Postmitotic neurons develop a p21‐dependent senescence‐like phenotype driven by a DNA damage response

• Published in: Aging cell 2012-12, Vol.11 (6), p.996-1004
• Main Authors: Jurk, Diana, Wang, Chunfang, Miwa, Satomi, Maddick, Mandy, Korolchuk, Viktor, Tsolou, Avgi, Gonos, Efstathios S., Thrasivoulou, Christopher, Jill Saffrey, M., Cameron, Kerry, von Zglinicki, Thomas
• Format: Article
• Language: English
• Subjects: Aging; Aging - genetics; Aging - metabolism; Aging - pathology; Animals; beta-Galactosidase - genetics; beta-Galactosidase - metabolism; brain; Caloric Restriction; Cell Count; Cellular Senescence - genetics; Cyclin-Dependent Kinase Inhibitor p21 - deficiency; Cyclin-Dependent Kinase Inhibitor p21 - genetics; DNA damage; DNA Damage - genetics; Gene Expression Regulation, Developmental; Genotype & phenotype; Humans; inflammation; Interleukin-6 - genetics; Interleukin-6 - metabolism; Mice; Mice, Inbred C57BL; Mitosis; Myenteric Plexus - metabolism; Myenteric Plexus - pathology; neurons; Original; oxidative stress; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; Phenotype; Purkinje Cells - metabolism; Purkinje Cells - pathology; Reactive Oxygen Species - metabolism; RNA - genetics; senescence; Signal Transduction; Telomerase - deficiency; Telomerase - genetics; Telomere - genetics; Telomere - metabolism; Telomere - pathology
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/j.1474-9726.2012.00870.x

Summary 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.