Constitutive autophagy is important for control of the quality of proteins and organelles to maintain cell function. Damaged proteins and organelles accumulate in aged organs. We have previously ...reported that cardiac-specific Atg5 (autophagy-related gene 5)-deficient mice, in which the gene was floxed out early in embryogenesis, were born normally, and showed normal cardiac function and structure up to 10 weeks old. In the present study, to determine the longer-term consequences of Atg5-deficiency in the heart, we monitored cardiac-specific Atg5-deficient mice for further 12 months. First, we examined the age-associated changes of autophagy in the wild-type mouse heart. The level of autophagy, as indicated by decreased LC3-II (microtubule-associated protein 1 light chain 3-II) levels, in the hearts of 6-, 14- or 26-month-old mice was lower than that of 10-week-old mice. Next, we investigated the cardiac function and life-span in cardiac-specific Atg5-deficient mice. The Atg5-deficient mice began to die after the age of 6 months. Atg5-deficient mice exhibited a significant increase in left ventricular dimension and decrease in fractional shortening of the left ventricle at the age of 10 months, compared to control mice, while they showed similar chamber size and contractile function at the age of 3 months. Ultrastructural analysis revealed a disorganized sarcomere structure and collapsed mitochondria in 3- and 10-month-old Atg5-deficient mice, with decreased mitochondrial respiratory functions. These results suggest that continuous constitutive autophagy has a crucial role in maintaining cardiac structure and function.
Mechanical stress and aging are major risk factors of cartilage degeneration. Human studies have previously reported that oxidative damage increased, while SOD2 protein was reciprocally downregulated ...in osteoarthritic degenerated cartilage. However, it remains unclear whether mitochondrial superoxide imbalance in chondrocytes causes cartilage degeneration. We herein demonstrate that mechanical loading promoted mitochondrial superoxide generation and selective Sod2 downregulation in chondrocytes in vivo and that mitochondrial superoxide inducer also downregulated Sod2 expression in chondrocytes in vitro. A genetically manipulated model revealed that Sod2 deficiency in chondrocytes also resulted in mitochondrial superoxide overproduction and dysfunction, thus leading to cartilage degeneration. Intra-articular injection of a permeable antioxidant effectively suppressed the mechanical loading-induced mitochondrial superoxide generation and cartilage degeneration in mice. Our findings demonstrate that mitochondrial superoxide plays a pivotal role in the development and progression of osteoarthritis, and the mitochondrial superoxide balance may therefore be a promising target for the treatment of cartilage degeneration.
In this study we tried to confirm the effect of an astaxanthin-rich Haematococcus pluvialis extract on cognitive function in 96 subjects by a randomised double-blind placebo-controlled study. Healthy ...middle-aged and elderly subjects who complained of age-related forgetfulness were recruited. Ninety-six subjects were selected from the initial screen, and ingested a capsule containing astaxanthin-rich Haematococcus pluvialis extract, or a placebo capsule for 12 weeks. Somatometry, haematology, urine screens, and CogHealth and Groton Maze Learning Test were performed before and after every 4 weeks of administration. Changes in cognitive performance and the safety of astaxanthin-rich Haematococcus pluvialis extract administration were evaluated. CogHealth battery scores improved in the high-dosage group (12 mg astaxanthin/day) after 12 weeks. Groton Maze Learning Test scores improved earlier in the low-dosage (6 mg astaxanthin/day) and high-dosage groups than in the placebo group. The sample size, however, was small to show a significant difference in cognitive function between the astaxanthin-rich Haematococcus pluvialis extract and placebo groups. No adverse effect on the subjects was observed throughout this study. In conclusion, the results suggested that astaxanthin-rich Haematococcus pluvialis extract improves cognitive function in the healthy aged individuals.
The oxygen consumption rate (OCR) in brain mitochondria is significantly lower in aged mice than in young mice, and the reduced OCR is rescued by administration of water-solubilized CoQ10 to aged ...mice via drinking water. However, the mechanism behind this remains unclear. Here, we show that the activity of respiratory complex IV (CIV) in brain mitochondria declined in aged mice than in young mice, with no significant change in individual respiratory complex levels and their supercomplex assembly. Reduced CIV activity in the aged mice coincided with reduced binding of optic atrophy 1 (OPA1) to CIV. Both reduced activity and OPA1 binding of CIV were rescued by water-solubilized CoQ10 administration to aged mice via drinking water. OCR and the activity and OPA1 binding of CIV in isolated brain mitochondria from aged mice were restored by incubation with CoQ10, but not in the presence of 15-deoxy-prostaglandin J2, an inhibitor of a GTPase effector domain-containing GTPase such as OPA1 and DRP1. By contrast, the CoQ10-responsive restoration of OCR in the isolated mitochondria was not inhibited by Mdivi-1, a selective inhibitor of DRP1. Thus, we propose a novel function of OPA1 in regulating the CIV activity in brain mitochondria in response to CoQ10.
•Respiratory complex CIV activity declines during normal aging.•Binding of OPA1 to CIV reduces during normal aging.•CoQ ameliorates reduced CIV activity and OPA1 binding to CIV.
