Ageing and cell senescence

COVID-19 statement:

Global data show that older people are hit the hardest by the new SARS-CoV-2 virus that causes COVID-19.  

It is vital that efforts to develop new treatments for COVID-19 factor in ageing and in particular how older people’s immune systems differ from those of younger people. Biogerontology, or the study of the biology of ageing, has helped to highlight ways in which it should be possible to strengthen the body's ability to fight off the virus without going into overdrive, called 'cytokine storm', that can result in critical illness and death. We are working with colleagues around the world to bring this research to the clinic to try to help fight the pandemic. If you feel your research is relevant to this endeavour, please contact us.

 

 

My lab studies the basic biology underpinning ageing and age-related diseases. We aim to use that knowledge to improve the health of older people through development of new interventions and treatments to promote healthy ageing by treating age-related diseases at cause.

Using a combination of model systems, we look at genes and biochemical pathways that influence health outcomes in ageing, with a particular focus on the process of cellular senescence. Our work aims to define molecular and genetic pathways that govern cell senescence and that underlie organismal ageing and frailty. We are following up our pathway discovery with targeted intervention using pharmacological agents to delay or inhibit senescence, or even reverse detrimental phenotypes. 

 

 

    Who we are and what we do

    Current lab members:

    Lynne Cox (PI)

    Adam Rolt (Elysium post-doctoral fellow)

    Lukeriya Zharova (Part II MBiochem student)

    Christopher Whiteman (DPhil student with Public Health England)

    Thibault Teissier (BIRAX/Diabetes UK post-doctoral scientist)

    Ivan Boubriak (UK SPINE postdoctoral scientist)

     

    Recent lab members and new positions:

    Hannah Walters (Humboldt post-doctoral Fellowship, Max Planck Insitute, Dresden, Germany)

    Sebastian Aguiar (biotech, USA)

    Hayley Lees (NHS Clinical Geneticist)

     

    DPhil position available from next academic year: 

    We are looking to recruit a new DPhil student on a Cell Senscence and Ageing scholarship funded through the generosity of Jim Mellon  and to be held at Oriel College, Oxford and the Department of Biochemistry.  Please contact lynne.cox@bioch.ox.ac.uk with expressions of interest: a formal advertisement will be posted in due cousre (we are experiencing delays because of the COVID-19 emergency)

     

     

    Recent papers:

    • Cox, LS.  (2020) The Economic and Scientific Case for Therapeutic Intervention in Ageing. Key paper I (p72-80) in "Health of the Nation: a Strategy for Healthier Longer Lives",  report of the APPG for Longevity, launched 12th February 2020, https://appg-longevity.org/events-publications
    • Cox, L and Goljanek-Whysall, K (2019) Ageing here and now: current research and transformative therapies. Biogerontology 20: 249. https://doi.org/10.1007/s10522-019-09814-5
    • Rolt, ACR, Nair, A and Cox, LS (2019) Optimisation of a screening platform for determining IL-6 associated inflammatory signalling in the senescence-associated secretory phenotype (SASP). Biogerontology https://doi.org/10.1007/s10522-019-09796-4
    • Walters, HA and Cox, LS (2019) Generation of a novel model of primary human cell senescence through Tenovin-6 mediated inhibition of sirtuins. Biogerontology https://doi.org/10.1007/s10522-018-09792-0
    • Walters, HW and Cox, LS (2018) mTORC Inhibitors as Broad-Spectrum Therapeutics for Age-Related Diseases Int J Mol Sci. 2018 Aug 8;19(8). pii: E2325. doi: 10.3390/ijms19082325.
    • Chennuri, P, Cox, LS and Saunders, RDC(2018) EXD2 and WRN exonucleases are required for interstrand crosslink repair in Drosophila. Preprint doi: https://doi.org/10.1101/284307
    • Cox, LS, Mason PA. (2018) Towards understanding the biological drivers of cell ageing. Chapter 8 in The New Dynamics of ageing, volume 2. Ed Walker, A. Policy Press (Bristol) ISBN 978-1-4473-1479-0.
    • Latorre E, Birar VC, Sheerin AN, Jeynes JCC, Hooper A, Dawe HR, Melzer D, Cox LS, Faragher RGA, Ostler EL, Harries LW. (2017) Small molecule modulation of splicing factor expression is associated with rescue from cellular senescence. BMC Cell Biol. 2017 Oct 17;18(1):31. doi: 10.1186/s12860-017-0147-7.
    • Cox, LS and Redman C. (2017) The role of cellular senescence in ageing of the placenta Placenta. 2017 Apr;52:139-145. doi: 10.1016/j.placenta.2017.01.116. Epub 2017.
    • Lees H, Walters H, Cox LS. (2016) Animal and human models to understand ageing. Maturitas. 2016 Nov;93:18-27. doi: 10.1016/j.maturitas.2016.06.008. 
    • Alimbetov D, Davis T, Brook AJ, Cox LS, Faragher RG, Nurgozhin T, Zhumadilov Z, Kipling D. (2016) Suppression of the senescence-associated secretory phenotype (SASP) in human fibroblasts using small molecule inhibitors of p38 MAP kinase and MK2. Biogerontology. 2016 Apr;17(2):305-15. doi: 10.1007/s10522-015-9610-z. 
    • Walters HE, Deneka-Hannemann S, Cox LS. (2016) Reversal of phenotypes of cellular senescence by pan-mTOR inhibition. Aging (Albany NY). 2016 Feb;8(2):231-44.

