The Achilles' heel of senescent cells: From transcriptome to senolytic drugs

Yi Zhu, Tamara Tchkonia, Tamar Pirtskhalava, Adam C. Gower, Husheng Ding, Nino Giorgadze, Allyson K. Palmer, Yuji Ikeno, Gene B. Hubbard, Marc Lenburg, Steven P. O'Hara, Nicholas F La Russo, Jordan D Miller, Carolyn M. Roos, Grace C. Verzosa, Nathan K LeBrasseur, Jonathan D. Wren, Joshua Farr, Sundeep Khosla, Michael B. StoutSara J. Mcgowan, Heike Fuhrmann-Stroissnigg, Aditi U. Gurkar, Jing Zhao, Debora Colangelo, Akaitz Dorronsoro, Yuan Yuan Ling, Amira S. Barghouthy, Diana C. Navarro, Tokio Sano, Paul D. Robbins, Laura J. Niedernhofer, James L Kirkland

Research output: Contribution to journalArticle

395 Citations (Scopus)

Abstract

The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and the burden of age-related chronic diseases. Here, we describe the rationale for identification and validation of a new class of drugs termed senolytics, which selectively kill senescent cells. By transcript analysis, we discovered increased expression of pro-survival networks in senescent cells, consistent with their established resistance to apoptosis. Using siRNA to silence expression of key nodes of this network, including ephrins (EFNB1 or 3), PI3Kδ, p21, BCL-xL, or plasminogen-activated inhibitor-2, killed senescent cells, but not proliferating or quiescent, differentiated cells. Drugs targeting these same factors selectively killed senescent cells. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse BM-MSCs. The combination of dasatinib and quercetin was effective in eliminating senescent MEFs. In vivo, this combination reduced senescent cell burden in chronologically aged, radiation-exposed, and progeroid Ercc1<sup>-/Δ</sup> mice. In old mice, cardiac function and carotid vascular reactivity were improved 5 days after a single dose. Following irradiation of one limb in mice, a single dose led to improved exercise capacity for at least 7 months following drug treatment. Periodic drug administration extended healthspan in Ercc1<sup>-/{increment}</sup> mice, delaying age-related symptoms and pathology, osteoporosis, and loss of intervertebral disk proteoglycans. These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan.

Original languageEnglish (US)
JournalAging Cell
DOIs
StateAccepted/In press - 2015

Fingerprint

Transcriptome
Pharmaceutical Preparations
Quercetin
Transgenic Suicide Genes
Ephrins
Intervertebral Disc
Plasminogen
Proteoglycans
Drug Delivery Systems
Phosphatidylinositol 3-Kinases
Adipocytes
Small Interfering RNA
Osteoporosis
Blood Vessels
Chronic Disease
Extremities
Endothelial Cells
Quality of Life
Radiation
Apoptosis

Keywords

  • Dasatinib
  • Dependence receptors
  • Ephrins
  • P21
  • PI3K delta
  • Plasminogen-activated inhibitor
  • Quercetin

ASJC Scopus subject areas

  • Cell Biology
  • Aging

Cite this

Zhu, Y., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., ... Kirkland, J. L. (Accepted/In press). The Achilles' heel of senescent cells: From transcriptome to senolytic drugs. Aging Cell. https://doi.org/10.1111/acel.12344

The Achilles' heel of senescent cells : From transcriptome to senolytic drugs. / Zhu, Yi; Tchkonia, Tamara; Pirtskhalava, Tamar; Gower, Adam C.; Ding, Husheng; Giorgadze, Nino; Palmer, Allyson K.; Ikeno, Yuji; Hubbard, Gene B.; Lenburg, Marc; O'Hara, Steven P.; La Russo, Nicholas F; Miller, Jordan D; Roos, Carolyn M.; Verzosa, Grace C.; LeBrasseur, Nathan K; Wren, Jonathan D.; Farr, Joshua; Khosla, Sundeep; Stout, Michael B.; Mcgowan, Sara J.; Fuhrmann-Stroissnigg, Heike; Gurkar, Aditi U.; Zhao, Jing; Colangelo, Debora; Dorronsoro, Akaitz; Ling, Yuan Yuan; Barghouthy, Amira S.; Navarro, Diana C.; Sano, Tokio; Robbins, Paul D.; Niedernhofer, Laura J.; Kirkland, James L.

In: Aging Cell, 2015.

Research output: Contribution to journalArticle

Zhu, Y, Tchkonia, T, Pirtskhalava, T, Gower, AC, Ding, H, Giorgadze, N, Palmer, AK, Ikeno, Y, Hubbard, GB, Lenburg, M, O'Hara, SP, La Russo, NF, Miller, JD, Roos, CM, Verzosa, GC, LeBrasseur, NK, Wren, JD, Farr, J, Khosla, S, Stout, MB, Mcgowan, SJ, Fuhrmann-Stroissnigg, H, Gurkar, AU, Zhao, J, Colangelo, D, Dorronsoro, A, Ling, YY, Barghouthy, AS, Navarro, DC, Sano, T, Robbins, PD, Niedernhofer, LJ & Kirkland, JL 2015, 'The Achilles' heel of senescent cells: From transcriptome to senolytic drugs', Aging Cell. https://doi.org/10.1111/acel.12344
Zhu Y, Tchkonia T, Pirtskhalava T, Gower AC, Ding H, Giorgadze N et al. The Achilles' heel of senescent cells: From transcriptome to senolytic drugs. Aging Cell. 2015. https://doi.org/10.1111/acel.12344
Zhu, Yi ; Tchkonia, Tamara ; Pirtskhalava, Tamar ; Gower, Adam C. ; Ding, Husheng ; Giorgadze, Nino ; Palmer, Allyson K. ; Ikeno, Yuji ; Hubbard, Gene B. ; Lenburg, Marc ; O'Hara, Steven P. ; La Russo, Nicholas F ; Miller, Jordan D ; Roos, Carolyn M. ; Verzosa, Grace C. ; LeBrasseur, Nathan K ; Wren, Jonathan D. ; Farr, Joshua ; Khosla, Sundeep ; Stout, Michael B. ; Mcgowan, Sara J. ; Fuhrmann-Stroissnigg, Heike ; Gurkar, Aditi U. ; Zhao, Jing ; Colangelo, Debora ; Dorronsoro, Akaitz ; Ling, Yuan Yuan ; Barghouthy, Amira S. ; Navarro, Diana C. ; Sano, Tokio ; Robbins, Paul D. ; Niedernhofer, Laura J. ; Kirkland, James L. / The Achilles' heel of senescent cells : From transcriptome to senolytic drugs. In: Aging Cell. 2015.
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AU - Ding, Husheng

AU - Giorgadze, Nino

AU - Palmer, Allyson K.

AU - Ikeno, Yuji

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AU - O'Hara, Steven P.

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AU - Farr, Joshua

AU - Khosla, Sundeep

AU - Stout, Michael B.

AU - Mcgowan, Sara J.

AU - Fuhrmann-Stroissnigg, Heike

AU - Gurkar, Aditi U.

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AU - Colangelo, Debora

AU - Dorronsoro, Akaitz

AU - Ling, Yuan Yuan

AU - Barghouthy, Amira S.

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AU - Sano, Tokio

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