Redefining the mechanisms that promote healthy ageing downstream of HSF1

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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.