The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs

Aging Cell

Yi Zhu⁵  Tamara Tchkonia⁵  Tamar Pirtskhalava⁵  Adam C. Gower¹  Husheng Ding⁵  Nino Giorgadze⁵  Allyson K. Palmer⁵  Yuji Ikeno²  Gene B. Hubbard²  Marc Lenburg¹  Steven P. O'Hara⁵  Nicholas F. LaRusso⁵  Jordan D. Miller⁵  Carolyn M. Roos⁵  Grace C. Verzosa⁵  Nathan K. LeBrasseur⁵  Jonathan D. Wren³  Joshua N. Farr⁵  Sundeep Khosla⁵  Michael B. Stout⁵  Sara J. McGowan⁴  Heike Fuhrmann-Stroissnigg⁴  Aditi U. Gurkar⁴  Jing Zhao⁴  Debora Colangelo⁴  Akaitz Dorronsoro⁴  Yuan Yuan Ling⁴  Amira S. Barghouthy⁴  Diana C. Navarro⁴  Tokio Sano⁴  Paul D. Robbins⁴  Laura J. Niedernhofer⁴ 

[1] Section of Computational Biomedicine, Boston University School of Medicine, Boston, MA, USA;Departments of Pathology, Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center, San Antonio, TX, USA;Department of Biochemistry and Molecular Biology, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA;Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL, USA;Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA

关键词: dasatinib;    dependence receptors;    ephrins;    p21;    PI3K delta;    plasminogen‐activated inhibitor;    quercetin;   

DOI  :  10.1111/acel.12344

来源: Wiley

【 摘 要 】

Summary

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^−/Δ 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.

【 授权许可】

CC BY   
© 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.