Integrating cellular space and time: inteplays between subcellular organisation and lifespan

在世界各地，由于老龄化，人口变得越来越虚弱，百岁老人是英国增长最快的年龄段。人口老龄化带来了严重的个人、医疗、经济和社会成本。衰老是一个复杂的过程，取决于过多的遗传和环境因素。营养在衰老过程和调节寿命方面发挥着重要作用；例如，限制卡路里摄入延长了所有受试生物体的寿命。最近的数据表明，低卡路里摄入量的有益影响可以通过限制饮食(限制而不是营养不良)，更具体地说，限制蛋白质来概括。细胞通过感受器蛋白感知营养环境。其中一种众所周知的传感器是一种被称为雷帕霉素机械靶点(MTOR)的酶。MTOR存在于所有含有细胞核的细胞中，并在很大程度上介导了饮食限制的影响：高饮食摄入量激活了mTOR，对衰老有不利影响，而低饮食摄入量降低了mTOR活性，对寿命有好处。降低mTOR活性的突变在基因表达、细胞代谢和寿命方面类似于饮食或蛋白质限制。重要的是，mTOR通路直接与年龄相关的疾病和病理有关，如癌症、慢性炎症、心脏病、神经退行性变和糖尿病。毫无疑问，这种酶在理解衰老的基本机制中起着核心作用。此外，mTOR或由mTOR控制的蛋白质可以成为预防或改善严重疾病的药物靶点。科学家们深入研究了营养可获得性、mTOR、寿命和疾病之间的关系，重点关注相关过程中涉及的基因。这些研究表明，mTOR控制着细胞内产生的蛋白质的数量和质量，以及材料如何回收(这一过程被称为“自噬”)。更多的蛋白质生产和更低的回收效率是有害的。我们和其他人已经发现了这种联系，并为治疗年龄相关疾病的药物开发提供了额外的潜在靶点。然而，我们实验室的最新结果表明，老化对细胞的外观以及细胞隔间、蛋白质或氨基酸在细胞空间内的排列方式有深远的影响。此外，我们还发现，这种空间排列的差异会影响细胞的健康和寿命。来自其他组织的其他报告表明，细胞结构的变化与疾病有关。然而，细胞空间和寿命之间的联系和工作原理还不是很清楚。我们在三个机构内组成了一个实验室联盟，由具有遗传学、分子生物学、显微镜和计算生物学(包括机器学习(人工智能)方法)专业知识的科学家组成。我们将分析衰老和寿命(称为‘细胞时间’)如何影响细胞外观以及蛋白质和氨基酸的分布(称为‘细胞空间’)。我们的计划还将允许系统地研究细胞内结构和分子的局部化如何影响寿命、老年率和细胞健康。我们已经建立了从酵母到人类等各种生物的细胞系统，以揭示进化上保守的机制，这些机制可能也在包括人类在内的多细胞生物中发挥作用。鉴于mTOR在衰老以及癌症和神经变性等疾病中的直接作用，了解细胞拓扑和衰老之间的关系将提供新的基因和蛋白质靶点，并为干预与年龄相关的疾病提供方向。

Throughout the world, populations become increasingly frail due to ageing with centenarians being the fastest growing age group in the UK. The ageing demographics bring serious personal, medical, financial and social costs. Ageing is a complex process and depends on a plethora of genetic and environmental factors. Nutrition plays an important role in the ageing process and the regulation of lifespan; for example, caloric restriction extends lifespan in all organisms tested. Recent data have shown that the beneficial effects of lower caloric intake can be recapitulated by dietary restriction (restriction without malnutrition) and more specifically, protein restriction. Cells perceive nutritional environment via sensor proteins. One of these well-known sensors is an enzyme known as the mechanistic Target of Rapamycin (mTOR). mTOR exists in all cells containing a nucleus and largely mediates the effects of dietary restriction: high dietary intake activates mTOR with detrimental ageing effects while lower dietary intake decreases mTOR activity with beneficial effects in lifespan. Mutations that lower mTOR activity resemble dietary or protein restriction in terms of gene expression, cellular metabolism and lifespan. Importantly, the mTOR pathway is directly implicated in age-related diseases and pathologies such as cancer, chronic inflammation, heart disease, neurodegeneration and diabetes. Without any doubt this enzyme is central in understanding basic mechanisms of ageing. In addition, mTOR or proteins that are controlled by mTOR can be a drug target to prevent or ameliorate serious diseases.Scientists have intensely studied the connections between nutrient availability, mTOR, length of life and disease focusing on the genes implicated in related processes. These studies showed that mTOR controls the amount and quality of proteins produced within the cells as well as how materials are recycled (a process known as 'autophagy'). More protein production and less effective recycling is detrimental. We and others have found such connections and have provided additional potential targets for drug development against age-related diseases. Nevertheless, recent results in our laboratory have shown that ageing has profound effects on the appearance of the cells and how cell compartments, proteins or amino acids are ordered within the space of the cell. Additionally, we also find that such differences in space arrangements affect the health and the lifespan of the cells. Other reports from other groups indicate that changes in cell architecture are linked to disease. However, the connections and the workings between cell space and lifespan are not well understood. We have formed a consortium of laboratories within three institutions comprised from scientists with expertise in genetics, molecular biology, microscopy and computational biology including machine learning (artificial intelligence) approaches. We will analyse how ageing and lifespan (termed 'cellular time') affects cellular appearance and distribution of proteins and amino acids (termed 'cellular space'). Our plan will also allow to systematically study how the localisation of structures and molecules within the cell affect lifespan, ageing rates and cellular health. We have established cell systems from organisms as diverse as yeast and human to reveal evolutionarily conserved mechanisms that are likely to also function in multicellular organisms, including humans. Given the direct implication of mTOR in ageing and diseases such as cancer and neurodegeneration, understanding the relationships between cellular topology and ageing will provide new gene and protein targets as well as directions for interventions on age-related diseases.