Lei Zhang, Rahagir Salekeen, Carolina Soto-Palma, Osama Elsallabi, Hongping Ye, Brian Hughes, Borui Zhang, Allancer Nunes, Kyoo-A Lee, Wandi Xu, Abdalla D. Mohamed, Ellie Piepgras, Sara J. McGowan, Luise Angelini, Ryan O’Kelly, Xianlin Han, Laura J. Niedernhofer, Paul D. Robbins
Cellular senescence is a key driver of the aging process and contributes to tissue dysfunction and age-related pathologies. Senolytics have emerged as a promising therapeutic intervention to extend healthspan and treat age-related diseases. Through a senescent-cell-based phenotypic screen, we identified conjugated polyunsaturated fatty acids (PUFAs), specifically α-eleostearic acid and its methyl ester derivative, as senolytics that effectively killed a broad range of senescent cells, reduced tissue senescence, and extended healthspan in mice. Importantly, these lipids induced senolysis through ferroptosis, rather than apoptosis or necrosis, by exploiting elevated iron, cytosolic PUFAs, and reactive oxygen species (ROS) levels in senescent cells. Mechanistic studies further revealed their key targets in the ferroptosis pathway, ACSL4, LPCAT3, and ALOX15, important for lipid-induced senolysis. These findings identify conjugated PUFAs as ferroptosis-inducing senolytics and establish ferroptosis as a targetable vulnerability of senescent cells.