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

Jeremy S Tilstra1, Andria R Robinson, Jin Wang

  • 1Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

The Journal of Clinical Investigation
|June 19, 2012
PubMed

Insights

Cellular DNA damage accumulation drives aging partly through activating NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells). Inhibiting this pathway delays aging symptoms and reduces DNA damage.

Area of Science:

  • Molecular Biology
  • Genetics
  • Gerontology

Background:

  • Cellular damage, particularly DNA damage, is linked to aging, but the underlying mechanisms remain unclear.
  • Accelerated aging diseases like XFE progeroid syndrome stem from DNA repair defects.
  • Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is activated by stress and shows increased activity with aging.

Purpose of the Study:

  • To investigate if NF-κB activation, driven by endogenous DNA damage, contributes to aging.
  • To explore the role of NF-κB in the aging process using progeroid mouse models.

Main Methods:

  • Measured NF-κB activation in wild-type (WT) and progeroid model mice during aging.
  • Utilized genetic depletion of the NF-κB p65 subunit.
  • Administered pharmacological inhibitors of the NF-κB-activating kinase, IKK.

Main Results:

  • NF-κB activation occurred stochastically in various cell types as mice aged.
  • Genetic or pharmacological inhibition of NF-κB delayed age-related symptoms and pathologies in progeroid mice.
  • NF-κB inhibition reduced oxidative DNA damage, stress, and delayed cellular senescence.

Conclusions:

  • DNA damage contributes to aging, in part, through NF-κB activation.
  • Inhibitors targeting the IKK/NF-κB pathway can mitigate age-related damage.
  • IKK/NF-κB inhibitors show potential for treating accelerated aging disorders and normal aging processes.

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