Chronic inflammation induces telomere dysfunction and accelerates ageing in mice

Diana Jurk, Caroline Wilson, João F. Passos, Fiona Oakley, Clara Correia-Melo, Laura Greaves, Gabriele Saretzki, Chris Fox, Conor Lawless, Rhys Anderson, Graeme Hewitt, Sylvia LF Pender, Nicola Fullard, Glyn Nelson, Jelena Mann, Bart van de Sluis, Derek A. Mann and Thomas von Zglinicki ()
Additional contact information
Diana Jurk: Institute for Ageing and Health, Newcastle University
Caroline Wilson: Fibrosis Laboratory, Liver Group, Institute of Cellular Medicine, Newcastle University
João F. Passos: Institute for Ageing and Health, Newcastle University
Fiona Oakley: Fibrosis Laboratory, Liver Group, Institute of Cellular Medicine, Newcastle University
Clara Correia-Melo: Institute for Ageing and Health, Newcastle University
Laura Greaves: Mitochondrial Research Group, Institute for Ageing and Health, Newcastle University
Gabriele Saretzki: Institute for Ageing and Health, Newcastle University
Chris Fox: Fibrosis Laboratory, Liver Group, Institute of Cellular Medicine, Newcastle University
Conor Lawless: Institute for Ageing and Health, Newcastle University
Rhys Anderson: Institute for Ageing and Health, Newcastle University
Graeme Hewitt: Institute for Ageing and Health, Newcastle University
Sylvia LF Pender: Faculty of Medicine, University of Southampton. Mailpoint 813, Sir Henry Wellcome Laboratories, Southampton General Hospital
Nicola Fullard: Fibrosis Laboratory, Liver Group, Institute of Cellular Medicine, Newcastle University
Glyn Nelson: Institute for Ageing and Health, Newcastle University
Jelena Mann: Fibrosis Laboratory, Liver Group, Institute of Cellular Medicine, Newcastle University
Bart van de Sluis: Molecular Genetics Laboratory, University of Groningen, University Medical Center Groningen
Derek A. Mann: Fibrosis Laboratory, Liver Group, Institute of Cellular Medicine, Newcastle University
Thomas von Zglinicki: Institute for Ageing and Health, Newcastle University

Nature Communications, 2014, vol. 5, issue 1, 1-14

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5172

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