Enhanced glycogenesis is involved in cellular senescence via GSK3/GS modulation.
Glycogen biogenesis and its response to physiological stimuli have often been implicated in age-related diseases. However, their direct relationships to cell senescence and aging have not been clearly elucidated. Here, we report the central involvement of enhanced glycogenesis in cellular senescence. Glycogen accumulation, glycogen synthase (GS) activation, and glycogen synthase kinase 3 (GSK3) inactivation commonly occurred in diverse cellular senescence models, including the liver tissues of aging F344 rats. Subcytotoxic concentrations of GSK3 inhibitors (SB415286 and LiCl) were sufficient to induce cellular senescence with increased glycogenesis. Interestingly, the SB415286-induced glycogenesis was irreversible, as were increased levels of reactive oxygen species and gain of senescence phenotypes. Blocking GSK3 activity using siRNA or dominant negative mutant (GSK3beta-K85A) also effectively induced senescence phenotypes, and GS knock-down significantly attenuated the stress-induced senescence phenotypes. Taken together, these results clearly demonstrate that augmented glycogenesis is not only common, but is also directly linked to cellular senescence and aging, suggesting GSK3 and GS as novel modulators of senescence, and providing new insight into the metabolic backgrounds of aging and aging-related pathogenesis.
Seo
Yong-Hak
YH
Department of Molecular Science and Technology, The Graduate School, Ajou University, Suwon 443-721, Korea.
Jung
Hyun-Jung
HJ
Shin
Hyun-Taek
HT
Kim
You-Mie
YM
Yim
Hyunee
H
Chung
Hae-Young
HY
Lim
In Kyoung
IK
Yoon
Gyesoon
G
D000367:Age Factors; D000627:Aminophenols / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D006003:Glycogen / Q000096:biosynthesis* / Q000378:metabolism; D006006:Glycogen Synthase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344
C417520:3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione; D000627:Aminophenols; D008301:Maleimides; D006003:Glycogen; D006006:Glycogen Synthase; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha