts Amplex red to resorufin: Implications for mitochondrial H2O2 release assays.
in Free radical biology & medicine
Miwa S
(2014)
Low abundance of the matrix arm of complex I in mitochondria predicts longevity in mice.
in Nature communications
Nelson G
(2012)
A senescent cell bystander effect: senescence-induced senescence.
in Aging cell
Nelson G
(2018)
The senescent bystander effect is caused by ROS-activated NF-?B signalling.
in Mechanisms of ageing and development
Ogrodnik M
(2019)
Obesity-Induced Cellular Senescence Drives Anxiety and Impairs Neurogenesis.
in Cell metabolism
Ogrodnik M
(2017)
Cellular senescence drives age-dependent hepatic steatosis.
in Nature communications
Pekovic V
(2011)
Conserved cysteine residues in the mammalian lamin A tail are essential for cellular responses to ROS generation.
in Aging cell
Short S
(2019)
Senolytics and senostatics as adjuvant tumour therapy.
in EBioMedicine
Tsolou A
(2012)
The 19S proteasome subunit Rpn7 stabilizes DNA damage foci upon genotoxic insult.
in IUBMB life
| 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 |