Identification of HSP90 inhibitors as a novel class of senolytics

Heike Fuhrmann-Stroissnigg, Yuan Yuan Ling, Jing Zhao, Sara J. McGowan, Yi Zhu, Robert W. Brooks, Diego Grassi, Siobhan Q. Gregg, Jennifer L. Stripay, Akaitz Dorronsoro, Lana Corbo, Priscilla Tang, Christina Bukata, Nadja Ring, Mauro Giacca, Xuesen Li, Tamara Tchkonia, James L. Kirkland, Laura J. Niedernhofer and Paul D. Robbins ()
Additional contact information
Heike Fuhrmann-Stroissnigg: The Scripps Research Institute
Yuan Yuan Ling: The Scripps Research Institute
Jing Zhao: The Scripps Research Institute
Sara J. McGowan: The Scripps Research Institute
Yi Zhu: University of Pittsburgh School of Medicine
Robert W. Brooks: The Scripps Research Institute
Diego Grassi: The Scripps Research Institute
Siobhan Q. Gregg: Robert and Arlene Kogod Center on Aging, Mayo Clinic
Jennifer L. Stripay: Robert and Arlene Kogod Center on Aging, Mayo Clinic
Akaitz Dorronsoro: The Scripps Research Institute
Lana Corbo: The Scripps Research Institute
Priscilla Tang: The Scripps Research Institute
Christina Bukata: The Scripps Research Institute
Nadja Ring: International Centre for Genetic Engineering and Biotechnology
Mauro Giacca: International Centre for Genetic Engineering and Biotechnology
Xuesen Li: The Scripps Research Institute
Tamara Tchkonia: University of Pittsburgh School of Medicine
James L. Kirkland: University of Pittsburgh School of Medicine
Laura J. Niedernhofer: The Scripps Research Institute
Paul D. Robbins: The Scripps Research Institute

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract Aging is the main risk factor for many chronic degenerative diseases and cancer. Increased senescent cell burden in various tissues is a major contributor to aging and age-related diseases. Recently, a new class of drugs termed senolytics were demonstrated to extending healthspan, reducing frailty and improving stem cell function in multiple murine models of aging. To identify novel and more optimal senotherapeutic drugs and combinations, we established a senescence associated β-galactosidase assay as a screening platform to rapidly identify drugs that specifically affect senescent cells. We used primary Ercc1 −/− murine embryonic fibroblasts with reduced DNA repair capacity, which senesce rapidly if grown at atmospheric oxygen. This platform was used to screen a small library of compounds that regulate autophagy, identifying two inhibitors of the HSP90 chaperone family as having significant senolytic activity in mouse and human cells. Treatment of Ercc1 −/∆ mice, a mouse model of a human progeroid syndrome, with the HSP90 inhibitor 17-DMAG extended healthspan, delayed the onset of several age-related symptoms and reduced p16INK4a expression. These results demonstrate the utility of our screening platform to identify senotherapeutic agents as well as identified HSP90 inhibitors as a promising new class of senolytic drugs.

Date: 2017
References: Add references at CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/s41467-017-00314-z Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00314-z

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-017-00314-z

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().