SRC
Proto-oncogene tyrosine-protein kinase Src (EC 2.7.10.2) (Proto-oncogene c-Src) (pp60c-src) (p60-Src) [SRC1]
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The systemic decline in autophagic activity with age impairs homeostasis in several tissues, leading to age-related diseases. A mechanistic understanding of adipocyte dysfunction with age could help to prevent age-related metabolic disorders, but the role of autophagy in aged adipocytes remains unclear. Here we show that, in contrast to other tissues, aged adipocytes upregulate autophagy due to a decline in the levels of Rubicon, a negative regulator of autophagy. Rubicon knockout in adipocytes causes fat atrophy and hepatic lipid accumulation due to reductions in the expression of adipogenic genes, which can be recovered by activation of PPARγ. SRC-1 and TIF2, coactivators of PPARγ, are degraded by autophagy in a manner that depends on their binding to GABARAP family proteins, and are significantly downregulated in Rubicon-ablated or aged adipocytes. Hence, we propose that age-dependent decline in adipose Rubicon exacerbates metabolic disorders by promoting excess autophagic degradation of SRC-1 and TIF2.
MeSH Terms
- Adipocytes
- Adipogenesis
- Adipose Tissue
- Adiposity
- Aging
- Animals
- Apoptosis Regulatory Proteins
- Autophagy
- Fatty Liver
- Gene Knockout Techniques
- Glucose
- HEK293 Cells
- Humans
- Intracellular Signaling Peptides and Proteins
- Lipid Metabolism
- Metabolic Diseases
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Microtubule-Associated Proteins
- Nuclear Receptor Coactivator 1
- Nuclear Receptor Coactivator 2
- PPAR gamma
Virtual memory T (T ) cells are antigen-naïve CD8 T cells that exist in a semi-differentiated state and exhibit marked proliferative dysfunction in advanced age. High spare respiratory capacity (SRC) has been proposed as a defining metabolic characteristic of antigen-experienced memory T (T ) cells, facilitating rapid functionality and survival. Given the semi-differentiated state of T cells and their altered functionality with age, here we investigate T cell metabolism and its association with longevity and functionality. Elevated SRC is a feature of T , but not T , cells and it increases with age in both subsets. The elevated SRC observed in aged mouse T cells and human CD8 T cells from older individuals is associated with a heightened sensitivity to IL-15. We conclude that elevated SRC is a feature of T , but not T , cells, is driven by physiological levels of IL-15, and is not indicative of enhanced functionality in CD8 T cells.
MeSH Terms
- Adult
- Aged
- Aging
- Animals
- CD8-Positive T-Lymphocytes
- Cell Differentiation
- Cell Proliferation
- Disease Models, Animal
- Female
- Humans
- Immunologic Memory
- Influenza A virus
- Influenza, Human
- Male
- Mice
- Microscopy, Electron, Transmission
- Mitochondria
- T-Lymphocyte Subsets
- Young Adult
Hyperglycemia is a major factor in vascular endothelial injury that finally leads to a cardiovascular event. Steroid receptor coactivators (SRCs) are a group of non-DNA binding proteins that induce structural changes in steroid receptors (nuclear receptors) critical for transcriptional activation. SRCs, namely, SRC-1, SRC-2, and SRC-3, are implicated in the regulation of vascular homeostasis. In this study we investigate the role of SRCs in hyperglycemia-induced endothelial injury. Aortic endothelial cells were prepared from normal and diabetic rats, respectively. Diabetic rats were prepared by injection of streptozotocin (50 mg/kg, i.p.). The expression levels of SRC-1 and SRC-3 were significantly decreased in endothelial cells from the diabetic rats. Similar phenomenon was also observed in aortic endothelial cells from the normal rats treated with a high glucose (25 mM) for 4 h or 8 h. The expression levels of SRC-2 were little affected by hyperglycemia. Overexpression of SRC-1 and SRC-3 in high glucose-treated endothelial cells significantly increased the cell viability, suspended cell senescence, and inhibited cell apoptosis compared with the control cells. We further showed that overexpression of SRC-1 and SRC-3 markedly suppressed endothelial injury through restoring nitric oxide production, upregulating the expression of antioxidant enzymes (SOD, GPX, and CAT), and activating the PI3K/Akt pathway. The beneficial effects of SRC-1 and SRC-3 overexpression were blocked by treatment with the PI3K inhibitor LY294002 (10 mM) or with the Akt inhibitor MK-2206 (100 nM). In conclusion, hyperglycemia decreased SRC-1 and SRC-3 expression levels in rat aortic endothelial cells. SRC-1 and SRC-3 overexpression might protect against endothelial injury via inhibition of oxidative stress and activation of PI3K/Akt pathway.
MeSH Terms
- Animals
- Aorta
- Apoptosis
- Cell Survival
- Cellular Senescence
- Chromones
- Diabetes Mellitus, Experimental
- Down-Regulation
- Endothelial Cells
- Endothelium
- Heterocyclic Compounds, 3-Ring
- Male
- Morpholines
- Nuclear Receptor Coactivator 1
- Nuclear Receptor Coactivator 3
- Phosphatidylinositol 3-Kinases
- Phosphoinositide-3 Kinase Inhibitors
- Proto-Oncogene Proteins c-akt
- Rats, Sprague-Dawley
- Signal Transduction
Keywords
- LY294002
- MK-2206
- PI3K/Akt pathway
- cell apoptosis
- cell senescence
- diabetics
- endothelial cells
- hyperglycemia
- oxidative stress
- steroid receptor coactivators
- streptozotocin
Alzheimer's disease (AD) is a neurodegenerative disorder contributing to rapid decline in cognitive function and ultimately dementia. Most cases of AD occur in elderly and later years. There is a growing need for understanding the relationship between aging and AD to identify shared and unique hallmarks associated with the disease in a region and cell-type specific manner. Although genomic studies on AD have been performed extensively, the molecular mechanism of disease progression is still not clear. The major objective of our study is to obtain a higher-order network-level understanding of aging and AD, and their relationship using the hippocampal gene expression profiles of young (20-50 years), aging (70-99 years), and AD (70-99 years). The hippocampus is vulnerable to damage at early stages of AD and altered neurogenesis in the hippocampus is linked to the onset of AD. We combined the weighted gene co-expression network and weighted protein-protein interaction network-level approaches to study the transition from young to aging to AD. The network analysis revealed the organization of co-expression network into functional modules that are cell-type specific in aging and AD. We found that modules associated with astrocytes, endothelial cells and microglial cells are upregulated and significantly correlate with both aging and AD. The modules associated with neurons, mitochondria and endoplasmic reticulum are downregulated and significantly correlate with AD than aging. The oligodendrocytes module does not show significant correlation with neither aging nor disease. Further, we identified aging- and AD-specific interactions/subnetworks by integrating the gene expression with a human protein-protein interaction network. We found dysregulation of genes encoding protein kinases (FYN, SYK, SRC, PKC, MAPK1, ephrin receptors) and transcription factors (FOS, STAT3, CEBPB, MYC, NFKβ, and EGR1) in AD. Further, we found genes that encode proteins with neuroprotective function (14-3-3 proteins, PIN1, ATXN1, BDNF, VEGFA) to be part of the downregulated AD subnetwork. Our study highlights that simultaneously analyzing aging and AD will help to understand the pre-clinical and clinical phase of AD and aid in developing the treatment strategies.
