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An expedited screening platform for the discovery of anti-ageing compounds in vitro and in vivo

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Title: An expedited screening platform for the discovery of anti-ageing compounds in vitro and in vivo
Authors: Lujan, Celia, Tyler, Eleanor Jane, Ecker, Simone, Webster, Amy Philomena, Stead, Eleanor Rachel, Martinez-Miguel, Victoria Eugenia, Milligan, Deborah, Garbe, James Charles, Stampfer, Martha Ruskin, Beck, Stephan, Lowe, Robert, Bishop, Cleo Lucinda, Bjedov, Ivana
Source: http://lobid.org/resources/99370670445306441#!, 16(1):85.
Publication Year: 2024
Collection: Publisso (ZB MED-Publikationsportal Lebenswissenschaften)
Subject Terms: Senescence, Rapamycin, Advances in healthy aging and age-related diseases, DNA Methylation/drug effects [MeSH], Humans [MeSH], CpG methylation, Longevity/drug effects [MeSH], Sirolimus/pharmacology [MeSH], Animals [MeSH], CellPopAge epigenetic Clock, Drosophila [MeSH], Drug Evaluation, Preclinical/methods [MeSH], Research, Cellular Senescence/drug effects [MeSH], Drug discovery, Drug Discovery/methods [MeSH], Cells, Cultured [MeSH], Ageing, Epigenesis, Genetic/drug effects [MeSH], Aging/drug effects [MeSH]
Description: Abstract 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 ...
Document Type: article in journal/newspaper
Language: English
Relation: https://repository.publisso.de/resource/frl:6518979; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11218148/
DOI: 10.1186/s13073-024-01349-w
Availability: https://repository.publisso.de/resource/frl:6518979
https://doi.org/10.1186/s13073-024-01349-w
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11218148/
Rights: https://creativecommons.org/licenses/by/4.0/
Accession Number: edsbas.B10522F7
Database: BASE
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PubType: Academic Journal
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  Data: An expedited screening platform for the discovery of anti-ageing compounds in vitro and in vivo
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  Data: <searchLink fieldCode="AR" term="%22Lujan%2C+Celia%22">Lujan, Celia</searchLink><br /><searchLink fieldCode="AR" term="%22Tyler%2C+Eleanor+Jane%22">Tyler, Eleanor Jane</searchLink><br /><searchLink fieldCode="AR" term="%22Ecker%2C+Simone%22">Ecker, Simone</searchLink><br /><searchLink fieldCode="AR" term="%22Webster%2C+Amy+Philomena%22">Webster, Amy Philomena</searchLink><br /><searchLink fieldCode="AR" term="%22Stead%2C+Eleanor+Rachel%22">Stead, Eleanor Rachel</searchLink><br /><searchLink fieldCode="AR" term="%22Martinez-Miguel%2C+Victoria+Eugenia%22">Martinez-Miguel, Victoria Eugenia</searchLink><br /><searchLink fieldCode="AR" term="%22Milligan%2C+Deborah%22">Milligan, Deborah</searchLink><br /><searchLink fieldCode="AR" term="%22Garbe%2C+James+Charles%22">Garbe, James Charles</searchLink><br /><searchLink fieldCode="AR" term="%22Stampfer%2C+Martha+Ruskin%22">Stampfer, Martha Ruskin</searchLink><br /><searchLink fieldCode="AR" term="%22Beck%2C+Stephan%22">Beck, Stephan</searchLink><br /><searchLink fieldCode="AR" term="%22Lowe%2C+Robert%22">Lowe, Robert</searchLink><br /><searchLink fieldCode="AR" term="%22Bishop%2C+Cleo+Lucinda%22">Bishop, Cleo Lucinda</searchLink><br /><searchLink fieldCode="AR" term="%22Bjedov%2C+Ivana%22">Bjedov, Ivana</searchLink>
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  Data: <i>http://lobid.org/resources/99370670445306441#!, 16(1):85</i>.
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  Data: 2024
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  Data: Publisso (ZB MED-Publikationsportal Lebenswissenschaften)
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  Data: <searchLink fieldCode="DE" term="%22Senescence%22">Senescence</searchLink><br /><searchLink fieldCode="DE" term="%22Rapamycin%22">Rapamycin</searchLink><br /><searchLink fieldCode="DE" term="%22Advances+in+healthy+aging+and+age-related+diseases%22">Advances in healthy aging and age-related diseases</searchLink><br /><searchLink fieldCode="DE" term="%22DNA+Methylation%2Fdrug+effects+[MeSH]%22">DNA Methylation/drug effects [MeSH]</searchLink><br /><searchLink fieldCode="DE" term="%22Humans+[MeSH]%22">Humans [MeSH]</searchLink><br /><searchLink fieldCode="DE" term="%22CpG+methylation%22">CpG methylation</searchLink><br /><searchLink fieldCode="DE" term="%22Longevity%2Fdrug+effects+[MeSH]%22">Longevity/drug effects [MeSH]</searchLink><br /><searchLink fieldCode="DE" term="%22Sirolimus%2Fpharmacology+[MeSH]%22">Sirolimus/pharmacology [MeSH]</searchLink><br /><searchLink fieldCode="DE" term="%22Animals+[MeSH]%22">Animals [MeSH]</searchLink><br /><searchLink fieldCode="DE" term="%22CellPopAge+epigenetic+Clock%22">CellPopAge epigenetic Clock</searchLink><br /><searchLink fieldCode="DE" term="%22Drosophila+[MeSH]%22">Drosophila [MeSH]</searchLink><br /><searchLink fieldCode="DE" term="%22Drug+Evaluation%22">Drug Evaluation</searchLink><br /><searchLink fieldCode="DE" term="%22Preclinical%2Fmethods+[MeSH]%22">Preclinical/methods [MeSH]</searchLink><br /><searchLink fieldCode="DE" term="%22Research%22">Research</searchLink><br /><searchLink fieldCode="DE" term="%22Cellular+Senescence%2Fdrug+effects+[MeSH]%22">Cellular Senescence/drug effects [MeSH]</searchLink><br /><searchLink fieldCode="DE" term="%22Drug+discovery%22">Drug discovery</searchLink><br /><searchLink fieldCode="DE" term="%22Drug+Discovery%2Fmethods+[MeSH]%22">Drug Discovery/methods [MeSH]</searchLink><br /><searchLink fieldCode="DE" term="%22Cells%22">Cells</searchLink><br /><searchLink fieldCode="DE" term="%22Cultured+[MeSH]%22">Cultured [MeSH]</searchLink><br /><searchLink fieldCode="DE" term="%22Ageing%22">Ageing</searchLink><br /><searchLink fieldCode="DE" term="%22Epigenesis%22">Epigenesis</searchLink><br /><searchLink fieldCode="DE" term="%22Genetic%2Fdrug+effects+[MeSH]%22">Genetic/drug effects [MeSH]</searchLink><br /><searchLink fieldCode="DE" term="%22Aging%2Fdrug+effects+[MeSH]%22">Aging/drug effects [MeSH]</searchLink>
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  Data: <jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>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.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>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 <jats:italic>Drosophila</jats:italic>, 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.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>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 ...
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  Data: https://repository.publisso.de/resource/frl:6518979; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11218148/
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  Data: 10.1186/s13073-024-01349-w
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  Data: https://repository.publisso.de/resource/frl:6518979<br />https://doi.org/10.1186/s13073-024-01349-w<br />https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11218148/
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        Value: 10.1186/s13073-024-01349-w
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      – Text: English
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