| Title: |
An expedited screening platform for the discovery of anti-ageing compounds in vitro and in vivo. |
| Authors: |
Lujan, C; Tyler, EJ; Ecker, S; Webster, AP; Stead, ER; Martinez-Miguel, VE; Milligan, D; Garbe, JC; Stampfer, MR; Beck, S; Lowe, R; Bishop, CL; Bjedov, I |
| Publisher Information: |
Springer Nature |
| Publication Year: |
2024 |
| Collection: |
Queen Mary University of London: Queen Mary Research Online (QMRO) |
| Subject Terms: |
Ageing; CellPopAge epigenetic Clock; CpG methylation; Drug discovery; Rapamycin; Senescence; Humans; Animals; DNA Methylation; Longevity; Aging; Epigenesis; Genetic; Cellular Senescence; Drug Evaluation; Preclinical; Drosophila; Cells; Cultured; Sirolimus |
| Description: |
BACKGROUND: Restraining or slowing ageing hallmarks at the cellular level have been proposed as a route to increased organismal lifespan and healthspan. Consequently, there is great interest in anti-ageing drug discovery. However, this currently requires laborious and lengthy longevity analysis. Here, we present a novel screening readout for the expedited discovery of compounds that restrain ageing of cell populations in vitro and enable extension of in vivo lifespan. METHODS: Using Illumina methylation arrays, we monitored DNA methylation changes accompanying long-term passaging of adult primary human cells in culture. This enabled us to develop, test, and validate the CellPopAge Clock, an epigenetic clock with underlying algorithm, unique among existing epigenetic clocks for its design to detect anti-ageing compounds in vitro. Additionally, we measured markers of senescence and performed longevity experiments in vivo in Drosophila, to further validate our approach to discover novel anti-ageing compounds. Finally, we bench mark our epigenetic clock with other available epigenetic clocks to consolidate its usefulness and specialisation for primary cells in culture. RESULTS: We developed a novel epigenetic clock, the CellPopAge Clock, to accurately monitor the age of a population of adult human primary cells. We find that the CellPopAge Clock can detect decelerated passage-based ageing of human primary cells treated with rapamycin or trametinib, well-established longevity drugs. We then utilise the CellPopAge Clock as a screening tool for the identification of compounds which decelerate ageing of cell populations, uncovering novel anti-ageing drugs, torin2 and dactolisib (BEZ-235). We demonstrate that delayed epigenetic ageing in human primary cells treated with anti-ageing compounds is accompanied by a reduction in senescence and ageing biomarkers. Finally, we extend our screening platform in vivo by taking advantage of a specially formulated holidic medium for increased drug bioavailability in Drosophila. We ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
85 - ? |
| Language: |
English |
| Relation: |
Genome Med; https://qmro.qmul.ac.uk/xmlui/handle/123456789/97943 |
| DOI: |
10.1186/s13073-024-01349-w |
| Availability: |
https://qmro.qmul.ac.uk/xmlui/handle/123456789/97943; https://doi.org/10.1186/s13073-024-01349-w |
| Rights: |
This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. ; © The Author(s) 2024. |
| Accession Number: |
edsbas.D7A87C56 |
| Database: |
BASE |