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

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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.