Jurk, Diana; Wang, Chunfang; Miwa, Satomi; Maddick, Mandy; Korolchuk, Viktor; Tsolou, Avgi; Gonos, Efstathios S.; Thrasivoulou, Christopher; Saffrey, M. Jill; Cameron, Kerry and von Zglinicki, Thomas
Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response.
Aging Cell, 11(6) pp. 996–1004.
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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 b-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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