Chronic inflammation induces telomere dysfunction and accelerates ageing in mice

Nat Commun. 2014 Jun 24;2:4172. doi: 10.1038/ncomms5172.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging, Premature / genetics*
  • Aging, Premature / immunology
  • Animals
  • Cellular Senescence / genetics
  • Cellular Senescence / immunology
  • Chronic Disease
  • Cyclooxygenase 2 / metabolism
  • DNA Damage / genetics
  • DNA Damage / immunology
  • Feedback, Physiological
  • Fibroblasts / immunology
  • Fibroblasts / metabolism*
  • Inflammation / genetics*
  • Inflammation / immunology
  • Liver Regeneration / genetics*
  • Liver Regeneration / immunology
  • Mice
  • Mice, Knockout
  • NF-kappa B / genetics
  • NF-kappa B / immunology
  • NF-kappa B p50 Subunit / genetics*
  • NF-kappa B p50 Subunit / immunology
  • Reactive Oxygen Species / metabolism
  • Regeneration / genetics
  • Regeneration / immunology
  • Telomere Homeostasis / genetics*
  • Telomere Homeostasis / immunology

Substances

  • NF-kappa B
  • NF-kappa B p50 Subunit
  • Reactive Oxygen Species
  • Nfkb1 protein, mouse
  • Cyclooxygenase 2
  • Ptgs2 protein, rat