Identification of genetic factors affecting cellular ageing in fission yeast

随着年龄的增长，我们逐渐在身体的不同层次上积累环境和内在产生的缺陷：从DNA（突变）、蛋白质（聚集）、细胞器（线粒体功能障碍）到细胞（癌症）和器官（心力衰竭）的错误。衰老是西方世界大多数人类疾病的最大风险因素，包括阿尔茨海默氏症和帕金森氏症等进行性疾病，发病率可变的癌症等疾病，以及心脏病和中风等灾难性系统故障。虽然对特定的衰老相关疾病过程的研究长期以来一直是生物医学和生物学研究的主要焦点，但越来越多的人认识到分析正常衰老过程本身作为问题的重要组成部分，以及探索减缓或逆转其影响的方法的重要性。衰老是一个多因素的问题，它可以被看作是时间的蹂躏和生物体生存的有害环境的不可避免的特征。然而，最近的发现表明，通过相对简单的干预，衰老可以以戏剧性的方式得到改变。例如，单基因突变和饮食限制可以延缓衰老，并普遍改善实验动物晚年的健康状况。此外，与衰老有关的途径在进化中是保守的，其组成部分的遗传变异与人类寿命的差异有关。然而，老龄化研究的一个核心挑战仍然是梳理出一幅决定寿命的遗传因素和机制的全面而统一的图景。我们计划利用裂变酵母作为一种模式生物来推进我们对衰老的复杂过程的理解。值得注意的是，现在已知酵母和人类的许多这些过程是相似的。酵母细胞在有限的营养条件下进入静止不分裂状态，这种状态下的寿命取决于遗传和环境因素。这种静止的酵母细胞为分析影响衰老和寿命的基本过程提供了一个有价值的系统。我们将分析基因和蛋白质的全局调控在衰老过程中是如何被修改的，以及任何变化如何影响寿命。我们还将利用所有可行的基因敲除突变体的集合来系统地识别那些导致寿命延长或缩短的基因。我们将进一步研究来自不同地理位置的野生酵母菌株的寿命如何变化，以及这种变化是否与基因表达的变化有关。最后，我们将整合这些互补的全球数据集，并追踪最有希望的发现，以揭示特定遗传因素在细胞衰老和寿命中的特定作用。重要的是，这项研究将为了解与人类衰老有关的遗传因素提供一个有价值的平台，最终开发出减缓衰老的干预措施，从而预防或延缓许多与年龄相关的疾病。

With age, we gradually accumulate both environmentally and intrinsically generated defects at different levels in our bodies: from errors in DNA (mutations), proteins (aggregates), organelles (mitochondrial dysfunction) to cells (cancer) and organs (heart failure). Ageing is the largest risk factor for the majority of human diseases in the Western world, including progressive diseases such as Alzheimer's and Parkinson's, diseases like cancer that show variable rates of onset, and catastrophic systems failures such as heart-attack and stroke. While the study of specific ageing-related disease processes has long been a major focus of biomedical and biological research, there is a growing realisation of the importance of analyzing the normal ageing process itself as an essential part of the problem, and of exploring ways to slow or reverse its effects. Ageing is a multi-factorial problem that can be seen as an inevitable feature of the ravages of time and the harmful environments in which organisms live. Recent discoveries, however, demonstrate that ageing can be modified in dramatic ways by relatively simple interventions. For example, single gene mutations and dietary restriction can delay ageing and provide a universal improvement in health late in the life of laboratory animals. Moreover, the pathways involved in ageing are conserved in evolution, and genetic variants in their components are associated with differences in lifespan in humans. A central challenge of ageing research, however, remains to tease out a comprehensive and unified picture of the genetic factors and mechanisms determining longevity. We plan to utilize fission yeast as a model organism to advance our understanding of complex processes with fundamental importance for ageing. Remarkably, many of these processes are now known to be similar from yeast to human. Yeast cells enter a quiescent, non-dividing state under limiting nutrients, and the lifespan in this state depends on both genetic and environmental factors. Such quiescent yeast cells provide a valuable system to analyze basic processes affecting ageing and longevity. We will analyze how the global regulation of genes and proteins is modified during ageing, and how any changes might affect longevity. We will also exploit a collection of all viable gene knock-out mutants to systematically identify those genes that lead to longer or shorter lifespan. We will further examine how lifespan varies among wild yeast strains from different geographical locations, and whether this variation goes with changes in gene expression. Finally, we will integrate these complementary global data sets and follow-up the most promising findings to uncover particular roles of specific genetic factors in cellular ageing and longevity. Importantly, this research will provide a valuable platform to understand the genetic factors involved in ageing in humans, to eventually develop interventions that slow ageing and thus prevent or delay the numerous age-associated diseases.