Postmitotic neurons develop a p21‐dependent senescence‐like phenotype driven by a DNA damage response |
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Authors: | Mandy Maddick Viktor Korolchuk Avgi Tsolou Efstathios S Gonos Christopher Thrasivoulou M Jill Saffrey Kerry Cameron Thomas von Zglinicki |
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Institution: | 1. Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne NE4 5PL, UK;2. National Hellenic Research Foundation, Institute of Biological Research and Biotechnology, Athens, Greece;3. Department of Anatomy and Developmental Biology, University College London, London WC1E 6DE, UK;4. Department of Life Sciences, The Open University, Milton Keynes MK7 6AA, UK |
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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. |
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Keywords: | aging brain inflammation oxidative stress neurons senescence |
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