Analysis Tools
mortality/aging
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• once weaned, female mice exhibit a shorter lifespan than wild-type controls
• in contrast, male mice show relatively normal life expectancies after weaning
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• 26% of mice exhibit preweaning mortality as compared with wild-type controls
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growth/size/body
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• aging males, but not females, show a significant reduction in body weight at 30 weeks of age
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hematopoietic system
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• in spleen, resting NK cells are increased whereas effector NK cells are decreased
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• Ly6C-positive CD11b-negative NK cells are increased in spleen
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• resting CD8-positive T cells are increased in spleen
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• in spleen, resting CD4-negative NK T cells are increased whereas effector CD4-negative NKT cells are decreased
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• resting immune cell populations, such as resting CD8-positive T cells, resting CD4-negative NKT cells, and resting NK cells are increased, whereas effector NK cells and effector CD4-negative NKT cells are decreased in spleen
• however, no major structural changes are observed in spleen sections
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cardiovascular system
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• optical coherence tomography indicates morphological changes in eye vasculature
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• retinal vessels are tortuous
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• retinal vessels are tortuous, branched, and bent in the superficial vascular plexus
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• in some heart sections, hypertrophic cardiomyocytes with enlarged nuclei are observed in the left ventricle
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• some heart sections exhibit vacuolated and fragmented cardiomyocytes
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• aging mice show a significant decrease in left ventricle diameter at 30 weeks of age
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• aging mice show a significant increase in left ventricle anterior wall thickness at 30 weeks of age
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• aging mice show a significant increase in left ventricle posterior wall thickness at 30 weeks of age
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• aging female, but not male, mice show a significant increase in fractional shortening (%) and ejection fraction (%) at 30 weeks of age
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vision/eye
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• optical coherence tomography indicates morphological changes in eye vasculature
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• retinal vessels are tortuous
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• retinal vessels are tortuous, branched, and bent in the superficial vascular plexus
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• retinas show an increased TUNEL-positive signal in the outer nuclear layer (ONL) and the inner nuclear layer (INL) as early as 15 weeks of age
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• at 30 weeks of age, thinning of the outer nuclear layer (ONL) indicates a lower number of photoreceptors cells
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• all eye sections show thinning of the outer nuclear layer (ONL) at 30 weeks, but not at 16 weeks, of age
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• 25% of mice show a reduction in outer plexiform layer (OPL) thickness
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• aging mice show a progressive decrease in retina thickness from 5 weeks to 30 weeks of age
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• mice exhibit a gradual degeneration of the retina with increasing age
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• scotopic a-wave amplitudes are significantly decreased at 30 weeks of age
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• electroretinography shows a defect specifically in retinal rod cells
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homeostasis/metabolism
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• differential gene expression analysis of liver samples shows an increase in several SERBP-dependent cholesterol biosynthesis genes including Hmgcr (3-hydroxy-3-methylglutaryl-Coenzyme A reductase), Sqle (squalene epoxidase), and Insig1 (insulin induced gene 1)
• however, no changes in the total amount of different classes of lipid species are detected in liver by mass spectrometry-based lipidomics
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• isolated brain mitochondria show significantly reduced translation of COX1 (the central mitochondrial-encoded subunit of complex IV) as determined by in organello [35S] methionine labelling of mitochondrial translation products
• pulse chase experiments show a slight effect on the stability of newly synthesized COX1, indicating that both translation and stability of COX1 are affected
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• mice display a significant increase in serum creatinine levels at 16 weeks of age
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• mice display a significant increase in serum cholesterol levels at 16 weeks of age
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• mice display a significant increase in serum alanine aminotransferase (ALT) levels at 16 weeks of age
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• mice display a significant increase in serum aspartate aminotransferase (AST) levels at 16 weeks of age
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liver/biliary system
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• liver mitochondria from 35-week-old mice show a significant reduction in respiration, as determined by oxygen consumption rates (OCR) under different metabolic conditions (pyruvate, oligomycin, CCCP, and KCN)
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• mice exhibit severe liver inflammation characterized by focal necrosis and mononuclear cell infiltration
• liver pathology is driven by the release of mitochondrial RNA (mtRNA) into the cytoplasm of hepatocytes triggering a type I interferon (IFN) response and local inflammation
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• isolated primary hepatocytes exhibit a significant increase in the number of lipid droplets per cell but no significant change in average lipid droplet area per cell
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• TEM analysis of primary hepatocytes shows drastic changes in mitochondrial morphology: mitochondrial cristae have lost their stacked organization and the mitochondrial outer membrane appears to be noncontiguous
