Aging, characterized by accumulation of senescent cells, is a driving factor of various age-related diseases. These conditions pose significant health risks globally due to their increasing prevalence and serious complications. Reduction of senescent cells therefore represents a promising strategy promoting healthy aging. Here we demonstrate that targeting tamoxifen to mitochondria via triphenyl and tricyclohexyl phosphine selectively eliminates senescent cells. Our findings show a complex effect of mitochondrially targeted tamoxifen on mitochondrial function and integrity of senescent cells, including inhibition of oxidative phosphorylation and activity of respiratory complex IV. These changes result in activation of ferroptosis as the major mode of cell death, which results in rejuvenation of tissues. Targeting mitochondria of senescent cells represents a general senolytic strategy and may extend the healthspan and improve the quality of life in aging populations.

1st Faculty of Medicine Charles University Prague 121 08 Prague Czech Republic

Centre for Experimental Medicine Institute for Clinical and Experimental Medicine 140 21 Prague Czech Republic

Department of Biochemistry and Microbiology University of Chemistry and Technology Prague Czech Republic

Diabetes Centre Institute for Clinical and Experimental Medicine 140 21 Prague Czech Republic

Faculty of Science Charles University Prague 121 08 Prague Czech Republic

Institute of Biotechnology Czech Academy of Sciences Prague West Czech Republic

School of Pharmacy and Medical Science Griffith University Southport Qld Australia

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