title: High glucose-induced replicative senescence: point of no return and effect of telomerase.
abstract: Primary human cells enter senescence after a characteristic number of population doublings (PDs). In the current study, human skin fibroblasts were propagated in culture under 5.5mM glucose (normoglycemia); addition of 16.5mM D-glucose to a concentration of 22 mM (hyperglycemia); and addition of 16.5mM L-glucose (osmotic control). Hyperglycemia induced premature replicative senescence after 44.42+/-1.5 PDs compared to 57.9+/-3.83 PDs under normoglycemia (p<0.0001). L-Glucose had no effect, suggesting that the effect of hyperglycemia was not attributed to hyperosmolarity. Activated caspase-3 measurement showed a significantly higher percentage of apoptotic cells in high glucose medium. Telomerase overexpression circumvented the effects of hyperglycemia on replicative capacity and apoptosis. The "point of no return," beyond which hyperglycemia resulted in irreversible progression to premature replicative senescence, occurred after exposure to hyperglycemia for as few as 20 PDs. These results may provide a biochemical basis for the relationship between hyperglycemia and those complications of diabetes, which are reminiscent of accelerated senescence.
authors.affiliation: Department of Neonatology, Rambam Medical Center, Bruce Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, P.O. Box 9602, 31096, Haifa, Israel. blazer@rambam.health.gov.il
authors.forename: Shraga
authors.initials: S
authors.lastname: Blazer
authors.forename: Eli
authors.initials: E
authors.lastname: Khankin
authors.forename: Yardena
authors.initials: Y
authors.lastname: Segev
authors.forename: Rachel
authors.initials: R
authors.lastname: Ofir
authors.forename: Michal
authors.initials: M
authors.lastname: Yalon-Hacohen
authors.forename: Zipora
authors.initials: Z
authors.lastname: Kra-Oz
authors.forename: Yossi
authors.initials: Y
authors.lastname: Gottfried
authors.forename: Sarit
authors.initials: S
authors.lastname: Larisch
authors.forename: Karl L
authors.initials: KL
authors.lastname: Skorecki
mesh_terms: D002455:Cell Division / Q000187:drug effects*; D016922:Cellular Senescence / Q000187:drug effects*; D003470:Culture Media; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D012867:Skin / Q000166:cytology / Q000187:drug effects*; D019098:Telomerase / Q000502:physiology*
chemical_list: D003470:Culture Media; D019098:Telomerase; D005947:Glucose