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

我们社会中老年人的比例正在增加。对于许多人来说，衰老意味着健康和福祉恶化、身心能力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力和社会经济成本，亟待解决。几个世纪以来，我们一直将衰老视为生命中不可改变的事实。当我们发现某些干预措施实际上可以改善老年健康时，我们感到非常惊讶。现在，科学努力致力于了解这些干预措施如何发挥作用，并利用这些知识来改善人类老年健康和福祉。下调指示营养素存在的信号，例如众所周知的激素、胰岛素，可以改善蠕虫、果蝇和小鼠等不同生物体的终生健康。人们越来越意识到类似的干预措施可能对人类有效。然而，这些关键营养传感机制的下调通常会产生重大有害影响，导致人类无法使用它们。例如，无法产生胰岛素或无法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得这些干预措施的好处。许多延长健康寿命的干预措施都是通过改变生物体 DNA 中携带的遗传信息的使用方式来发挥作用。它们经常专门改变遗传信息表达的第一步，即 DNA 代码被转录为 RNA 分子。转录的调节是由转录因子执行的，其中一种称为 FoxO 的因子能够强有力地改善所有受检生物体的终生健康和福祉。事实上，编码 FoxO 的基因的某些变体也存在于特别长寿的人类中，从而有助于他们的长寿。然而，与其他抗衰老干预措施类似，FoxO 激活可能是有害的。因此，FoxO 提供了一个很好的模型来建立区分两种相反结果的分子事件。我最近发现 FoxO 的有害影响依赖于果蝇中的另外两种转录因子，即 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 正在进行拉锯战，Aop 通过反作用 Pnt 来促进 FoxO 的有益效果。因此，老年健康不仅仅取决于 FoxO 活动，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 激活的好与坏结果的分子事件。我建议使用遗传和生化方法来探究 Pnt 如何将 FoxO 激活的影响从好转为坏。我将首先在试管和完整细胞中检查 FoxO 和 Pnt/Aop 之间在转录受调节的 DNA 部分上的物理和功能相互作用。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。这将对那些与 FoxO 激活的有害影响相关的基因进行分类。 Pnt 和 Aop 是基因家族的成员 - 一组相关且可能执行相似功能的基因。我将检查这个家族的所有成员是否在一组果蝇器官中表现出与 FoxO 相似的相互作用，以确定这些发现是否更广泛适用。我提议的研究是多方面的，不同的方面将汇聚在一起，让我们在分子尺度上清楚地了解这些事件，从而区分 FoxO 激活的有益影响和潜在的有害结果。这些知识对于制定可用于改善人类老年健康和福祉且不会产生不良后果的策略非常重要。

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.