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, Paul D. Robbins

Research output: Contribution to journalArticle

87 Citations (Scopus)

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.

Original languageEnglish (US)
Article number422
JournalNature Communications
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2017
Externally publishedYes

Fingerprint

inhibitors
drugs
Aging of materials
17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
mice
platforms
Screening
Galactosidases
Pharmaceutical Preparations
screening
Autophagy
Drug Combinations
Fibroblasts
Stem cells
Age of Onset
DNA Repair
stem cells
Assays
fibroblasts
Repair

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Fuhrmann-Stroissnigg, H., Ling, Y. Y., Zhao, J., McGowan, S. J., Zhu, Y., Brooks, R. W., ... Robbins, P. D. (2017). Identification of HSP90 inhibitors as a novel class of senolytics. Nature Communications, 8(1), [422]. https://doi.org/10.1038/s41467-017-00314-z

Identification of HSP90 inhibitors as a novel class of senolytics. / Fuhrmann-Stroissnigg, Heike; Ling, Yuan Yuan; Zhao, Jing; McGowan, Sara J.; Zhu, Yi; Brooks, Robert W.; Grassi, Diego; Gregg, Siobhan Q.; Stripay, Jennifer L.; Dorronsoro, Akaitz; Corbo, Lana; Tang, Priscilla; Bukata, Christina; Ring, Nadja; Giacca, Mauro; Li, Xuesen; Tchkonia, Tamara; Kirkland, James L; Niedernhofer, Laura J.; Robbins, Paul D.

In: Nature Communications, Vol. 8, No. 1, 422, 01.12.2017.

Research output: Contribution to journalArticle

Fuhrmann-Stroissnigg, H, Ling, YY, Zhao, J, McGowan, SJ, Zhu, Y, Brooks, RW, Grassi, D, Gregg, SQ, Stripay, JL, Dorronsoro, A, Corbo, L, Tang, P, Bukata, C, Ring, N, Giacca, M, Li, X, Tchkonia, T, Kirkland, JL, Niedernhofer, LJ & Robbins, PD 2017, 'Identification of HSP90 inhibitors as a novel class of senolytics', Nature Communications, vol. 8, no. 1, 422. https://doi.org/10.1038/s41467-017-00314-z
Fuhrmann-Stroissnigg H, Ling YY, Zhao J, McGowan SJ, Zhu Y, Brooks RW et al. Identification of HSP90 inhibitors as a novel class of senolytics. Nature Communications. 2017 Dec 1;8(1). 422. https://doi.org/10.1038/s41467-017-00314-z
Fuhrmann-Stroissnigg, Heike ; Ling, Yuan Yuan ; Zhao, Jing ; McGowan, Sara J. ; Zhu, Yi ; Brooks, Robert W. ; Grassi, Diego ; Gregg, Siobhan Q. ; Stripay, Jennifer L. ; Dorronsoro, Akaitz ; Corbo, Lana ; Tang, Priscilla ; Bukata, Christina ; Ring, Nadja ; Giacca, Mauro ; Li, Xuesen ; Tchkonia, Tamara ; Kirkland, James L ; Niedernhofer, Laura J. ; Robbins, Paul D. / Identification of HSP90 inhibitors as a novel class of senolytics. In: Nature Communications. 2017 ; Vol. 8, No. 1.
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