1. The Achilles' heel of senescent cells: from transcriptome to senolytic drugs.
- Author
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Zhu Y, Tchkonia T, Pirtskhalava T, Gower AC, Ding H, Giorgadze N, Palmer AK, Ikeno Y, Hubbard GB, Lenburg M, O'Hara SP, LaRusso NF, Miller JD, Roos CM, Verzosa GC, LeBrasseur NK, Wren JD, Farr JN, 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, and Kirkland JL
- Subjects
- Adipocytes drug effects, Adipocytes metabolism, Adipocytes pathology, Aging genetics, Aging metabolism, Aging pathology, Animals, Carotid Arteries drug effects, Carotid Arteries pathology, Cellular Senescence genetics, Class I Phosphatidylinositol 3-Kinases, Cyclin-Dependent Kinase Inhibitor p21 genetics, Cyclin-Dependent Kinase Inhibitor p21 metabolism, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Drug Combinations, Endonucleases genetics, Endonucleases metabolism, Endothelial Cells drug effects, Endothelial Cells metabolism, Endothelial Cells pathology, Ephrins genetics, Ephrins metabolism, Fibroblasts drug effects, Fibroblasts metabolism, Fibroblasts pathology, Gene Expression Profiling, Heart drug effects, Heart physiopathology, Intervertebral Disc chemistry, Intervertebral Disc drug effects, Intervertebral Disc pathology, Mesenchymal Stem Cells drug effects, Mesenchymal Stem Cells metabolism, Mesenchymal Stem Cells pathology, Mice, Mice, Knockout, Osteoporosis genetics, Osteoporosis metabolism, Osteoporosis pathology, Phosphatidylinositol 3-Kinases genetics, Phosphatidylinositol 3-Kinases metabolism, Plasminogen Activator Inhibitor 2 genetics, Plasminogen Activator Inhibitor 2 metabolism, bcl-X Protein genetics, bcl-X Protein metabolism, Aging drug effects, Cellular Senescence drug effects, Dasatinib pharmacology, Osteoporosis prevention & control, Quercetin pharmacology, Transcriptome
- 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(-/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.)
- Published
- 2015
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