Elucidating novel roles of selective autophagy in inflammation during ageing
Lead Research Organisation:
University of Warwick
Department Name: School of Life Sciences
Abstract
Global human population over the age of 60 will increase more than threefold (to nearly 2 billion individuals) during the first half of the twenty-first century, and that by 2050 it will exceed the size of the global population of young individuals (those individuals who are less than 15 years of age). For the first time in history, there are 11 million people aged 65 or over in the UK and also there are more pensioners than there are children under 16. Ageing population puts an enormous pressure on health care and pension system. Thus, understanding the biology of ageing is an urgently required task in order to ensure a viable and sustainable future for our human community.
One of the phenotypic hallmarks of ageing cells is chronic, systemic inflammation in the absence of any apparent infection, and is a significant risk factor for mortality in the elderly. We discovered that a protein called Kenny, which participates in the control of inflammation, is selectively degraded by a cellular process called autophagy. Autophagy, which means 'self-eating', is an essential process that involves the degradation of cytoplasmic material. Cells use autophagy to generate materials and energy when conditions become unfavourable. They also use this process to clear damaged cellular components or specific proteins in order to abolish their function when it is not needed in the cell.
We will use the fruit fly Drosophila melanogaster as a genetically modifiable model organism to understand at the molecular level how selective autophagy regulates inflammation during ageing. These mechanisms are very similar between fruit flies and humans, so the results will have direct relevance to human health.
This project will make a major contribution to our understanding of the fundamental mechanisms of autophagy and inflammation during ageing and could potentially be used in applied research aimed towards developing new strategies to fight age-related diseases and to promote healthy ageing.
One of the phenotypic hallmarks of ageing cells is chronic, systemic inflammation in the absence of any apparent infection, and is a significant risk factor for mortality in the elderly. We discovered that a protein called Kenny, which participates in the control of inflammation, is selectively degraded by a cellular process called autophagy. Autophagy, which means 'self-eating', is an essential process that involves the degradation of cytoplasmic material. Cells use autophagy to generate materials and energy when conditions become unfavourable. They also use this process to clear damaged cellular components or specific proteins in order to abolish their function when it is not needed in the cell.
We will use the fruit fly Drosophila melanogaster as a genetically modifiable model organism to understand at the molecular level how selective autophagy regulates inflammation during ageing. These mechanisms are very similar between fruit flies and humans, so the results will have direct relevance to human health.
This project will make a major contribution to our understanding of the fundamental mechanisms of autophagy and inflammation during ageing and could potentially be used in applied research aimed towards developing new strategies to fight age-related diseases and to promote healthy ageing.
Technical Summary
Ageing is associated with the lifelong, gradual accumulation of molecular and cellular damage and this has been observed in species ranging from yeast to humans. One of the phenotypic hallmarks of ageing tissues is chronic inflammation. We found that a protein called Kenny, which participates in the control of inflammation in Drosophila, is selectively degraded by the cellular catabolic process of autophagy. Autophagy is an essential process that involves the degradation of cytoplasmic material through the lysosomal pathway. Accumulating evidence indicates that autophagic degradation declines with age and this gradual reduction of autophagy might have a causative role in the functional impairment of biological systems during ageing. Our proposal aims to elucidate how selective autophagic degradation of Kenny regulates innate immunity and inflammation during ageing.
We will 1) examine how selective autophagic degradation of Kenny controls the production of antimicrobial peptides (AMPs), 2) examine the role of Kenny in the selective degradation of invading bacteria as a xenophagy receptor , 3) examine the role of Kenny in the selective degradation of mitochondria and how this is related to inflammation and ageing, 4) elucidate the physiological significance of elevated AMPs in autophagy mutants and how this is related to ageing.
We will address our objectives using a combination of cell and molecular biology, genetics, biochemistry, and advanced imaging. Using this approach we expect to identify novel mechanisms that regulate inflammation during ageing.
We will 1) examine how selective autophagic degradation of Kenny controls the production of antimicrobial peptides (AMPs), 2) examine the role of Kenny in the selective degradation of invading bacteria as a xenophagy receptor , 3) examine the role of Kenny in the selective degradation of mitochondria and how this is related to inflammation and ageing, 4) elucidate the physiological significance of elevated AMPs in autophagy mutants and how this is related to ageing.
We will address our objectives using a combination of cell and molecular biology, genetics, biochemistry, and advanced imaging. Using this approach we expect to identify novel mechanisms that regulate inflammation during ageing.
