O. Tirosh, I. Zusman, S. Yahav, R. Miskin

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, reduced calcium uptake, reduced expression and activity of MnSOD, enhanced glutathione (GSH) levels, and enhanced capacity to release cytochrome c. 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, an anti-apoptotic hormone. In addition, alphaMUPA mice showed a decreased rate of spontaneously occurring lung tumors at an old age, and a decreased incidence of skin and stomach DMBA-induced tumors at a young age. Short-term (8 weeks) calorically restricted WT mice also showed an increase of mitochondrial swelling and caspase-3 activity compared with ad libitum fed WT mice. These results provide the first indication that CR can enhance mitochondrion-mediated apoptotic capacity. In addition, the results show that the alphaMUPA model presents a state of continuously enhanced apoptosis, and suggest that modulation of the levels of serum IGF-1 and mitochondrial MnSOD and GSH could be involved in the tuning of apoptosis in calorically restricted animals. Collectively, the results are consistent with the possibility that, long lasting, moderately increased apoptotic capacity could play a role in the CR-induced anti-aging influence in mice.

Keywords (Optional): 
caloric restriction
alphaMUPA transgenic mice