Regulation of DNA damage signaling by autophagy in senescence
Lead Research Organisation:
Newcastle University
Department Name: Institute for Ageing and Health
Abstract
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Technical Summary
This application investigates cellular and molecular mechanisms that control cell and tissue ageing. Cellular senescence is an important tumor suppression mechanism, but also contributes to tissue and organismal ageing. DNA damage signaling, dysfunctional mitochondria and reactive oxygen species (ROS) are established triggers and effectors of the senescence program.
Autophagy is a cellular recycling process, whereby double membrane vesicles, called autophagosomes, sequester cytoplasmic content and organelles and deliver it to lysosomes for degradation. Like senescence, autophagy is implicated in control of tumor suppression and ageing. In fact, recent studies have demonstrated a role for autophagy in control of cell senescence. However, the precise role played by autophagy and whether it serves as an activator or repressor of senescence is unclear. To understand the contribution of autophagy to tumor suppression and ageing, it is essential to understand its role in cell senescence.
Building on extensive preliminary data from the labs of Drs. Adams and Passos, we propose that autophagy antagonizes the senescence program in at least two ways. First, we hypothesize that autophagy suppresses accumulation of dysfunctional mitochondria, thereby suppressing accumulation of ROS and DNA damage. Second, we hypothesize that autophagy degrades fragments of DNA damage-containing chromatin that accumulate in the cytoplasm of senescent cells. By suppressing such DNA damage signals, autophagy antagonizes onset or maintenance of cell senescence and tissue aging. We will investigate these hypotheses through the following two Aims.
Aim 1. Investigate the role of autophagy in suppression of DDR via elimination of dysfunctional mitochondria and ROS.
Aim 2. Investigate the role of autophagy in degradation of senescence-inducing cytoplasmic chromatin fragments (CCF) containing damaged DNA.
Autophagy is a cellular recycling process, whereby double membrane vesicles, called autophagosomes, sequester cytoplasmic content and organelles and deliver it to lysosomes for degradation. Like senescence, autophagy is implicated in control of tumor suppression and ageing. In fact, recent studies have demonstrated a role for autophagy in control of cell senescence. However, the precise role played by autophagy and whether it serves as an activator or repressor of senescence is unclear. To understand the contribution of autophagy to tumor suppression and ageing, it is essential to understand its role in cell senescence.
Building on extensive preliminary data from the labs of Drs. Adams and Passos, we propose that autophagy antagonizes the senescence program in at least two ways. First, we hypothesize that autophagy suppresses accumulation of dysfunctional mitochondria, thereby suppressing accumulation of ROS and DNA damage. Second, we hypothesize that autophagy degrades fragments of DNA damage-containing chromatin that accumulate in the cytoplasm of senescent cells. By suppressing such DNA damage signals, autophagy antagonizes onset or maintenance of cell senescence and tissue aging. We will investigate these hypotheses through the following two Aims.
Aim 1. Investigate the role of autophagy in suppression of DDR via elimination of dysfunctional mitochondria and ROS.
Aim 2. Investigate the role of autophagy in degradation of senescence-inducing cytoplasmic chromatin fragments (CCF) containing damaged DNA.
Planned Impact
-------Who will benefit from this research?
The pharmaceutical and drug discovery industry; government policy makers; the wider general public.
The importance of research on ageing is recognised as a high strategic priority not only by BBSRC but also by other UK Research Councils, government departments and other agencies. There is a need for much deeper understanding of the biology of ageing, if society is to appreciate how to secure the best possible lifelong health and prepare for a world in which a much greater fraction of the population will be old.
------How will they benefit from this research?
Research needs to be done at many levels, ranging from fundamental mechanistic studies through to translation into healthspan and quality of life for older people, and economically important innovation in a broad range of business sectors. It is well accepted that ageing is an extremely complex process which involves the interaction of many gene products and biological process. The research programme presented in this application will allow the understanding of basic mechanisms of ageing and ultimately aims to identify potential targets for therapies to ameliorate the ageing process and age-related diseases.
The pharmaceutical and drug discovery industry will benefit from an improved understanding of the molecular basis of senescence-associated tissue ageing and tumour suppression. This will aid them in the rational selection of target molecules for drug discovery efforts. Possible opportunities for engagement with industrial partners and commercialisation will be explored with support from existing mechanisms at both Newcastle and Glasgow university (see pathways to impact).
