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Title: Pharmacogenetics of ageing and neurodegeneration
Author: Castillo Quan, J. I.
ISNI:       0000 0004 5352 4174
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2014
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Genetic manipulations and dietary restriction in model organisms have proven that lifespan extension is achievable. Moreover these same interventions can protect against age-related diseases and improve general healthiness. Therefore, current efforts are being put forward to identify drugs that mimic healthy lifespan. Lithium has been documented to be able to extend the lifespan of the worm Caenorhabditis elegans, reduce mortality in Drosophila and a recent report has suggested that lithium concentrations in drinking water correlate with reduced mortality for all causes in a human population. The main objective of the project presented here was to determine the anti-ageing properties of lithium using the fruit fly and to determine the mechanism by which lithium exerts its broad health benefits and anti-ageing properties. My results showed that lithium extended lifespan independent of sex and genetic background. Lithium treated flies were also resistant to multiple stressors and showed reduced triglyceride levels. Lithium did not modify fecundity and it further extended lifespan of DR flies. The pro-longevity effects seemed to also be independent of the nutrient sensing network as it could further extend lifespan of flies with reduced signalling though the insulin/IGF-1 and the mechanistic target of rapamycin (mTOR) network. I performed transcriptional and translational microarrays in lithium treated flies and found out that lithium up-regulated a transcriptional response to stress regulated by the transcription factor cap’n’collar/NRF-2 and down-regulated functional categories implicated in mitochondrial complex I. By performing epistasis experiments I found out that lithium and shaggy, the fly homologue of GSK-3, regulate ageing by acting in the same molecular pathway. However, shaggy seemed to modulate ageing in a tissue-specific manner. The combination of lithium and genetic manipulations of shaggy revealed a very complex regulation of ageing and neurodegeneration. I also explored the nature of neurodegeneration induced by over-expression of Aβ1-42 and found out that some of the changes induced by Aβ1-42 impact general physiology and not only neurons. For example, our results suggest that altered metabolism is a prominent feature of the toxicity of Aβ1-42 in Drosophila.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available