Stead, Eleanor Rachel;
(2019)
Pharmacological Anti-Ageing Interventions for Cancer Prevention.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Ageing is the biggest risk factor for cancer, both share several common hallmarks including genomic instability. Preserving genomic integrity requires intricate DNA damage response and repair networks, however the efficiency of these pathways deteriorates with age. Recent advances in ageing research uncovered rapamycin and trametinib as anti-ageing pharmacological interventions, however their effect on genomic integrity is not well documented. This thesis aimed to investigate whether such anti-ageing drugs have the potential to reduce cancer risk by impeding the accumulation of mutations with age, and, given that damage induced by genotoxic agents heavily increases cancer risk, provide protection against DNA damage induced from exogenous sources. In Drosophila, the mTORC1 inhibitor, rapamycin, improved survival and reduced mutation frequency in old age and following exposure to ionising radiation. These effects were more striking when rapamycin was used in combination with the MEK inhibitor, trametinib. The effects of rapamycin were conserved in human cells, with improved survival and reduced DNA damage at both old age and following exposure to ionising radiation. The effects of trametinib were equivocal. In both Drosophila and human cells, rapamycin potentiated the phosphorylation of downstream ATM/ATR substrates following irradiation, suggesting a heightened response to damage which is evolutionarily conserved. Fewer γH2AX foci, a marker of DSBs, were detected in rapamycin treated cells indicating a protective mechanism which may be conferred by altered chromatin composition. Finally, rapamycin prolonged the cell cycle arrest and prevented human cells entering senescence. This suggests several key cellular processes are altered by rapamycin. Our results demonstrate the potential of anti-ageing drugs to alter the DNA damage response and reduce the likelihood of carcinogenesis. Cancer prevention is a neglected field of study and current cancer preventative measures are based largely on lifestyle changes, our observations could fundamentally change the approach to cancer prevention.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Pharmacological Anti-Ageing Interventions for Cancer Prevention |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10088826 |
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