Government policy makers will gain, indirectly, from an improved understanding of the fundamental mechanisms underpinning the ageing process. It is critical that future decisions can be traced back to a solid scientific literature particularly when society is facing an unprecedented demographic shift resulting in a remarkable increase in the fraction of older people.
The general public will benefit from an improved understanding of the molecular basis of cancer, ageing and age-associated disease, to help them make better lifestyle choices.
The pharmaceutical and drug discovery industry; government policy makers; the wider general public.
The importance of research on ageing is recognised as a high strategic priority not only by BBSRC but also by other UK Research Councils, government departments and other agencies. There is a need for much deeper understanding of the biology of ageing, if society is to appreciate how to secure the best possible lifelong health and prepare for a world in which a much greater fraction of the population will be old.
------How will they benefit from this research?
Research needs to be done at many levels, ranging from fundamental mechanistic studies through to translation into healthspan and quality of life for older people, and economically important innovation in a broad range of business sectors. It is well accepted that ageing is an extremely complex process which involves the interaction of many gene products and biological process. The research programme presented in this application will allow the understanding of basic mechanisms of ageing and ultimately aims to identify potential targets for therapies to ameliorate the ageing process and age-related diseases.
The pharmaceutical and drug discovery industry will benefit from an improved understanding of the molecular basis of senescence-associated tissue ageing and tumour suppression. This will aid them in the rational selection of target molecules for drug discovery efforts. Possible opportunities for engagement with industrial partners and commercialisation will be explored with support from existing mechanisms at both Newcastle and Glasgow university (see pathways to impact).
Government policy makers will gain, indirectly, from an improved understanding of the fundamental mechanisms underpinning the ageing process. It is critical that future decisions can be traced back to a solid scientific literature particularly when society is facing an unprecedented demographic shift resulting in a remarkable increase in the fraction of older people.
The general public will benefit from an improved understanding of the molecular basis of cancer, ageing and age-associated disease, to help them make better lifestyle choices.
People |
ORCID iD |
Joao Passos (Principal Investigator) |
Publications
Anderson R
(2018)
Mechanisms driving the ageing heart.
in Experimental gerontology
Anderson R
(2019)
Length-independent telomere damage drives post-mitotic cardiomyocyte senescence.
in The EMBO journal
Bianchi A
(2021)
Moderate Exercise Inhibits Age-Related Inflammation, Liver Steatosis, Senescence, and Tumorigenesis.
in Journal of immunology (Baltimore, Md. : 1950)
Birch J
(2016)
Telomere Dysfunction and Senescence-associated Pathways in Bronchiectasis.
in American journal of respiratory and critical care medicine
Birch J
(2017)
Targeting the SASP to combat ageing: Mitochondria as possible intracellular allies?
in BioEssays : news and reviews in molecular, cellular and developmental biology
Birch J
(2018)
Mitochondria, telomeres and cell senescence: Implications for lung ageing and disease.
in Pharmacology & therapeutics
Birch J
(2015)
DNA damage response at telomeres contributes to lung aging and chronic obstructive pulmonary disease.
in American journal of physiology. Lung cellular and molecular physiology
Brand T
(2019)
Length doesn't matter-telomere damage triggers cellular senescence in the ageing heart
in The EMBO Journal
Carroll B
(2018)
Oxidation of SQSTM1/p62 mediates the link between redox state and protein homeostasis.
in Nature communications
Carroll B
(2016)
Control of TSC2-Rheb signaling axis by arginine regulates mTORC1 activity.