    We are delighted to announce the launch of Health of the Nation: a Strategy for Healthier Longer Lives on 12th February, with the Secretary of State for Health and Social Care, the Right Honourable Matt Hacock

    see:  https://www.youtube.com/watch?time_continue=5&v=tl7lJ1bj2lw&feature=emb_logo

    Link to the published strategy report: https://appg-longevity.org/events-publications

    Achieving an extra 5 years of healthy life expectancy (HLE+5)

    This launch of the strategy paper was the culmination of many months of work with the All-Party Pparliamentary Group (APPG) for Longevity, on which Lynne Cox serves on both the Strategic Advisory Board and the Science, Genomics and Technology board : https://appg-longevity.org

     

    Lynne also gave evidence to the House of Lords Science and Technology Select Committee on Ageing: Science, Technology and Healthy Living: 

    •Parliament TV (live recording of the hearing)

    https://parliamentlive.tv/Event/Index/1c0e8f76-2e8a-4e27-a297-4b4f2e9cb5f3 (session 2, starting at 11:27:40)

    •Written evidence

    http://data.parliament.uk/writtenevidence/committeeevidence.svc/evidencedocument/science-and-technology-committee-lords/ageing-science-technology-and-healthy-living/written/105595.html

    Lynne at the House of Lords

     

    Biochemistry Society Clinical and Translational Science Theme: https://biochemistry.org/events-and-training/theme-panels/clinical-and-translational-research/

     

    Trustee: British Society for Research on Ageing: https://bsra.org.uk

    DPhil position available from next academic year: 

    We are looking to recruit a new DPhil student on a Cell Senscence and Ageing scholarship funded through the generosity of Jim Mellon and to be held at Oriel College, Oxford and the Department of Biochemistry.  Please contact lynne.cox@bioch.ox.ac.uk with expressions of interest: a formal advertisement will be posted in due course (we are experiencing delays because of the COVID-19 emergency)

     

    Lynne has been interviewed for the Longevity Forum and the podcast The Big Middle:

    The Big Middle podcast

    listen here:

    https://podcasts.apple.com/gb/podcast/prof-lynne-cox/id1435522193?i=1000468245260

     

    Guardian newspaper interview December 2019:

    https://www.theguardian.com/science/2019/dec/21/scientists-harness-ai-to-reverse-ageing-in-billion-dollar-industry

     

    Longevity Forum panel: How can the UK add five years of healthy lifespan by 2030?

    https://www.youtube.com/watch?time_continue=4&v=PKXG5Z4VPYw&feature=emb_logo

    Longevity Forum panel November 2019

     

    BIRAX grant award: https://www.britishcouncil.org/organisation/press/£28-million-awarded-seven-new-joint-medical-research-projects-british-and-israeli

     

    We have recently been awarded a BIRAX grant jointly to Prof Lynne Cox and Prof Rivka Dressner Pollak of Hadassah Medical Center, Jerusalem, to study the role of cell senescence in bone fragility associated with type 1 diabetes. It is funded through the BIRAX scheme together with partner Diabetes UK. Lynne was invited to give an acceptance speech on behalf of all awardees at a reception held at the residency of the Israeli Amabassador His Excellency Mark Negev, in London in October 2019.

     

    birax award 231019 png

    This grant will suppost two post-doctoral researchers, one based in Jerusalem and one in Oxford.

