Long-living Ames dwarf mouse hepatocytes readily undergo apoptosis.

Ames dwarf mice live 50-64% longer and exhibit upregulated antioxidative defenses and lower cellular damage when compared to age-matched wild-type littermates. Due to the relationship between aging and apoptosis, the purpose of this study was to compare basal levels of apoptosis-related proteins in dwarf and wild-type tissues and to compare the response of dwarf and wild-type primary hepatocytes to oxidative stress. Hepatocytes from dwarf and wild-type mice (6 month-old) were isolated using collagenase perfusion and treated with hydrogen peroxide. Viability, activity, protein levels, and morphological changes were evaluated. Procaspase-3 protein levels were increased in dwarf kidney and liver (p<0.05) while Bcl-2 protein levels were significantly higher in dwarf liver at 24 months of age. Bax protein levels were markedly elevated in several tissues at different ages and Bcl-2/Bax ratios were lower in many dwarf tissues. In culture, peroxide-treated dwarf hepatocytes showed lower viability (p<0.03) and higher caspase-3 activity induction when compared to peroxide-treated wild-type cells. Peroxide-treated dwarf hepatocytes frequently showed morphological characteristics reminiscent of apoptosis, which were not observed in peroxide-treated wild-type hepatocytes. This suggests that when experiencing an oxidative challenge, Ames dwarf hepatocytes more readily undergo apoptosis than wild-type cells, providing an advantage to dwarf mice, whereby they more efficiently eliminate damaged cells, thus contributing to their longer lives.