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The role of decreasing protein synthesis in delaying ageing – emphasis on translation accuracy

Martinez Miguel, Victoria Eugenia; (2019) The role of decreasing protein synthesis in delaying ageing – emphasis on translation accuracy. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Ageing is a malleable process and outstanding discoveries demonstrate that: 1) a single point mutation can double the lifespan of model organisms, 2) these long-lived animals are healthier and 3) the effect of these interventions is evolutionary conserved from yeast to mammals. This offers the possibility that the insights gained from research in ageing could be translated to improve health in the elderly and to prevent age-related diseases. Major interventions leading to longevity and health improvements include dietary restriction, mild down-regulation of insulin and target-of-rapamycin (TOR) signalling. Interestingly, a common underlying characteristic of all these lifespan-extending treatments is that they all lead to a reduction of protein synthesis and, in addition, directly lowering translation can also improve longevity. However, the underlying mechanism of this effect on longevity is largely elusive. The aim of this project was to test a largely neglected hypothesis that lowered translation improves fidelity of the proteins synthetized, thereby leading to improved health and longevity. To explore this, Drosophila melanogaster was used as a model organism in which a focused longevity RNAi longevity screen was performed, and we found that downregulating translation-associated factors can extend lifespan in flies. Furthermore, a dual-reporter luciferase assay was developed in Drosophila-derived S2R+ cells to study translation fidelity and we have found that several drugs known to extend lifespan decrease the level of translation errors. In addition, a mutant with a single residue substitution in a ribosomal protein was generated by CRISPR/Cas9 and we found that directly improving translation fidelity can extend lifespan and improve healthspan in flies. Thus, in vitro and in vivo techniques have been used to understand the molecular and cellular mechanisms behind the effect of translation, especially its fidelity, in ageing.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The role of decreasing protein synthesis in delaying ageing – emphasis on translation accuracy
Event: UCL (University College London)
Language: English
Additional information: Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) Licence (https://creativecommons.org/licenses/by-nc-nd/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 > 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 Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
URI: https://discovery.ucl.ac.uk/id/eprint/10073410
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