in eLife
Description | We discovered that autophagy regulates the rate of DNA damage repair via p62, a protein that targets polyubiquitylated proteins for degradation via autophagy and the proteasome. The paper was published in the journal Autophagy (Hewitt et al. 2016). In collaboration with Viktor Korolchuk, we have recently identified a new role for p62 in survival against stress (Carroll et al. 2018 Nature Communications) Also, as part of this research grant we identified a new mechanism by which mitochondria impact on cellular senescence: The paper published in EMBO J 2016 has provided the first evidence that mitochondria are required for many of the features of senescence, particularly the Senescence-Associated Secretory Phenotype (SASP). Our work has shown that the SASP can promote ageing of tissues (Jurk et al. Nature Communications 2014) and cancer (Wilson et al. Nature Communications 2015). My group has also been involved in investigating the impact of senescence and the SASP in age-related diseases such as NAFLD (Ogrodnik et al. 2017 Nature Communications 2017), fibrotic pulmonary disease (Schafer et al. 2017) and others in collaboration with partners at Mayo Clinic. |
Exploitation Route | Based on this work, we believe that by targeting mitochondria we will be able to impact on the "ageing-promoting" features of senescence (such as the SASP). As a basis of new applications, my laboratory is now focusing on understanding the mechanisms by which mitochondria impact on the SASP and testing the impact of pharmacological interventions targeting mitochondria on organism ageing (using ageing mouse models). In collaboration with industry (particularly through the BBSRC, Unilever case studentship) we are exploring these pathways and potential interventions in the context of skin ageing. |
Sectors | Healthcare |
Description | Publication in EMBO J in 2016 which is an outcome of both BB/H022384/1 and BB/K017314/1 has received significant press attention (Daily Mail, Chronicle, Sun, Channel 4, The Economist) It was also featured in the BBSRC website: http://www.bbsrc.ac.uk/news/fundamental-bioscience/2016/160208-pr-mitochondria-shown-to-trigger-cell-ageing/ Publication in Nature Protocols 2017 of new method to investigate mitochondrial function in cells. Publication in Autophagy 2016- paper which describes role of p62 in the DDR. This work served as a basis for further grant applications to BBSRC and MRC. |
First Year Of Impact | 2016 |
Sector | Healthcare |
Impact Types | Societal |
Description | Funding by Unilever |
Amount | £202,000 (GBP) |
Organisation | Unilever |
Sector | Private |
Country | United Kingdom |
Start | 12/2016 |
End | 11/2018 |
Title | Method for generating human cells without mitochondria via widespread mitophagy |
Description | By overexpression of the ubiquitin-ligase Parkin and short-term treatment with the chemical CCCP we have induced widespread mitophagy and succeeded in generating mammalian cells with virtually no mitochondria. In these mitochondrial-depleted cells we could not detect mitochondrial respiration, proteins or DNA, but strikingly no mitochondrial organelles were observed by 3D electron microscopy. Furthermore, we have developed the adequate culture conditions to keep mitochondrial-depleted cells in culture with minimal loss of viability for relatively long periods of time at least 1 month in human fibroblasts. This methodology had previously been used in other cell types but we found that using primary human fibroblasts and certain culture conditions we could keep mitochondrial depleted cells for long periods of time. This methodology is far superior to others relying on the depletion of mtDNA (using chemical or genetic means), which result in a severe impairment of the mitochondrial electron transport chain but still preserve many of the functions of mitochondria. Furthermore, we anticipate that this method may revolutionize the study of mtDNA diseases, since it will allow the generation of "cleaner" transmitochondrial cybrids- (cells with a mix of nuclear genes from one cell and mitochondrial genes carrying different degrees of mtDNA mutations from another), without the use of rho(0) cells where mtDNA is depleted by long-term ethidium bromide treatment. Using this powerful method, we were recently able to effectively interrogate whether mitochondria were necessary for processes such as cellular senescence (Correia-Melo et al. 2016 Embo J http://emboj.embopress.org/content/early/2016/02/02/embj.201592862) |
Type Of Material | Cell line |
Year Produced | 2016 |
Provided To Others? | Yes |
Impact | The method was recently published in EMBO Journal and Nature Protocols. |
URL | http://emboj.embopress.org/content/early/2016/02/02/embj.201592862 |
Description | Collaboration with Beatson Institute |
