Title: Dunhill Medical Trust Institute of Healthy Ageing (DMT IHA) PhD Studentships
Funder: Dunhill Medical Trust

Abstract: Although ageing is the primary determinant of disease, its causes and mechanisms are not understood at a fundamental level. At the Institute of Healthy Ageing (IHA), we use various genetic model organisms to investigate basic mechanisms and universal principles of ageing, and their relationships to diseases of ageing. This research fits squarely in the Dunhill Medical Trust’s strategic priority ‘Improving our understanding of the underlying mechanisms of ageing and age-related disease’. Ageing is the main risk factor for complex human diseases in the developed world, including neurodegeneration, cardiovascular and metabolic disorders or cancer, as well as for infectious diseases like COVID-19. This situation generates ever-increasing economic and societal burdens for our ageing society. Biomedical research has long focused on specific disease mechanisms. But there is a growing realization of the importance of the ageing process itself having a key role in disease aetiology, and to explore ways to slow its effects and thus broadly delay or remedy ageing-related diseases. Age-associated decline is not invariably fixed: simple genetic, nutritional or pharmacological interventions in model organisms can extend healthy lifespan. Ageing is a multi-factorial process, involving mitochondrial dysfunction, nutrient-sensing, epigenetic alterations, and stem cell exhaustion, among other hallmarks. A key challenge is to understand and dissect all genes and basic biological processes that directly contribute to ageing and underpin mechanisms of associated diseases. Ageing-related processes are remarkably conserved from yeast to humans, with short-lived model organisms remaining the most potent platform to discover and study universal mechanisms that determine healthy ageing or disease and to dissect cause-effect relationships among these complex processes. Within this framework, the proposed studentships would provide valuable opportunities for cross-species studies, catalyzing interactions between research groups and building new links between subject areas. Below, we outline five exemplar PhD projects that could be pursued within the IHA. Title: Epigenetic mechanisms ensuring old-age health and longevity Supervisors: Dr Nazif Alic (primary); Prof Jürg Bähler (secondary) The rate of ageing can be altered; understanding the mechanisms underlying this plasticity presents an opportunity to intervene in the ageing process itself, thus ensuring health in older humans. Recent studies have shown that several complex animal phenotypes, including ageing, can be epigenetically modulated, but the underlying mechanisms remain unclear. Our work on Foxo, an evolutionarily conserved anti-ageing transcription factor, has allowed us to establish models of inter- and intra-generational epigenetic modulation of ageing in the fruit fly. We will employ these unique models, allowing us to capitalize on the power of fly genetics, genomics and ageing physiology, to understand the mechanistic basis of epigenetic determinants of health and longevity. Collaboration with the Bähler lab will allow testing mechanisms for evolutionary conservation in yeast and killifish. Title: Genome rearrangements in quiescent cells as a universal ageing signature? Supervisors: Prof Jürg Bähler (primary); Dr Maria Secrier (secondary) Genomic instability is an ageing hallmark. Using sensitive analyses in older yeast and human brain cells, we have recently uncovered distinctive signatures of genome rearrangements. We will test whether different organs from turquoise killifish (Nothobranchius furzeri) feature such age-dependent rearrangements and whether genetic manipulation of these rearrangements in yeast or killifish directly affects ageing. Killifish live for only 4-6 months and show ageing hallmarks typical for mammals. The short adult lifespan and genetic tractability of killifish allow rapid, cost-effective assays to study ageing-related processes, thus bridging the gap between short-lived invertebrate and long-lived vertebrate models. Collaboration with the Secrier lab will allow us to computationally mine human whole-genome sequence data, including different tissues and ages, to study the link between genome rearrangements and ageing. Title: Establishing new pathways that protect the ageing proteome Supervisors: Dr John Labbadia (primary); Dr Teresa Niccoli (secondary) The loss of protein homeostasis is a key feature of age-associated tissue dysfunction in humans and model organisms. Therefore, finding means to maintain proteome integrity in aged cells may be a potent way to prolong healthy tissue function. We have recently discovered two new protein quality-control pathways that are activated by mitochondrial or endoplasmic reticulum signals and that potently suppress protein aggregation. However, it remains unclear how these pathways protect the ageing proteome and how this prolongs healthy tissue function. This project will use mass-spectrometry based proteomics, high-throughput genetic screening, molecular biology and computational tools in multiple model systems to address these questions and identify new anti-ageing targets. Title: Unravelling the roles of glial dysfunction and lipid droplet formation in the ageing brain Supervisors: Dr Kerri Kinghorn (primary); Prof Linda Partridge (secondary) Microglia accumulate lipid droplets and display defective phagocytosis in human and murine ageing brains. Using a Parkinson’s Drosophila model, we have recently found an increase in glial lipid droplets and the glial phagocytic receptor during brain ageing. Glial lipid droplets may play a neuroprotective role by sequestering oxidized lipids. Our data show that young flies display increased numbers of glial lipid droplets on exposure to oxidative stress, a response absent in aged flies. This project will employ flow cytometry to separate GFP-labelled glia from young and old fly brains and RNA-sequencing to profile the glial transcriptome during ageing. Differentially expressed genes will then be genetically modulated in fly glia to investigate their effects on lifespan and age-related neuronal function. We will also test whether pharmacological or dietary interventions targeting lipid metabolism affect glial lipid droplet formation to promote healthy ageing. Title: Roles in brain ageing of genes associated with common neurodegenerative diseases Supervisors: Dr Teresa Niccoli (primary); Dr John Labbadia (secondary) A recent large-scale human GWAS study has highlighted how several genes are implicated in a number of age-related neurodegenerative disorders. We hypothesize that these genes modulate the process of brain ageing itself. This project will investigate the role of these genes in ageing fly brains. Fly homologues of these human genes will be modulated specifically in fly neurons and their effects on lifespan and brain ageing will be assessed. Molecular and cellular processes identified as important will be validated in worms. Mechanisms conserved between these two evolutionary distant species are highly likely conserved throughout evolution and therefore relevant to human brain ageing too.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE