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

主题：生物科学促进健康通过饮食干预可以延缓衰老的发现增加了通过改变生活方式或长期药物治疗来延长寿命和健康寿命的前景。没有营养不良的饮食限制(DR)对模式生物和人类的健康都有好处，但形成了一种不具吸引力的生活方式选择。寻找更令人满意的DR替代品需要更好地理解生物为什么以及如何对食物做出反应。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，我们最近已经表明，在酵母中，一种对DR反应良好的经典衰老模式生物，简单地改变但不限制饮食显著地改善了健康跨度，以至于细胞实际上在正常年龄死亡之前随着年龄的增长变得更适合！这意味着寿命和健康是可以分开的，所以衰老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引发了表观遗传重新编程事件，导致基因表达模式改变，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性质以及它们如何对老化的细胞产生积极影响。各种信号通路介导DR的影响，然而，与DR相关的表观遗传变化可能中介长期后果，这一点还远未被探索。因此，围绕长期DR作用机制的相当大的争论，无助于LIFESPAN本身是一个不准确和多变的记者这一事实。使用通过转录学的直接读数应该有助于剖析多个重叠的表观遗传机制，这些机制明显增强了DR博士在数百万年的真核生物中以非常相似的方式改变寿命，从而允许使用强大的遗传模式生物，如酵母来阐明潜在的机制。我们的实验室已经开发出在老化的酵母中进行转录切割和染色质分析的改进方法，并发现组蛋白修饰对老化的转录组的明显影响。该项目将初步确定在不同的DR方案下与衰老相关的转录变化。然后，它将使用一系列组蛋白修饰突变，包括乙酰基转移酶、甲基转移酶和去乙酰基酶，研究组蛋白修饰在介导DR短期和长期后果中的重要性，这些突变在基因表达调控或衰老表型中具有已知的作用。选定的破坏DR介导的基因表达变化的突变体将被用来评估短期食物利用和寿命之间的适应性权衡。最后，在这些研究的基础上，将设计实验来重建由DR介导的长期表观遗传变化。技术：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