Aging - DNA damage

p a p21-dependent senescence-like phenotype driven by a DNA damage response

1. Diana Jurk^1,†, 
2. Chunfang Wang^2,†, 
3. Satomi Miwa^1,†, 
4. Mandy Maddick¹, 
5. Viktor Korolchuk¹, 
6. Avgi Tsolou³, 
7. Efstathios S. Gonos³, 
8. Christopher Thrasivoulou⁴, 
9. M. Jill Saffrey², 
10. Kerry Cameron¹, 
11. Thomas von Zglinicki¹

Article first published online: 12 SEP 2012

DOI: 10.1111/j.1474-9726.2012.00870.x

© 2012 The Authors. Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland

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Aging Cell

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Keywords:

• aging;
• brain;
• inflammation;
• oxidative stress;
• neurons;
• senescence

Summary

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
.