Multi-level regulation of mitochondrial function in ageing and under caloric restriction

Lead Research Organisation: Newcastle University
Department Name: Institute for Ageing and Health

Abstract

Age is the most important risk factor for all major chronic diseases in the developed world. Therefore, slowing down the biological process of ageing might be a very effective strategy against tumours, cardiovascular disease, diabetes, arthritis and many more. There is not a single mechanism that causes ageing. However, there is strong evidence that the loss of function of mitochondria is an important driver of the ageing process at a cellular level. Mitochondria are the 'power houses' of a cell: they use oxygen to burn fuels derived from nutrients to generate energy that sustains all cellular functions. This process is almost perfect, but not completely: some oxygen gets released as free radicals, i.e. molecules that can react with and destroy almost any other molecule in the cell. Loss of mitochondrial function in ageing therefore reduces the energy available to the cell, disturbs its metabolism because of sub-optimal fuel processing and may induce more and more molecular damage. There are some interventions that can prolong healthy life and postpone the decrease of mitochondrial function. Caloric restriction, reducing the food intake to about half of what an animal would eat normally, is the most robust of these. Long-term caloric restriction is evidently not acceptable to humans (and it is not clear whether it would work there). However, it provides an experimental tool: If we identify the regulatory mechanisms that are activated by caloric restriction and help maintain normal mitochondrial function, we might have found processes that regulate the rate of biological ageing and that, if activated by less draconian measures than hunger, might help to postpone age-related disease and prolong healthy lifespan. This is the goal of the present application. We do know already major signalling pathways that are altered in ageing and where signalling is restored under caloric restriction. However, we do know less well how these signalling pathways interact with each other and how they impinge on the function of individual mitochondrial proteins and complexes. To gain such knowledge is important, because all these pathways are multifunctional, meaning that interventions at that level are prone to multiple side effects, which would not be tolerable in the context of ageing. Therefore, much more specific information is needed. To gain this, we make use of recent developments in high throughput analytical techniques, which now allow to obtain precise genome-wide information about the regulation of gene expression and protein abundance at multiple levels. So far, multi-level data integration has been seriously hampered by biological (different animals), technical and methodological (experiments being performed in different labs with sometimes unknown variation of parameters) variation. For the first time in ageing research, we will combine genome-wide information ranging from the epigenetic regulation of gene expression over the transcriptional level to the mitochondrial proteome, all generated within a single experiment and from the very same animals. As part of the development of a BBSRC-funded Centre for Integrative Systems Biology of Ageing, we developed powerful software for data integration and pathway analysis, which we will use now to integrate the information. This data analysis will allow us to understand how interactions between mitochondrial proteins change during ageing and under caloric restriction, how these changes can induce changed mitochondrial function and at which regulatory level they are triggered. Analysis of the interaction networks will lead to the identification of novel candidates for interventions aimed at maintaining mitochondrial function during ageing. We will test those candidates by manipulating their expression levels in cultured cells and measuring the consequences of these interventions for mitochondrial function.

Technical Summary

Mitochondrial function declines during ageing in many tissues, and interventions that prolong healthy lifespan, including caloric restriction, often compensate for this decline. Multiple lines of evidence suggest that mitochondrial dysfunction is a significant cause for tissue ageing. However, the molecular mechanisms responsible for the decline of mitochondrial function in ageing tissues and for its restoration under caloric restriction are still elusive, limiting our abilities to develop specific and efficient interventions that might extend healthy lifespan. Genome-wide analyses have so far not yet provided coherent datasets encompassing multiple levels of regulation during ageing. For the first time, we will generate genome-wide promoter methylation, transcriptome and mitochondrial proteome datasets from liver and skeletal muscle from mice at different ages, ad-libitum fed and under caloric restriction. Each dataset will be exclusively from the same animal, minimizing the confounding effects of biological variation and maximizing comparability between the levels. We will integrate these datasets with each other and with data characterizing mitochondrial function obtained from the same groups of mice, using a powerful probabilistic functional interaction network tool developed and tested for application in ageing research in our Centre for Integrated Systems Biology of Ageing and Nutrition. This will allow us to (i) define network(s) of interacting mitochondrial proteins that are changed in ageing and under CR; (ii) identify the pre-transcriptional and transcriptional regulation for proteins that influence mitochondrial function; (iii) derive candidate regulatory pathways and model these; (iv) derive candidate nodes from these networks and test their impact on mitochondrial function by inhibition and over-expression experiments. This approach will identify novel candidates for biomarkers of ageing and for efficient and specific intervention concepts.

