Ageing is accompanied by numerous metabolic changes and age-related diseases. Calorie restriction (CR) is a well-established non-invasive method that reduces the rate of ageing and increases lifespan in a wide range of taxa. Previous studies have highlighted a relationship between the extent of restriction and the extent to which lifespan is increased. However, the mechanisms by which CR mediates its beneficial effects on ageing are yet to be fully understood. I therefore tested three hypotheses which examined the role of metabolic changes in the hypothalamus, the epididymal white adipose tissue and liver on the beneficial effects of CR. A three month graded CR study was performed on 5 month old male C57BL/6 mice. Six different treatments were used: 24 hours ad libitum (AL) feeding, 12 hours AL feeding, 10% CR, 20% CR, 30% CR and 40% CR. Behavioural, physiological and molecular information from each tissue of individual mice were collected. Using this comprehensive data set, I analysed the changes in the transcriptome when exposed to graded CR at both the individual gene level and also using network inferential approaches in the three tissues. My results suggest that CR leads to an overall reduction in the state of inflammation in adipose tissue which may be signalled via secreted cytokines leading to a corresponding reduction in signalling to other tissues. Signal molecules, including those from the adipose tissue, activated the hunger signalling pathway via receptors in the hypothalamus during CR. Responses to CR in the liver were consistent with several current theories reported in the literature and are likely to reflect the combined role of multiple ageing related processes. By constructing multitissue, multi-gene networks I was able to identify potential mechanisms underpinning CR. In conclusion, CR affected multiple biological processes across several different organs in a way consistent with increased healthspan.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:731605 |
| Date | January 2017 |
| Creators | Derous, Davina |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=233943 |
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