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The activation of NF-kappaB through Akt-induced FOXO1 phosphorylation during aging and its modulation by calorie

Dae Hyun Kim1, Ji Young Kim, Byung Pal Yu

  • 1Department of Pharmacy, College of Pharmacy, Pusan National University, Longevity Life Science and Technology Institutes, Pusan National University, Busan, Korea.

Biogerontology
|November 1, 2007
PubMed

Insights

Aging increases FOXO1 phosphorylation and NF-kappaB activation, linked to oxidative stress. Calorie restriction (CR) suppresses this pathway, suggesting a therapeutic target for age-related inflammation.

Area of Science:

  • Molecular Biology
  • Aging Research
  • Cell Signaling

Background:

  • Insulin signaling via PI3K/Akt inhibits Forkhead transcription factors (FOXO).
  • FOXO inhibition and oxidative stress are linked to inflammation via NF-kappaB.
  • Aging is associated with increased oxidative stress and inflammation.

Purpose of the Study:

  • To investigate the relationship between FOXO1 and NF-kappaB activation during aging.
  • To determine the effect of calorie restriction (CR) on this relationship.
  • To elucidate the role of PI3K/Akt signaling in insulin-mediated FOXO1 and NF-kappaB regulation.

Main Methods:

  • Analysis of FOXO1 and NF-kappaB activation in aged rat kidneys (ad libitum fed vs. calorie restricted).
  • HEK293T cell transfections with FOXO-mutant plasmids.
  • Insulin treatment and PI3K/Akt pathway modulation in cell culture experiments.

Main Results:

  • Old rats exhibited significantly increased phosphorylation of FOXO1 and NF-kappaB activation compared to younger controls.
  • Calorie restriction (CR) significantly reduced FOXO1 phosphorylation and NF-kappaB activation in aged rats.
  • Insulin treatment in HEK293T cells promoted NF-kappaB activation via PI3K/Akt-mediated FOXO1 phosphorylation.

Conclusions:

  • Insulin promotes NF-kappaB activation through PI3K/Akt-dependent FOXO1 phosphorylation.
  • FOXO1 phosphorylation regulates NF-kappaB nuclear translocation via PI3K/Akt activation during aging.
  • Calorie restriction suppresses this aging-associated inflammatory pathway through hypoinsulinemic action.

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