Keywords
- PPI network
- aging
- co-expression network
- glial cells
- graph theory
- hippocampus
- neurodegenerative disease
Circadian rhythmicity is a fundamental process that synchronizes behavioral cues with metabolic homeostasis. Disruption of daily cycles due to jet lag or shift work results in severe physiological consequences including advanced aging, metabolic syndrome, and even cancer. Our understanding of the molecular clock, which is regulated by intricate positive feedforward and negative feedback loops, has expanded to include an important metabolic transcriptional coregulator, Steroid Receptor Coactivator-2 (SRC-2), that regulates both the central clock of the suprachiasmatic nucleus (SCN) and peripheral clocks including the liver. We hypothesized that an environmental uncoupling of the light-dark phases, termed chronic circadian disruption (CCD), would lead to pathology similar to the genetic circadian disruption observed with loss of SRC-2 We found that CCD and ablation of SRC-2 in mice led to a common comorbidity of metabolic syndrome also found in humans with circadian disruption, non-alcoholic fatty liver disease (NAFLD). The combination of SRC-2(-/-) and CCD results in a more robust phenotype that correlates with human non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) gene signatures. Either CCD or SRC-2 ablation produces an advanced aging phenotype leading to increased mortality consistent with other circadian mutant mouse models. Collectively, our studies demonstrate that SRC-2 provides an essential link between the behavioral activities influenced by light cues and the metabolic homeostasis maintained by the liver.
MeSH Terms
- Aging
- Animals
- Carcinoma, Hepatocellular
- Circadian Clocks
- Circadian Rhythm
- Disease Models, Animal
- Humans
- Liver
- Liver Neoplasms
- Mice
- Non-alcoholic Fatty Liver Disease
- Nuclear Receptor Coactivator 2
- Period Circadian Proteins
- Photoperiod
- Suprachiasmatic Nucleus
Keywords
- NAFLD
- SRC-2
- chronic circadian disruption
- liver
- metabolism
- non-alcoholic fatty liver disease
Aging is usually accompanied by alterations of cognitive control functions such as conflict processing. Recent research suggests that aging effects on cognitive control seem to vary with degree and source of conflict, and conflict specific aging effects on performance measures as well as neural activation patterns have been shown. However, there is sparse information whether and how aging affects different stages of conflict processing as indicated by event related potentials (ERPs) such as the P2, N2 and P3 components. In the present study, 19 young and 23 elderly adults performed a combined Flanker conflict and stimulus-response-conflict (SRC) task. Analysis of the reaction times (RTs) revealed an increased SRC related conflict effect in elderly. ERP analysis furthermore demonstrated an age-related increase of the P2 amplitude in response to the SRC task. In addition, elderly adults exhibited an increased P3 amplitude modulation induced by incongruent SRC and Flanker conflict trials.
Keywords
- Fanker conflict
- N2
- P2
- aging
- event-related potentials
- stimulus-response conflict
Multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) is an alternative to established multiecho T2 -based approaches for quantifying myelin water fraction, affording increased volumetric coverage and spatial resolution. A concern with mcDESPOT, however, is the large number of model parameters that must be estimated, which may lead to nonunique solutions and sensitivity to fitting constraints. Here we explore mcDESPOT performance under different experimental conditions to better understand the method's sensitivity and reliability. To obtain parameter estimates, mcDESPOT uses a stochastic region contraction (SRC) approach to iteratively contract a predefined solution search-space around a global optimum. The sensitivity of mcDESPOT estimates to SRC boundary conditions, and tissue parameters, was examined using numerical phantoms and acquired in vivo human data. The SRC approach is described and shown to return robust myelin water estimates in both numerical phantoms and in vivo data under a range of experimental conditions. However, care must be taken in choosing the initial SRC boundary conditions, ensuring they are broad enough to encompass the "true" solution. Results suggest that under the range of conditions examined, mcDESPOT can provide stabile and precise values.
MeSH Terms
- Algorithms
- Body Water
- Brain
- Computer Simulation
- Data Interpretation, Statistical
- Female
- Humans
- Image Interpretation, Computer-Assisted
- Infant
- Male
- Middle Aged
- Models, Statistical
- Molecular Imaging
- Multiple Sclerosis
- Myelin Sheath
- Reproducibility of Results
- Sensitivity and Specificity
- Stochastic Processes
Keywords
- aging
- brain development
- multicomponent relaxation
- white matter