title: Mitochondrion-mediated apoptosis is enhanced in long-lived alphaMUPA transgenic mice and calorically restricted wild-type mice.
abstract: Caloric restriction (CR) can extend the life-span of multiple species and is the only intervention known to attenuate aging in mammals. Mechanisms mediating the CR influence are as yet unclear. To get insight into these mechanisms we took advantage of alphaMUPA transgenic mice that have previously been reported to spontaneously eat less and live longer compared with their wild-type (WT) control. Here we report that mitochondria isolated from young adult alphaMUPA livers showed increased susceptibility to calcium-induced high-amplitude swelling, increased cytochrome c release and enhanced glutathione levels. Furthermore, young adult alphaMUPA mice showed significantly enhanced caspase-3 activity in liver homogenates, increased fraction of apoptotic hepatocytes, and a lower level of serum IGF-1. In addition, alphaMUPA mice showed a decreased rate of spontaneously occurring lung tumors at an old age. Short-term (8 weeks) calorically restricted WT mice also showed an increase of mitochondrial swelling and caspase-3 activity compared with ad libitum (AL) fed WT mice. These results provide the first indication that CR can enhance mitochondrion-mediated apoptotic capacity. Collectively, the results are consistent with the possibility that long lasting, moderately increased apoptotic capacity, possibly linked in part to IGF-1 and GSH modulation, could play a role in the CR-induced anti-aging influence in mice.
authors.affiliation: Institute of Biochemistry, Food Science and Nutrition, Hebrew University of Jerusalem, Rehovot 76100, Israel.
authors.forename: Oren
authors.initials: O
authors.lastname: Tirosh
authors.forename: Anna
authors.initials: A
authors.lastname: Aronis
authors.forename: Igor
authors.initials: I
authors.lastname: Zusman
authors.forename: George
authors.initials: G
authors.lastname: Kossoy
authors.forename: Shlomo
authors.initials: S
authors.lastname: Yahav
authors.forename: Dima
authors.initials: D
authors.lastname: Shinder
authors.forename: Rene
authors.initials: R
authors.lastname: Abramovitz
authors.forename: Ruth
authors.initials: R
authors.lastname: Miskin
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D002149:Energy Intake / Q000502:physiology; D005260:Female; D005508:Food Deprivation / Q000502:physiology*; D005978:Glutathione / Q000502:physiology; D022781:Hepatocytes / Q000166:cytology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008136:Longevity / Q000502:physiology*; D008175:Lung Neoplasms / Q000517:prevention & control; D051379:Mice; D008822:Mice, Transgenic; D008930:Mitochondria, Liver / Q000378:metabolism* / Q000502:physiology; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics
chemical_list: D007334:Insulin-Like Growth Factor I; D045304:Cytochromes c; D014568:Urokinase-Type Plasminogen Activator; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D005978:Glutathione; D002118:Calcium