title: Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response.
abstract: 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.
authors.affiliation: Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne NE4 5PL, UK.
authors.forename: Diana
authors.initials: D
authors.lastname: Jurk
authors.forename: Chunfang
authors.initials: C
authors.lastname: Wang
authors.forename: Satomi
authors.initials: S
authors.lastname: Miwa
authors.forename: Mandy
authors.initials: M
authors.lastname: Maddick
authors.forename: Viktor
authors.initials: V
authors.lastname: Korolchuk
authors.forename: Avgi
authors.initials: A
authors.lastname: Tsolou
authors.forename: Efstathios S
authors.initials: ES
authors.lastname: Gonos
authors.forename: Christopher
authors.initials: C
authors.lastname: Thrasivoulou
authors.forename: M Jill
authors.initials: MJ
authors.lastname: Saffrey
authors.forename: Kerry
authors.initials: K
authors.lastname: Cameron
authors.forename: Thomas
authors.initials: T
authors.lastname: von Zglinicki
mesh_terms: D000375:Aging / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D031204:Caloric Restriction; D002452:Cell Count; D016922:Cellular Senescence / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000172:deficiency / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008938:Mitosis; D009197:Myenteric Plexus / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011689:Purkinje Cells / Q000378:metabolism* / Q000473:pathology; D012313:RNA / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D019098:Telomerase / Q000172:deficiency / Q000235:genetics*; D016615:Telomere / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D015850:Interleukin-6; D017382:Reactive Oxygen Species; C422952:telomerase RNA; D012313:RNA; D048051:p38 Mitogen-Activated Protein Kinases; D019098:Telomerase; D001616:beta-Galactosidase