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DNA damage response and cellular senescence in tissues of aging mice

Lookup NU author(s): Chunfang Wang, Dr Diana Jurk, Mandy Maddick, Dr Glyn Nelson, Dr Carmen Martin-Ruiz, Professor Thomas von Zglinicki

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Abstract

The impact of cellular senescence onto aging of organisms is not fully clear, not at least because of the scarcity of reliable data on the mere frequency of senescent cells in aging tissues. Activation of a DNA damage response including formation of DNA damage foci containing activated H2A.X (gamma-H2A.X) at either uncapped telomeres or persistent DNA strand breaks is the major trigger of cell senescence. Therefore, gamma-H2A.X immunohistochemistry (IHC) was established by us as a reliable quantitative indicator of senescence in fibroblasts in vitro and in hepatocytes in vivo and the age dependency of DNA damage foci accumulation in ten organs of C57Bl6 mice was analysed over an age range from 12 to 42 months. There were significant increases with age in the frequency of foci-containing cells in lung, spleen, dermis, liver and gut epithelium. In liver, foci-positive cells were preferentially found in the centrilobular area, which is exposed to higher levels of oxidative stress. Foci formation in the intestine was restricted to the crypts. It was not associated with either apoptosis or hyperproliferation. That telomeres shortened with age in both crypt and villus enterocytes, but telomeres in the crypt epithelium were longer than those in villi at all ages were confirmed by us. Still, there was no more than random co-localization between gamma-H2A.X foci and telomeres even in crypts from very old mice, indicating that senescence in the crypt enterocytes is telomere independent. The results suggest that stress-dependent cell senescence could play a causal role for aging of mice.


Publication metadata

Author(s): Wang CF, Jurk D, Maddick M, Nelson G, Martin-Ruiz C, von Zglinicki T

Publication type: Article

Publication status: Published

Journal: Aging Cell

Year: 2009

Volume: 8

Issue: 3

Pages: 311-323

ISSN (print): 1474-9718

ISSN (electronic): 1474-9726

Publisher: Wiley-Blackwell Publishing Ltd.

URL: http://dx.doi.org/10.1111/j.1474-9726.2009.00481.x

DOI: 10.1111/j.1474-9726.2009.00481.x


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