title: The essential role of FoxO6 phosphorylation in aging and calorie restriction.
abstract: Changes in the activities of FoxOs caused by phosphorylation, acetylation, or ubiquitination induce expressional changes in the genes involved in the modulation of oxidative stress by modifying histones and chromatins and can substantially alter cellular functions during aging and age-related diseases. However, the precise role that FoxO6, a novel member of the FoxO class of transcription factors, plays in the aging kidney has not been determined. The purpose of this study was to determine the role played by FoxO6 in the maintenance of redox homeostasis in HEK293T cells and aged kidney tissues isolated from ad libitum (AL)-fed and 40 % calorie restriction (CR) rats. The results obtained from AL-fed rats showed that diminished FoxO6 activity during aging was caused by FoxO6 phosphorylation, which disabled its transcriptional activity. In contrast, CR rats were found to have significantly higher FoxO6 activities and maintained redox balance. To determine the molecular mechanism responsible for FoxO6 modification by age-related oxidative stress, we examined H2O2-treated HEK293T cells in which FoxO6 was inactivated by phosphorylation and found that H2O2-induced oxidative stress promoted FoxO6 phosphorylation via PI3K/Akt signaling. The results of this study show that the protective role of FoxO6 in the aging process may in part be related to its ability to attenuate oxidative stress by upregulating catalase expression, as shown in CR. This delineation of the role of FoxO6 expands understanding of the pathological and physiological mechanisms of aging.
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University, Gumjung-gu, Busan, 609-735, Republic of Korea.
authors.forename: Dae Hyun
authors.initials: DH
authors.lastname: Kim
authors.forename: Min Hi
authors.initials: MH
authors.lastname: Park
authors.forename: Ki Wung
authors.initials: KW
authors.lastname: Chung
authors.forename: Min Jo
authors.initials: MJ
authors.lastname: Kim
authors.forename: Yu Ri
authors.initials: YR
authors.lastname: Jung
authors.forename: Ha Ram
authors.initials: HR
authors.lastname: Bae
authors.forename: Eun Ji
authors.initials: EJ
authors.lastname: Jang
authors.forename: Jun Sik
authors.initials: JS
authors.lastname: Lee
authors.forename: Dong Soon
authors.initials: DS
authors.lastname: Im
authors.forename: Byung Pal
authors.initials: BP
authors.lastname: Yu
authors.forename: Hae Young
authors.initials: HY
authors.lastname: Chung
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D031204:Caloric Restriction / Q000379:methods*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D010766:Phosphorylation; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D051858:Forkhead Transcription Factors; C562177:Foxo6 protein, rat