Award details

Redefining the mechanisms that promote healthy ageing downstream of HSF1

Reference	BB/T013273/1
Principal Investigator / Supervisor	Dr Johnathan Labbadia
Co-Investigators / Co-Supervisors
Institution	University College London
Department	Genetics Evolution and Environment
Funding type	Research
Value (£)	398,850
Status	Current
Type	Research Grant
Start date	01/11/2020
End date	31/10/2023
Duration	36 months

Abstract

A dramatic rise in the number of individuals suffering from age-associated maladies and infirmities means that finding ways to promote healthy ageing across the population is now a social imperative. Among the many hallmarks of ageing, the loss of protein homeostasis (proteostasis) is considered to be a primary driver of age-related tissue dysfunction in multiple species. While the precise mechanisms that contribute to age-related proteostasis collapse are poorly understood, it is well-established that increasing HSF1 activity is a powerful way to protect against protein aggregation and promote longevity. These effects have been attributed to increased levels of heat shock proteins, however, the precise mechanisms that act downstream of HSF1 to protect the ageing proteome remain obscure. Correcting this is essential if we are to develop anti-ageing therapies that harness the protective power of HSF1 without unwanted side-effects. Using Caenorhabditis elegans as a model system, we have performed an RNAi screen for genes that act downstream of HSF1 to extend lifespan. Surprisingly, we have identified ubiquilin-1 as a key mediator of lifespan extension in worms overexpressing HSF1. Ubiquilin-1 has a central role in protein degradation by ensuring the efficient execution of endoplasmic reticulum associated degradation (ERAD). This raises the intriguing possibility that HSF1 maintains proteostasis and promotes healthy ageing by eliminating misfolded proteins from aged cells through enhanced ERAD. To investigate this, we will use C. elegans and mammalian tissue culture models to establish the relationship between increased HSF1 activity, ubiquilin-1 levels, protein degradation, ERAD, proteostasis and healthy ageing. We predict that this will redefine our understanding of the mechanisms that act downstream of HSF1 to promote healthy ageing and establish ubiquilin-1 as a central mediator of long-term health.

Summary

Advances in medicine, hygiene, social care and social awareness have resulted in an increase in the number of people living into late-life. While this is laudable, our failure to extend health span to a similar extent has resulted in a concomitant increase in the number of individuals suffering from age-associated morbidities or diseases. This is causing a significant emotional and financial strain on individuals, families, and communities that must be urgently corrected. Increasing the activity of the transcription factor HSF1, either pharmacologically or genetically, is known to suppress ageing across species by maintaining proteome integrity. However, the precise mechanisms that act downstream of HSF1 to protect the ageing proteome and promote healthy ageing are poorly understood. Addressing this is crucial, as it will allow us to develop therapeutics that enhance or mimic specific aspects of HSF1 activity, thereby promoting healthy ageing without causing unwanted side-effects. To realise this goal, we used the nematode worm Caenorhabditis elegans as a model system to screen for conserved genes that promote lifespan extension downstream of HSF1. Through this approach, we have discovered that the gene ubql-1 (UBQLN1 in humans) is crucial for HSF1-mediated lifespan extension in worms. Ubql-1 encodes the protein ubiquilin-1, a key player in the elimination of misfolded proteins from cells through endoplasmic reticulum (ER) associated degradation (ERAD). ERAD allows cells to remove damaged or misfolded proteins from the ER and degrade them via proteasomes, which reside in the cytosol and nucleus. Ubiquilin-1 has been shown to transport ER proteins through the cytosol and couple them with proteasomes for degradation in yeast, worms and humans. Furthermore, increased HSF1 activity is known to up-regulate levels of ubiquilin 1 in human cells, and levels of ubiquilin-1 have been found to decline with age in C. elegans and mice. These observations raise the possibility that increased HSF1 activity may safeguard the ageing proteome and prolong healthy tissue function by elevating ubiquilin-1 levels and enhancing the elimination of misfolded proteins from aged cells through ERAD. To investigate this, we will model the effects of increased HSF1 activity on ageing in C. elegans. Using a combination of genetic approaches, molecular biology techniques, and phenotypic assays, we will establish whether the ability of HSF1 to suppress ageing through ubiquilin-1 is observed in different tissue types (muscles, intestine, neurons), and whether increased ubiquilin-1 levels are sufficient to recapitulate the anti-ageing effects of increased HSF1 activity. In addition, we will determine if the pro-longevity effects of the HSF1-ubiquilin axis are mediated by increasing the degradation of misfolded proteins in aged cells through ERAD. Finally, we will complement our C. elegans-based experiments by defining the HSF-ubiquilin network in human cells. In contrast to C. elegans, humans possess two broadly expressed HSFs (HSF1 and HSF2) and three widely expressed ubiquilins (ubiquilin-1, 2, and 4). Therefore, we will ascertain whether HSF2 is required for maximal expression of ubiquilin-1 and determine if the expression of ubiquilin-2 and ubiquilin-4 is also regulated by HSFs in human cells. In addition, we will use siRNA to perturb ubiquilins, individually or in combination, and establish whether ubiquilin-2 and ubiquilin-4 cooperate with the HSF1-ubiquilin-1 axis to protect the ageing proteome in human cells. Together, these experiments will greatly expand our understanding of protein quality control pathways and redefine existing models of the relationship between HSF1 and longevity, thereby setting the stage for future work aimed at developing ubiquilin-1 activators or mimics that promote healthy ageing in humans.

Impact Summary

I anticipate that the research programme conducted during the period of this grant will have short and long-term impacts on academia, society, and the economy. This will be achieved through effects on academics working in a variety of fields, the general public, scientific policy makers, and the pharmaceutical industry. To maximize the potential impact of this work, I will proactively ensure that our findings, methodologies, and tools reach as broad an audience as possible. In addition, individuals associated with this grant will be trained to a high-standard and will develop skills that allow them to contribute to the UK knowledge base and economy by excelling within academia, or by pursuing job opportunities in alternative sectors. This work will benefit the academic research community by redefining our understanding of the mechanisms that act downstream of HSF1 to maintain protein homeostasis and promote healthy ageing. By establishing ubiquilin-1 as a new determinant of proteome integrity and long-term tissue health, we will create a new area of focus for individuals working on stress response pathways, protein quality control, protein conformational disease, and ageing. This knowledge will drive scientific advancement and enhance the knowledge economy of the UK through the establishment of a new area of research. It is my hope that the opportunity to work in this new area will attract international students and postdoctoral research associates to pursue novel research in the UK, thereby enhancing society intellectually and financially. Furthermore, this research will have an impact on international efforts to negate the rising incidence and cost of age-related disease. Finally, during the course of this grant, the UK knowledge base will be enhanced through the training of students and a postdoctoral research associate, thereby promoting passion, excellence, and integrity in the UK workforce. In addition to academia, this work will be of interest to privatecompanies based in the UK and abroad who are attempting to develop treatments for age-related protein conformational diseases (e.g. Alzheimer's disease, Parkinson's disease, cardiovascular disease, and cancer), as these are all associated with the aberrant regulation of protein homeostasis pathways with age. Any genes or pathways found to be crucial for the maintenance of protein homeostasis with age will therefore have the potential to broadly influence various disease states. As such, this work will highlight new targets to test and pursue for the suppression of various age-related diseases. I also expect this work to have an impact on the UK workforce. By training the individuals associated with this grant to adopt core philosophies of hard work, good organisation, and responsibility, and to acquire skills in analytical thinking, public speaking, and writing, this work will produce individuals that excel in academic or non-academic occupations. In addition, by effectively disseminating my research and promoting science to students and lay-audiences alike, we will enhance the general public's understanding of, and appreciation for, the scientific method, the importance of basic research using model organisms, and the biology behind ageing, all of which will contribute to the UKs knowledge and cultural base. Finally, in addition to the short-term benefits described, I am also hopeful that in the long-term, this work will impact decisions regarding future funding strategies and policy decisions surrounding research and education. While it will undoubtedly take a significant amount of time and effort for this to be realized, the work performed 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	X – not assigned to a current Research Topic
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

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