Cellular senescence is a form of cell cycle arrest that limits the proliferative potential of cells, including tumour cells. However, inability of immune cells to subsequently eliminate senescent cells from the organism may lead to tissue damage, inflammation, enhanced carcinogenesis and development of age-related diseases. We found that the anticancer agent mitochondria-targeted tamoxifen (MitoTam), unlike conventional anticancer agents, kills cancer cells without inducing senescence in vitro and in vivo. Surprisingly, it also selectively eliminates both malignant and non-cancerous senescent cells. In naturally aged mice treated with MitoTam for 4 weeks, we observed a significant decrease of senescence markers in all tested organs compared to non-treated animals. Mechanistically, we found that the susceptibility of senescent cells to MitoTam is linked to a very low expression level of adenine nucleotide translocase-2 (ANT2), inherent to the senescent phenotype. Restoration of ANT2 in senescent cells resulted in resistance to MitoTam, while its downregulation in non-senescent cells promoted their MitoTam-triggered elimination. Our study documents a novel, translationally intriguing role for an anticancer agent targeting mitochondria, that may result in a new strategy for the treatment of age-related diseases and senescence-associated pathologies.

Academy of Geriatric Cancer Research Department of Oncology Odense University Hospital 5000 Odense Denmark

Department of Cancer and Inflammation Research Institute of Molecular Medicine University of Southern Denmark 5000 Odense Denmark

Department of Genome Integrity Institute of Molecular Genetics of the Academy of Sciences of the Czech Republic v v i Prague 142 20 Czech Republic

Laboratory of Angiogenesis and Vascular Metabolism VIB KU Leuven Center for Cancer Biology Department of Oncology KU Leuven Campus Gasthuisberg O and N 4 Herestraat 49 B 912 3000 Leuven Belgium

Laboratory of Molecular Therapy Institute of Biotechnology Czech Academy of Sciences Prague 252 50 Czech Republic

Laboratory of Service Technology Institute of Biotechnology Czech Academy of Sciences Prague 252 50 Czech Republic

School of Medical Science Menzies Health Institute Queensland Griffith University Southport QLD 4222 Australia

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