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Nat Commun. 2014 Jun 24;2:4172. doi: 10.1038/ncomms5172.

Chronic inflammation induces telomere dysfunction and accelerates ageing in mice.

Author information

1
Institute for Ageing and Health, Newcastle University, NE4 5PL, UK.
2
Fibrosis Laboratory, Liver Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
3
Mitochondrial Research Group, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
4
1] Institute for Ageing and Health, Newcastle University, NE4 5PL, UK [2] Institute for Cell and Molecular Biosciences, Newcastle University, Catherine Cookson Building, Framlington Place, Newcastle Upon Tyne NE2 4HH, UK.
5
Faculty of Medicine, University of Southampton. Mailpoint 813, Sir Henry Wellcome Laboratories, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK.
6
Molecular Genetics Laboratory, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, The Netherlands.
7
1] Fibrosis Laboratory, Liver Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK [2].
8
1] Institute for Ageing and Health, Newcastle University, NE4 5PL, UK [2].

Abstract

Chronic inflammation is associated with normal and pathological ageing. Here we show that chronic, progressive low-grade inflammation induced by knockout of the nfkb1 subunit of the transcription factor NF-κB induces premature ageing in mice. We also show that these mice have reduced regeneration in liver and gut. nfkb1(-/-) fibroblasts exhibit aggravated cell senescence because of an enhanced autocrine and paracrine feedback through NF-κB, COX-2 and ROS, which stabilizes DNA damage. Preferential accumulation of telomere-dysfunctional senescent cells in nfkb1(-/-) tissues is blocked by anti-inflammatory or antioxidant treatment of mice, and this rescues tissue regenerative potential. Frequencies of senescent cells in liver and intestinal crypts quantitatively predict mean and maximum lifespan in both short- and long-lived mice cohorts. These data indicate that systemic chronic inflammation can accelerate ageing via ROS-mediated exacerbation of telomere dysfunction and cell senescence in the absence of any other genetic or environmental factor.

PMID:
24960204
PMCID:
PMC4090717
DOI:
10.1038/ncomms5172
[Indexed for MEDLINE]
Free PMC Article

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