     

     

    #OSEF2020: Oxford Said Entrepreneurship Forum: Lynne was a speaker at in the Said Business Schools' annual flagship event, discussing "immortality"  

    https://www.sbs.ox.ac.uk/research/centres-and-initiatives/entrepreneurship-centre/oxford-said-entrepreneurship-forum

    #OSEF2020 Immortality panel

     

    Please note the planned Ageing Science seminar series for Trinity Term 2020 (https://www.archub.ox.ac.uk/2020/03/13/trinity-2020-seminar-series-pre-announcement/) has been postponed because of COVID-19. We hope to be able to run this exciting series of seminars by global leaders in the science of ageing in the future.

     

    Healthy Ageing: From molecules to organisms: POSTPONED DUE TO COVID-19

    27 - 29 May 2020 Wellcome Genome Campus, UK

    The third conference in this series will focus on recent discoveries and current challenges in ageing research, with a focus on translating basic research insights into health improvement for older people.

    Ageing can lead to declining health and function, and it is the major risk factor for cancer, neurodegenerative and cardiovascular disease. We aim to explore the mechanisms of ageing in cells, tissues and organisms in order to identify interventions that can ameliorate its negative effects.

    The conference will focus on how recent developments in cell- and immune-senescence, neuroinflammation, stem cells and epigenetics are leading to an increased understanding of the ageing process. This year’s meeting will also highlight research into the ageing brain and nervous system and discuss lifestyle interventions for health improvement.

    The meeting is aimed at scientists, clinicians and drug developers involved in research into ageing and other relevant fields.

    https://coursesandconferences.wellcomegenomecampus.org/our-events/health...

    What causes age-related disease and can ageing be treated?

     

    Ageing and age-related diseases affect some people much more than others: there is no one fixed way to age and everyone is different. While we know that a good diet, exercise and plenty of sleep are important to maintain health, other factors out of our control (e.g. genes, environment) can lead to significant ill health and disability in later life. The vast majority of older people suffer from several chronic age-related diseases simultaneously - this is termed co-morbidity. 

     

    We now know that changes to cells as they age, termed cell senescence, can be critical in causing many different diseases of ageing. Exciting new research from labs around the world has shown that removing senescent cells can improve health in later life, and even extend lifespan in mice. 

     

    Cells undergo senescence in several different ways in response to DNA damage, activation of oncogenes or simply after they have undergone a large number of cell divisions until their telomeres (repetitive DNA structures at the ends of the chromosomes that shorten at every cell division cycle) have become critically short. Senescence is an important tumour suppressor mechanism to prevent damaged cells from dividing, but the many changes cells undergo as they become senescent leads to them altering their local environment, including degrading tissue structure and promoting a pro-inflammatory and pro-cancer environment. 

     

    By identifying the biochemical pathways and specific molecules involved, we aim to develop ways of altering the rate or outcomes of cell senescence, in order to better treat age-associated diseases and frailty. 

    email: lynne.cox@bioch.ox.ac.uk

    Tel. +44(0)1865 613243

    NB I am working from home during the COVID-19 crisis: mobile +44 (0) 7432 680147

    Oxford Ageing Network - OxAgeN

    The Oxford Ageing Network, OxAgeN, welcomes scientists and clinicians from around the Oxford area to meet and discuss latest advances in ageing research. 

    We are delighted to announce funding for OxAgen from the John Fell fund to support 6 future meetings of the newtork over the next 2 years. 

    Please follow the link to the OxAgeN webpage: https://coxlab.web.ox.ac.uk/oxagen

    Approaches we take to understand and treat ageing

    Expand All

    Cell senescence is a state of cell cycle arrest with cell growth, morphological changes and alteration in gene expression patterns leading to secretion of pro-inflammatory mediators and enzymes that damage tissue structure.

    Senescent cells are pro-inflammatory and damaging, leading to diseases of ageing

     

     

    We are also interested in investigating the role of a gene WRN which when mutated in humans leads to the premature ageing Werner’s syndrome. That a single gene can result in the early development of many age-related diseases including atherosclerosis, diabetes, cataracts, osteoporosis and cancer provides very strong evidence that there is a central underlying cause of many of the diseases of later life. Mutation of a closely related gene EXD2 also leads to genome instability and we are interested in the interplay between efficient DNA repair and maintenance of cellular longevity. We are studying the effect of WRN loss and its biochemcial activities in worms, flies and humans.

    fig1

    Cell senescence can occur as a result of many different cellular stresses. These can include DNA damage signalling arising from shorted telomeres after many rounds of cell division, more acute forms of DNA damage e.g. after exposure to ionising radiation or UV light, activation of cellular oncogenes, high levels of nutrients which drive cells into a hyper-growth phenotype, hormones (including insulin and insulin-like growth factor) as well as generalised intracellular and extracellular stresses (e.g. high ROS). These feed into key pathways that modulate the cell's response. Our focus is particularly on mTOR as master regulator, WRN as a key DNA damage response protein implicated in ageing, and p53, the tumour suppressor protein that when hyperactive causes ageing.

