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

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.

Connections between nutrient availability and nutrient-responsive pathways in lifespan regulation and age-related disease are subject to intense study. The evolutionarily conserved and pro-ageing mechanistic Target of Rapamycin (mTOR) signalling pathway coordinates basic cellular processes such as protein translation and autophagy. mTOR activity is linked to ageing rates as well as diseases such as cancer and neurodegeneration. mTOR-related gene expression networks during lifespan have been analysed in a multitude of model organisms. Nevertheless, the relationships between nutrient and mTOR-related subcellular localisation of molecules or cellular architecture (altogether termed 'cellular space' hereafter) with lifespan (termed 'cellular time') are poorly understood. Studies have indicated that age-related pathological conditions are linked to changes in cytoarchitecture. Our preliminary data strongly indicate that lifespan has profound effects in cellular space while changes in cytoarchitecture affect lifespan. Utilising our established fission yeast and human tissue culture models and our expertise in transcriptomics, proteomics, metabolomics, genome-wide genetic interactions, cellular fitness analysis, phenomics and microscopy we will investigate the following questions:
1. What are the changes in cellular space during the course of cellular lifespan?
2. How cellular lifespan is modulated due to cellular space changes?
This project will contribute towards a mechanistic understanding of the circuitry and regulation of mTOR-related genes and cell structure as well as subcellular protein and metabolite localisation that affect ageing and contributes to disease. Given the importance of cytoarchitecture and cytoskeleton in neurodegeneration, stem cell and cancer stem cell biology, illuminating their role in this context is pivotal in developing new targeted therapies.