Ageing is one of the leading health problems faced by society today. An understanding of the fundamental mechanisms of ageing has the potential to provide preventative therapies for multiple degenerative diseases. Drosophila melanogaster is a powerful model organism in which to study the ageing process because the rate of ageing in fly populations is easy to manipulate by either genetic or environmental means. Drosophila are also inexpensive, short lived, easy to collect and can be raised in large numbers (allowing sex and age- specific effects to be determined). Although a large body of data exists m mammals linking ageing and age-related degeneration to the accumulation of molecular cross-links such as advanced glycation end- products (AGEs) prior to the work presented in this thesis only one paper had studied such cross links in Drosophila. Accordingly I hypothesised: [1] That acid stable chemical species existed within Drosophila melanogaster (of which AGE-like entities represent a subset) • .• 1 I,. [2] That such chemical species !represented the stable products of damage to macromolecules within Drosophila' melanogaster and as such had the potential to play either a causal or a correlative role in the ageing process within this organism. To pursue this line of investigation it was first necessary to develop novel analytical methods to investigate the accumulation of damaged compounds in flies. Simple preparative techniques were developed to produce digests of whole Drosophila melanogaster for use in three dimensional (3D) fluorimetry, H NMR spectrometry and mass spectrometry. My initial data clearly indicated the presence of species which either increased or were lost with advancing population age. If they played a role in ageing then interventions that altered the rate of this process would be expected to alter the rates of accumulation or disappearance of these species. Accordingly, environmental (DR and low temperature) and genetic interventions (mutated IIS activity) were used to alter the rates of ageing of multiple cohorts of Drosophila. Populations subject to interventions which slowed ageing rates also showed a reduced rate of accumulation of signals consistent with damage (putative advanced glycation end products) as compared to cohorts under normal conditions. IH NMR spectrometry and mass spectrometry also revealed distinct age associated spectral changes. 3 My recognition that AGE-like molecules had the potential to activate Phase II detoxification mechanisms, together with the body of data on chemical changes within ageing flies that I generated using my novel techniques allowed the first critical test of the broad spectrum detoxification hypothesis of ageing (sometimes known as the "Green Theory" of ageing). The results I obtained were entirely consistent with the predictions of this theory. In conclusion, my work represents the first application of a range of analytical techniques to identify and quantify compounds associated with, and possibly causing, different rates of ageing in Drosophila melanogaster. These techniques will facilitate the identification of novel compounds that either increase or decrease during ageing in this organism and will improve our understanding of the ageing process in this key model system.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:590019 |
| Date | January 2012 |
| Creators | Iqbal, Aamira |
| Publisher | University of Brighton |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://research.brighton.ac.uk/en/studentTheses/e2d197d5-560a-4449-b450-190e0fa1f6db |
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