title: Long-living Ames dwarf mouse hepatocytes readily undergo apoptosis.
abstract: 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.
authors.affiliation: Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota School of Medicine and Health Sciences, 501 N Columbia Road, Grand Forks, ND 58203, USA.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Kennedy
authors.forename: Sharlene G
authors.initials: SG
authors.lastname: Rakoczy
authors.forename: Holly M
authors.initials: HM
authors.lastname: Brown-Borg
mesh_terms: D000375:Aging / Q000235:genetics / Q000473:pathology* / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D004392:Dwarfism / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004792:Enzyme Precursors / Q000378:metabolism; D022781:Hepatocytes / Q000648:ultrastructure*; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008136:Longevity / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051028:bcl-2-Associated X Protein
chemical_list: C494827:Bax protein, mouse; D004792:Enzyme Precursors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases