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

1. Aging Cell. 2015 Aug;14(4):644-58. doi: 10.1111/acel.12344. Epub 2015 Apr 22. The Achilles' heel of senescent cells: from transcriptome to senolytic drugs. Zhu Y(1), Tchkonia T(1), Pirtskhalava T(1), Gower AC(2), Ding H(1), Giorgadze N(1), Palmer AK(1), Ikeno Y(3)(4), Hubbard GB(3)(4), Lenburg M(2), O'Hara SP(1), LaRusso NF(1), Miller JD(1), Roos CM(1), Verzosa GC(1), LeBrasseur NK(1), Wren JD(5), Farr JN(1), Khosla S(1), Stout MB(1), McGowan SJ(6), Fuhrmann-Stroissnigg H(6), Gurkar AU(6), Zhao J(6), Colangelo D(6), Dorronsoro A(6), Ling YY(6), Barghouthy AS(6), Navarro DC(6), Sano T(6), Robbins PD(6), Niedernhofer LJ(6), Kirkland JL(1). Author information: (1)Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA. (2)Section of Computational Biomedicine, Boston University School of Medicine, Boston, MA, USA. (3)Departments of Pathology, Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center, San Antonio, TX, USA. (4)Research Service, Geriatric Research and Education Clinical Center, Audie L. Murphy VA Hospital South Texas Veterans Health Care System, San Antonio, TX, USA. (5)Department of Biochemistry and Molecular Biology, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA. (6)Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL, USA. 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. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. DOI: 10.1111/acel.12344 PMCID: PMC4531078 PMID: 25754370 [Indexed for MEDLINE]