Distinguishing between beneficial and detrimental effects of FoxO in Drosophila ageing: interactions between FoxO and ETS transcription factors.

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The proportion of aged individuals is increasing in our society. For many, ageing means deteriorating health and wellbeing, loss of physical and mental abilities and increased susceptibility to numerous diseases. We are thus exposed to ever-increasing human and socioeconomic costs of ageing that need to be urgently addressed. For centuries we have understood ageing as an immutable fact of life. It came as a big surprise when we discovered that certain interventions can actually improve health in old age. Scientific effort is now invested into understanding how these interventions act and harnessing that knowledge to improve human health and wellbeing into old age.Down-regulation of the signals that indicate the presence of nutrients, such as the well-known hormone, insulin, improve life-long health in organisms as different as worms, fruit flies and mice. There is a growing awareness that similar interventions may work in humans. However, down-regulation of these pivotal nutrient sensing mechanisms often has major detrimental effects precluding them from human use. For example, inability to produce or respond to insulin results in diabetes. We now need to understand how to capture the benefits of these interventions without causing harm. Numerous interventions that extend healthy lifespan act by changing how the genetic information, carried in the organism's DNA, is used. They often specifically alter the first step in the expression of genetic information where the DNA code is transcribed into an RNA molecule. The regulation of transcription is performed by transcription factors and one such factor, called FoxO, has the ability to robustly improve life-long health and well being in all organisms examined. Indeed, certain variants of the gene encoding FoxO are also present in exceptionally long-lived humans, contributing to their longevity. However, similar to other anti-ageing interventions, FoxO activation can be detrimental. Hence, FoxO provides a good model to establish the molecular events that differentiate the two opposing outcomes.I have recently discovered that the detrimental effects of FoxO are dependent on two other transcription factors called Pnt and Aop in the fruit fly. FoxO activated alone is beneficial but becomes detrimental if Pnt is activated as the same time. Pnt and Aop are engaged in a tug of war and Aop fosters beneficial effects of FoxO by counter-acting Pnt. Hence, health in old age is not solely determined by FoxO activity but is a matter negotiated between FoxO and Pnt/Aop. Understanding the intricacies of FoxO and Pnt/Aop exchange will define the molecular events that distinguish the good from the bad outcomes of FoxO activation.I propose to use genetic and biochemical approaches to query how Pnt swings the effects of FoxO activation from good to bad. I will firstly examine the physical and functional interactions between FoxO and Pnt/Aop on the parts of DNA from which transcription is regulated, both in a test tube and in an intact cell. Secondly, I will determine how Pnt alters the pattern of gene regulation by FoxO in the relevant organs of the adult fruit fly. This will triage the genes that underlie the beneficial from those associated with the detrimental effects of FoxO activation. Pnt and Aop are members of a gene family - a set of genes that are related and likely perform similar functions. I will examine whether all members of this family show similar interactions with FoxO in a panel of fly organs, to determine whether the findings are more broadly applicable.The study I am proposing is multifaceted, and the different aspect will converge to give us a clear understanding of the events, at a molecular scale, that differentiate the beneficial effects of FoxO activation from the potential detrimental outcomes. This knowledge will be important in devising strategies that can be used to improve human health and well being in old age, without unwanted, detrimental consequences.