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Unravelling effects of anti‐ageing drugs on C. elegans using liposomes

Zhang, Aihan; (2024) Unravelling effects of anti‐ageing drugs on C. elegans using liposomes. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

While Caenorhabditis elegans is a good model organism for ageing research, its utility in anti-ageing drug studies faces several challenges. Firstly, C. elegans is bacterivorous and typically cultured on Escherichia coli as a food source. Bacterial infection can shorten lifespan, which means that some drugs appear to slow ageing when in fact they merely reduce bacterial pathogenicity. Furthermore, bacteria can effect drug biotransformation, thereby affecting their efficacy and toxicity. Also, the C. elegans pharynx only ingests particulate matter, which can limit the consumption of drugs in solution, and many compounds do not effectively cross from the intestinal lumen into the worm body. Encapsulation of drugs in liposomes, spherical vesicles bounded by a phospholipid membrane, offer a potential solution to all of these issues. Such encapsulation can prevent bacterial-drug interactions and facilitate the ingestion of drugs, as liposomes are particulate. Moreover, liposomes can enhance drug transport across cell membranes, potentially reducing the dosage needed and, consequently, experimental costs. This work explores the capability of liposomes to transform C. elegans into a more effective model for anti-ageing drug research. Using fluorescent dyes encapsulated in liposomes to model drug delivery, we observed an increase in the ingestion of these compounds through the pharynx and into the intestinal lumen. However this was not true for one membrane impermeable dye (Texas red), suggesting that liposome encapsulation cannot ensure uptake of all compounds. We also tested the effects of liposome-mediated delivery of anti-ageing drugs. For some compounds, e.g. thioflavin T, previously reported life-extending effects were nullified by antibiotics, and this compound proved to possess antibiotic action. In contrast, rapamycin, an mTOR inhibitor, more robustly extended lifespan when bacterial infection was controlled, pointing to its direct anti-ageing effects, which are partially masked by bacterial infection. Additionally, life-extension by rapamycin varied in effectiveness depending on the stage of life at which it was administered: treatment during larval stages modestly extended lifespan and reduced fertility, while initiation later in life, even from day 16, robustly increased lifespan. However, rapamycin dose optimisation was able to achieve only relatively modest increases in lifespan. In summary, while liposome encapsulation does not enable universal uptake of all drugs in C. elegans, it significantly enhances this model’s utility for investigating anti-ageing drugs by overcoming physiological barriers to drug delivery. These findings describes should inform future experimental design and help optimise rapamycin and other drug treatments to extend lifespan effectively.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Unravelling effects of anti‐ageing drugs on C. elegans using liposomes
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2024. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/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 > 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
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment
UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10200283
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