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 L.F. Pender, Nicola Fullard, Glyn Nelson, Jelena Mann, Bart Van De Sluis, Derek A. Mann, Thomas Von Zglinicki

Research output: Contribution to journalArticle

295 Scopus citations

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-κ B 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-κ B, 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.

Original languageEnglish (US)
Article number4172
JournalNature communications
Volume2
DOIs
StatePublished - Jun 24 2014

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Jurk, D., Wilson, C., Passos, J. F., Oakley, F., Correia-Melo, C., Greaves, L., Saretzki, G., Fox, C., Lawless, C., Anderson, R., Hewitt, G., Pender, S. L. F., Fullard, N., Nelson, G., Mann, J., Van De Sluis, B., Mann, D. A., & Von Zglinicki, T. (2014). Chronic inflammation induces telomere dysfunction and accelerates ageing in mice. Nature communications, 2, [4172]. https://doi.org/10.1038/ncomms5172