Mitochondrial Membrane Disrupting Molecules for Selective Killing of Senescent Cells

Cellular senescence, a stable form of cell cycle arrest, facilitates protection from tumorigenesis and aids in tissue repair as they accumulate in the body at an early age. However, long‐term retention of senescent cells causes inflammation, aging of the tissue, and progression of deadly diseases such as obesity, diabetes, and atherosclerosis. Various attempts have been made to achieve selective elimination of senescent cells from the body, yet little has been explored in designing the mitochondria‐targeted senolytic agent. Many characteristics of senescence are associated with mitochondria. Here we have designed a library of alkyl‐monoquaternary ammonium‐triphenyl phosphine (TPP) and alkyl‐diquaternary ammonium‐TPP of varying alkyl chain lengths, which target the mitochondria; we also studied their senolytic properties. It was observed that the alkyl‐diquaternary ammonium‐TPP with the longest chain length induced apoptosis in senescent cells selectively via an increase of reactive oxygen species (ROS) and mitochondrial membrane disruption. This study demonstrates that mitochondria could be a potential target for designing new small molecules as senolytic agents for the treatment of a variety of dysfunctions associated with pathological aging. Many characteristics of senescence are associated with mitochondria. Here, we showcase the importance of hydrophobicity and charge during the design of new mitochondria‐targeted small molecules as a senolytic agents for the treatment of a variety of dysfunctions associated with pathological aging.