Chronic inflammation induces telomere dysfunction and accelerates ageing in mice.

Author: Jurk D1, Wilson C2, Passos JF1, Oakley F2, Correia-Melo C1, Greaves L3, Saretzki G1, Fox C2, Lawless C4, Anderson R1, Hewitt G1, Pender SL5, Fullard N2, Nelson G1, Mann J2, van de Sluis B6, Mann DA7, von Zglinicki T8.
Affiliation: 1Institute for Ageing and Health, Newcastle University, NE4 5PL, UK. 2Fibrosis Laboratory, Liver Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. 3Mitochondrial Research Group, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. 41] 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. 5Faculty of Medicine, University of Southampton. Mailpoint 813, Sir Henry Wellcome Laboratories, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK. 6Molecular Genetics Laboratory, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, The Netherlands. 71] Fibrosis Laboratory, Liver Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK [2]. 81] Institute for Ageing and Health, Newcastle University, NE4 5PL, UK [2].
Conference/Journal: Nat Commun.
Date published: 2014 Jun 24
Other: Volume ID: 2 , Pages: 4172 , Special Notes: doi: 10.1038/ncomms5172 , Word Count: 152



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