Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Age-associated changes in human CD4+ T cells point to mitochondrial dysfunction consequent to impaired autophagy

ABSTRACT: To gain understanding on the mechanisms that drive immunosenescence in humans, we examined CD4+ T cells obtained from younger (20-39 years-old) and older (70+ years-old) healthy participants of the Baltimore Longitudinal Study on Aging (BLSA). We found that mitochondrial proteins involved in the electron transport chain were overrepresented in cells from older participants, with prevalent dysregulation of oxidative phosphorylation and energy metabolism molecular pathways. Surprisingly, gene transcripts coding for mitochondrial proteins pertaining to oxidative phosphorylation and electron transport chain pathways were underrepresented in older individuals. Paralleling the observed decrease in gene expression, mitochondrial respiration was impaired in CD4+ T cells from older subjects. Though mitochondrial number in both naïve and memory cells visualized with electron microcopy was similar in older versus younger participants, there were a significantly higher number of autophagosomes, many of them containing undegraded mitochondria, in older individuals. The presence of mitochondria inside the accumulated autophagic compartments in CD4+ T cells from older individuals was confirmed by immunofluorescence. These findings suggest that older age is associated with persistence of dysfunctional mitochondria in CD4+ T lymphocytes caused by defective mitochondrial turnover by autophagy, which may trigger chronic inflammation and contribute to the impairment of immune defense in older persons.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): T Cell, Blood

DISEASE(S): Disease Free

SUBMITTER: Arsun Bektas

LAB HEAD: Luigi Ferrucci

PROVIDER: PXD016039 | Pride | 2019-11-27

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Similar Datasets

Reduced insulin/IGF-1 signaling restores the dynamic properties of key stress granule proteins during aging

Project description:Low complexity “prion-like” domains in key RNA-binding proteins (RBPs) mediate the reversible assembly of RNA granules. Individual RBPs harboring these domains have been linked to specific neurodegenerative diseases. Although their aggregation in neurodegeneration has been extensively characterized, it remains unknown how the process of aging disturbs RBP dynamics. We show that a wide variety of RNA granule components including stress granule proteins become highly insoluble with age in C. elegans and that reduced insulin/IGF-1 daf-2 receptor signaling efficiently prevents their aggregation. Importantly, stress granule-related RBP aggregates are associated with reduced fitness. We show that HSF-1 is a main regulator of stress granule-related RBP aggregation in both young and aged animals. During aging, increasing DAF-16 activity restores dynamic stress granule-related RBPs partly by reducing the build-up of other misfolded proteins that seed RBP aggregation. Longevity-associated mechanisms found to maintain dynamic RBPs during aging could be relevant for neurodegenerative diseases.

2017-01-16 | PXD003451 | Pride

Age-associated changes in human CD4+ T cells point to mitochondrial dysfunction consequent to impaired autophagy.

Project description:To gain understanding on the mechanisms that drive immunosenescence in humans, we examined CD4+ T cells obtained from younger (20-39 years-old) and older (70+ years-old) healthy participants of the Baltimore Longitudinal Study on Aging (BLSA). We found that mitochondrial proteins involved in the electron transport chain were overrepresented in cells from older participants, with prevalent dysregulation of oxidative phosphorylation and energy metabolism molecular pathways. Surprisingly, gene transcripts coding for mitochondrial proteins pertaining to oxidative phosphorylation and electron transport chain pathways were underrepresented in older individuals. Paralleling the observed decrease in gene expression, mitochondrial respiration was impaired in CD4+ T cells from older subjects. Though mitochondrial number in both naïve and memory cells visualized with electron microcopy was similar in older versus younger participants, there were a significantly higher number of autophagosomes, many of them containing undegraded mitochondria, in older individuals. The presence of mitochondria inside the accumulated autophagic compartments in CD4+ T cells from older individuals was confirmed by immunofluorescence. These findings suggest that older age is associated with persistence of dysfunctional mitochondria in CD4+ T lymphocytes caused by defective mitochondrial turnover by autophagy, which may trigger chronic inflammation and contribute to the impairment of immune defense in older persons.

2019-11-12 | GSE131407 | GEO

Metadata Entered in Submitting Proteomic Data to PRIDE

Project description:For the identification of potential pathways and their interactions that underlie a complex change in cellular state, such as neurite outgrowth, we stimulated the neuroblastoma cell line N2A with HU210, a potent activator of the cannabinoid receptor type I, followed by transcriptomic and proteomic analysis. Differentially expressed genes and proteins obtained at multiple timepoints were subjected to standard and dynamic enrichment analysis using the Molecular Biology of the Cell Ontology. Many of the identified pathways described constitutive cellular functions. Involvement of predicted pathways in neurite outgrowth was confirmed by siRNA knock-down of pathway representative genes in primary rat cortical neurons. Dynamic modeling of pathway activities suggested that the identified increase in vesicle membrane back-transported from the growth cone to the cell body ensures recycling of components needed by forward moving vesicle.

2022-10-14 | PXD036706 | Pride

Genome wide DNA methylation changes with age in disease free human skeletal muscle

Project description:A decline in skeletal muscle mass and function with aging is well recognized, but remains poorly characterized at the molecular level. Here we report for the first time a genome-wide study of DNA methylation dynamics in skeletal muscle of healthy male individuals during normal human aging. We predominantly observed hypermethylation throughout the genome within the aged group as compared to the young subjects. Differentially methylated CpG (dmCpG) nucleotides tend to arise intragenically, and are underrepresented in promoters and are overrepresented in the middle and 3’ end of genes. The intragenic methylation changes are over represented in genes which guide the formation of the junction of the motor neuron and myofibers. We report a low level of correlation between previous gene expression studies of aged muscle with our current analysis of DNA methylation status. For those genes that had both changes in methylation and gene expression with age, we observed a reverse correlation, with the exception of intragenic hypermethylated genes, that were correlated with increased gene expression. We argue that a minimal number of dmCpG sites or select sites are required to be altered in order to correlate with gene expression changes. Finally, we identified 500 dmCpG biomarkers that perform well in a prediction of human biological age within our cohorts. Our findings highlight epigenetic links between aging post-mitotic skeletal muscle and DNA methylation. 48 experimental samples (24 young and 24 older individuals) were used overall. There were 4 replicates per group.

2013-12-03 | E-GEOD-50498 | biostudies-arrayexpress

Dietary intervention improves health metrics and life expectancy of the genetically obese Titan mouse

Project description:Suitable animal models are essential for translational research, especially in the case of complex, multifactorial conditions, such as obesity. The non-inbred mouse (Mus musculus) line Titan, also known as DU6, is one of the world’s longest selection experiments for high body mass and was previously described as a model for metabolic healthy (benign) obesity. The present study further characterizes the geno- and phenotypes of this non-inbred mouse line and testes its suitability as an interventional obesity model. In contrast to previous findings, our data suggest that Titan mice are metabolically unhealthy obese and short-lived. Line-specific patterns of genetic invariability are in accordance with observed phenotypic traits. Titan mice also show modifications in the liver transcriptome, proteome, and epigenome linked to metabolic (dys)regulations. Importantly, dietary intervention partially reversed the metabolic phenotype in Titan mice and significantly extended their life expectancy. Therefore, the Titan mouse line is a valuable resource for translational and interventional obesity research

2022-05-04 | PXD019030 | Pride

Alterations in lipid profile of the aging kidney identified by MALDI imaging mass spectrometry

Project description:During aging, the kidney undergoes functional and physiological changes that are closely affiliated with chronic kidney disease (CKD). There is increasing evidence supporting the role of lipid or lipid-derived mediators in the pathogenesis of CKD and other aging-related diseases. To understand the role of lipids in various metabolic processes during kidney aging, we conducted MALDI imaging mass spectrometry (MALDI-IMS) analysis in kidneys harvested from young (2 months old, n=3) and old mice (24 months old, n=3). MALDI-IMS analysis showed an increase in ceramide level and a decrease in sphingomyelin (SM) and phosphatidylcholine (PC) levels in kidneys of old mice. The increased expression of cPLA2 and SMPD1 protein in aged kidney was confirmed by immunohistochemistry and western blot analysis. Our MALDI-IMS data showed the altered distribution of lipids in aged kidney as indicative of aging-related functional changes of the kidney. Combined analysis of MALDI-IMS and IHC confirmed lipidomic changes and expression levels of responsible enzymes as well as morphological changes.

2019-06-10 | PXD013860 | Pride

Further evidence for sustainable alternatives to replace threatened animal horn based on quantitative proteomic analysis

Project description:In the present study, a quantitative proteomic approach was used to analyse and compare the proteome in horns from endangered species (rhinoceros, Saiga antelope, and Tibetan antelope) and common species (yak, water buffalo, and goat) based on the isobaric tag for relative and absolute quantification (iTRAQ) techniques. In total, 591 proteins were identified, and 321 were quantified and categorised based on molecular function, cellular component, and biological process. Principal component analysis (PCA) and hierarchical clustering analysis (HCA) results based on differences in the amount of protein identified three major clusters, and proteins including transglutaminase, desmocollin, and elongation factors were selected as trait components from proteomic patterns of horn samples from different species. Quantitative proteomic analysis-based strategies can therefore provide further evidence for sustainable alternatives to replace animal horn from threatened species.

