The activation of NF-κB through Akt-induced FOXO1 phosphorylation during aging and its modulation by calorie restriction
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.
KeywordsInsulin FOXO1 NF-κB PI3K/Akt pathway Calorie restriction Aging
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.
- Coschigano KT, Holland AN, Riders ME, List EO, Flyvbjerg A, Kopchick JJ (2003) Deletion, but not antagonism, of the mouse growth hormone receptor results in severely decreased body weights, insulin, and insulin-like growth factor 1 levels and increased life span. Endocrinology 144:3799–3810PubMedCrossRefGoogle Scholar
- Iwasaki K, Gleiser CA, Masoro EJ, McMahan CA, Seo EJ, Yu BP (1988) The influence of dietary protein source on longevity and age-related disease processes of Fischer rats. J Gerontol 43:5–12Google Scholar
- Tomita M, Shimokawa I, Higami Y, Yanagihara-Outa K, Kawahara T, Tanaka K, Ikeda T, Shindo H (2001) Modulation by dietary restriction in gene expression related to insulin-like growth factor-1 in rat muscle. Aging (Milano) 13:273–281Google Scholar
- Yu BP (2005) Calorie restriction as a potent anti-aging intervention: suppression of oxidative stress. In: Rattan SIS (ed) Aging intervention and therapies, World Sci Pub, pp 193–217Google Scholar