|Brown-Borg, Holly -|
|Rakoczy, Sharlene -|
Submitted to: Age
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: January 24, 2011
Publication Date: February 1, 2012
Citation: Brown-Borg, H.M., Johnson, W.T., Rakoczy, S.G. 2012. Expression of oxidative phosphorylation components in mitochondria of long-living Ames dwarf mice. Age. 34:43-57. Interpretive Summary: Nutrition, particularly food intake, and genetic makeup are important factors that influence life span. For instance, reduced food intake has been shown to increase the lifespan of laboratory rodents and some primates. Longevity also tends to run in families, suggesting that inheritance is a determinant of lifespan. The mechanisms through which nutrition and genes exert their effects on life span are not clearly understood and are still being investigated. However, mitochondria may be important components in mechanisms that contribute to increased life span. Mitochondria are central to regulating cellular energy metabolism and programmed cell death, two processes that contribute to longevity. Although mitochondria produce the energy that cells need to function properly, they also produce harmful oxygen free radicals as a byproduct that damage mitochondrial components. As the damage to mitochondria by oxygen free radicals accumulates, mitochondrial function declines. The accumulated damage eventually causes the reduction in mitochondrial energy output to a level below what is needed for normal cellular function. It has been hypothesized that the decline in mitochondrial function resulting from oxygen free radical damage contributes to the aging process. In the current study, mitochondrial function was assessed in a mouse strain, the Ames dwarf mouse that is predisposed to having a longer that normal lifespan. It was found that the activities and content of components called respiratory complexes involved in mitochondrial energy production were higher in the livers, kidneys and brains in 20 month-old Ames mice and declined less with age compared to normal control mice. These results demonstrate that preservation of the activities and contents of the mitochondrial components directly involved in energy production likely contribute to the extended life span of the Ames mouse. They also suggest that dietary or pharmacological interventions can be developed that will promote healthy, extended life spans by maintaining better mitochondrial function during ageing.
Technical Abstract: Reduced signaling of the growth hormone (GH)/insulin-like growth factor-1(IGF-1) pathway is associated with extended life span in several species. Ames dwarf mice are GH and IGF-1 deficient and live 50-68% longer than wild type littermates (males and females, respectively). Previously, we have shown that tissues from Ames mice exhibit elevated levels of antioxidative enzymes, less H2O2 production and lower oxidative damage. These findings suggested that mitochondrial function may differ between dwarf and wild type mice. To explore the relationship between hormone deficiency in mice with extended longevity, we evaluated activity, protein and gene expression of oxidative phosphorylation components in mitochondria from several tissues of dwarf and wild type mice at varying ages. Liver complex I+III activity was higher in dwarf mice compared to wild type mice. The activity of I+III decreased between 3 and 20 months of age in both genotypes with greater declines in wild type mice in liver, brain and skeletal muscle. Complex IV activities in the kidney were elevated in 3 and 20 month old dwarf mice relative to wild type mice. In Ames mice, protein levels of the 39 kDa Complex I subunit were elevated at 20 months of age when compared to wild type mouse mitochondria for every tissue examined. Kidney and liver mitochondria from 20 month old dwarf mice had elevated levels of both mitochondrially-encoded and nuclear-encoded Complex IV proteins compared to wild type mice (p<0.05). Higher liver ANT1 and PGC-1a mRNA levels were also observed in dwarf mice compared to age-matched wild type mice. Overall, we found that several components of the OXPHOS system were elevated in Ames mice. The mitochondrial-to-nuclear DNA ratios were not different between genotypes despite the marked increase in PGC-1a levels in dwarf mice. The increased OXPHOS activities, along with lower ROS production in dwarf mice, predict enhanced mitochondrial function and efficiency, two factors likely contributing to long-life in Ames mice.