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. Larusso, Jordan D. Miller, Carolyn M. Roos, Grace C. Verzosa, Nathan K. Lebrasseur, Jonathan D. Wren, Joshua N. 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

510 Scopus citations

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 prosurvival 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), PI3Kd, 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/D 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 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)
Pages (from-to)644-658
Number of pages15
JournalAging Cell
Volume14
Issue number4
DOIs
StatePublished - 2015

Keywords

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

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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    Zhu, Y., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., Palmer, A. K., Ikeno, Y., Hubbard, G. B., Lenburg, M., O’hara, S. P., Larusso, N. F., Miller, J. D., Roos, C. M., Verzosa, G. C., Lebrasseur, N. K., Wren, J. D., Farr, J. N., Khosla, S., ... Kirkland, J. L. (2015). The achilles’ heel of senescent cells: From transcriptome to senolytic drugs. Aging Cell, 14(4), 644-658. https://doi.org/10.1111/acel.12344