Award details

Elucidating novel roles of selective autophagy in inflammation during ageing

Reference	BB/P005691/1
Principal Investigator / Supervisor	Professor Petros Ligoxygakis
Co-Investigators / Co-Supervisors
Institution	University of Oxford
Department	Biochemistry
Funding type	Research
Value (£)	45,530
Status	Completed
Type	Research Grant
Start date	01/03/2017
End date	29/02/2020
Duration	36 months

Abstract

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.

Summary

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.

Impact Summary

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 terminate 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 fulfils 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.

Committee	Research Committee D (Molecules, cells and industrial biotechnology)
Research Topics	Ageing, Immunology
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

Associated awards:

BB/P007856/1 Elucidating novel roles of selective autophagy in inflammation during ageing

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