Cellular senescence is characterized by an irreversible cell cycle arrest as well as a pro‐inflammatory phenotype, thought to contribute to aging and age‐related diseases. Neutrophils have essential roles in inflammatory responses; however, in certain contexts their abundance is associated with a number of age‐related diseases, including liver disease. The relationship between neutrophils and cellular senescence is not well understood. Here, we show that telomeres in non‐immune cells are highly susceptible to oxidative damage caused by neighboring neutrophils. Neutrophils cause telomere dysfunction both in vitro and ex vivo in a ROS‐dependent manner. In a mouse model of acute liver injury, depletion of neutrophils reduces telomere dysfunction and senescence. Finally, we show that senescent cells mediate the recruitment of neutrophils to the aged liver and propose that this may be a mechanism by which senescence spreads to surrounding cells. Our results suggest that interventions that counteract neutrophil‐induced senescence may be beneficial during aging and age‐related disease.
Bibliographical noteFunding Information:
The authors acknowledge support from NIH grants: R01 AG068048 (JFP), R01 AG068182-01 (DJ), R37 AG013925 (JLK, TT), R01 AG050582 (NN) and P01 AG062413 (SK, JLK, DJ, TT, JFP), the Connor Fund (JLK, TT), Robert J. and Theresa W. Ryan (JLK, TT), and the Noaber Foundation (JLK, TT). F.O and D.A.M are supported by MRC program Grants MR/K0019494/1 and MR/R023026/1. D.A.M is supported by a CRUK program grant, reference C18342/A23390. JFP, DJ, AL, and SV would like to thank the Ted Nash Long Life Foundation, UL1 TR0002377 from the National Centre for Advancing Translational Sciences (NCATS) and BBSRC [grants BB/L502066/1; BB/K017314/1]. DG is supported by the Newcastle CRUK Clinical Academic Training Programme. AC is funded by the W.E. Harker Foundation. PH is supported by the AASLD Foundation. DJ and PH are supported by P30DK084567. CAM was supported by a fellowship from Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior?Brasil (Capes)?Finance Code 001. MCAT mice were a kind gift from Prof. Owen Samson at the Cancer Research UK Beatson Institute. We also thank the technical support provided by Dr. Glyn Nelson and the Newcastle University Bioimaging unit.
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