Oxidative stress has long been linked to the pathogenesis of neurodegenerative diseases; however, whether it is a cause or merely a consequence of the degenerative process is still unknown. We show ...that mice deficient in Cu, Zn-superoxide dismutase (SOD1) have features typical of age-related macular degeneration in humans. Investigations of senescent$Sodl1^{-/-}$mice of different ages showed that the older animals had drusen, thickened Bruch's membrane, and choroidal neovascularization. The number of drusen increased with age, and exposure of young$Sod1^{-/-}$mice to excess light induced drusen. The retinal pigment epithelial cells of$Sod1^{-/-}$mice showed oxidative damage, and their$\beta-cateninmediated$cellular integrity was disrupted, suggesting that oxidative stress may affect the junctional proteins necessary for the barrier integrity of the retinal pigment epithelium. These observations strongly suggest that oxidative stress may play a causative role in age-related retinal degeneration, and our findings provide evidence for the free radical theory of aging. In addition, these results demonstrate that the$Sod1^{-/-}$mouse is a valuable animal model to study human age-related macular degeneration.
We have shown that platinum nanoparticles (nano-Pt) are a superoxide dismutase (SOD)/catalase mimetic. Various data have shown extension of the
Caenorhabditis elegans lifespan by antioxidant ...treatment. The present study was designed to elucidate the survival benefit conferred by nano-Pt, as compared to the well-known SOD/catalase mimetic EUK-8. At 0.5
mM, nano-Pt significantly extended the lifespan of wild-type N2 nematodes and at 0.25 and 0.5
mM, nano-Pt recovered the shortened lifespan of the
mev-1(
kn1) mutant, which is due to excessive oxidative stress. In both instances, EUK-8 at 0.05, 0.5, and 5
mM did not extend nematode lifespan. Even when 0.4
M paraquat was loaded exogenously, nano-Pt (0.1 and 0.5
mM) and EUK-8 (0.5 and 5
mM) were effective in rescuing worms. Moreover, 0.5
mM nano-Pt significantly reduced the accumulation of lipofuscin and ROS induced by paraquat. We measured the in vitro dose-dependent quenching of O
2
− and H
2O
2, indicating that nano-Pt is a more potent SOD/catalase mimetic than EUK-8. Nano-Pt prolonged the worm lifespan, regardless of thermotolerance or dietary restriction. Taken together, nano-Pt has interesting anti-ageing properties.
Elevated hepatic reactive oxygen species play an important role in pathogenesis of liver diseases, such as alcohol-induced
liver injury, hepatitis C virus infection, and nonalcoholic steatohepatitis. ...In the present study, we investigated and compared
the hepatic lipid metabolisms of liver-specific Sod2 (superoxide dismutase 2) knock-out ( Sod2 KO), Sod1 knock-out ( Sod1 KO), and Sod1 /liver-specific Sod2 double knock-out mice (double KO). We observed significant increases in lipid peroxidation and triglyceride (TG) in the liver
of Sod1 KO and double KO mice but not in the liver of Sod2 KO mice. We also found that high fat diet enhanced fatty changes of the liver in Sod1 KO and double KO mice but not in Sod2 KO mice. These data indicated that CuZn-SOD deficiency caused lipid accumulation in the liver. To investigate the molecular
mechanism of hepatic lipid accumulation in CuZn-SOD-deficient mice, we measured TG secretion rate from liver using Triton
WR1339. We found significant decrease of TG secretion in CuZn-SOD-deficient mice. Furthermore, we observed marked degradation
of apolipoprotein B (apoB) in the liver and plasma of CuZn-SOD-deficient mice, indicating that degradation of apoB impairs
secretion of lipoprotein from the liver. Our data suggest that oxidative stress enhances hepatic lipid accumulation by impaired
lipoprotein secretion due to the degradation of apoB in liver.
The oxygen consumption rate (OCR) and cytochrome c oxidase (CcO) activity of respiratory complex IV (CIV) in brain mitochondria significantly decline in middle-aged male mice compared to younger male ...mice. To explore the mechanisms underlying the regulation of brain mitochondrial function, we examined CIV-associated proteins, and identified actin inside the isolated brain mitochondria. Inhibiting actin polymerization using cytochalasin B (CB) significantly enhanced the OCR and CcO activity of CIV in the mitochondria. These changes were accompanied by a significant reduction in the amount of CIV-bound cytochrome c (cyt c). Actin was also associated with respiratory complex III (CIII); however, the amount of CIII-bound cyt c increased significantly after treatment of the mitochondria with CB. In contrast, no significant alteration in the assembly or the CcO activity of CIV in CIV-containing supercomplexes or CIV monomers was induced by CB. These results suggest that mitochondrial actin plays a crucial role in the regulation of the CcO activity and OCR of CIV with modification of the retention of cyt c between CIV and CIII.
Abstract We have shown that platinum nanoparticle species (nano-Pt) is a superoxide dismutase/catalase mimetic that scavenges superoxide and hydrogen peroxide. In Caenorhabditis elegans , nano-Pt ...functions as an effective antioxidant that induces an extension in lifespan and strong resistance against excessive oxidative stress. Our study with C. elegans was the first trial to use nano-Pt as a bio-active substance. However, a high concentration of nano-Pt was required for these survival effects, probably due to limited membrane permeability. Here, we show that the conjugation of nano-Pt with an HIV-1 TAT fusion protein C-terminally linked to a peptide with high affinity for platinum improves internalization, eliciting a similar level of antioxidant effects at one hundredth the concentration of unconjugated nano-Pt. This approach is a potential method to facilitate translocation of bio-active nanoparticles into living organisms and could be a model assay for estimate the effects of antioxidant in living organism.
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