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The diet dilemma: can you eat what you like and live happily ever after?

饮食困境：你能吃自己喜欢的东西并从此过上幸福的生活吗？

基本信息

批准号：
1947502
负责人：
金额：
--
依托单位：
University of Cambridge
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=studentship-1947502
关键词：
diet dilemma eat what like

项目摘要

Theme: Bioscience for HealthThe discovery that ageing can be slowed by dietary intervention raises the prospect of extending lifespan and healthspan through lifestyle change or long-term drug treatment. Dietary restriction (DR) without malnutrition has beneficial health effects for model organisms as well as humans but forms an unattractive lifestyle choice. Finding more palatable alternatives to DR requires a better understanding of why and how organisms respond to food. It is widely (and mistakenly) assumed that DR simply slows down metabolism leading directly to an increase in lifespan. Remarkably, we have recently shown that in yeast, a classic model organism for ageing that responds well to DR, simply changing but not restricting diet dramatically improves health-span, such that cells actually became fitter with age prior to death at a normal age! This means that life-span and health can be separated, so ageing cannot be the inevitable decline towards death that we culturally perceive. In fact lifespan extension by DR requires chromatin modifying enzymes, at least in lower eukaryotes, suggesting that DR instigates an epigenetic reprogramming event, leading to altered gene expression patterns that increase lifespan and promote healthy ageing. We aim to determine the nature of these gene expression changes and how they positively impact the ageing cell.Various signalling pathways mediate the effects of DR, however, the epigenetic changes associated with DR that likely mediate long-term consequences are vastly unexplored. In consequence, considerable debate surrounds themechanism of long term DR action, not helped by the fact that lifespan itself is an inaccurate and pleotropic reporter. Using a direct readout through transcriptomics should facilitate dissection of the multiple overlapping epigeneticmechanisms that clearly potentiate DR. DR alters lifespan in remarkably similar ways across eukaryotes diverged by millions of years, allowing the use of genetically powerful model organisms such as yeast to elucidate underlyingmechanisms.Our lab has developed improved methods for transcriptomic and chromatin analysis in ageing yeast, and discovered clear impacts of histone modification on the ageing transcriptome. This project will initially define the transcriptomic changes associated with ageing under various DR regimens. It will then examine the importance of histone modifications in mediating short and long-term consequences of DR using a range of histone modification mutants including acetyltransferases, methyltransferases and deacetylases with known roles in gene expression regulation or ageing phenotypes. Selected mutants that impair DR-mediated gene expression change will be used to assess the fitness trade-off between short-term food utilization and longevity. Finally, based on these studies, experiments will be designed to reconstitute the long term epigenetic changes mediated by DR.Techniques: Yeast genetics and ageing cell purification; RNAseq, ChIPseq and bioinformatics.ENWW: Data driven biology

布景主题：健康生物科学通过饮食干预可以减缓衰老的发现，提高了通过改变生活方式或长期药物治疗延长寿命和健康寿命的前景。没有营养不良的饮食限制（DR）对模式生物和人类都有有益的健康影响，但形成了一种没有吸引力的生活方式选择。寻找更可口的DR替代品需要更好地了解生物体对食物的反应原因和方式。人们普遍（错误地）认为DR只是减缓了新陈代谢，直接导致寿命延长。值得注意的是，我们最近已经证明，在酵母中，一种对DR反应良好的经典衰老模型生物，简单地改变但不限制饮食可以显着改善健康寿命，这样细胞在正常年龄死亡之前实际上变得更适合年龄！这意味着寿命和健康是可以分开的，所以衰老不是我们文化上认为的不可避免的走向死亡。事实上，通过DR延长寿命需要染色质修饰酶，至少在低等真核生物中，这表明DR引发了表观遗传重编程事件，导致改变基因表达模式，从而延长寿命并促进健康衰老。我们的目标是确定这些基因表达变化的性质，以及它们如何积极影响衰老细胞。各种信号通路介导DR的影响，然而，与DR相关的可能介导长期后果的表观遗传变化还远远未被探索。因此，相当多的争论围绕着长期DR作用的机制，而不是由寿命本身是一个不准确的和多向性的报告。通过转录组学的直接读出应该有助于解剖明显增强DR的多种重叠的表观遗传机制。DR以非常相似的方式改变了数百万年来分化的真核生物的寿命，允许使用遗传上强大的模式生物如酵母来阐明潜在的机制。我们的实验室已经开发了用于老化酵母的转录组学和染色质分析的改进方法，并发现了组蛋白修饰对衰老转录组的明显影响。该项目将初步确定在各种DR方案下与衰老相关的转录组学变化。然后，它将检查组蛋白修饰的重要性，在调解短期和长期的DR后果使用一系列的组蛋白修饰突变体，包括乙酰转移酶，甲基转移酶和脱乙酰酶与已知的作用，在基因表达调控或老化表型。选定的突变体，损害DR介导的基因表达的变化将被用来评估短期的食物利用和寿命之间的健身权衡。最后，基于这些研究，将设计实验来重建DR介导的长期表观遗传变化。技术：酵母遗传学和衰老细胞纯化; RNAseq，ChIPseq和生物信息学。ENWW：数据驱动的生物学