Transcriptomic Analysis of Small Extracellular Vesicles (sEVs) from Mouse Liver Tissue Across Age Groups: Implications for Aging and Lipid Metabolism
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ABSTRACT: The present study investigates the transcriptomic profiles of small extracellular vesicles (sEVs) isolated from the liver tissues of mice at different ages to understand the role of sEVs in aging and lipid metabolism. We hypothesize that age-related changes in sEVs could reflect alterations in cellular communication and contribute to the development of age-associated diseases. Through a comprehensive analysis of miRNA expression, we aim to identify biomarkers and potential therapeutic targets for liver aging and metabolic disorders. The study involved the extraction and characterization of sEVs from the liver tissues of mice at various ages.The age distribution and corresponding numbers of mice included 10 mice at 1 week (1 W), 5 mice at 6 weeks (6 W), 5 mice at 6 months (6 M), 5 mice at 12 months (12 M), and 5 mice at 14 months (14 M). Transcriptome analysis was performed to identify differentially expressed miRNAs.
Project description:Tissue stem cell senescence leads to stem cell exhaustion, which results in tissue homeostasis imbalance and a decline in regeneration capacity. However, whether neural stem cells (NSCs) senescence occurs and causes neurogenesis reduction during aging is unknown. In this study, mice at different ages were used to detect age-related hippocampal NSCs (H-NSCs) senescence, as well as the function and mechanism of embryonic stem cells derived small extracellular vesicles (ESC-sEVs) in rejuvenating H-NSCs senescence. We found a progressive cognitive impairment, as well as age-related H-NSCs senescence, in mice. ESC-sEVs treatment significantly alleviated H-NSCs senescence, recovered compromised self-renewal and neurogenesis capacities, and reversed cognitive impairment. Transcriptome analysis revealed that Myelin transcription factor 1 (MYT1) is downregulated in senescent H-NSCs but upregulated by ESC-sEV treatment. In addition, knockdown of MYT1 in young H-NSCs accelerated age-related phenotypes and impaired proliferation and differentiation capacities. Mechanistically, ESC-sEVs rejuvenated senescent H-NSCs partly by transferring SMAD4 and SMAD5 to activate MYT1, which downregulated Egln3, followed by activation of HIF2α, NAMPT, and Sirt1 successively. Taken together, our results indicated that H-NSCs senescence caused cellular exhaustion, neurogenesis reduction and cognitive impairment during aging, which can be reversed by ESC-sEVs. Thus, ESC-sEVs may be promising therapeutic candidates for age-related diseases.
Project description:The project aims to investigate the proteomic changes in small extracellular vesicles (sEVs) derived from mouse liver tissue across different age groups to identify proteins associated with aging. The study employs a comprehensive proteomic analysis to reveal age-dependent alterations in protein expression, which could provide insights into the molecular mechanisms of aging and potentially identify biomarkers for age-related diseases.
Project description:Aging and the chronic diseases associated with aging have become a great burden to modern society. Recent animal studies on heterochronic parabiosis have revealed that young blood has a powerful rejuvenating effect on aged tissues, but which components of the young blood are responsible for the rejuvenating effects remains unclear. In this study, we found that small extracellular vesicles (sEVs) purified from the plasma of young mice could counteract pre-existing aging at the molecular, mitochondrial, cellular and physiological levels. In detail, injection of young sEVs into aged mice extended lifespan, attenuated senescent phenotypes and mitigate age-associated impairments on various tissues (hippocampus, muscle, heart, testis, bone, etc). Mechanistical studies using iTRAQ-based quantitative proteomic analyses combined with GO term cluster revealed that the altered proteomes in aged tissues of young sEVs-treated mice were specifically related to their roles in regulating cellular senescence, metabolic process, epigenetic modification, genomic stability, etc, which are the cardinal features associated with aging. Particularly, the sEVs derived from young mice and young human donors could stimulate PGC-1α (a master regulator of mitochondrial biogenesis and energy metabolism) expression in vitro and in vivo through their rejuvenating miRNA cargos, thereby facilitating mitochondrial regeneration and counteracting mitochondrial deficits in aged tissues. Taken together, this study demonstrates that young sEVs can reverse degenerative changes and age-related dysfunctions through stimulating PGC-1α expression and regenerating intact mitochondria.
