Proliferative stress in hematopoietic stem cells partially drives their functional decline during aging by DNA methylation imprints
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ABSTRACT:
PROVIDER: PRJNA1146326 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR30184200.fastq.gz | Fastqsanger.gz | |||
| SRR30184201.fastq.gz | Fastqsanger.gz | |||
| SRR30184202.fastq.gz | Fastqsanger.gz | |||
| SRR30184203.fastq.gz | Fastqsanger.gz |
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Project description:Aging of the vasculature is associated with detrimental changes in vascular smooth muscle cell (VSMC) mechanosensitivity to extrinsic forces in their surrounding microenvironment. However, how chronological aging alters VSMCs’ ability to sense and adapt to mechanical perturbations remains unexplored. Here, we show defective VSMC mechanosensation in aging measured with ultrasound tweezers-based micromechanical system, force instantaneous frequency spectrum and transcriptome analyses. The mechanobiological study reveals thataged VSMCs adapt a relatively inert solid-like state with altered actin cytoskeletal integrity, resulting in an impairment in their mechanosensitivity and dynamic mechanoresponse to mechanical perturbations. The aging-associated decline in mechanosensation behaviors is mediated by hyperactivity of Piezo1-dependent calcium signaling. Inhibition of Piezo1 alleviates vascular aging and partially restores the loss in dynamic contractile properties in aged cells. Altogether, our study reveals the novel signaling pathway underlying aging-associated aberrant mechanosensation in VSMC and identifies Piezo1 as a potential therapeutic mechanobiological target to alleviate vascular aging.
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Project description:Aging is the progressive decline in organismal function that leads to an increased risk of multiple diseases and mortality. The molecular basis of this decline is unknown. Using quantitative PCR for mitochondrial mRNA from multiple tissues from the same animals, we found that the rate of change in mouse mitochondrial expression is tissue-specific, with cardiac expression declining early (8-10 months), adipose expression declining late (25-30 months), and no change in kidney or skin. In cardiac tissue, mitochondria-derived mRNA levels declined more slowly than nuclear encoded mRNAs, suggesting a potential dysregulation. These changes were independent of alteration in mitochondrial number, as measured by quantitative PCR of mitochondrial DNA and citrate synthase activity. We found no change in the variability between mitochondrial mRNA levels with age, suggesting that the changes are not due to random dysregulation at the level of gene expression. Caloric restriction (CR), a lifespan-extending intervention proposed to act through mitochondrial biogenesis, delayed the decline in both cardiac and adipose mitochondrial mRNA levels of F344 rats. CR caused an increase in citrate synthase activity but did not alter mitochondrial DNA content, indicating increased translation or reduced turnover of mitochondrial proteins. These results demonstrate that mitochondrial gene expression changes with age are not coupled to mitochondrial number, are likely to be regulated, and are governed by tissue-specific processes. These findings indicate that aging is neither a programmed organism-wide change orchestrated in a top-down fashion nor a product of random dysregulation of gene expression but that tissue-specific factors may independently control aging in different organ compartments. Keywords: aging Cardiac ventricle total RNA from 10 young (4-6 month) and 10 young (25-28 month) mice were compared.
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Project description:Leptin receptor (LEPR) identifies a subpopulation of hematopoietic stem cells (HSCs) with high repopulating potential. In this study, we demonstrated that LEPR-expressing HSCs while exhibiting significantly higher engrafting potential and self-renewing capacity in young mice showed early age-associated decline in these functions as compared to the LEPR- HSCs. LEPR+ HSCs have transcriptomic profiles significantly different from LEPR- HSCs in young mouse bone marrow, but middle-aged HSCs do not have distinct transcriptomic profiles based on LEPR status. The age-related phenotypes were associated with a proinflammatory transcriptomic profile at baseline in young LEPR+ HSCs, which was further exacerbated by age. In contrast, LEPR- HSCs did not show age-associated functional impairment at the ages tested. This suggested that subsets of HSCs are susceptible to age-related decline in function at varying ages and that LEPR+ HSCs are a potential target for early cellular therapeutic interventions in delaying the detrimental effects of aging in hematopoiesis.