Planned Impact

Who will benefit? Ageing is a major challenge of the 21st century, and consequently BBSRC has recognized research on ageing as a strategic priority. Understanding the underlying biology of ageing at a level good enough to develop safe, long-term preventive and interventive measures is the only way to cope in a sustainable way with the personal and societal challenges of an ageing society. Our programme constitutes a significant step towards this goal. The first beneficiary is thus the international community of ageing researchers (see section on Academic Beneficiaries). We expect this work to lead to the identification of novel candidates for biomarkers of ageing as well as novel candidates and candidate pathways for intervention into the ageing process. Both of these are of great interest for applied biological and medical sciences and, potentially, for industry. Finally, ageing research is an area that has lagged behind for long on the political agenda and has only recently begun to be developed at a rate more commensurate with its societal importance. In this situation, policy makers, especially in science, health and social policy, need up-to-date advice to guide their decisions. How will they benefit? 1. There has been a long-standing quest for sensitive and specific biomarkers of ageing. They are urgently needed in geriatrics to assess rehabilitation measures and guide prevention. Interventive medicine in the old is associated with significant risks of precipitating frailty. Prospective biomarkers of ageing would help to assess such risks and guide therapeutic decisions. Frailty itself might become recognized as a syndrome that needs treatment in the future, and this would rise the need for sensitive biomarkers. We and others have developed promising biomarker candidates from approaches that were less comprehensive than the present proposal. We have the proven ability to recognize potential biomarkers of ageing, to test and validate them in human cohort studies and to guide their implementation by health services and industry. 2. There are few intervention strategies known that can prolong healthy lifespan in mammals. They typically work by suppressing very central metabolic regulatory nodes (for instance IGF1, mTOR) and are thus bound to have multiple serious side effects, which could not be tolerated in human long-term use. Our approach is directed at defining networks of pathways that are relevant for ageing and extension of healthy lifespan. While this is not an intervention study itself, we hope to be able to propose novel candidate pathways for future interventions. Again, we have the potential to drive such studies forward in collaboration with users from industry and the health service. 3. Results from this research will not directly be implicated in advice to policy makers. However, these results will inform such advice at both the national and international level. We were repeatedly engaged in such activities, and we will continue to do so (see section Pathways to Impact).

Publications

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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

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Cameron KM (2011) Gross energy metabolism in mice under late onset, short term caloric restriction. in Mechanisms of ageing and development

 
Description Support 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 data will help to find drugs that can slow down the ageing process and postpone the onset of age-related disease and disability.
Sectors Healthcare

 
Description Evaluation of senolytic interventions in skin ageing
Amount £880,000 (GBP)
Funding ID BB/S006710/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 02/2019 
End 03/2022
 
Description H2020 Widespread 2014-1
Amount € 500,000 (EUR)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 05/2015 
End 05/2016
 
Description MIA - Multidisciplinary Institute for Ageing Portugal
Amount € 15,000,000 (EUR)
Organisation European Commission H2020 
Sector Public
Country Belgium
Start 01/2020 
End 12/2026
 
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 Nuchido Collaboration 
Organisation Nuchido
Sector Private 
PI Contribution We screen and validate possible senolytic drug candidates predicted by the company. We also provide specific background knowledge in ageing biology.
Collaborator Contribution Nuchido Ltd predicts novel candidates for senolytic drugs.
Impact additional research funding
Start Year 2015
 
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