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Title: Functional genomics of ageing and its modulation by diet
Author: Wuttke, Daniel A.
ISNI:       0000 0004 7658 0013
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2017
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Ageing is a widespread phenomenon limiting the lifespan of almost all species. Virtually all organisms age, however what controls the ageing process remains enigmatic. A lot of human disease and death are affected by ageing or age-related diseases. Understanding the ageing process is crucial to benefit humanity including intervention of human disease or life extension. The work presented here allows to gain insights into the ageing process which can be manipulated by targeting ageing genes via genetic modifications, environmental factors, or pharmacological interventions. Biological information is increasing at an exponential pace. Information technology is also advancing at a fast pace. The combination of these two trends may allow us to understand biological processes such as ageing. Ageing is plastic; many studies have shown that the ageing process can be sped up, slowed down, stopped, or even reversed. For example, the ageing process can be slowed down by dietary restriction (DR), the most powerful non-genetic intervention known to counteract the basic ageing process. In addition, the ageing process can be modulated by genetic as well as environmental means including dietary as well as pharmacological interventions. Here it is hypothesized that ageing genes do not only play an important role in the ageing process but also in its modulation by diet. In this thesis, functional genomics approaches are applied to genomic data such as transcriptomics and interactomics. Graph theoretic concepts like guilt-by-association and shortest path are applied on ageing and its dietary manipulations. This methodology enabled to gather new insights into the underlying mechanisms of the ageing process and its interference with interventions like dietary restriction, as well as to predict original hypotheses, new ageing genes, and novel pharmaceuticals. Firstly, a curated knowledge base was established which includes loss- and gain-of-function experiments that impact on lifespan of organisms including human, mouse, fruit fly, nematode, and yeast, among others. Genes controlling the ageing process (ageing genes) were classified based on their effect on lifespan resulting from genetic manipulations in the common biomedical model organisms as well as in humans. Those classes were characterized for common associations and potential novel ageing genes were predicted by applying graph theory like the guilt-by-association principle. Specifically, this thesis classifies ageing genes that control the ageing process into two main classes: 1) gerontogenes that mediate the ageing process, therefore decrease lifespan of the organism; 2) ageing-suppressor genes that suppress the ageing process, thus increase lifespan of the organism. Further analysis shows that: Gerontogenes are associated with translation, positive regulation of apoptosis, inflammation, TOR signalling, positive regulation of multicellular organism growth and development, as well as transcription regulation. In contrast, ageing-suppressor genes are associated with DNA metabolism (including DNA repair, telomere maintenance, and chromatin organization), stress response, negative regulation of apoptosis, protein homeostasis (including protein repair, regulation of protein stability, lysosome/autophagy, and the ubiquitin-proteasome system), and endocytosis, as well as transcriptional regulation. Thus, gerontogenes were found to be involved in growth/development and translation, while ageing-suppressor genes are involved in stress response and diverse repair processes. Secondly, a class of genes, denoted here as dietary restriction-essential genes (DR genes for short), which are necessary for the lifespan-extending effect of dietary restriction in commonly used biomedical models organisms was found. DR genes were defined and characterized as well as new candidate genes predicted. It was found that DR genes are evolutionary conserved on the molecular (sequence) level more than expected by chance (even more than ageing genes which are conserved) and are more likely to interact with each other based on molecular interactions than expected by chance. The predicted genes were experimentally validated and prediction accuracy was found to be up to 89%. The new DR genes, which were predicted by guilt-by-association, include FRE6, RCR2, and OPT2. FRE6 and OPT2 were found to be induced on the transcriptional level upon DR, while RCR2 found to be transcriptionally repressed. OPT2 was one of the greatest upregulated genes upon DR. Potential transcription factors controlling the DR response were identified. Thirdly, tissue-specific and common molecular signatures of gene activity changes during ageing and dietary restriction for different organisms (human and common biomedical models) were generated. Those signatures were characterized for their associations and the associations common to multiple species identified. Ageing commonly upregulates inflammation, MAPK and TOR signalling, and downregulates proteostasis, cell cycle, and epigenetic modifications. Accelerated ageing commonly upregulates inflammation as well as Notch signalling and downregulates Wnt signalling. Cellular senescence commonly upregulates inflammation and negatively regulates cell cycle and apoptosis. DR commonly upregulates specific gene regulation and nuclear processes including chromatin silencing while downregulating MAPK signalling and other transcriptional regulation. DR in particular modulates stress response, circadian clock, and proteostasis. Lastly, via graph theory and pattern matching, drugs that target specific classes of ageing genes as well as potentially reverse ageing-related gene expression changes or mimic the effect of dietary restriction on the level of the transcriptome were predicted. Drug mesalazine, among others, was predicted as the top compound to transcriptionally mimic the effect of dietary restriction while others like LY-294002 seem also capable of additionally reversing ageing, accelerated ageing and cellular senescence. Among the top drugs and supplements were well-known anti-ageing compounds as well dietary restriction mimetics validating the approach. The ageing process and its modulation by diet appear to be governed by specific gene classes, that are conserved and interact with each other. These features can be used to identify lifespan extending processes, functions, components, and entities via the utilization of different omics like interactomics and transcriptomics that allow to investigate the interactions and activities of genes. Gerontogenes by their very activity drive processes that mediate ageing, while ageing-suppressor genes control processes that counteract ageing. DR genes mediate the effect of a restricted diet to modulate those activities in order to slow down ageing. Small molecules were identified that potentially target specific ageing gene classes, reverse ageing, Hutchinson-Gilford progeria syndrome, and cellular senescence, or mimic the effect of DR and may therefore enable to intervene with the ageing process pharmacologically.
Supervisor: De Magalhaes, Joao Pedro ; Merry, Brian Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral