GPI
Glucose-6-phosphate isomerase (EC 5.3.1.9) (GPI) (Autocrine motility factor) (AMF) (Neuroleukin) (NLK) (Phosphoglucose isomerase) (PGI) (Phosphohexose isomerase) (PHI) (Sperm antigen 36) (SA-36)
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Reversing brain aging may be possible through systemic interventions such as exercise. We found that administration of circulating blood factors in plasma from exercised aged mice transferred the effects of exercise on adult neurogenesis and cognition to sedentary aged mice. Plasma concentrations of glycosylphosphatidylinositol (GPI)-specific phospholipase D1 (Gpld1), a GPI-degrading enzyme derived from liver, were found to increase after exercise and to correlate with improved cognitive function in aged mice, and concentrations of Gpld1 in blood were increased in active, healthy elderly humans. Increasing systemic concentrations of Gpld1 in aged mice ameliorated age-related regenerative and cognitive impairments by altering signaling cascades downstream of GPI-anchored substrate cleavage. We thus identify a liver-to-brain axis by which blood factors can transfer the benefits of exercise in old age.
MeSH Terms
- Aging
- Animals
- Blood Circulation
- Brain
- Cognition
- Cognitive Dysfunction
- Glycosylphosphatidylinositols
- Liver
- Mice
- Neurogenesis
- Phospholipase D
- Physical Conditioning, Animal
- Regeneration
- Signal Transduction
Recent studies have shown that glucose-6-phosphate isomerase (GPI)-which is a glycolysis interconversion enzyme-reduces oxidative stress. However, these studies are limited to tumors such as fibrosarcoma, and there are no studies that have examined the effects of exercise on GPI expression in mice skeletal muscle. Furthermore, GPI acts in an autocrine manner thorough its receptor, autocrine motility factor receptor (AMFR); therefore, we investigated expression level changes of secreted GPI from skeletal muscle in in vitro study to examine the potential role of GPI on skeletal muscle. First, we performed an in vitro study, to identify the condition that upregulates GPI levels in skeletal muscle cells; we treated C2C12 muscle cells with an exercise-mimicking chemical, AICAR. AICAR treatment upregulated GPI expression level in C2C12 cell and its secretomes. To confirm the direct effect of GPI on skeletal muscle cells, we treated C2C12 cells with GPI recombinant protein. We found that GPI improved the viability of C2C12 cells. In the in vivo study, the exercise-treated mice group showed upregulated GPI expression in skeletal muscle. Based on the in vitro study results, we speculated that expression level of GPI in skeletal muscle might be associated with muscle function. We analyzed the association between GPI expression level and the grip strength of the all mice group. The mice group's grip strengths were upregulated after 2 weeks of treadmill exercise, and GPI expression level positively correlated with the grip strength. These results suggested that the exercise-induced GPI expression in skeletal muscle might have a positive effect on skeletal muscle function.
Keywords
Aging
A subset of the red blood cells (RBCs) of patients with paroxysmal nocturnal hemoglobinuria (PNH) lacks GPI-anchored proteins. Some of these proteins, such as CD59, inhibit complement activation and protect against complement-mediated lysis. This pathology thus provides the possibility to explore the involvement of complement in red blood cell homeostasis and the role of GPI-anchored proteins in the generation of microvesicles (MVs) [i]in vivo[/i]. Detailed analysis of morphology, volume, and density of red blood cells with various CD59 expression levels from patients with PNH did not provide indications for a major aberration of the red blood cell aging process in patients with PNH. However, our data indicate that the absence of GPI-anchored membrane proteins affects the composition of red blood cell-derived microvesicles, as well as the composition and concentration of platelet-derived vesicles. These data open the way toward a better understanding on the pathophysiological mechanism of PNH and thereby to the development of new treatment strategies.
Keywords
- aging
- microvesicles
- paroxysmal nocturnal hemoglobinuria
- red blood cells
- thrombosis
The Institute for Economics and Peace has ranked 162 territories within the United Nations according to how they score on a scale of 1.0 (most peaceful) to 5.0 (least peaceful) in a 'Global Peace Index' (GPI). The GPI 2015 values range from 1.148 (Iceland) to 3.645 (Syria). In this pilot study, we report significant correlations (Spearman rank coefficients) between each country's GPI and indicators of the health of its citizens (life expectancies, death rates and health expenditures): these significances are marginally enhanced when Sub-Saharan African countries are excluded. Our findings may indicate avenues for promoting a healthy global society, but more detailed and comprehensive analyses should be conducted in order for the factors behind the correlations to be identified and applied with more certainty.
MeSH Terms
- Africa South of the Sahara
- Armed Conflicts
- Asia
- Crime
- Europe
- Female
- Health Expenditures
- Health Status
- Health Status Indicators
- Humans
- Infant
- Infant Mortality
- Infant, Newborn
- Life Expectancy
- Male
- Pilot Projects
- South America
- United States
Keywords
- Global peace index
- Spearman rank correlation
- World Bank
- World Health Organization
- health indicators
The gene encoding the neural cell adhesion molecule Contactin-6 (Cntn6 a.k.a. NB-3) has been implicated as an autism risk gene, suggesting that its mutation is deleterious to brain development. Due to its GPI-anchor at Cntn6 may exert cell adhesion/receptor functions in complex with other membrane proteins, or serve as a ligand. We aimed to uncover novel phenotypes related to Cntn6 functions during development in the cerebral cortex of adult Cntn6(-/-) mice. We first determined Cntn6 protein and mRNA expression in the cortex, thalamic nuclei and the hippocampus at P14, which decreased specifically in the cortex at adult stages. Neuroanatomical analysis demonstrated a significant decrease of Cux1 projection neurons in layers II-IV and an increase of FoxP2 projection neurons in layer VI in the visual cortex of adult Cntn6(-/-) mice compared to wild-type controls. Furthermore, the number of parvalbumin (PV) interneurons was decreased in Cntn6(-/-) mice, while the amount of NPY interneurons remained unchanged. In the hippocampus the delineation and outgrowth of mossy fibers remained largely unchanged, except for the observation of a larger suprapyramidal bundle. The observed abnormalities in the cerebral cortex and hippocampus of Cntn6(-/-) mice suggests that Cntn6 serves developmental functions involving cell survival, migration and fasciculation. Furthermore, these data suggest that Cntn6 engages in both trans- and cis-interactions and may be involved in larger protein interaction networks.
