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

在我们的社会中，老年人的比例正在增加。对许多人来说，老龄化意味着健康和福祉的恶化，身体和精神能力的丧失，以及对多种疾病的易感性增加。因此，我们面临着日益增加的老龄化带来的人类和社会经济代价，这些代价亟待解决。几个世纪以来，我们一直将衰老理解为生活中不可改变的事实。当我们发现某些干预措施实际上可以改善老年健康时，我们大吃一惊。现在，人们投入了大量的科学努力来了解这些干预措施是如何起作用的，并利用这些知识来改善人类的健康和老年福祉。下调指示营养物质存在的信号，如众所周知的激素、胰岛素，可以改善蠕虫、果蝇和老鼠等不同生物体的终身健康。人们越来越意识到，类似的干预措施可能会在人类身上奏效。然而，下调这些关键的营养感知机制往往会产生重大的有害影响，使人类无法使用它们。例如，不能产生或对胰岛素做出反应会导致糖尿病。我们现在需要了解如何在不造成伤害的情况下获取这些干预措施的好处。许多延长健康寿命的干预措施通过改变生物体DNA中携带的遗传信息的使用方式来发挥作用。它们经常特别地改变遗传信息表达的第一步，在那里DNA密码被转录成RNA分子。转录调控是由转录因子完成的，其中一种被称为FoxO的因子能够有力地改善所有被检查的生物体的终身健康和福祉。事实上，编码FoxO的基因的某些变体也存在于异常长寿的人类中，这是导致他们长寿的原因之一。然而，与其他抗衰老干预措施类似，激活FoxO可能是有害的。因此，FoxO提供了一个很好的模型来建立区分这两个相反结果的分子事件。我最近发现，FoxO的有害作用依赖于果蝇中的另外两个转录因子PNT和AOP。单独激活FOXO是有益的，但如果同时激活PNT，则会变得有害。PNT和AOP正在进行一场拔河比赛，AOP通过对抗PNT来促进FoxO的有益效果。因此，老年的健康并不完全由FoxO的活动决定，而是FoxO和PNT/AOP之间协商的问题。了解FoxO和PNT/AOP交换的复杂性将定义区分FoxO激活的好结果和坏结果的分子事件。我建议使用遗传和生化方法来询问PNT如何将FoxO激活的效果从好到坏。我将首先研究FoxO和PNT/AOP在DNA转录调控部分的物理和功能相互作用，无论是在试管中还是在完整的细胞中。其次，我将确定PNT如何改变FoxO在成年果蝇相关器官中的基因调控模式。这将对与FoxO激活的有害影响相关的基因进行分类，使其受益。PNT和AOP是一个基因家族的成员--一组相互关联并可能执行相似功能的基因。我将研究这个家族的所有成员是否都在一个苍蝇器官小组中显示出与FoxO类似的相互作用，以确定这些发现是否更适用于更广泛的应用。我提议的研究是多方面的，不同的方面将汇聚在一起，让我们在分子水平上清楚地了解哪些事件区分了FoxO激活的有利影响和潜在的有害结果。这些知识将在制定可用于改善人类老年健康和福祉的战略时发挥重要作用，而不会产生不必要的有害后果。

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.