Planned Impact
INTRODUCTION: One of the phenotypic hallmarks of ageing tissues is chronic inflammation. Age-related inflammation is the low-grade, systemic inflammation in the absence of any apparent infection, and is a significant risk factor for mortality in the elderly. However the molecular and cellular mechanisms of age-related inflammation remain elusive. We recently found that autophagy, a cellular degradation process, selectively degrades Kenny, the fruit fly homologue of IKKgamma/NEMO, in order to regulate the innate immune response. Our proposal aims to understand at molecular level how autophagy, a cellular catabolic process, regulates innate immunity and chronic inflammation during ageing.
BASIC SCIENCE: This is a basic science project; it addresses fundamental, yet unresolved issues that will allow us to identify the cellular and molecular pathways involved in inflammation during ageing and potential new targets for therapeutic intervention. The project is most likely to have long term impact in the biomedical and health science areas.
IMPACT ON HUMAN HEALTH, PHARMA AND BIOTECH: Our research project will elucidate the role of autophagy in chronic inflammation during ageing. This will have a major impact on understanding how treatments that regulate autophagy can modulate inflammation during ageing and may be beneficial for healthy ageing during the life course. In other words, our research proposal is likely to have a potential long-term impact on human ageing. This impact will be realised through dissemination of our research findings to industry, healthcare professionals, government and public sector bodies and charities. Dr Nezis is currently establishing relationships with industrial partners (GlaxoSmithKline and Unilever) and will continue to do so.
IMPACT ON WIDER PUBLIC: The project will also provide scope for public engagement having impact on better understanding and appreciation of basic science of chronic inflammation during ageing among the local community. The general public will benefit from the proposed project not only because of the potential therapeutic applications developed from our discoveries, but also because of our efforts to enhance public understanding of our research by engaging school students and participating in University activities directed to a general audience such as Open Days and Research Showcases.
IMPACT ON GENERATION OF SCIENTIFICALLY LITERATE WORK FORCE: One of the more immediate outcomes of the project will be the professional training of the post-doctoral researcher employed. The post-doc scientist will have an opportunity to learn and improve a wide range of techniques in genetics, molecular and cell biology as well as in vivo techniques. This will equip him/her well for a career as scientist in academia or in a private sector. The highly skilled post-doc that we produce will most certainly lead ultimately to wealth creation through the applications of this transferable skills base.
BBSRC STRATEGIC PRIORITIES: The proposed project fulfills a number of BBSRC strategic aims such as: "maintaining world-class UK Bioscience by supporting the best people and best ideas" and "providing skilled researchers needed for academic research". It also has particular relevance to BBSRC's strategic priorities in "Ageing research: lifelong health and wellbeing" and "The replacement, refinement and reduction (3Rs) in research using animals".
CONCLUSION: This study will directly and indirectly contribute to both improved health and economic wealth.
BASIC SCIENCE: This is a basic science project; it addresses fundamental, yet unresolved issues that will allow us to identify the cellular and molecular pathways involved in inflammation during ageing and potential new targets for therapeutic intervention. The project is most likely to have long term impact in the biomedical and health science areas.
IMPACT ON HUMAN HEALTH, PHARMA AND BIOTECH: Our research project will elucidate the role of autophagy in chronic inflammation during ageing. This will have a major impact on understanding how treatments that regulate autophagy can modulate inflammation during ageing and may be beneficial for healthy ageing during the life course. In other words, our research proposal is likely to have a potential long-term impact on human ageing. This impact will be realised through dissemination of our research findings to industry, healthcare professionals, government and public sector bodies and charities. Dr Nezis is currently establishing relationships with industrial partners (GlaxoSmithKline and Unilever) and will continue to do so.
IMPACT ON WIDER PUBLIC: The project will also provide scope for public engagement having impact on better understanding and appreciation of basic science of chronic inflammation during ageing among the local community. The general public will benefit from the proposed project not only because of the potential therapeutic applications developed from our discoveries, but also because of our efforts to enhance public understanding of our research by engaging school students and participating in University activities directed to a general audience such as Open Days and Research Showcases.
IMPACT ON GENERATION OF SCIENTIFICALLY LITERATE WORK FORCE: One of the more immediate outcomes of the project will be the professional training of the post-doctoral researcher employed. The post-doc scientist will have an opportunity to learn and improve a wide range of techniques in genetics, molecular and cell biology as well as in vivo techniques. This will equip him/her well for a career as scientist in academia or in a private sector. The highly skilled post-doc that we produce will most certainly lead ultimately to wealth creation through the applications of this transferable skills base.
BBSRC STRATEGIC PRIORITIES: The proposed project fulfills a number of BBSRC strategic aims such as: "maintaining world-class UK Bioscience by supporting the best people and best ideas" and "providing skilled researchers needed for academic research". It also has particular relevance to BBSRC's strategic priorities in "Ageing research: lifelong health and wellbeing" and "The replacement, refinement and reduction (3Rs) in research using animals".
