Award details

Investigating the relationship between mitochondrial activity, programmed repression of the heat shock response, protein homeostasis and ageing

Reference	BB/P005535/1
Principal Investigator / Supervisor	Dr Johnathan Labbadia
Co-Investigators / Co-Supervisors
Institution	University College London
Department	Genetics Evolution and Environment
Funding type	Research
Value (£)	797,849
Status	Current
Type	Fellowships
Start date	01/05/2017
End date	30/04/2023
Duration	72 months

Abstract

Ageing is a fundamental feature of biology yet the principles that underlie ageing remain elusive. Among the molecular changes documented in aged species, the loss of protein homeostasis (proteostasis) has emerged as a conserved feature of old age. It is widely assumed that the loss of proteostasis with age occurs stochastically due to the progressive dysregulation of protein quality control pathways. My work challenges this view and suggests that proteostasis collapse is a programmed event triggered by pathways that promote reproduction. Using C. elegans as a model system I have found that the heat shock response (HSR), a central regulator of proteostasis, is actively repressed as animals reach reproductive maturity, leaving cells vulnerable to protein misfolding later in life. Repression of the HSR and proteostasis collapse can be suppressed through the removal of germ line stem cells (GSCs) or mild perturbation of the mitochondrial electron transport chain (mETC), both of which also extend lifespan. I have previously demonstrated that GSCs promote repression of the HSR, proteostasis collapse and ageing through changes in chromatin architecture, however, it remains unknown how reduced mETC activity early in life prevents the programmed repression of the HSR and maintains proteostasis. To address this, I will use well defined molecular assays and C. elegans genetics to elucidate the precise mechanism by which mild perturbation of the mETC prevents repression of the HSR. In addition, I will employ reporters of protein folding capacity and tissue specific genetic manipulation to understand the mechanisms by which mETC activity can influence organismal proteostasis and ageing. My work will provide valuable new insight into the mechanisms that drive proteostasis collapse and ageing and establish the extent to which HSF1 and the age-dependent decline of the HSR are regulated by mitochondrial activity early in life.

Summary

Ageing is a fundamental feature of biology yet the root causes of ageing remain a mystery. My work within the institute of healthy ageing at University College London uses the small worm C. elegans to understand the processes that drive ageing in the hope of one day designing interventions that can promote long-term health in humans. It is widely thought that ageing is the consequence of a gradual accumulation of damage to cells, primarily due to the failure of pathways that protect us from environmental and physiological stresses. This model of ageing fits intuitively with our experiences of the world around us in which "wear and tear" is closely associated with the age of the items that surround us. However, recent evidence suggests that the fundamentals of ageing are much more complex than this. Among the many age-associated changes observed in worms, flies, mice, and humans, an increase in the quantity of damaged and non-functional proteins is a fundamental feature of old age. Proteins are an important component of all cells and must function properly for cells to remain healthy; therefore, it is possible that this "loss of protein homeostasis" underlies ageing. In support of this theory, strategies that maintain protein homeostasis are associated with increased lifespan whereas treatments that accelerate the loss of protein homeostasis result in early ageing and age-related disease. Therefore, by understanding why proteostasis declines with age and how this impacts longevity, it may be possible to identify genes and pathways that can be targeted to maintain proteostasis and promote healthy ageing. Despite their simplicity and short lifespan (2-3 weeks), C. elegans have multiple tissue types (muscle, intestine, nerves) and exhibit many of the changes that accompany ageing in humans, including a loss of protein homeostasis. Because protein homeostasis is fundamental for life, the genes necessary to maintain protein homeostasis in humans are also found in C. elegans, therefore, worms represent an excellent model system with which to use genetics to understand the relationship between changes in protein homeostasis and ageing. My work has revealed that many protective pathways decline early in adulthood, including the heat shock response, a pathway that is essential to prevent the accumulation of damaged and malfunctioning proteins in cells. This leaves animals vulnerable to environmental stress and protein misfolding later in adulthood. Surprisingly, my data suggest that the heat shock response does not decline gradually with age but is instead actively repressed as animals become reproductively mature. I have found that this phenomenon is controlled by two distinct pathways linked to reproduction (germ line stem cells) and growth (mitochondrial activity). I have previously identified the mechanism by which the germ line can maintain the heat shock response and proteostasis, however, it is unknown how impairing the activity of mitochondria (the energy factories of each cell) early in life prevents repression of the heat shock response, maintains proteostasis, and promotes long-term health. During my Fellowship period I will address these questions using the power of C. elegans genetics coupled with sensors that allow protein homeostasis to be monitored in different tissues throughout adulthood in living animals, something only possible in C. elegans. My work will answer critical questions regarding how pathways early in life control proteostasis with age. In particular, I will establish a previously unidentified link between mitochondrial activity and the programmed repression of the heat shock response during adulthood. This will lead to the identification of new targets for the promotion of long-term health and provide important insight into the principles that govern ageing.

