Transcriptomics-based screening identifies pharmacological inhibition of hsp90 as a means to defer aging

Janssens, Georges E.; Lin, Xin-Xuan; Millán Ariño, Lluís, 1984-; Kavšek, Alan; Sen, Ilke; Seinstra, Renée I.; Stroustrup, Nicholas; Nollen, Ellen A. A.; Riedel, Christian G.

Transcriptomics-based screening identifies pharmacological inhibition of hsp90 as a means to defer aging

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dc.contributor.author Janssens, Georges E.
dc.contributor.author Lin, Xin-Xuan
dc.contributor.author Millán Ariño, Lluís, 1984-
dc.contributor.author Kavšek, Alan
dc.contributor.author Sen, Ilke
dc.contributor.author Seinstra, Renée I.
dc.contributor.author Stroustrup, Nicholas
dc.contributor.author Nollen, Ellen A. A.
dc.contributor.author Riedel, Christian G.
dc.date.accessioned 2019-07-16T09:27:22Z
dc.date.available 2019-07-16T09:27:22Z
dc.date.issued 2019
dc.description.abstract Aging strongly influences human morbidity and mortality. Thus, aging-preventive compounds could greatly improve our health and lifespan. Here we screened for such compounds, known as geroprotectors, employing the power of transcriptomics to predict biological age. Using age-stratified human tissue transcriptomes and machine learning, we generated age classifiers and applied these to transcriptomic changes induced by 1,309 different compounds in human cells, ranking these compounds by their ability to induce a "youthful" transcriptional state. Testing the top candidates in C. elegans, we identified two Hsp90 inhibitors, monorden and tanespimycin, which extended the animals' lifespan and improved their health. Hsp90 inhibition induces expression of heat shock proteins known to improve protein homeostasis. Consistently, monorden treatment improved the survival of C. elegans under proteotoxic stress, and its benefits depended on the cytosolic unfolded protein response-inducing transcription factor HSF-1. Taken together, our method represents an innovative geroprotector screening approach and was able to identify a class that acts by improving protein homeostasis.
dc.description.sponsorship N.S. was supported by funding from the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) to the EMBL partnership, the Centro de Excelencia Severo Ochoa, the CERCA Programme/Generalitat de Catalunya, and an award from the Glenn Foundation for Medical Research. E.A.A.N. was supported by the European Research Council (ERC) and the alumni chapter of Gooische Groningers facilitated by Ubbo Emmius Fonds. C.G.R. was supported by the Swedish Research Council (VR) grant 2015-03740, the COST grant BM1408 (GENiE), and an ICMC project grant
dc.format.mimetype application/pdf
dc.identifier.citation Janssens GE, Lin XX, Millan-Ariño L, Kavšek A, Sen I, Seinstra RI et al. Transcriptomics-based screening identifies pharmacological inhibition of hsp90 as a means to defer aging. Cell Rep. 2019 Apr 9;27(2):467-80. DOI: 10.1016/j.celrep.2019.03.044
dc.identifier.doi http://dx.doi.org/10.1016/j.celrep.2019.03.044
dc.identifier.issn 2211-1247
dc.identifier.uri http://hdl.handle.net/10230/42004
dc.language.iso eng
dc.publisher Elsevier
dc.relation.ispartof Cell Reports. 2019 Apr 9;27(2):467-80
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri https://creativecommons.org/licenses/by/4.0/
dc.subject.other Envelliment
dc.subject.other Farmacologia
dc.subject.other Genètica
dc.title Transcriptomics-based screening identifies pharmacological inhibition of hsp90 as a means to defer aging
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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