title: Chronic inflammation induces telomere dysfunction and accelerates ageing in mice.
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.
authors: Institute for Ageing and Health, Newcastle University, NE4 5PL, UK.
authors: Diana
authors: D
authors: Jurk
authors: Fibrosis Laboratory, Liver Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors: Caroline
authors: C
authors: Wilson
authors: Institute for Ageing and Health, Newcastle University, NE4 5PL, UK.
authors: João F
authors: JF
authors: Passos
authors: Fibrosis Laboratory, Liver Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors: Fiona
authors: F
authors: Oakley
authors: Institute for Ageing and Health, Newcastle University, NE4 5PL, UK.
authors: Clara
authors: C
authors: Correia-Melo
authors: Mitochondrial Research Group, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors: Laura
authors: L
authors: Greaves
authors: Institute for Ageing and Health, Newcastle University, NE4 5PL, UK.
authors: Gabriele
authors: G
authors: Saretzki
authors: Fibrosis Laboratory, Liver Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors: Chris
authors: C
authors: Fox
authors: 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.
authors: Conor
authors: C
authors: Lawless
authors: Institute for Ageing and Health, Newcastle University, NE4 5PL, UK.
authors: Rhys
authors: R
authors: Anderson
authors: Institute for Ageing and Health, Newcastle University, NE4 5PL, UK.
authors: Graeme
authors: G
authors: Hewitt
authors: Faculty of Medicine, University of Southampton. Mailpoint 813, Sir Henry Wellcome Laboratories, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK.
authors: Sylvia Lf
authors: SL
authors: Pender
authors: Fibrosis Laboratory, Liver Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors: Nicola
authors: N
authors: Fullard
authors: Institute for Ageing and Health, Newcastle University, NE4 5PL, UK.
authors: Glyn
authors: G
authors: Nelson
authors: Fibrosis Laboratory, Liver Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors: Jelena
authors: J
authors: Mann
authors: Molecular Genetics Laboratory, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, The Netherlands.
authors: Bart
authors: B
authors: van de Sluis
authors: 1] Fibrosis Laboratory, Liver Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK [2].
authors: Derek A
authors: DA
authors: Mann
authors: 1] Institute for Ageing and Health, Newcastle University, NE4 5PL, UK [2].
authors: Thomas
authors: T
authors: von Zglinicki
mesh_terms: D019588:Aging, Premature / Q000235:genetics* / Q000276:immunology; D000818:Animals; D016922:Cellular Senescence / Q000235:genetics / Q000276:immunology; D002908:Chronic Disease; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics / Q000276:immunology; D025461:Feedback, Physiological; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics* / Q000276:immunology; D008115:Liver Regeneration / Q000235:genetics* / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D052002:NF-kappa B p50 Subunit / Q000235:genetics* / Q000276:immunology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012038:Regeneration / Q000235:genetics / Q000276:immunology; D059505:Telomere Homeostasis / Q000235:genetics* / Q000276:immunology
chemical_list: D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D017382:Reactive Oxygen Species; C073701:Nfkb1 protein, mouse; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat