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

在世界范围内，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组。人口老龄化带来了严重的个人、医疗、财务和社会成本。衰老是一个复杂的过程，取决于大量的遗传和环境因素。营养在衰老过程和寿命调节中起着重要作用；例如，热量限制延长了所有被测试生物的寿命。最近的数据表明，低热量摄入的有益影响可以通过饮食限制（没有营养不良的限制），更具体地说，是蛋白质限制来概括。细胞通过感应蛋白感知营养环境。这些众所周知的传感器之一是一种被称为雷帕霉素机械靶标（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饮食限制的影响：高饮食摄入激活mTOR，对衰老有不利影响，而低饮食摄入会降低mTOR的活性，对寿命有有益影响。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通路直接涉及与年龄相关的疾病和病理，如癌症、慢性炎症、心脏病、神经变性和糖尿病。毫无疑问，这种酶是理解衰老基本机制的核心。此外，mTOR或受mTOR控制的蛋白可以成为预防或改善严重疾病的药物靶点。科学家们已经深入研究了营养可利用性、mTOR、寿命长短和疾病之间的联系，重点关注与相关过程有关的基因。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，以及物质的回收方式（这一过程被称为“自噬”）。更多的蛋白质生产和更少的有效回收是有害的。我们和其他人已经发现了这种联系，并为针对年龄相关疾病的药物开发提供了额外的潜在目标。然而，我们实验室最近的结果表明，衰老对细胞的外观以及细胞间室、蛋白质或氨基酸在细胞空间内的排列顺序有深远的影响。此外，我们还发现这种空间安排的差异会影响细胞的健康和寿命。其他研究小组的其他报告表明，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作用还没有被很好地理解。我们在三个机构内组建了一个实验室联盟，由遗传学、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）方面的专家组成。我们将分析衰老和寿命（称为“细胞时间”）如何影响细胞外观和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定位如何影响寿命、衰老速度和细胞健康。我们已经从酵母和人类等多种生物中建立了细胞系统，以揭示可能也在包括人类在内的多细胞生物中起作用的进化保守机制。鉴于mTOR在衰老和癌症、神经退行性疾病中的直接意义，了解细胞拓扑结构与衰老之间的关系将为衰老相关疾病的干预提供新的基因和蛋白质靶点以及方向。

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.