NF-κB inhibition delays DNA damage-induced senescence and aging in mice

J Clin Invest. 2012 Jul;122(7):2601-12. doi: 10.1172/JCI45785. Epub 2012 Jun 18.

Abstract

The accumulation of cellular damage, including DNA damage, is thought to contribute to aging-related degenerative changes, but how damage drives aging is unknown. XFE progeroid syndrome is a disease of accelerated aging caused by a defect in DNA repair. NF-κB, a transcription factor activated by cellular damage and stress, has increased activity with aging and aging-related chronic diseases. To determine whether NF-κB drives aging in response to the accumulation of spontaneous, endogenous DNA damage, we measured the activation of NF-κB in WT and progeroid model mice. As both WT and progeroid mice aged, NF-κB was activated stochastically in a variety of cell types. Genetic depletion of one allele of the p65 subunit of NF-κB or treatment with a pharmacological inhibitor of the NF-κB-activating kinase, IKK, delayed the age-related symptoms and pathologies of progeroid mice. Additionally, inhibition of NF-κB reduced oxidative DNA damage and stress and delayed cellular senescence. These results indicate that the mechanism by which DNA damage drives aging is due in part to NF-κB activation. IKK/NF-κB inhibitors are sufficient to attenuate this damage and could provide clinical benefit for degenerative changes associated with accelerated aging disorders and normal aging.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / drug effects*
  • Aging / genetics
  • Animals
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Cellular Senescence*
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • DNA Damage*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Endonucleases / genetics
  • Endonucleases / metabolism
  • Gene Expression Regulation / drug effects
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Hepatocytes / physiology
  • I-kappa B Kinase / antagonists & inhibitors*
  • I-kappa B Kinase / metabolism
  • Mice
  • Mice, Transgenic
  • Oxidative Stress
  • Peptides / pharmacology
  • Phosphorylation
  • Progeria / drug therapy
  • Progeria / pathology
  • Protein Binding
  • Signal Transduction
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism*
  • Transcriptional Activation

Substances

  • Cdkn2a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p16
  • DNA-Binding Proteins
  • NBD peptide, mouse
  • Peptides
  • Rela protein, mouse
  • Transcription Factor RelA
  • I-kappa B Kinase
  • Endonucleases
  • Ercc1 protein, mouse