2022-03-02 | PXD010901 | Pride

Characterization of gastric tumor organoids with specific oncogenic pathway activations

Project description:Gastric cancer ranks the fifth most common malignancy and the third leading cause of cancer related death worldwide. Classical chemotherapy is still the standard treatment in advanced stages, with only two targeted therapies currently in clinical use. Several targeted trials have failed, likely due to missing relevant biomarkers that predict response. Patient derived cancer organoids (PDOs) constitute a three dimensional cell culture system showing self renewal, self organization and regularly unlimited proliferation while faithfully recapitulating many aspects of the tumor they are derived from. Nevertheless, the complex individual mutational landscape hampers the use of PDOs for basic and translational research. We therefore characterized three murine tumor organoid models with defined mutational patterns altering specific oncogenic pathways: a RAS activated (KrasG12D, Tp53R172H), a WNT activated (Apcfl/fl, Tp53R172H) and a diffuse (Cdh1fl/fl, Apcfl/fl) tumor model. The models were analyzed phenotypically, a proteome signature was established and a drug screen performed. The models were morphologically diverse, were characterized by individual protein expression signatures and showed differential drug sensitivities. The developed organoid models allow functional assays as well as pathway specific drug interference testing in a genetically defined setting.

2022-08-22 | PXD022015 | Pride

Plants encode a general siRNA suppressor that is induced and suppressed by viruses

Project description:Small RNAs play essential regulatory roles in genome stability, development and stress responses in most eukaryotes. Plants encode DICER-LIKE (DCL) RNaseIII enzymes, including DCL1, which produces miRNAs, and DCL2, DCL3 and DCL4, which produce diverse size classes of siRNA. Plants also encode RNASE THREE-LIKE (RTL) enzymes that lack DCL-specific domains and whose function is largely unknown. Small RNA sequencing in plants over-expressing RTL1 or RTL2 or lacking RTL2 revealed that RTL1 over-expression inhibits the accumulation of all types of small RNAs produced by DCL2, DCL3 and DCL4, indicating that RTL1 is a general suppressor of plant siRNA pathways. By contrast, RTL2 plays minor, if any, role in the small RNA repertoire. In vivo and in vitro assays revealed that RTL1 prevents siRNA production by degrading dsRNA before they are processed by DCL2, DCL3 and DCL4. The substrate of RTL1 cleavage is likely long perfect (or near-perfect) dsRNA, consistent with the RTL1-insensitivity of miRNAs, which derive from short imperfect dsRNA. RTL1 is naturally expressed only weakly in roots, but virus infection strongly induces its expression in leaves, suggesting that RTL1 induction is a general strategy used by viruses to counteract the siRNA-based plant antiviral defense. Accordingly, transgenic plants over-expressing RTL1 are more sensitive to TYMV infection than wild-type plants, likely because RTL1 prevents the production of antiviral siRNAs. However, TCV, TVCV and CMV, which encode stronger suppressors of RNA silencing (VSR) than TYMV, are insensitive to RTL1 over-expression. Indeed, TCV VSR inhibits RTL1 activity, suggesting that inducing RTL1 expression and dampening RTL1 activity is a dual strategy used by viruses to establish a successful infection. These results reveal another level of complexity in the evolutionary battle between viruses and plant defenses. Flower sRNA profiles in diverse conditions involving RTL1 and RTL2

2013-09-10 | E-GEOD-49866 | biostudies-arrayexpress

Enhanced epigenetic profiling of classical human monocytes reveals a specific signature of healthy aging in the DNA methylome

Project description:The impact of healthy aging on molecular programming of immune cells is poorly understood. Here, we report comprehensive characterization of healthy aging in human classical monocytes, with a focus on epigenomic, transcriptomic, and proteomic alterations, as well as the corresponding proteomic and metabolomic data for plasma, using healthy cohorts of 20 young and 20 older males (~27 and ~64 years old on average). For each individual, we performed eRRBS-based DNA methylation profiling, which allowed us to identify a set of age-associated differentially methylated regions (DMRs) – a novel, cell-type specific signature of aging in DNA methylome. Hypermethylation events were associated with H3K27me3 in the CpG islands near promoters of lowly-expressed genes, while hypomethylated DMRs were enriched in H3K4me1 marked regions and associated with age-related increase of expression of the corresponding genes, providing a link between DNA methylation and age-associated transcriptional changes in primary human cells.

2022-02-16 | PXD021821 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data