Expression of oxidative phosphorylation components in mitochondria of long-living Ames dwarf mice

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-deficient and live >50% longer than wild-type littermates. Previously, we have shown that tissues from Ames mice exhibit elevated levels of antioxidative enzymes, less H 2 O 2 production, and lower oxidative damage suggesting that mitochondrial function may differ between genotypes. To explore the relationship between hormone deficiency and mitochondria in mice with extended longevity, we evaluated activity, protein, and gene expression of oxidative phosphorylation components in dwarf and wild-type mice at varying ages. Liver complex I+III activity was higher in dwarf mice compared to wildtype 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 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-1α mRNA levels were also observed in dwarf mice. Overall, we found that several components of the oxidative phosphorylation (OXPHOS) system were elevated in Ames mice. Mitochondrial to nuclear DNA ratios were not different between genotypes despite the marked increase in PGC-1α 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.

Reduced Expression of MYC Increases Longevity and Enhances Healthspan

“…All of these phenotypes oppose the effects of normal aging and are shared with many other long-lived mouse models (Figure 7, Table S7). For example, CR and Ames dwarf mice also have an increased metabolic rate (Bartke and Westbrook, 2012); CR and metformin-treated mice have lower cholesterol (Martin-Montalvo et al, 2013; Tsuchiya et al, 2004); Ames dwarf, CR and rapamycin or metformin administration ameliorate cancer (Ikeno et al, 2003; Martin-Montalvo et al, 2013; Neff et al, 2013); and CR, Ames dwarf, and metformin-treated mice have better motor coordination (Brown-Borg et al, 2012; Lanza et al, 2012; Martin-Montalvo et al, 2013). All of these long-lived models show reduced body mass.…”

GH and ageing: Pitfalls and new insights

“…Reduced ROS production can be viewed as evidence for improved efficiency of mitochondrial function. More recent studies described organ-specific differences between Ames dwarf and normal mice in the expression and activity of various components of the mitochondrial electron transport chain [57, 58] and in the expression and activation of PGC1α, a key regulator of mitochondrial biogenesis [58]. The alterations in mitochondrial function in GH-related mutants provide a likely explanation of differences in whole-animal energy metabolism uncovered by indirect calorimetry [59], and may be related to the enhanced thermogenesis in these animals maintained at the “standard” animal room ambient temperature.…”

Impaired Insulin/IGF1 Signaling Extends Life Span by Promoting Mitochondrial L-Proline Catabolism to Induce a Transient ROS Signal

“…These mechanisms by which impaired IIS promotes life span are not well understood, but presumably involve increasing resistance against various stressors, such as thermal and oxidative stress (Brys et al, 2010; Honda and Honda, 1999; Lithgow et al, 1995; Murphy et al, 2003; Vanfleteren, 1993; Vanfleteren and De Vreese, 1995). On the other hand, impaired IIS has also been shown to increase metabolic rate and mitochondrial metabolism in both C. elegans (Houthoofd et al, 2005; Vanfleteren and De Vreese, 1995) and mice (Brown-Borg et al, 2012; Katic et al, 2007). …”