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Project description:Aging is the predominant risk factor for neurodegenerative diseases. One key phenotype as brain ages is the aberrant innate immune response characterized by proinflammation. However, the molecular mechanisms underlying aging-associated proinflammation are poorly defined. Whether chronic inflammation plays a causal role in cognitive decline in aging and neurodegeneration has not been established. Here we established a mechanistic link between chronic inflammation and aging microglia, and demonstrated a causal role of aging microglia in neurodegenerative cognitive deficits. Expression of microglial SIRT1 reduces with the aging of microglia. Genetic reduction of microglial SIRT1 elevates IL-1β selectively, and exacerbates cognitive deficits in aging and in transgenic mouse models of frontotemporal dementia (FTD). Interestingly, the selective activation of IL-1β transcription by SIRT1 deficiency is likely mediated through hypomethylating the proximal promoter of IL-1β. Consistent with our findings in mice, selective hypomethylation of IL-1β at two CpG sites are found in normal aging humans and demented patients with tauopathy. Our findings reveal a novel epigenetic mechanism in aging microglia that contributes to cognitive deficits in neurodegenerative diseases. Study of changes related to alterations of SIRT1 levels in microglia of young and aged animals and in models of neurodegenerative dementia
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Project description:Recent microarray studies in the hippocampus of rodents or Alzheimerâs disease (AD) subjects have identified a substantial number of cellular pathways/processes correlated with aging and cognitive decline. However, the temporal relationships among these expression changes or with cognitive impairment have not been studied in depth. Here, using Affymetrix microarrays, immunohistochemistry and Morris water maze cognitive testing across 5 age groups of male F344 rats (n=9-15/group, one microarray per animal), we systematically analyzed the temporal sequence and cellular localization of aging changes in expression. These were correlated with performance scores on the hippocampus-dependent Morris Water Maze task. Significant microarray results were sorted in to Early, Intermediate, Midlife, and Late patterns of expression, and functionally categorized (Early- downregulated neural development, lipid synthesis and energy-utilization; upregulated ribosomal synthesis, growth, stress/inflammatory, lysosome and protein/lipid degradation. Intermediate- increased defense/inflammatory activation and decreased transporter activity; Midlife- downregulated energy-dependent signaling and neurite growth, upregulated astroglial activation, Ca2+-binding, cholesterol/lipid trafficking, myelinogenic processes and additional lysosome/inflammation; Late- further recruitment of genes in already-altered pathways). Immunohistochemistry revealed a primarily astrocytic localization of the processes upregulated in midlife, as well as increased density of myelin proteins. Evidence of cognitive impairment first appeared in the 12-month-old group (midlife) and was increased further in the 23-month-old group, exhibiting the highest correlations with some upregulated genes related to cholesterol transport (e.g., Apoe, Abca2), protein management and ion binding. Some upregulated genes for inflammation (Il6st) and myelinogenesis (Pmp22) also correlated with impairment. Together, the data are consistent with a novel sequential cascade model of brain aging in which metabolic alterations early in maturity are followed by inflammation and midlife activation of an astrocyte-centered cholesterol trafficking pathway that stimulates oligodendrocyte remyelination programs. Importantly, this cholesterol trafficking pathway also may compete for astroglial bioenergetic support of neurons, in turn, leading to downregulation of energy-dependent pathways needed to sustain cognitive functions. Experiment Overall Design: Fisher 344 rats aged 3 (n = 9), 6 (n = 9), 9 (n = 9), 12 (n = 9), or 25 (n = 15; but see below) months were behaviorally characterized on the Morris water maze. Briefly, animals were placed in a circular water bath chamber with a partially submerged platform. Three times per day for three days, animals were placed at randomized starting points with the goal of locating the hidden platform. Generally, animals became better at locating the platform, and by the third day of training, were reliably swimming directly to the platform despite randomized starting loci. On the fourth day, the platform was removed and the degree to which the animals focused their searches on the area that previously contained the platform was measured. On the last day of behavior, animals were given a cue trial in which the platform was raised above the water level so that the rats could see it. Measures taken from the behavior study included path length (how long did the animal swim prior to locating the platform/ platform area), latency to platform in seconds, and velocity (centimeters/ second; swim speed). Two aged animals (E2 and E12) were removed from the study for poor health, reducing the 23 month cohort (n = 13). Twelve to twenty four hours after the last behavioral session, animals were killed and their hippocampi removed. The right hippocampus went to immunohistochemistry for quantification and localization of selected protein products. The left hippocampus was dissected, the CA1 region removed and frozen in dry ice prior to microarray processing. mRNA was extracted from each animal's tissue by standard Affymetrix protocols (see Blalock et al., 2003) and hybridized to individual microarrays (RAE 230A; N = 49 arrays in total). Results were processed with the MAS5 algorithm and subjected to âall probe setâ scaling with a target intensity of 500. Probe sets were filtered for presence (> = 5 presence calls study wide) and gene symbol level annotation prior to statistical analysis. 1-ANOVA across age was used to identify aging-related probe sets/genes (p <= 0.05). Aging-related genes were subjected to post hoc template correlation to determine the pattern of age-related change, and further, within the 12 and 23 month old groups, Pearson's correlation with behavioral scores was used to identify genes whose expression levels correlated significantly (p <= 0.05) with behavior. Twelve and 23 month old groups were chosen for this correlation analysis as they showed the greatest variability among similarly aged animals, suggesting that these ages show important cognitive transition phases during aging-related cognitive decline. Functional grouping analysis was performed using the DAVID suite of on-line tools.
2009-01-25 | E-GEOD-9990 | biostudies-arrayexpress