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Cell Rep. 2019 Apr 9;27(2):467-480.e6. doi: 10.1016/j.celrep.2019.03.044.

Transcriptomics-Based Screening Identifies Pharmacological Inhibition of Hsp90 as a Means to Defer Aging.

Author information

1
Integrated Cardio Metabolic Centre (ICMC), Karolinska Institute, 14157 Huddinge, Sweden.
2
Integrated Cardio Metabolic Centre (ICMC), Karolinska Institute, 14157 Huddinge, Sweden; Department of Biosciences and Nutrition, Karolinska Institute, 14157 Huddinge, Sweden.
3
European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, 9700AD Groningen, the Netherlands.
4
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08002 Barcelona, Spain.
5
Integrated Cardio Metabolic Centre (ICMC), Karolinska Institute, 14157 Huddinge, Sweden; Department of Biosciences and Nutrition, Karolinska Institute, 14157 Huddinge, Sweden. Electronic address: christian.riedel@ki.se.

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.

KEYWORDS:

Caenorhabditis elegans; Hsp90; aging; drug discovery; geroprotectors; healthspan; lifespan; machine learning; monorden; tanespimycin

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