• TEM analysis of liver sections reveals mitochondria that wrap around a lipid droplet
• FIB-SEM of liver tissue samples indicates that mitochondria are in close contact with lipid droplets at varying degrees; in extreme cases, the mitochondria engulf the lipid droplet, while in some cases they just have a single point of contact
• however, real time respirometry of free (cytoplasmic) and lipid droplet-associated (peridroplet) liver mitochondria shows no preferential substrate utilization between these two populations, suggesting that liver lipid metabolism is not significantly altered
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• liver sections show spots of focal necrosis demarcated by mononuclear cell infiltrate
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immune system
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• in spleen, resting NK cells are increased whereas effector NK cells are decreased
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• Ly6C-positive CD11b-negative NK cells are increased in spleen
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• resting CD8-positive T cells are increased in spleen
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• in spleen, resting CD4-negative NK T cells are increased whereas effector CD4-negative NKT cells are decreased
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• resting immune cell populations, such as resting CD8-positive T cells, resting CD4-negative NKT cells, and resting NK cells are increased, whereas effector NK cells and effector CD4-negative NKT cells are decreased in spleen
• however, no major structural changes are observed in spleen sections
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• mice exhibit severe liver inflammation characterized by focal necrosis and mononuclear cell infiltration
• liver pathology is driven by the release of mitochondrial RNA (mtRNA) into the cytoplasm of hepatocytes triggering a type I interferon (IFN) response and local inflammation
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• release of mitochondrial RNA (mtRNA) into the cytoplasm of hepatocytes triggers a type I interferon (IFN) response via the RIG-I pathway
• liver shows a significant upregulation of Interferon Stimulated Genes (ISGs) both at RNA and protein levels and is the only organ with a high type I IFN response
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cellular
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• TEM analysis of primary hepatocytes shows drastic changes in mitochondrial morphology: mitochondrial cristae have lost their stacked organization and the mitochondrial outer membrane appears to be noncontiguous
• TEM analysis of liver sections reveals mitochondria that wrap around a lipid droplet
• FIB-SEM of liver tissue samples indicates that mitochondria are in close contact with lipid droplets at varying degrees; in extreme cases, the mitochondria engulf the lipid droplet, while in some cases they just have a single point of contact
• however, real time respirometry of free (cytoplasmic) and lipid droplet-associated (peridroplet) liver mitochondria shows no preferential substrate utilization between these two populations, suggesting that liver lipid metabolism is not significantly altered
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• TEM analysis of primary hepatocytes shows that mitochondrial cristae have lost their stacked organization
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• retinas show an increased TUNEL-positive signal in the outer nuclear layer (ONL) and the inner nuclear layer (INL) as early as 15 weeks of age
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• differential gene expression analysis of liver samples shows an increase in several SERBP-dependent cholesterol biosynthesis genes including Hmgcr (3-hydroxy-3-methylglutaryl-Coenzyme A reductase), Sqle (squalene epoxidase), and Insig1 (insulin induced gene 1)
• however, no changes in the total amount of different classes of lipid species are detected in liver by mass spectrometry-based lipidomics
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• liver mitochondria from 35-week-old mice show a significant reduction in respiration, as determined by oxygen consumption rates (OCR) under different metabolic conditions (pyruvate, oligomycin, CCCP, and KCN)
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• primary hepatocytes exhibit a significantly lower mitochondrial membrane potential along with a significant increase in mitochondrial ROS production relative to wild-type cells
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• liver mitochondria show a decrease in both nuclear- and mitochondrial-encoded cytochrome c oxidase subunits
• mitochondria isolated from brain, liver, heart, and skeletal muscle tissue show a significant reduction in complex IV activity and amount; liver is the most affected of all tested tissues
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• isolated brain mitochondria show significantly reduced translation of COX1 (the central mitochondrial-encoded subunit of complex IV) as determined by in organello [35S] methionine labelling of mitochondrial translation products
• pulse chase experiments show a slight effect on the stability of newly synthesized COX1, indicating that both translation and stability of COX1 are affected
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• primary hepatocytes exhibit a significant increase in mitochondrial ROS production relative to wild-type cells
• increase in mitochondrial ROS production triggers mitochondrial damage and subsequent release of mitochondrial RNA into the cytoplasm esp. in liver (which displays the most severe complex IV phenotype), leading to induction of type I IFN inflammation and liver pathology
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muscle
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• in some heart sections, hypertrophic cardiomyocytes with enlarged nuclei are observed in the left ventricle
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• some heart sections exhibit vacuolated and fragmented cardiomyocytes
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• aging female, but not male, mice show a significant increase in fractional shortening (%) and ejection fraction (%) at 30 weeks of age
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• skeletal muscle sections exhibit a few areas of fibers with more basophilic central nuclei
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• skeletal muscle sections exhibit a few areas of fibers with more basophilic central nuclei, indicating localized myopathy and regeneration
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nervous system
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• at 30 weeks of age, thinning of the outer nuclear layer (ONL) indicates a lower number of photoreceptors cells
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