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

Aging Cell. 2012 Dec;11(6):996-1004. doi: 10.1111/j.1474-9726.2012.00870.x. Epub 2012 Sep 12.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics*
  • Aging / metabolism
  • Aging / pathology
  • Animals
  • Caloric Restriction
  • Cell Count
  • Cellular Senescence / genetics*
  • Cyclin-Dependent Kinase Inhibitor p21 / deficiency
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics*
  • DNA Damage / genetics*
  • Gene Expression Regulation, Developmental
  • Humans
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mitosis
  • Myenteric Plexus / metabolism
  • Myenteric Plexus / pathology
  • Phenotype
  • Purkinje Cells / metabolism*
  • Purkinje Cells / pathology
  • RNA / genetics*
  • Reactive Oxygen Species / metabolism
  • Signal Transduction
  • Telomerase / deficiency
  • Telomerase / genetics*
  • Telomere / genetics
  • Telomere / metabolism
  • Telomere / pathology
  • beta-Galactosidase / genetics
  • beta-Galactosidase / metabolism
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Cyclin-Dependent Kinase Inhibitor p21
  • Interleukin-6
  • Reactive Oxygen Species
  • telomerase RNA
  • RNA
  • p38 Mitogen-Activated Protein Kinases
  • Telomerase
  • beta-Galactosidase