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

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Abstract

Insulin-induced PI3K/Akt activation is known to inhibit a family of Forkhead transcription factors (FOXO), which can lead to increased oxidative stress in several model organisms. One of major transcription factors activated by oxidative stress and responsible for the production of many proinflammatory cytokines is NF-κB. In the present study, We were carried out to determine the relationship between FOXO1 and NF-κB activation using HEK293T cells and aged kidney isolated from ad libitum fed (AL) and 40% calorie restriction (CR) rats. Results showed that phosphorylation of FOXO1 and NF-κB activation were significantly increased in old rats. Moreover, FOXO1 phosphorylation and NF-κB activation were shown to be significantly lower in the CR rats compared with 24–month-old AL rats. To further explore the molecular link between FOXO and NF-κB, we performed transfection experiments with FOXO-mutant plasmid in cultured HEK293T cells. Treatment of the cell with insulin led to NF-κB activation through the phosphorylation of FOXO via the PI3K/Akt pathway. These results indicate that insulin promoted NF-κB activation through phosphorylation of FOXO1 by upregulating PI3K/Akt signaling. We conclude that the phosphorylation of FOXO1 regulates NF-κB nuclear translocation by activating PI3K/Akt during aging, which was suppressed by the hypoinsulinemic action of CR.

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Acknowledgements

This research was supported by KOSEF and MOST through National Nuclear Technology Program (2006–04978 and 2007–00376). We are thankful to the “Aging Tissue Bank” (R21–2000–000–00021–0) granted by Korea Science and Engineering Foundation.

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Authors and Affiliations

  1. Department of Pharmacy, College of Pharmacy, Pusan National University, Longevity Life Science and Technology Institutes, Pusan National University, San 30, Jangjun-dong, Gumjung-gu, Busan, 609-735, Korea

    Dae Hyun Kim, Ji Young Kim & Hae Young Chung

  2. Longevity Life Science and Technology, Institutes, Pusan National University, Gumjung-gu, Busan, Korea

    Byung Pal Yu & Hae Young Chung

  3. Department of Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA

    Byung Pal Yu

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  1. Dae Hyun Kim
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  2. Ji Young Kim
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  4. Hae Young Chung
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Correspondence to Hae Young Chung.

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Kim, D.H., Kim, J.Y., Yu, B.P. et al. The activation of NF-κB through Akt-induced FOXO1 phosphorylation during aging and its modulation by calorie restriction. Biogerontology 9, 33–47 (2008). https://doi.org/10.1007/s10522-007-9114-6

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  • DOI: https://doi.org/10.1007/s10522-007-9114-6

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