Cell Senescence, DNA Damage, and Metabolism

2020 ◽  
Author(s):  
Riva Shmulevich ◽  
Valery Krizhanovsky
Keyword(s):  
Dna Damage ◽  
Cell Senescence

scholarly journals Telomere damage promotes vascular smooth muscle cell senescence and immune cell recruitment after vessel injury

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Anna K. Uryga ◽  
Mandy O. J. Grootaert ◽  
Abel M. Garrido ◽  
Sebnem Oc ◽  
Kirsty Foote ◽  
...  
Keyword(s):  
Dna Damage ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Immune Cell ◽  
Cell Senescence ◽  
Telomeric Dna ◽  
Neointimal Formation ◽  
Persistent Inflammation ◽  
Vessel Injury ◽  
Stress Induced Premature Senescence

AbstractAccumulation of vascular smooth muscle cells (VSMCs) is a hallmark of multiple vascular pathologies, including following neointimal formation after injury and atherosclerosis. However, human VSMCs in advanced atherosclerotic lesions show reduced cell proliferation, extensive and persistent DNA damage, and features of premature cell senescence. Here, we report that stress-induced premature senescence (SIPS) and stable expression of a telomeric repeat-binding factor 2 protein mutant (TRF2T188A) induce senescence of human VSMCs, associated with persistent telomeric DNA damage. VSMC senescence is associated with formation of micronuclei, activation of cGAS-STING cytoplasmic sensing, and induction of multiple pro-inflammatory cytokines. VSMC-specific TRF2T188A expression in a multicolor clonal VSMC-tracking mouse model shows no change in VSMC clonal patches after injury, but an increase in neointima formation, outward remodeling, senescence and immune/inflammatory cell infiltration or retention. We suggest that persistent telomere damage in VSMCs inducing cell senescence has a major role in driving persistent inflammation in vascular disease.

scholarly journals The ESCRT protein CHMP5 restrains skeletal progenitor cell senescence by preserving endo-lysosomal-mitochondrial network

2020 ◽  
Author(s):  
Xianpeng Ge ◽  
Lizhi He ◽  
Haibo Liu ◽  
Cole M. Haynes ◽  
Jae-Hyuck Shim
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Dna Damage ◽  
Progenitor Cell ◽  
Joint Stiffness ◽  
Cell Senescence ◽  
Endocytic Pathway ◽  
Skeletal Growth ◽  
Oxygen Species ◽  
Mitochondrial Network

AbstractThe endocytic pathway actively interacts with mitochondria in maintaining cellular homeostasis. However, how the dysfunction of this inter-organelle interaction causing pathological outcomes remains less understood. Here we show that an aberrant endocytic pathway from the deficiency of CHMP5 in skeletal progenitor cells causes accumulation of functionally compromised mitochondria, which induce cellular senescence via reactive oxygen species (ROS)-mediated oxidative stress and DNA damage. These senescent progenitors can lead to distorted skeletal growth via a combination of cell-autonomous and non-autonomous mechanisms. Consequently, mice lacking Chmp5 in Ctsk-expressing periskeletal progenitors or Dmp1-expressing musculoskeletal progenitors develop multiple skeletal/muscular abnormalities, including robust bone overgrowth, progressive joint stiffness, and myopathy. Targeting senescent cells using senolytic drugs significantly alleviates these lesions and improves animal motility. Overall, our results reveal that CHMP5 restricts skeletal progenitor cell senescence through maintaining the endo-lysosomal-mitochondrial network and cell senescence represents a yet unexplored mechanism for detrimental alterations from the perturbed organelle network.

scholarly journals Effects of Hypocalcemic Vitamin D Analogs in the Expression of DNA Damage Induced in Minilungs from Hescs: Implications for Lung Fibrosis

2021 ◽  
Author(s):  
Esmeralda Magro-Lopez ◽  
Irene Chamorro-Herrero ◽  
Alberto Zambrano
Keyword(s):  
Vitamin D ◽  
Dna Damage ◽  
Cell Line ◽  
Lung Fibrosis ◽  
Cell Senescence ◽  
Biologically Active ◽  
Therapeutic Effects ◽  
Lung Pathology ◽  
Alveolar Cells ◽  
Vitamin D Analogs

Abstract BackgroundIn our previous work, we evaluated the therapeutic effects of 1α,25-Dihydroxyvitamin D3, the biologically active form of vitamin D, in the context of bleomycin-induced lung fibrosis. Contrary to the expected, vitamin D supplementation increased DNA damage expression and cellular senescence in alveolar epithelial type II cells and aggravated the overall lung pathology induced in mice by bleomycin. These effects were probably due to an alteration of the cellular DNA double-strand breaks repair capability. In the present work we have evaluated the effects of two hypocalcemic vitamin D analogs (calcipotriol and paricalcitol) in the expression of DNA damage in the context of minilungs derived from human embryonic stem cells and in the cell line A549.ResultsAs in the case of the cell line A549, bleomycin can induce DNA damage in the generated minilungs enriched in alveolar cells. The results indicate that, in contrast to vitamin D, the treatment of the minilungs with the hypocalcemic analogs reduce significantly the bulk of DNA damage expression in both bidimensional arrays of epithelial cells (2D minilungs) and lung bud organoids (3D minilungs). The initial evaluation of a battery of commercially available vitamin D analogs shows a significant reduction in A549 cells of gH2AFX expression levels, a marker of DNA damage, cell senescence and aging.ConclusionsThe treatments based in hypocalcemic vitamin D analogs might be used to reduce the bulk of DNA damage and eventually the subsequent cell senescence expression that underlie lung conditions as those that can evolve with fibrosis.