Project description:Transcriptomic Analysis of Small Extracellular Vesicles (sEVs) from Mouse Liver Tissue Across Age Groups: Implications for Aging and Lipid Metabolism
Project description:aCGH analysis of murine transgenic liver tissues affected with HCC, hybridized with age (12 months) and sex matched alb cre mice. Keywords: Array comparative genomic hybridization analysis (aCGH).
Project description:Aging is a key driver of cognitive decline and the predominant risk factor for several neurodegenerative diseases. Recent behavioral studies as well as structural and functional MRI data suggest that aging does not impact the brain in a uniform manner but follows region- and age-specific trajectories. Yet so far, quantitative analyses of the molecular dynamics in the aging brain have been limited to few regions at low temporal resolution. Here we use the 10X Visium platform to perform spatial transcriptomics (Spatial-seq) of equivalent coronal sections of the mouse brain at young (6 months), middle (18 months) and old (21 months) age.
Project description:The current study aims were to determine the differential expression of Myo-sEVs derived from normal or HG/HL.Mouse primary myocardial cells were isolated and cultured in normal and HG/HL culture medium. Myo-sEVs were separated by ultracentrifugation.Differential myo-sEVs-miRNA expression obtained through Unbiased miRNA array analysis.
Project description:Understanding the molecular mechanisms underlying age-related changes in the heart is challenging due to the contributions from numerous genetic and environmental factors. Genetically diverse outbred mice provide a model to study the genetic regulation of aging processes in healthy tissues from individuals undergoing natural aging in a controlled environment. We analyzed transcriptome and proteome data from outbred mice at 6, 12 and 18 months of age to reveal a scenario of cardiac hypertrophy, fibrosis, extracellular matrix remodeling, and reemergence of fetal gene expression patterns. We observed widespread changes in protein trafficking and sorting, and post-translational disruption of the stoichiometry of the protein quality control system itself. We identified genome hotspots of age-by-genetic effects that regulate proteins from the proteasome and endoplasmic reticulum stress response, suggesting that genetic variation in these modules may contribute to individual variation in the aging heart.
Project description:Sirtuin 1 (SIRT1) is involved in both aging and circadian-clock regulation, yet the link between the two processes in relation to SIRT1 function is not clear. Using Sirt1-deficient mice, we found that Sirt1 and Period 2 (Per2) constitute a reciprocal negative regulation loop that plays important roles in modulating hepatic circadian rhythmicity and aging. Sirt1-deficient mice exhibited profound premature aging and enhanced acetylation of histone H4 on lysine16 (H4K16) in the promoter of Per2, the latter of which leads to its overexpression; in turn, Per2 suppresses Sirt1 transcription through binding to the Sirt1 promoter at the Clock/Bmal1 site. This negative reciprocal relationship between SIRT1 and PER2 was also observed in human hepatocytes. We further demonstrated that the absence of Sirt1 or the ectopic overexpression of Per2 in the liver resulted in a dysregulated pace of the circadian rhythm. The similar circadian rhythm was also observed in aged wild type mice. The interplay between Sirt1 and Per2 modulates aging gene expression and circadian-clock maintenance. To investigate hepatic SIRT1-dependent aging related genes, livers from wild type mice at 3 months (young), 12 months (middle age), and 19 months (old) of age, as well as Sirt1-deficient mice at 3 months of age were snap frozen and subject to RNA isolation and microarray analysis.
Project description:Dietary interventions are effective ways to extend or shorten lifespan. By examining midlife hepatic gene expressions in mice under different dietary conditions, which resulted in different lifespans and aging-related phenotypes, we were able to identify genes and pathways that modulate the aging process. To determine how our dietary intervention-based transcriptomic approach for predicting aging-regulatory genes compares to more traditional approach of using age-dependent transcriptional changes, we examined the hepatic gene expression changes in LF-fed mice during aging at 4, 8, 13 and 21 months. Male C57BL/6J mice at 4 weeks of age were purchased from Shanghai Animal Co, Ltd. Mice were maintained under a 12-hour dark/light cycle (lights on at 6:30 am) at a temperature of 22 ± 3 °C in accredited animal facilities. Prior to the start of experiment, mice were maintained on a low-fat diet (Research Diets Inc., New Brunswick, NJ) for one week. Liver RNAs extracted from six male C57BL/6J mice of the same age were pooled at each age point to obtain an average microarray profile at 4, 8, 13 and 21 months.