Programming of lifespan by insulin/IGF-like signalling in Drosophila.

果蝇中胰岛素/IGF 样信号传导的寿命编程。

• 批准号: BB/R014507/1
• 负责人: Nazif Alic
• 金额: $ 67.82万
• 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: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FR014507%2F1
• 关键词: Programming; lifespan; insulin; IGF; like

The proportion of older individuals is steadily increasing in our societies. Since age is the main risk factor for a number of debilitating, chronic diseases, this demographic change is resulting in ever-increasing human and socioeconomic costs. Understanding the biology of ageing is a key research priority because it has the potential to provide us with means to maintain health into old age. Early-life nutrition can impact subsequent health in older humans. While the existence of this phenomenon is supported by a wealth of epidemiological evidence and corroborated by direct experimentation in mammals, the mechanistic links between early nutritional environment and age-related phenotypes remain unclear. We have recently used the fruit fly Drosophila melanogaster to elucidate the mechanisms whereby the diet consumed by young adults influences their subsequent ageing. We found that a relatively short exposure to a diet rich in sugar activates insulin/IGF-like signalling (IIS) inhibiting the transcription factor dFOXO to programme adult lifespan, curtailing subsequent survival despite a dietary improvement. IIS pathway is present in all animals. It signals the animal's nutritional status to fine-tune its physiology. The importance of the IIS pathway is manifest in the role it plays in ageing: inhibition of IIS activity promotes longevity in all animals tested. At the same time, the pathway is a important determinant of human metabolic health. Our preliminary data show that modulating this pathway directly, independently of a dietary intervention, in early adulthood in Drosophila is sufficient to programme subsequent lifespan. Animal responses to nutrition are complex, simultaneously mediated by several signalling pathways in response to relative and absolute amounts of multiple dietary components. To start tackling this complexity, we propose to examine directly the molecular mechanisms whereby modulation of IIS in early adult life can shape subsequent longevity in Drosophila. This will provide us with a simpler, more tractable experimental system, focused on a single, relevant, nutrient-signalling pathway. In turn, the findings will start building a coherent and comprehensive picture of how early-life nutrition affects ageing. Our recent findings show that short-term modulation of IIS activity in just the fat body of the fly (equivalent to mammalian adipose and liver) is sufficient to change the animal's subsequent longevity. We will determine if there are other organs from which the long-term effects on ageing can be elicited. We will also determine which effectors of the pathway play a role. Work by us and others has revealed the most-likely mechanism for the long-term effects of IIS modulation on animal physiology: IIS activity appears able to change chromatin, which is the packaging of the animal's genetic material, with long-term consequences for gene expression. We will determine the impact of IIS modulation on chromatin structure and long-term gene expression in the relevant adult tissues.We and other groups have established that several enzymes capable of modifying or re-organising chromatin are engaged by the IIS pathway. We will examine whether any of these genes are mediating the long-term effects of IIS activity.In summary, the project will elucidate how relatively short-term changes in the levels of IIS can cause long-term effects in an adult animal, in vivo. This will help us understand how early-life nutrition can have an impact on human ageing. This knowledge, in the long-term, has the potential to provide us with means to ensure human health and wellbeing throughout the life course.

在我们的社会中，老年人的比例正在稳步增加。由于年龄是多种使人衰弱的慢性疾病的主要危险因素，因此这种人口变化导致人类和社会经济成本不断增加。了解衰老的生物学是一个关键的研究优先事项，因为它有可能为我们提供维持健康状况的手段。早期生活营养可能会影响年龄较大的人的后续健康。尽管这种现象的存在得到了大量流行病学证据的支持，并通过哺乳动物的直接实验证实了这种现象，但早期营养环境与年龄相关表型之间的机械联系仍然不清楚。我们最近使用了果蝇果蝇Melanogaster来阐明年轻人消耗的饮食会影响其随后的衰老机制。我们发现，富含糖的饮食的相对较短的暴露会激活胰岛素/IGF样信号传导（IIS），抑制了转录因子DFOXO为成人寿命编程，尽管饮食有所改善，但仍会减少随后的生存。所有动物中都存在IIS途径。它标志着动物的营养状况，以微调其生理学。 IIS途径的重要性体现在其在衰老中所扮演的作用：抑制IIS活性促进了所有测试的动物的寿命。同时，该途径是人类代谢健康的重要决定因素。我们的初步数据表明，在果蝇的成年初期，直接与饮食干预无关调节这一途径足以编程随后的寿命。动物对营养的反应是复杂的，同时由几种信号通路介导，以响应相对和绝对量的多种饮食成分。为了开始解决这种复杂性，我们建议直接检查分子机制，从而在成年早期生命中调节IIS可以塑造果蝇的后续寿命。这将为我们提供一个更简单，更具处理性的实验系统，重点是单个相关的，营养的信号途径。反过来，这些发现将开始建立一个连贯而全面的描述，说明营养如何影响衰老。我们最近的发现表明，仅在苍蝇的脂肪体（相当于哺乳动物脂肪和肝脏）中对IIS活性的短期调节足以改变动物随后的寿命。我们将确定是否有其他器官可以从中引起对衰老的长期影响。我们还将确定该路径的哪些效应子起着作用。我们和其他人的工作揭示了IIS调节对动物生理学的长期影响的最明显的机制：IIS活性似乎能够改变染色质，这是动物遗传物质的包装，对基因表达产生了长期后果。我们将确定IIS调节对相关成年组织中染色质结构和长期基因表达的影响。我们和其他组已经确定了几种能够修饰或重新组织染色质的酶由IIS途径参与。我们将研究这些基因中的任何一个是否正在介导IIS活动的长期影响。总而言之，该项目将阐明IIS水平相对短期变化如何在Vivo中对成年动物产生长期影响。这将有助于我们了解早期的营养如何对人类衰老产生影响。从长远来看，这些知识有可能为我们提供确保人类健康和福祉的手段。

项目成果

In silico identification of Drosophila melanogaster genes encoding RNA polymerase subunits.

• DOI: 10.17912/micropub.biology.000320
• 发表时间: 2020-10-20
• 期刊: microPublication biology
• 作者: Marygold SJ;Alic N;Gilmour DS;Grewal SS
• 通讯作者: Grewal SS

RNA Polymerase III, Ageing and Longevity.

• DOI: 10.3389/fgene.2021.705122
• 发表时间: 2021
• 期刊: Frontiers in genetics
• 影响因子: 3.7
• 作者: Kulaberoglu Y;Malik Y;Borland G;Selman C;Alic N;Tullet JMA
• 通讯作者: Tullet JMA

The neuronal receptor tyrosine kinase Alk is a target for longevity.

神经元受体酪氨酸激酶 Alk 是长寿的目标。

• DOI: 10.1111/acel.13137
• 发表时间: 2020
• 期刊: Aging cell
• 影响因子: 7.8
• 作者: Woodling NS

Mendelian randomization analyses implicate biogenesis of translation machinery in human aging.

• DOI: 10.1101/gr.275636.121
• 发表时间: 2022-03
• 期刊: Genome research
• 影响因子: 7
• 作者: Javidnia S;Cranwell S;Mueller SH;Selman C;Tullet JMA;Kuchenbaecker K;Alic N
• 通讯作者: Alic N

Transcriptional memory of dFOXO activation in youth curtails later-life mortality through chromatin remodeling and Xbp1.

• DOI: 10.1038/s43587-022-00312-x
• 发表时间: 2022-12
• 期刊: Nature aging
• 作者: Martínez Corrales G;Li M;Svermova T;Goncalves A;Voicu D;Dobson AJ;Southall TD;Alic N
• 通讯作者: Alic N