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Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL

Author

Listed:
  • Reut Yosef

    (The Weizmann Institute of Science)

  • Noam Pilpel

    (The Weizmann Institute of Science)

  • Ronit Tokarsky-Amiel

    (Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School)

  • Anat Biran

    (The Weizmann Institute of Science)

  • Yossi Ovadya

    (The Weizmann Institute of Science)

  • Snir Cohen

    (The Weizmann Institute of Science)

  • Ezra Vadai

    (The Weizmann Institute of Science)

  • Liat Dassa

    (Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School)

  • Elisheva Shahar

    (Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School)

  • Reba Condiotti

    (Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School)

  • Ittai Ben-Porath

    (Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School)

  • Valery Krizhanovsky

    (The Weizmann Institute of Science)

Abstract

Senescent cells, formed in response to physiological and oncogenic stresses, facilitate protection from tumourigenesis and aid in tissue repair. However, accumulation of such cells in tissues contributes to age-related pathologies. Resistance of senescent cells to apoptotic stimuli may contribute to their accumulation, yet the molecular mechanisms allowing their prolonged viability are poorly characterized. Here we show that senescent cells upregulate the anti-apoptotic proteins BCL-W and BCL-XL. Joint inhibition of BCL-W and BCL-XL by siRNAs or the small-molecule ABT-737 specifically induces apoptosis in senescent cells. Notably, treatment of mice with ABT-737 efficiently eliminates senescent cells induced by DNA damage in the lungs as well as senescent cells formed in the epidermis by activation of p53 through transgenic p14ARF. Elimination of senescent cells from the epidermis leads to an increase in hair-follicle stem cell proliferation. The finding that senescent cells can be eliminated pharmacologically paves the way to new strategies for the treatment of age-related pathologies.

Suggested Citation

  • Reut Yosef & Noam Pilpel & Ronit Tokarsky-Amiel & Anat Biran & Yossi Ovadya & Snir Cohen & Ezra Vadai & Liat Dassa & Elisheva Shahar & Reba Condiotti & Ittai Ben-Porath & Valery Krizhanovsky, 2016. "Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL," Nature Communications, Nature, vol. 7(1), pages 1-11, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11190
    DOI: 10.1038/ncomms11190
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    Citations

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    Cited by:

    1. Ines Sturmlechner & Chance C. Sine & Karthik B. Jeganathan & Cheng Zhang & Raul O. Fierro Velasco & Darren J. Baker & Hu Li & Jan M. Deursen, 2022. "Senescent cells limit p53 activity via multiple mechanisms to remain viable," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Vanessa Smer-Barreto & Andrea Quintanilla & Richard J. R. Elliott & John C. Dawson & Jiugeng Sun & Víctor M. Campa & Álvaro Lorente-Macías & Asier Unciti-Broceta & Neil O. Carragher & Juan Carlos Acos, 2023. "Discovery of senolytics using machine learning," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    3. Imanol Duran & Joaquim Pombo & Bin Sun & Suchira Gallage & Hiromi Kudo & Domhnall McHugh & Laura Bousset & Jose Efren Barragan Avila & Roberta Forlano & Pinelopi Manousou & Mathias Heikenwalder & Domi, 2024. "Detection of senescence using machine learning algorithms based on nuclear features," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    4. Carlos Anerillas & Allison B. Herman & Rachel Munk & Amanda Garrido & Kwan-Wood Gabriel Lam & Matthew J. Payea & Martina Rossi & Dimitrios Tsitsipatis & Jennifer L. Martindale & Yulan Piao & Krystyna , 2022. "A BDNF-TrkB autocrine loop enhances senescent cell viability," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    5. Jaskaren Kohli & Chen Ge & Eleni Fitsiou & Miriam Doepner & Simone M. Brandenburg & William J. Faller & Todd W. Ridky & Marco Demaria, 2022. "Targeting anti-apoptotic pathways eliminates senescent melanocytes and leads to nevi regression," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    6. Miyoung Lee & Jamie A. G. Hamilton & Ganesh R. Talekar & Anthony J. Ross & Langston Michael & Manali Rupji & Bhakti Dwivedi & Sunil S. Raikar & Jeremy Boss & Christopher D. Scharer & Douglas K. Graham, 2022. "Obesity-induced galectin-9 is a therapeutic target in B-cell acute lymphoblastic leukemia," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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