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

主题：促进健康的生物科学饮食干预可延缓衰老的发现，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。无营养的饮食限制（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替代品需要更好地理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只是减缓新陈代谢，直接导致寿命延长。值得注意的是，我们最近发现，酵母是一种典型的衰老模式生物，对DR反应良好，只需改变而不限制饮食，就能显著提高健康寿命，以至于在正常年龄死亡之前，细胞实际上会随着年龄的增长而变得更健康！这意味着寿命和健康是可以分开的，所以老龄化不可能是我们文化上认为的不可避免的走向死亡的衰退。事实上，DR延长寿命需要染色质修饰酶，至少在低等真核生物中是这样，这表明DR引发了一种表观遗传重编程事件，导致基因表达模式的改变，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本质，以及它们如何对衰老细胞产生积极影响。多种信号通路介导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尚未得到广泛探索。因此，围绕长期DR作用的机制存在相当大的争论，而寿命本身是一个不准确和多效性的报告这一事实并没有帮助。通过转录组学直接读取数据，将有助于解剖多个重叠的表观遗传机制，这些机制清楚地增强了DR。DR以非常相似的方式改变了真核生物的寿命，这些真核生物已经分化了数百万年，允许使用遗传功能强大的模式生物，如酵母，来阐明潜在的机制。我们的实验室已经开发了改进的方法，用于老化酵母的转录组和染色质分析，并发现了组蛋白修饰对老化转录组的明显影响。该项目将初步确定在各种DR方案下与衰老相关的转录组变化。然后，它将使用一系列组蛋白修饰突变体，包括乙酰转移酶、甲基转移酶和去乙酰化酶，研究组蛋白修饰在介导DR的短期和长期后果中的重要性，这些突变体已知在基因表达调节或衰老表型中起作用。受损dr介导的基因表达变化的选定突变体将用于评估短期食物利用与长寿之间的适应性权衡。最后，在这些研究的基础上，设计实验来重建dr介导的长期表观遗传变化：酵母遗传学和老化细胞纯化；RNAseq， ChIPseq和生物信息学。ENWW：数据驱动生物学

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