Organisation | Beatson Institute for Cancer Research |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have provided preliminary data on the role of mitochondria in senescence which allowed a joint application to BBSRC, which was awarded. |
Collaborator Contribution | Prof. Peter Adams (Beatson Institute) in collaboration with our group discovered a new role for autophagy in processing of chromatin during senescence: A Ivanov, J Pawlikowski, J van Tuyn, I Manoharan, T Singh Rai, DM Nelson, PP Shah, H Wu, G Hewitt, V Korolchuk, JF Passos, SL Berger, PD Adams Lysosome-mediated processing of chromatin in senescence Journal of Cell Biology (IF 9.834). 2013 8;202(1):129-43. |
Impact | Publications: 1-A Ivanov, J Pawlikowski, J van Tuyn, I Manoharan, T Singh Rai, DM Nelson, PP Shah, H Wu, G Hewitt, V Korolchuk, JF Passos, SL Berger, PD Adams Lysosome-mediated processing of chromatin in senescence Journal of Cell Biology (IF 9.834). 2013 8;202(1):129-43. 2-C Correia-Melo, F DM Marques, R Anderson, G Hewitt, R Hewitt, BM Carroll, SMiwa, A Merz, MD Rushton, M Charles, D Jurk, SWG Tait, R Czapiewski, J Birch, LC Greaves, G Nelson, M Bohlooly-Y, S Rodriguez-Cuenca, A Vidal-Puig, DA Mann, G Saretzki, G Quarato, D Green, PD Adams, T von Zglinicki, VI Korolchuk, JF Passos. Mitochondria are required for pro-ageing features of the senescent phenotype. EMBO J (2016) doi:10.15252/embj.201592862 Grant application: Regulation of DNA damage signaling by autophagy in senescence and ageing BBSRC (funded ~300,000 for Newcastle and ~300,000 for Glasgow Universities. |
Start Year | 2013 |
Description | Collaboration with Dr. Stephen Tait, Beatson Institute |
Organisation | Beatson Institute for Cancer Research |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have conducted experiments with the aim of investigating the role of mitochondria in cellular senescence. |
Collaborator Contribution | Dr. Tait has conducted experiments in collaboration with the purpose of setting up a tool to investigate mitochondria during senescence. |
Impact | Publications: Correia-Melo C, Ichim G, Tait SW, Passos JF.Depletion of mitochondria in mammalian cells through enforced mitophagy. Nat Protoc. 2017 Jan;12(1):183-194. doi: 10.1038/nprot.2016.159. Correia-Melo C, Marques FD, Anderson R, Hewitt G, Hewitt R, Cole J, Carroll BM, Miwa S, Birch J, Merz A, Rushton MD, Charles M, Jurk D, Tait SW, Czapiewski R, Greaves L, Nelson G, Bohlooly-Y M, Rodriguez-Cuenca S, Vidal-Puig A, Mann D, Saretzki G, Quarato G, Green DR, Adams PD, von Zglinicki T, Korolchuk VI, Passos JF.Mitochondria are required for pro-ageing features of the senescent phenotype. EMBO J. 2016 Apr 1;35(7):724-42. doi: 10.15252/embj.201592862 |
Start Year | 2015 |
Description | Collaboration with Institute of genetic Medicine |
Organisation | Newcastle University |
Department | Institute of Genetic Medicine |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have collaborated with Gavin Richardson and provided evidence for new mechanisms driving senescence in cardiomyocytes. This allowed us to submit a grant to BHF which was awarded. |
Collaborator Contribution | Gavin Richardson provided expertise in the field of cardiac ageing and cardiomyocyte regeneration. |
Impact | Grant to BHF which was successful. |
Start Year | 2014 |
Description | Collaboration with Mayo Clinic Rochester, Minnesota, US |
Organisation | Mayo Clinic |
Country | United States |
Sector | Charity/Non Profit |
PI Contribution | In collaboration with the Mayo Clinic we have investigated the role of senescence in the context of IPF and cardiac ageing. My team has investigated senescence in IPD patients and the results of this collaborative work were recently published in Nature Communications 2017. Hanna Salmonowicz a PhD student in my team is currently at the Mayo Clinic in the Lab of Nathan LeBrasseur conducting experiments in the context of mitochondrial dysfunction and senescence. |
Collaborator Contribution | Our collaborators have allowed us access to the p16-INKATTAC mouse model which allows the specific elimination of p16 positive senescent cells. |
Impact | Schafer MJ, White TA, Iijima K, Haak AJ, Ligresti G, Atkinson EJ, Oberg AL, Birch J, Salmonowicz H, Zhu Y, Mazula DL, Brooks RW, Fuhrmann-Stroissnigg H, Pirtskhalava T, Prakash YS, Tchkonia T, Robbins PD, Aubry MC, Passos JF, Kirkland JL, Tschumperlin DJ, Kita H, LeBrasseur NK. Cellular senescence mediates fibrotic pulmonary disease. Nat Commun. 2017 Feb 23;8:14532. doi: 10.1038/ncomms14532. |
Start Year | 2015 |
Description | Interviewed by "The Economist" |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Interviewed by a journalist from "The Economist" |
Year(s) Of Engagement Activity | 2016 |
URL | http://www.economist.com/news/briefing/21704788-fight-cheat-death-hotting-up-adding-ages |