TY - JOUR
T1 - Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL
AU - Yosef, Reut
AU - Pilpel, Noam
AU - Tokarsky-Amiel, Ronit
AU - Biran, Anat
AU - Ovadya, Yossi
AU - Cohen, Snir
AU - Vadai, Ezra
AU - Dassa, Liat
AU - Shahar, Elisheva
AU - Condiotti, Reba
AU - Ben-Porath, Ittai
AU - Krizhanovsky, Valery
N1 - European Research Council under the European Union's FP7; Israel Science Foundation [1009/13]; Jacob and Lena Joels Memorial Foundation Senior Lectureship
PY - 2016/4/6
Y1 - 2016/4/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84963650460&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/ncomms11190
DO - https://doi.org/10.1038/ncomms11190
M3 - مقالة
C2 - 27048913
SN - 2041-1723
VL - 7
JO - Nature Communications
JF - Nature Communications
M1 - 11190
ER -
