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

区分 FoxO 对果蝇衰老的有益和有害影响：FoxO 和 ETS 转录因子之间的相互作用。

• 批准号: BB/M029093/1
• 负责人: Nazif Alic
• 金额: $ 53.49万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FM029093%2F1
• 关键词: Distinguishing; between; beneficial; detrimental; effects

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.

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、身心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人力和社会经济成本，迫切需要加以解决。几个世纪以来，我们一直认为衰老是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人的健康时，这是一个很大的惊喜。科学家们现在正致力于了解这些干预措施是如何发挥作用的，并利用这些知识来改善人类的健康和老年生活。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、果蝇和小鼠等不同生物的终身健康。人们越来越意识到类似的干预措施可能对人类有效。然而，这些关键的营养感应机制的下调通常具有重大的不利影响，使其无法用于人类。例如，无法产生或对胰岛素产生反应会导致糖尿病。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。它们通常特异性地改变遗传信息表达的第一步，其中DNA代码被转录成RNA分子。转录的调节是由转录因子进行的，其中一种称为FoxO的因子能够有力地改善所有受检生物的终身健康和福祉。事实上，编码FoxO的基因的某些变体也存在于特别长寿的人类中，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这两种相反结果的分子事件。我最近发现，FoxO的有害影响取决于果蝇中另外两种称为Pnt和Aop的转录因子。单独激活FoxO是有益的，但如果同时激活Pnt则变得有害。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，老年人的健康不仅仅取决于FoxO活性，而是FoxO和Pnt/Aop之间协商的问题。理解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物化学方法来查询Pnt如何使FoxO激活的效果从好到坏。首先，我将在试管和完整细胞中研究FoxO和Pnt/Aop在DNA转录调控部分的物理和功能相互作用。其次，我将确定Pnt如何改变成年果蝇相关器官中FoxO的基因调控模式。这将对那些与FoxO激活的有害影响相关的有益基因进行分类。Pnt和Aop是一个基因家族的成员-一组相关的基因，可能执行类似的功能。我将研究是否这个家族的所有成员都在一组果蝇器官中表现出与FoxO类似的相互作用，以确定这些发现是否更广泛地适用。我提出的研究是多方面的，不同的方面将汇集在一起，让我们在分子水平上清楚地了解FoxO激活的有益影响与潜在的有害结果。这些知识对于制定可用于改善老年人健康和福祉的战略非常重要，而不会产生不必要的有害后果。

项目成果

Sexually dimorphic effects of dietary sugar on lifespan, feeding and starvation resistance in Drosophila.

• DOI: 10.18632/aging.101335
• 发表时间: 2017-12-04
• 期刊: Aging
• 作者: Chandegra B;Tang JLY;Chi H;Alic N
• 通讯作者: Alic N

Of FOXes and Forgetful Worms.

狐狸和健忘的蠕虫。

• DOI: 10.1016/j.cmet.2016.02.013
• 发表时间: 2016
• 期刊: Cell metabolism
• 影响因子: 29
• 作者: Alic N

Nutritional Programming of Lifespan by FOXO Inhibition on Sugar-Rich Diets.

Foxo抑制糖饮食的寿命的营养编程。

• DOI: 10.1016/j.celrep.2016.12.029
• 发表时间: 2017-01-10
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Dobson AJ;Ezcurra M;Flanagan CE;Summerfield AC;Piper MDW;Gems D;Alic N
• 通讯作者: Alic N

A family of transcription factors that limit lifespan: ETS factors have conserved roles in longevity

限制寿命的转录因子家族：ETS 因子在长寿中发挥保守作用

• DOI: 10.1101/438879
• 发表时间: 2018
• 作者: Dobson A

Intestinal Fork Head Regulates Nutrient Absorption and Promotes Longevity.

• DOI: 10.1016/j.celrep.2017.09.042
• 发表时间: 2017-10-17
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Bolukbasi E;Khericha M;Regan JC;Ivanov DK;Adcott J;Dyson MC;Nespital T;Thornton JM;Alic N;Partridge L
• 通讯作者: Partridge L