Mitochondrion-mediated apoptosis is enhanced in long-lived αMUPA transgenic mice and calorically restricted wild-type mice

Oren Tirosh, Anna Aronis, Igor Zusman, George Kossoy, Shlomo Yahav, Dima Shinder, Rene Abramovitz, Ruth Miskin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


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 αMUPA 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 αMUPA livers showed increased susceptibility to calcium-induced high-amplitude swelling, increased cytochrome c release and enhanced glutathione levels. Furthermore, young adult αMUPA 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, αMUPA 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.

Original languageAmerican English
Pages (from-to)955-963
Number of pages9
JournalExperimental Gerontology
Issue number9
StatePublished - 1 Sep 2003


  • Aging
  • Apoptosis
  • Caloric restriction
  • Mitochondria
  • Plasminogen activator
  • uPA
  • αMUPA transgenic mice


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