In senescent cells, a DNA damage response drives not only irreversible loss of replicative capacity but also production and secretion of reactive oxygen species (ROS) and bioactive peptides including pro‐inflammatory cytokines. This makes senescent cells a potential cause of tissue functional decline in aging. To our knowledge, we show here for the first time evidence suggesting that DNA damage induces a senescence‐like state in mature postmitotic neurons in vivo . About 40–80% of Purkinje neurons and 20–40% of cortical, hippocampal and peripheral neurons in the myenteric plexus from old C57Bl/6 mice showed severe DNA damage, activated p38MAPkinase, high ROS production and oxidative damage, interleukin IL‐6 production, heterochromatinization and senescence‐associated β‐galactosidase activity. Frequencies of these senescence‐like neurons increased with age. Short‐term caloric restriction tended to decrease frequencies of positive cells. The phenotype was aggravated in brains of late‐generation TERC−/− mice with dysfunctional telomeres. It was fully rescued by loss of p21(CDKN1A) function in late‐generation TERC−/−CDKN1A−/− mice, indicating p21 as the necessary signal transducer between DNA damage response and senescence‐like phenotype in neurons, as in senescing fibroblasts and other proliferation‐competent cells. We conclude that a senescence‐like phenotype is possibly not restricted to proliferation‐competent cells. Rather, dysfunctional telomeres and/or accumulated DNA damage can induce a DNA damage response leading to a phenotype in postmitotic neurons that resembles cell senescence in multiple features. Senescence‐like neurons might be a source of oxidative and inflammatory stress and a contributor to brain aging.

Acknowledgments The study was supported by BBSRC grants BB/C008200/1 (CISBAN) and BB/I020748/1 and by MRC grant G0601333 to TvZ.

Author contributions DJ, CW, SM, MM, AT, CT, VK and KC performed experiments, DJ, CW, SM and TvZ analysed data, ESG and JS supervised individual experiments, SM and TvZ designed the study, TvZ supervised the study and wrote the paper with input from all authors.

Conflict of interest All authors declare that they have no conflict of interest.

Supporting Information Fig S1 Further DDR markers in Purkinje neurons from old mice. Fig S2 Negative controls for immunofluorescence and immunohistochemistry. Fig S3 Purkinje neurons in old mice are positive for multiple markers of the senescent phenotype as shown by immunohistochemistry. Fig S4 Cortical neurons in old mice are positive for multiple markers of the senescent phenotype as shown by immunohistochemistry. Fig S5 Markers of a senescence‐like phenotype in hippocampal neurons. Fig S6 Protein oxidation increases in old mice brains. Fig S7 The same cells are positive for multiple markers of the senescent phenotype. Filename Description acel870_sm_870_Supplementary-Methods.doc47 KB Supporting info item acel870_sm_FigS1.tif770.3 KB Supporting info item acel870_sm_FigS2.jpg1 MB Supporting info item acel870_sm_FigS3.tif4.1 MB Supporting info item acel870_sm_FigS4.tif8.6 MB Supporting info item acel870_sm_FigS5.jpg773.8 KB Supporting info item acel870_sm_FigS6.tif66.4 KB Supporting info item acel870_sm_FigS7.jpg571.7 KB Supporting info item acel870_sm_Supplementary-Legends.doc31 KB Supporting info item Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.