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

Diana Jurk, Chunfang Wang, Satomi Miwa, Mandy Maddick, Viktor Korolchuk, Avgi Tsolou, Efstathios S. Gonos, Christopher Thrasivoulou, M. Jill Saffrey, Kerry Cameron, Thomas von Zglinicki

Research output: Contribution to journalArticle

169 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)996-1004
Number of pages9
JournalAging Cell
Volume11
Issue number6
DOIs
StatePublished - Dec 1 2012
Externally publishedYes

Fingerprint

DNA Damage
Phenotype
Neurons
Telomere
Interleukin-6
Reactive Oxygen Species
Cell Proliferation
Galactosidases
Myenteric Plexus
Caloric Restriction
Cell Aging
Purkinje Cells
Brain
Transducers
Oxidative Stress
Fibroblasts
Cytokines
Peptides
telomerase RNA

Keywords

  • Aging
  • Brain
  • Inflammation
  • Neurons
  • Oxidative stress
  • Senescence

ASJC Scopus subject areas

  • Aging
  • Cell Biology

Cite this

Jurk, D., Wang, C., Miwa, S., Maddick, M., Korolchuk, V., Tsolou, A., ... von Zglinicki, T. (2012). Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response. Aging Cell, 11(6), 996-1004. https://doi.org/10.1111/j.1474-9726.2012.00870.x

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

In: Aging Cell, Vol. 11, No. 6, 01.12.2012, p. 996-1004.

Research output: Contribution to journalArticle

Jurk, D, Wang, C, Miwa, S, Maddick, M, Korolchuk, V, Tsolou, A, Gonos, ES, Thrasivoulou, C, Jill Saffrey, M, Cameron, K & von Zglinicki, T 2012, 'Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response', Aging Cell, vol. 11, no. 6, pp. 996-1004. https://doi.org/10.1111/j.1474-9726.2012.00870.x
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. / Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response. In: Aging Cell. 2012 ; Vol. 11, No. 6. pp. 996-1004.
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