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.