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

Academic Article
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Overview

authors

  • Tilstra, J. S.
  • Robinson, A. R.
  • Wang, J.
  • Gregg, S. Q.
  • Clauson, C. L.
  • Reay, D. P.
  • Nasto, L. A.
  • St Croix, C. M.
  • Usas, A.
  • Vo, N.
  • Huard, J.
  • Clemens, P. R.
  • Stolz, D. B.
  • Guttridge, D. C.
  • Watkins, S. C.
  • Garinis, G. A.
  • Wang, Y. S.
  • Niedernhofer, Laura
  • Robbins, Paul D.

publication date

  • July 2012

journal

  • Journal of Clinical Investigation  Journal

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.

subject areas

  • Aging
  • Animals
  • Cell Aging
  • Cell Nucleus
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p16
  • DNA Damage
  • DNA-Binding Proteins
  • Endonucleases
  • Gene Expression Regulation
  • Hepatocytes
  • I-kappa B Kinase
  • Mice
  • Mice, Transgenic
  • Oxidative Stress
  • Peptides
  • Phosphorylation
  • Progeria
  • Protein Binding
  • Signal Transduction
  • Transcription Factor RelA
  • Transcriptional Activation
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Identity

PubMed Central ID

  • PMC3386805

International Standard Serial Number (ISSN)

  • 0021-9738

Digital Object Identifier (DOI)

  • 10.1172/jci45785

PubMed ID

  • 22706308
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Additional Document Info

start page

  • 2601

end page

  • 2612

volume

  • 122

issue

  • 7

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