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

Reut Yosef, Noam Pilpel, Ronit Tokarsky-Amiel, Anat Biran, Yossi Ovadya, Snir Cohen, Ezra Vadai, Liat Dassa, Elisheva Shahar, Reba Condiotti, Ittai Ben-Porath () and Valery Krizhanovsky ()
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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

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11190

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