Systemic comparison of molecular characteristics in different skin fibroblast senescent models
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE262932 | GEO | 2024/04/10
REPOSITORIES: GEO
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Project description:Senescent cells exhibit a reduced response to intrinsic and extrinsic stimuli. This reduction could be explained by disrupted nuclear transmission of signals. However, this hypothesis required more evidence to complete as a new modality of cellular senescence. Proteomic analysis of the cytoplasmic and nuclear fractions from young and senescent cells revealed disruption of nucleocytoplasmic trafficking (NCT) as an essential feature of replicative senescence (RS) at the global level. Blocking NCT either chemically or genetically induced RS-like senescence phenotypes, named as nuclear barrier-induced senescence (NBIS). Transcriptomic analysis revealed that NBIS had the most similar gene expression pattern to RS, compared with other stress-induced types of cellular senescence. Core proteomic and transcriptomic shared patterns between RS and NBIS included upregulation of endocytosis-lysosome network and downregulation of NCT in senescent cells, which were also conserved in yeast aging model. These results implicate an aging-dependent coordinated reduction in the transmission of extrinsic signals to the nucleus and in the nucleus-to-cytoplasm supply of proteins/RNAs. We further showed that the aging-associated decrease in Sp1 transcription factor expression was responsible for downregulation of NCT. Our results suggest that NBIS is a modality of cellular senescence that can represent the nature of physiological aging in eukaryotes.
2021-06-18 | PXD025618 | Pride
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2022-08-15 | GSE210285 | GEO
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Project description:In mammalian females, quiescent primordial follicles serve as the ovarian reserve and sustain normal ovarian function and egg production via folliculogenesis. The loss of primordial follicles causes ovarian aging. Cellular senescence, characterized by cell cycle arrest and production of the senescence-associated secretory phenotype (SASP), is associated with tissue aging. In the present study, we report that some quiescent primary oocytes in primordial follicles become senescent in adult mouse ovaries. The senescent primary oocytes share senescence markers characterized in senescent somatic cells. The senescent primary oocytes were observed in young adult mouse ovaries, remained at approximately 15% of the total primary oocytes during ovarian aging from 6 months to 12 months, and accumulated in aged ovaries. Administration of a senolytic drug ABT263 to 3-month-old mice reduced the percentage of senescent primary oocytes and the transcription of the SASP cytokines in the ovary. In addition, led to increased numbers of primordial and total follicles and a higher rate of oocyte maturation and female fertility. Our study provides experimental evidence that primary oocytes, a germline cell type that is arrested in meiosis, become senescent in adult mouse ovaries and that senescent cell clearance reduced primordial follicle loss and mitigated ovarian aging phenotypes.
2024-04-30 | GSE253194 | GEO
Project description:Decline in tissue NAD levels during aging has been linked to aging-associated diseases, such as age-related metabolic disease, physical decline, and Alzheimers disease. However, the mechanism for aging-associated NAD decline remains unclear. Here we report that pro-inflammatory M1 macrophages, but not naive or M2 macrophages, highly express the NAD consuming enzyme CD38 and have enhanced CD38-dependent NADase activity. Furthermore, we show that aging is associated with enhanced inflammation due to increased senescent cells, and the accumulation of CD38 positive M1 macrophages in visceral white adipose tissue. We also find that inflammatory cytokines found in the supernatant from senescent cells (Senescence associated secretory proteins, SASP) induces macrophages to proliferate and express CD38. As senescent cells progressively accumulate in adipose tissue during aging, these results highlight a new causal link between visceral tissue senescence and tissue NAD decline during aging and may present a novel therapeutic opportunity to maintain NAD levels during aging.
2019-04-25 | MSV000083726 | MassIVE
Project description:Senescent cells are a major cause of organismal aging and a key target for anti-aging therapies. Persistent DNA damage signaling is a primary driver of the induction and maintenance of cellular senescence. However, many DNA damaging stimuli that induce senescence, such as irradiation or transient exposure to genotoxic drugs, are transient. The mechanisms underlying persistent damage signaling in senescent cells, and why senescent cells fail to repair damaged DNA, remain unknown. Here, we were able to assess the mechanisms underlying persistence of DNA damage and senescence maintenance by designing a precisely controllable senescence system that does not require potent stressors to induce senescence. We demonstrate that sustained mTORC1 signaling in senescent cells causes gradually accumulating DNA damage and an inflammatory response that maintains cell-cycle arrest. Markedly, activation of E2F transcription, which promotes expression of DNA repair proteins, can reverse accumulated DNA damage. Thus, persistent DNA damage signaling arises in senescent cells by uncoupling of mTORC1 and E2F signaling, whereby prolonged mTORC1 activity causes gradually increasing DNA damage that cannot be sufficiently repaired without induction of protective E2F target genes.
2023-06-01 | GSE153683 | GEO
Project description:The presence of senescent cells in the aging/degenerating human disc is now well-recognized. Senescent cells are viable, cannot divide, remain metabolically active and accumulate within the disc over time. Molecular analysis of senescent cells in tissue, however, offers a special challenge since there are no cell surface markers for senescence which would let one use fluorescence-activated cell sorting as a method for separating out senescent cells. Here we use a novel experimental design using laser capture microdissection to selectively separately harvest senescent and non-senescent annulus cells in paraffin-embedded tissue, and then compare their gene expression with microarray analysis. An initial in vitro study using cultured human annulus cells was first performed to test whether there was any difference in identification of senescent cells using the accepted histochemical methodology vs. the immunofluoresent identification of cells positive for senescence-associated-ß-galactosidase in control cells and cells induced into stress-induced premature senescence via hydrogen peroxide exposure. No statistically significant difference was found between the 2 methods. Laser capture microdissection was used to separately harvest senescent and non-senescent cells from 11 human annulus specimens, and microarray analysis was used to determine gene expression levels. Genes with established relationships to senescence were found to be significantly upregulated in senescent cells vs. non-senescent cells. Additional genes related to cytokines, cell proliferation, and other cell processes were also identified. Disc Tissue samples were obtained from surgical disc procedures performed on patients with herniated discs and degenerative disc disease. Tissue was fixed and paraffin embedded. Standard laser capture microdissection (LCM) techniques were used to collect senescent cells. Remaining non-senescent cells were scraped from the histology slide. Total RNA was isolated and analyzed via mircoarray. Gene expression from senescent cells was compared to non-senescent cells. Eight histological samples were used to obtain both senescent and non-senescent cells. From an additional 3 samples, only senescent cells were harvested.
2009-07-15 | E-GEOD-17077 | biostudies-arrayexpress
Project description:RNAseq analyses of NHEKs in replicative-like senescence, i.e. in growth arrest after about ten passages in culture, or in premature senescence induced by repeated UVB exposures (UVB-SIPS), at 3 days and at 5 days after the last UVB stress.
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