CONCLUSION: This study will directly and indirectly contribute to both improved health and economic wealth.
People |
ORCID iD |
| Ioannis Nezis (Principal Investigator) |
Publications
Chang K
(2020)
TGFB-INHB/activin signaling regulates age-dependent autophagy and cardiac health through inhibition of MTORC2.
in Autophagy
Demeter A
(2022)
Computational prediction and experimental validation of Salmonella Typhimurium SopE-mediated fine-tuning of autophagy in intestinal epithelial cells.
in Frontiers in cellular and infection microbiology
Gohel R
(2020)
Molecular mechanisms of selective autophagy in Drosophila.
in International review of cell and molecular biology
Gohel R
(2022)
Selective autophagy and Golgi quality control in <i>Drosophila</i>
in Autophagy
Jacomin A
(2020)
Degradation of arouser by endosomal microautophagy is essential for adaptation to starvation in Drosophila
in Life Science Alliance
Jacomin AC
(2019)
Assays to Monitor Aggrephagy in Drosophila Brain.
in Methods in molecular biology (Clifton, N.J.)
Jacomin AC
(2017)
iLIR@viral: A web resource for LIR motif-containing proteins in viruses.
in Autophagy
Jacomin AC
(2020)
Selective autophagic degradation of the IKK complex in Drosophila is mediated by Kenny/IKK? to control inflammation.
in Molecular & cellular oncology
| Description | Colon cancer, Crohn's, and other gut diseases could be better treated or prevented, thanks to a new link between inflammation and a common cellular process, found by University of Warwick Autophagy - an essential process whereby cells break down and recycle harmful elements to keep our bodies healthy - causes tissue inflammation when dysfunctional, which in turn leaves us susceptible to diseases, particularly in the gut Pomegranates, red grapes, pears, mushrooms, lentils, soybeans and green peas contain natural compounds which can activate autophagy, helping to prevent inflammation and gut diseases. New link could lead to more effective treatments for diseases - giving healthcare professionals ability to target root cause of disease, by regulating autophagy Paper published in Nature Communications Colon cancer, Crohn's, and other diseases of the gut could be better treated - or even prevented - thanks to a new link between inflammation and a common cellular process, established by the University of Warwick Led by Dr Ioannis Nezis at Warwick's School of Life Sciences, new research demonstrates that autophagy - an essential process whereby cells break down and recycle harmful or damaged elements within themselves to keep our bodies healthy - causes tissue inflammation when dysfunctional, which in turn leaves us susceptible to harmful diseases, particularly in the gut. Understanding this link could lead to more effective treatments for gut diseases - such as colon cancer, irritable bowel syndrome, Crohn's disease and ulcerative colitis - giving healthcare professionals the ability to target the root cause of these diseases, by regulating and controlling autophagy. Foods such as pomegranates, red grapes, pears, mushrooms, lentils, soybeans and green peas contain natural compounds which can activate autophagy, helping to prevent inflammation and gut diseases. In a new paper published in Nature Communications, Dr Nezis and colleagues have identified - for the first time - a protein which is regulated by autophagy. Called Kenny, the protein contains a motif of amino acids that causes itself to be broken down by autophagy. When autophagy is dysfunctional, Kenny accumulates and causes inflammation. The researchers identified this phenomenon in fruit flies, by turning Kenny fluorescent - so it would be visible - and observing at a microscopic level that the protein was present in the cell where autophagy was occurring. They also noted that dysfunctional autophagy causes serious inflammation in fruit flies - particularly in the gut - which makes tissue inflamed, causing disease, and making the lifespan of a fruit fly half that of other flies. To prevent serious diseases of the gut caused by inflammation, Dr Nezis and his colleagues state that it is necessary to find ways to control and regulate autophagy. Humans are in even more danger from the link between autophagy, inflammation, and a dysfunctional or diseased gut - because our bodies lack the regular motif of amino acids which Kenny uses in fruit flies, making its breakdown by autophagy difficult to control or regulate. Dr Ioannis Nezis, the lead author of the research, commented: "Understanding the molecular mechanisms of selective autophagy and inflammation will help to use interventions to activate the autophagic pathway to prevent inflammation and promote healthy well-being during the life course. "Natural compounds contained in fruits and vegetables like pomegranates, red grapes, pears, mushrooms, lentils, soybeans and green peas have been shown to activate autophagy, therefore inclusion of the above in our diet would help to prevent inflammation and alleviate the symptoms of gut diseases." |