MeSH Terms
- Aging
- Animals
- Cell Adhesion Molecules, Neuronal
- Cell Count
- Cerebral Cortex
- Hippocampus
- Interneurons
- Mice, Inbred C57BL
- Mossy Fibers, Hippocampal
- Neuropeptide Y
- Parvalbumins
- Pyramidal Cells
- RNA, Messenger
- Visual Cortex
Keywords
- ASD
- CAMs
- Cntn6
- NB-3
- autism
- cell adhesion molecule
- contactin
- hippocampus
- visual cortex
Rapamycin has been shown to extend lifespan in rodent models, but the effects on metabolic health and function have been widely debated in both clinical and translational trials. Prior to rapamycin being used as a treatment to extend both lifespan and healthspan in the human population, it is vital to assess the side effects of the treatment on metabolic pathways in animal model systems, including a closely related non-human primate model. In this study, we found that long-term treatment of marmoset monkeys with orally-administered encapsulated rapamycin resulted in no overall effects on body weight and only a small decrease in fat mass over the first few months of treatment. Rapamycin treated subjects showed no overall changes in daily activity counts, blood lipids, or significant changes in glucose metabolism including oral glucose tolerance. Adipose tissue displayed no differences in gene expression of metabolic markers following treatment, while liver tissue exhibited suppressed G6Pase activity with increased PCK and GPI activity. Overall, the marmosets revealed only minor metabolic consequences of chronic treatment with rapamycin and this adds to the growing body of literature that suggests that chronic and/or intermittent rapamycin treatment results in improved health span and metabolic functioning. The marmosets offer an interesting alternative animal model for future intervention testing and translational modeling.
MeSH Terms
- Adipose Tissue
- Animals
- Callithrix
- Glucose
- Lipids
- Liver
- Models, Animal
- Sirolimus
Keywords
- animal models
- antiaging
- healthspan
- longevity
- nonhuman primate
- sirolimus
The urokinase receptor (uPAR) is a GPI-anchored membrane protein, which regulates protease activity at the cell surface and, in collaboration with a system of co-receptors, triggers cell-signaling and regulates gene expression within the cell. In normal tissues, uPAR gene expression is limited; however, in cancer, uPAR is frequently over-expressed and the gene may be amplified. Hypoxia, which often develops in tumors, further increases uPAR expression by cancer cells. uPAR-initiated cell-signaling promotes cancer cell migration, invasion, metastasis, epithelial-mesenchymal transition, stem cell-like properties, survival, and release from states of dormancy. Newly emerging data suggest that the pro-survival cell-signaling activity of uPAR may allow cancer cells to "escape" from the cytotoxic effects of targeted anticancer drugs. Herein, we review the molecular properties of uPAR that are responsible for its activity in cancer cells and its ability to counteract the activity of anticancer drugs.
Keywords
- cancer stem cell
- cellular senescence
- epithelial-mesenchymal transition
- fibrinolysis
- metastasis
- plasmin
- uPAR
Neurodegenerative diseases represent an increasing burden in our aging society, yet the underlying metabolic factors influencing onset and progression remain poorly defined. The relationship between impaired IGF-1/insulin-like signaling (IIS) and lifespan extension represents an opportunity to investigate the interface of metabolism with age-associated neurodegeneration. Using data sets of established DAF-2/IIS-signaling components in Caenorhabditis elegans, we conducted systematic RNAi screens in worms to select for daf-2-associated genetic modifiers of α-synuclein misfolding and dopaminergic neurodegeneration, two clinical hallmarks of Parkinson's disease. An outcome of this strategy was the identification of GPI-1/GPI, an enzyme in glucose metabolism, as a daf-2-regulated modifier that acts independent of the downstream cytoprotective transcription factor DAF-16/FOXO to modulate neuroprotection. Subsequent mechanistic analyses using Drosophila and mouse primary neuron cultures further validated the conserved nature of GPI neuroprotection from α-synuclein proteotoxicity. Collectively, these results support glucose metabolism as a conserved functional node at the intersection of proteostasis and neurodegeneration.
MeSH Terms
- Aging
- Animals
- Caenorhabditis elegans
- Caenorhabditis elegans Proteins
- Cells, Cultured
- Cytokines
- Disease Models, Animal
- Dopaminergic Neurons
- Drosophila
- Drosophila Proteins
- Forkhead Transcription Factors
- Glucose
- Glucose-6-Phosphate Isomerase
- Glycolysis
- Insulin Receptor Substrate Proteins
- Insulin-Like Growth Factor I
- Male
- Mice
- Parkinson Disease
- RNA Interference
- RNA, Small Interfering
- Receptor, Insulin
- Signal Transduction
- Transcription Factors
- alpha-Synuclein