Chronic inflammation induces telomere dysfunction and accelerates ageing in mice

Jurk, Diana; Wilson, Caroline; Passos, João F.; Oakley, Fiona; Correia-Melo, Clara; Greaves, Laura; Saretzki, Gabriele; Fox, Chris; Lawless, Conor; Anderson, Rhys; Hewitt, Graeme; Pender, Sylvia LF; Fullard, Nicola; Nelson, Glyn; Mann, Jelena; van de Sluis, Bart; Mann, Derek A.; von Zglinicki, Thomas

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.

Citation

Jurk, D., Wilson, C., Passos, J. F., Oakley, F., Correia-Melo, C., Greaves, L., …von Zglinicki, T. (2014). Chronic inflammation induces telomere dysfunction and accelerates ageing in mice. Nature Communications, 5(1), https://doi.org/10.1038/ncomms5172

• Journal Article Type: Article
• Acceptance Date: May 20, 2014
• Online Publication Date: Jun 24, 2014
• Publication Date: Jun 24, 2014
• Deposit Date: Aug 9, 2021
• Journal: Nature Communications
• Electronic ISSN: 2041-1723
• Publisher: Nature Research
• Peer Reviewed: Peer Reviewed
• Volume: 5
• Issue: 1
• DOI: https://doi.org/10.1038/ncomms5172
• Public URL: https://durham-repository.worktribe.com/output/1268706