Mech Ageing Dev. 2011 Dec 13. [Epub ahead of print]
Effects of age and caloric restriction on mitochondrial protein oxidative damage in mice.
Source
Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, United States.
Abstract
The hypothesis that life-span extension by caloric restriction (CR) is contingent upon the attenuation of macromolecular oxidative damage was tested in two different strains of mice: the C57BL/6, whose life span is extended by CR, and the DBA/2, in which CR has relatively minor or no impact on longevity. Mice were fed ad libitum (AL) or restricted to 40% lesser food, starting at 4 months of age. Protein damage was measured as protein-linked adducts of 4-hydroxy-2-nonenal (HNE) and malondialdehyde (MDA) in skeletal muscle mitochondria at 6 and 23 months of age. Protein-HNE and -MDA content increased with age in C57BL/6 mice and CR significantly attenuated these augmentations. Metalloprotease 1, NADP-dependent mitochondrial malic enzyme (isoform 2) and citrate synthase were identified by mass spectroscopy to contain HNE/MDA adducts. DBA/2 mice exhibited little effect of age or CR on protein HNE/MDA content in skeletal muscle mitochondria. In contrast, protein-HNE levels in liver mitochondria showed a significant increase with age in AL-fed mice of both strains, and CR caused significant attenuation of this damage. Overall, results indicated that the age-related increase in protein oxidative damage and its abatement by CR are genotype- and tissue-specific, and not a universal phenomenon.
An interesting paragraph from the discussion:
In a previous study, CR was found to have a varied effect on the redox state in these two strains of mice. Both strains showed a comparable age-related pro-oxidizing shift in the thiol redox state, indicated by levels of GSH and GSSG, GSSG:GSH ratios and the amounts of protein mixed disulfides. Relatively long-term CR (19 months) prevented these pro-oxidizing changes in the skeletal muscle and liver of C57BL/6 mice, but not in the DBA/2 mice. Even a relatively short-term CR (7 weeks) reversed the age-associated pro-oxidizing shift in the glutathione redox state in the erythrocytes of C57BL/6, but not in the DBA/2 mice. A comparison of the activities of enzymes associated with glutathione metabolism and redox state indicated that in DBA/2 mice, CR elevated the activities of glutathione peroxidase and glutathione reductase, but not glutamate-cysteine ligase, the rate-limiting enzyme in GSH synthesis. In contrast, CR enhanced the activities of glutathione peroxidase as well as GCL in the C57BL/6 mice. Thus CR failed to attenuate the pro-oxidant changes in the mouse strain (DBA/2), whose life span is not robustly prolonged by CR, suggesting that thiol redox state rather than the steady-state levels of protein oxidative damage, may be more closely associated with longevity extension by CR.
