Search results for "cellular senescence"
showing 10 items of 109 documents
YAP/TAZ activity in stromal cells prevents ageing by controlling cGAS-STING
2022
Ageing is intimately connected to the induction of cell senescence(1,2), but why this is so remains poorly understood. A key challenge isthe identification of pathways that normally suppress senescence, are lost during ageing and are functionally relevant to oppose ageing(3). Here we connected the structural and functional decline of ageing tissues to attenuated function of the master effectors of cellular mechanosignalling YAP and TAZ. YAP/TAZ activity declines during physiological ageing in stromal cells, and mimicking such decline through genetic inactivation of YAP/TAZ in these cells leads to accelerated ageing. Conversely, sustaining YAP function rejuvenates old cells and opposes the e…
Tif1γ regulates the TGF-β1 receptor and promotes physiological aging of hematopoietic stem cells.
2014
The hematopoietic system declines with age. Myeloid-biased differentiation and increased incidence of myeloid malignancies feature aging of hematopoietic stem cells (HSCs), but the mechanisms involved remain uncertain. Here, we report that 4-mo-old mice deleted for transcription intermediary factor 1γ (Tif1γ) in HSCs developed an accelerated aging phenotype. To reinforce this result, we also show that Tif1γ is down-regulated in HSCs during aging in 20-mo-old wild-type mice. We established that Tif1γ controls TGF-β1 receptor (Tgfbr1) turnover. Compared with young HSCs, Tif1γ(-/-) and old HSCs are more sensitive to TGF-β signaling. Importantly, we identified two populations of HSCs specifical…
Progerin expression induces a significant downregulation of transcription from human repetitive sequences in iPSC-derived dopaminergic neurons.
2019
Repetitive DNA sequences represent about half of the human genome. They have a central role in human biology, especially neurobiology, but are notoriously difficult to study. The purpose of this study was to quantify the transcription from repetitive sequences in a progerin-expressing cellular model of neuronal aging. Progerin is a nuclear protein causative of the Hutchinson–Gilford progeria syndrome that is also incrementally expressed during the normal aging process. A dedicated pipeline of analysis allowed to quantify transcripts containing repetitive sequences from RNAseq datasets oblivious of their genomic localization, tolerating a sufficient degree of mutational noise, all with low c…
B cells and immunosenescence: a focus on IgG+IgD-CD27- (DN) B cells in aged humans.
2010
Immunosenescence contributes to the decreased ability of the elderly to control infectious diseases, which is also reflected in their generally poor response to new antigens and vaccination. It is known that the T cell branch of the immune system is impaired in the elderly mainly due to expansion of memory/effector cells that renders the immune system less able to respond to new antigens. B lymphocytes are also impaired in the elderly in terms of their response to new antigens. In this paper we review recent work on B cell immunosenescence focusing our attention on memory B cells and a subset of memory B cells (namely IgG(+)IgD(-)CD27(-)) that we have demonstrated is increased in healthy el…
Nociceptin/orphanin FQ opioid receptor (NOP) selective ligand MCOPPB links anxiolytic and senolytic effects
2021
Accumulation of senescent cells may drive age-associated alterations and pathologies. Senolytics are promising therapeutics that can preferentially eliminate senescent cells. Here, we performed a high-throughput automatized screening (HTS) of the commercial LOPAC®Pfizer library on aphidicolin-induced senescent human fibroblasts, to identify novel senolytics. We discovered the nociceptin receptor FQ opioid receptor (NOP) selective ligand 1-[1-(1-methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole (MCOPPB, a compound previously studied as potential anxiolytic) as the best scoring hit. The ability of MCOPPB to eliminate senescent cells in in vitro models was further tested…
The emerging role of miRNA-132/212 cluster in neurologic and cardiovascular diseases: Neuroprotective role in cells with prolonged longevity
2021
Abstract miRNA-132/212 are small regulators of gene expression with a function that fulfills a vital function in diverse biological processes including neuroprotection of cells with prolonged longevity in neurons and the cardiovascular system. In neurons, miRNA-132 appears to be essential for controlling differentiation, development, and neural functioning. Indeed, it also universally promotes axon evolution, nervous migration, plasticity as well, it is suggested to be neuroprotective against neurodegenerative diseases. Moreover, miRNA-132/212 disorder leads to neural developmental perturbation, and the development of degenerative disorders covering Alzheimer’s, Parkinson’s, and epilepsy’s …
Impaired calcium homeostasis in aged hippocampal neurons
2009
Abstract Development of neurodegenerative diseases such as Alzheimer's and Parkinson's disease is strongly age-associated. The impairment of calcium homeostasis is considered to be a key pathological event leading to neuronal dysfunction and cell death. However, the exact impact of aging on calcium homeostasis in neurons remains largely unknown. In the present work we have investigated intracellular calcium levels in cultured primary hippocampal neurons from young (2 months) and aged (24 months) rat brains. Upon stimulation with glutamate or hydrogen peroxide aged neurons in comparison to young neurons demonstrated an increased vulnerability to these disease-related toxins. Measurement of c…
Inflammation, genes and zinc in ageing and age-related diseases.
2006
Lifelong antigenic burden determines a condition of chronic inflammation, with increased lymphocyte activation and pro-inflammatory cytokine production. A large number of studies have documented changes in Zn metabolism in experimental animal models of acute and chronic inflammation and in human chronic inflammatory diseases. In particular, modification of zinc plasma concentration as well as intracellular disturbance of antioxidant intracellular pathways have been found associated to age-related inflammatory diseases, like atherosclerosis. Zinc deficiency is extremely diffused in aged people that are educated to avoid meat and other high Zn-content foods due to fear of cholesterol. Rather,…
Protein quality control during aging involves recruitment of the macroautophagy pathway by BAG3.
2009
The Hsc/Hsp70 co-chaperones of the BAG (Bcl-2-associated athanogene) protein family are modulators of protein quality control. We examined the specific roles of BAG1 and BAG3 in protein degradation during the aging process. We show that BAG1 and BAG3 regulate proteasomal and macroautophagic pathways, respectively, for the degradation of polyubiquitinated proteins. Moreover, using models of cellular aging, we find that a switch from BAG1 to BAG3 determines that aged cells use more intensively the macroautophagic system for turnover of polyubiquitinated proteins. This increased macroautophagic flux is regulated by BAG3 in concert with the ubiquitin-binding protein p62/SQSTM1. The BAG3/BAG1 ra…
Carbocysteine counteracts the effects of cigarette smoke on cell growth and on the SIRT1/FoxO3 axis in bronchial epithelial cells
2016
Abstract Background Cigarette smoke may accelerate cellular senescence by increasing oxidative stress. Altered proliferation and altered expression of anti-aging factors, including SIRT1 and FoxO3, characterise cellular senescence. The effects of carbocysteine on the SIRT1/FoxO3 axis and on downstream molecular mechanisms in human bronchial epithelial cells exposed to cigarette smoke are largely unknown. Aims Aim of this study was to explore whether carbocysteine modulated SIRT1/FoxO3 axis, and downstream molecular mechanisms associated to cellular senescence, in a bronchial epithelial cell line (16-HBE) exposed to cigarette smoke. Methods 16HBE cells were stimulated with/without cigarette …