     

    We are exploiting the power of multiplex proteomics to identify molecular pathways important in senescence.

    signalling pathways regulate cell senescence

    Key molecules involved in driving and maintaining cellular senescence are the tumour suppressor proteins p16 and p53, and the p53-activated cyclin-dependent kinase inhibitor p21, while the mTORC1 kinase and its downstream effectors are antagonistic and promote cell growth and proliferation.  

    The fruit fly Drosophila allows us to explore how changes in certain age-related genes influence the overall stability of the genome. We have identified a WRN-like exonuclease in flies (Saunders et al 2008 Aging Cell 7 (3) 418-425) and are using this to study the relationship between DNA repair, genome instability and ageing, as well as studying ageing in normal (wild type) flies and those with stem cell defects. Fly work is carried out in collaboration with Dr Robert Saunders of the Open University, together with Prof Petros Ligoxygakis in Oxford. 

    Drosophila WRN exonuclease

    We are taking two approaches towards developing novel senomodifying interventions: target-based against molecules identified as important in our proteomics studies, together with phenotypic screens for correction of senescent phenotypes.

    We are actively designing new ways to identify drugs that can modify senescence and hence help to treat or even prevent the diseases of ageing. We have recently optimised a screening platform based on a biosensor that can detect very low levels of pro-inflammatory IL-6.

    Teaching and external appointments

    Expand All

    I am course organiser for the undergraduate Molecular Biology and Genetics paper. I lecture on DNA replication and tools in molecular biology. 

    https://weblearn.ox.ac.uk/portal/site/:medsci:bioch:ug:y2:molecular

    I am the George Moody fellow and Tutor in Biochemistry at Oriel College, Oxford, where I help to organise and deliver tutorial teaching for the Oriel Biochemists.

    I am also resposnible for admisision of undergraduates to read biochemistry at Oriel.

     

    https://www.oriel.ox.ac.uk/people/professor-lynne-cox

    I run practical classes in biochemistry for first year medical students throughout the year. 

     

    I also help with CPD training for clincal geronotologists as they approach their MRCP exmainations, giving lectures on the biology of ageing.

    Trustee of the British Society for Research on Ageing

    www.bsra.org.uk

     

    Clincial and Translational Research theme, the Biochemical Society

    https://biochemistry.org/events-and-training/theme-panels/clinical-and-translational-research/

     

    All Party Parliamentary working group (APPG) on Longevity (Houses of Parliament, UK)

    Strageic Advisory Board and Science, genomics and technology board

    https://appg-longevity.org/advisory-board

     

     

    NO-Age, The Norwegian Centre on Healthy Ageing

    Primary international member

    https://noage100.com/people/

     

    EU Geriatric Medicine Society

    Co-chair, special interest group on Ageing Biology

     

    Model systems we use to study ageing:

     

    Human cells cultured in the lab allow us to identify biochemical pathways of senescence and to test drugs directly in human cells with direct relevance to human ageing.

     

    Werner syndrome, a premature ageing disease in humans, is cause by mutation of a single gene WRN. Working out how WRN acts in cells to prevent premature ageing, and how loss of function of just one gene causes multiple diseases of ageing is important in working out how to treat age-related diseases.

     

    The fruit fly Drosophila melanogaster: we have identified the WRN exonuclease gene in flies, and have tested its roles in development, DNA replication, repair and recombination. We have also carried out biochemical analysis of the WRN nuclease activity.

     

    The nematode worm C. elegans allows us to test the effect of genes and/or chemical interventions on whole organism ageing within a very short time frame. Worms share more than 50% of genes with humans and show very similar ageing pathways, including premature ageing when the worm version of WRN (wrn-1) is mutated. 