| Exploitation Route | Colon cancer, Crohn's, and other gut diseases could be better treated or prevented, thanks to a new link between inflammation and a common cellular process, found by University of Warwick Autophagy - an essential process whereby cells break down and recycle harmful elements to keep our bodies healthy - causes tissue inflammation when dysfunctional, which in turn leaves us susceptible to diseases, particularly in the gut Pomegranates, red grapes, pears, mushrooms, lentils, soybeans and green peas contain natural compounds which can activate autophagy, helping to prevent inflammation and gut diseases. New link could lead to more effective treatments for diseases - giving healthcare professionals ability to target root cause of disease, by regulating autophagy Paper published in Nature Communications Colon cancer, Crohn's, and other diseases of the gut could be better treated - or even prevented - thanks to a new link between inflammation and a common cellular process, established by the University of Warwick. Led by Dr Ioannis Nezis at Warwick's School of Life Sciences, new research demonstrates that autophagy - an essential process whereby cells break down and recycle harmful or damaged elements within themselves to keep our bodies healthy - causes tissue inflammation when dysfunctional, which in turn leaves us susceptible to harmful diseases, particularly in the gut. Understanding this link could lead to more effective treatments for gut diseases - such as colon cancer, irritable bowel syndrome, Crohn's disease and ulcerative colitis - giving healthcare professionals the ability to target the root cause of these diseases, by regulating and controlling autophagy. Foods such as pomegranates, red grapes, pears, mushrooms, lentils, soybeans and green peas contain natural compounds which can activate autophagy, helping to prevent inflammation and gut diseases. In a new paper published in Nature Communications, Dr Nezis and colleagues have identified - for the first time - a protein which is regulated by autophagy. Called Kenny, the protein contains a motif of amino acids that causes itself to be broken down by autophagy. When autophagy is dysfunctional, Kenny accumulates and causes inflammation. The researchers identified this phenomenon in fruit flies, by turning Kenny fluorescent - so it would be visible - and observing at a microscopic level that the protein was present in the cell where autophagy was occurring. They also noted that dysfunctional autophagy causes serious inflammation in fruit flies - particularly in the gut - which makes tissue inflamed, causing disease, and making the lifespan of a fruit fly half that of other flies. To prevent serious diseases of the gut caused by inflammation, Dr Nezis and his colleagues state that it is necessary to find ways to control and regulate autophagy. Humans are in even more danger from the link between autophagy, inflammation, and a dysfunctional or diseased gut - because our bodies lack the regular motif of amino acids which Kenny uses in fruit flies, making its breakdown by autophagy difficult to control or regulate. Dr Ioannis Nezis, the lead author of the research, commented: "Understanding the molecular mechanisms of selective autophagy and inflammation will help to use interventions to activate the autophagic pathway to prevent inflammation and promote healthy well-being during the life course. "Natural compounds contained in fruits and vegetables like pomegranates, red grapes, pears, mushrooms, lentils, soybeans and green peas have been shown to activate autophagy, therefore inclusion of the above in our diet would help to prevent inflammation and alleviate the symptoms of gut diseases." |
| Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |
| URL | https://nezislab.wordpress.com/ |
| Title | Transgenic flies |
| Description | We generated transgenic lines that express Kenny-GFP and Kenny LIR mutant GFP. These lines are used to monitor the activation of innate immune response in Drosophila and how it is regulated by autophagy |
| Type Of Material | Biological samples |
| Year Produced | 2017 |
| Provided To Others? | Yes |
| Impact | We had a lot of requests by other researcher for these transgenic flies |
| Description | mathematical modeling |
| Organisation | University of Warwick |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Dr Bridget Penman developed a mathematical model to study pathogen co evolution with host cell autophagy receptors |
| Collaborator Contribution | Dr Bridget Penman developed a mathematical model to study pathogen co evolution with host cell autophagy receptors |
| Impact | https://warwick.ac.uk/newsandevents/pressreleases/colon_cancer_breakthrough |
| Start Year | 2017 |
| Description | Public science event on ageing |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Public/other audiences |
| Results and Impact | My lab participated in School of Life Sciences Public event on ageing 'Who wants to live forever' General public attended the event. They asked a lot of questions about autophagy and ageing and how we can boost autophagy through our diet to live a healthier and longer life |
| Year(s) Of Engagement Activity | 2018 |
| Description | School visit Leek Wootton Warwickshire |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | I visited All Saints primary school in Leek Wootton Warwickshire. 30 Year 6 pupils attended a presentation and hands on practical about 'Autophagy, fruit flies and ageing'. The pupils were very enthusiastic and the school reported increased interest . |
| Year(s) Of Engagement Activity | 2018 |