Impact Summary

Who will benefit from this research? I expect the research produced as part of this proposal to have academic, societal, and economic impacts in the short and long-term through effects on academics working in a diverse range of fields, the general public, and possibly scientific policy makers and the pharmaceutical industry. To maximize this, I will strive to ensure that my findings reach the broadest possible audience and ensure that individuals that I train are well equipped to contribute to the UK knowledge base and economy by continuing to work within academia, or by pursuing job opportunities in the public or private sectors. How will they benefit from this research? During the Fellowship period my work will benefit the academic research community by establishing a new understanding of how mitochondrial activity early in life can influence pathways that maintain protein homeostasis, and promote healthy ageing. This will create new knowledge and drive scientific advancement, thereby enhancing the knowledge economy of the UK through the establishment of a new area of research that is concerned with the importance of developmental and reproductive signals in the regulation of protein homeostasis. It is my hope that within ten years this will have created a new area of research that attracts skilled investigators to pursue novel research in the UK, thereby further enhancing society. Furthermore, my findings will have an immediate impact on an international effort to solve a matter of global concern;the rising incidence and cost of age-related disease in developed countries. Finally, my work will also impact the wider academic community and contribute to the UK knowledge base through the training of students, thereby promoting passion, excellence and integrity in the next generation of scientific researchers. My work will also be of interest to companies within the commercial sector attempting to develop treatments for age-related disease, many of which are caused by the loss of protein homeostasis. Therefore, any novel genes or pathways that I find to be crucial for the maintenance of protein homeostasis with age will have the potential to broadly influence various disease states, particularly those associated with protein aggregation. My work will highlight new targets to test and pursue for the suppression of various age-related diseases (during the fellowship period) and hopefully lead to the development of treatments to suppress age-related diseases (> 30 years). I also expect my work to have an impact on the general public through several avenues. By training and mentoring students and research technicians to adopt core philosophies of hard work, organization, and responsibility, and to acquire skills in analytical thinking, public speaking, and writing, I will provide individuals that excel in non-academic occupations, thereby enhancing the UK workforce. In addition, I will commit to the dissemination of my research and the promotion of science to students of various ages (secondary school, college, and university). This will provide individuals with a greater appreciation of the scientific method, the importance of basic research using model organisms, and a fundamental understanding of the biology behind ageing, all of which will contribute to the knowledge and cultural base of the greater public. As well as the short term benefits of my research, I also expect my work to contribute to the long-term enhancement of society through strategies that promote healthy ageing throughout the population. While it will undoubtedly take a significant amount of time (> 30 years) and effort for this to be realized, the work I will perform as part of this proposal will allow us to refine our approaches to the intervention and treatment of ageing and age-related disease through commercial, academic, and governmental action, all of which will eventually result in greater health throughout society.

Committee	Research Committee D (Molecules, cells and industrial biotechnology)
Research Topics	Ageing
Research Priority	X – Research Priority information not available
Research Initiative	Fellowship - David Phillips Fellowship (DF) [1995-2015]
Funding Scheme	X – not Funded via a specific Funding Scheme

I accept the terms and conditions of use (opens in new window)

export PDF file

back to list new search