     

    Lab members

    Current lab members:

    Lynne Cox (PI)

    Adam Rolt (Elysium post-doctoral fellow)

    Lukeriya Zharova (Part II MBiochem student)

    Christopher Whiteman (DPhil student with Public Health England)

    Thibault Teissier (BIRAX/Diabetes UK postdoctoral scientist)

     

    Recent lab members

    Hannah Walters (Humboldt post-doctoral fellowship, Germany)

    Sebastian Aguiar (Biotech startup on ageing, USA)

    Hayley Lees (Clinical Geneticist, NHS)

    Stephanie Gover (Medical School)

     

    Publications and online content

    For information on publications, awards, positions held etc, see https://orcid.org/0000-0002-5306-285X

     

     

    Achieving an extra 5 years of healthy life expectancy (HLE+5)

    "Health of the Nation: a Strategy for Healthier Longer Lives" report of the All Party Parliamentary Group for Longevity, launched 12th February 2020

    see Key chapter I (Lynne Cox): 'The Economic and Scientific Case for Therapeutic Intervention in Ageing'  (https://appg-longevity.org/events-publications)

     

     

    Video:

     

    Audio:

     

    Books:

    Cox, LS.(Ed) (2009) Molecular Themes in DNA Replication. Royal Society of Chemistry (Cambridge) ISBN 978-0-85404-164-0 (research text)

    Cox, LS, Harris, DA, Pears, CJ. (2012) Thrive in Biochemistry and Molecular Biology. OUP (Oxford). ISBN: 978-0-19-964548-0 (undergraduate teaching/revision text)

     

    Written evidence to House of Lords select committee Science and Technology Committee (Ageing: Science, Technology and Healthy Living)

    http://data.parliament.uk/writtenevidence/committeeevidence.svc/evidence...

     

     

    "Health of the Nation: a Strategy for Healthier Longer Lives" report of the All Party Parliamentary Group for Longevity, launched 12th February 2020

     

    see Key chapter I (Lynne Cox): 'The Economic and Scientific Case for Therapeutic Intervention in Ageing'  (https://appg-longevity.org/events-publications)

     

     

    Recent papers:

     

    • Cox, L and Goljanek-Whysall, K (2019) Ageing here and now: current research and transformative therapies. Biogerontology 20: 249. https://doi.org/10.1007/s10522-019-09814-5
    • Rolt, ACR, Nair, A and Cox, LS (2019) Optimisation of a screening platform for determining IL-6 associated inflammatory signalling in the senescence-associated secretory phenotype (SASP). Biogerontology https://doi.org/10.1007/s10522-019-09796-4
    • Walters, HA and Cox, LS (2019) Generation of a novel model of primary human cell senescence through Tenovin-6 mediated inhibition of sirtuins. Biogerontology https://doi.org/10.1007/s10522-018-09792-0
    • Walters, HW and Cox, LS (2018) mTORC Inhibitors as Broad-Spectrum Therapeutics for Age-Related Diseases Int J Mol Sci. 2018 Aug 8;19(8). pii: E2325. doi: 10.3390/ijms19082325.
    • Chennuri, P, Cox, LS and Saunders, RDC(2018) EXD2 and WRN exonucleases are required for interstrand crosslink repair in Drosophila. Preprint doi: https://doi.org/10.1101/284307
    • Cox, LS, Mason PA. (2018) Towards understanding the biological drivers of cell ageing. Chapter 8 in The New Dynamics of ageing, volume 2. Ed Walker, A. Policy Press (Bristol) ISBN 978-1-4473-1479-0.
    • Latorre E, Birar VC, Sheerin AN, Jeynes JCC, Hooper A, Dawe HR, Melzer D, Cox LS, Faragher RGA, Ostler EL, Harries LW. (2017) Small molecule modulation of splicing factor expression is associated with rescue from cellular senescence. BMC Cell Biol. 2017 Oct 17;18(1):31. doi: 10.1186/s12860-017-0147-7.
    • Cox, LS and Redman C. (2017) The role of cellular senescence in ageing of the placenta Placenta. 2017 Apr;52:139-145. doi: 10.1016/j.placenta.2017.01.116. Epub 2017.
    • Lees H, Walters H, Cox LS. (2016) Animal and human models to understand ageing. Maturitas. 2016 Nov;93:18-27. doi: 10.1016/j.maturitas.2016.06.008. 
    • Alimbetov D, Davis T, Brook AJ, Cox LS, Faragher RG, Nurgozhin T, Zhumadilov Z, Kipling D. (2016) Suppression of the senescence-associated secretory phenotype (SASP) in human fibroblasts using small molecule inhibitors of p38 MAP kinase and MK2. Biogerontology. 2016 Apr;17(2):305-15. doi: 10.1007/s10522-015-9610-z. 
    • Walters HE, Deneka-Hannemann S, Cox LS. (2016) Reversal of phenotypes of cellular senescence by pan-mTOR inhibition. Aging (Albany NY). 2016 Feb;8(2):231-44.