An intimate alliance of DNA-damage response network with cell-cycle checkpoints amid events of uncontrolled cellular proliferation- a mini review

2020 ◽  
Author(s):  
Rajni Khan
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Cellular Proliferation ◽  
Signal Transmission ◽  
Cell Senescence ◽  
Effector Proteins ◽  
Cell Cycle Checkpoints ◽  
Response Network ◽  
Damage Response

There is a close interdependence between the cell survival, cell senescence, events of cell cycle, apoptosis, malignancy development and tumor responses to cancer treatment. Intensive studies and elaborate researches have been conducted on the functional aspects of oncogenes, tumor suppressor genes, apoptotic genes and members guiding cell cycle regulation. These disquisitions have put forward the existence of a highly organized response pathway termed as DNA-damage response network. The pathways detecting DNA damage and signaling are intensively linked to the events of cell-cycle arrest, cell proliferation, apoptosis and cell senescence. DNA damage responses are complex systems that incorporate specific "sensor" and "transducer" proteins, for assessment of damage and signal transmission respectively. These signals are thereafter relayed upon various "effector" proteins involved in different cellular pathways. It may include those governing cell-cycle checkpoints, participating in DNA repair, cell senescence, and apoptosis.

scholarly journals Cellular Senescence in Age-Related Macular Degeneration: Can Autophagy and DNA Damage Response Play a Role?

2017 ◽  
Vol 2017 ◽  
pp. 1-15 ◽  
Author(s):  
Janusz Blasiak ◽  
Malgorzata Piechota ◽  
Elzbieta Pawlowska ◽  
Magdalena Szatkowska ◽  
Ewa Sikora ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Macular Degeneration ◽  
Dna Damage Response ◽  
Cellular Senescence ◽  
Cell Senescence ◽  
Age Related Macular Degeneration ◽  
Rpe Cells ◽  
Age Related ◽  
Damage Response

Age-related macular degeneration (AMD) is the main reason of blindness in developed countries. Aging is the main AMD risk factor. Oxidative stress, inflammation and some genetic factors play a role in AMD pathogenesis. AMD is associated with the degradation of retinal pigment epithelium (RPE) cells, photoreceptors, and choriocapillaris. Lost RPE cells in the central retina can be replaced by their peripheral counterparts. However, if they are senescent, degenerated regions in the macula cannot be regenerated. Oxidative stress, a main factor of AMD pathogenesis, can induce DNA damage response (DDR), autophagy, and cell senescence. Moreover, cell senescence is involved in the pathogenesis of many age-related diseases. Cell senescence is the state of permanent cellular division arrest and concerns only mitotic cells. RPE cells, although quiescent in the retina, can proliferate in vitro. They can also undergo oxidative stress-induced senescence. Therefore, cellular senescence can be considered as an important molecular pathway of AMD pathology, resulting in an inability of the macula to regenerate after degeneration of RPE cells caused by a factor inducing DDR and autophagy. It is too early to speculate about the role of the mutual interplay between cell senescence, autophagy, and DDR, but this subject is worth further studies.

IFNγ induces oxidative stress, DNA damage and tumor cell senescence via TGFβ/SMAD signaling-dependent induction of Nox4 and suppression of ANT2

Oncogene ◽  
2015 ◽  
Vol 35 (10) ◽  
pp. 1236-1249 ◽  
Author(s):  
S Hubackova ◽  
A Kucerova ◽  
G Michlits ◽  
L Kyjacova ◽  
M Reinis ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Tumor Cell ◽  
Cell Senescence ◽  
Smad Signaling

scholarly journals PBX1 Attenuates Hair Follicle-Derived Mesenchymal Stem Cell Senescence and Apoptosis by Alleviating Reactive Oxygen Species-Mediated DNA Damage Instead of Enhancing DNA Damage Repair

2021 ◽  
Vol 9 ◽  
Author(s):  
Yuan Wang ◽  
Yutong Sui ◽  
Aobo Lian ◽  
Xing Han ◽  
Feilin Liu ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Stem Cells ◽  
Dna Damage ◽  
Dna Repair ◽  
Stem Cell ◽  
Hair Follicle ◽  
Cellular Senescence ◽  
Cell Senescence ◽  
Oxygen Species ◽  
Age Related

Tissues and organs undergo structural deterioration and functional decline during aging. DNA damage is considered a major cause of stem cell senescence. Although stem cells develop sophisticated DNA repair systems, when the intrinsic and extrinsic insults exceed the DNA repair capacity, cellular senescence, and age-related diseases inevitably occur. Therefore, the prevention and alleviation of DNA damage is an alternative to DNA repair in attenuating stem cell senescence and preventing age-related diseases. Pre-B-cell leukaemia homeobox 1 (PBX1) participates in maintaining the pluripotency of human embryonic and haematopoietic stem cells. Our recent studies showed that PBX1 promotes hair follicle-derived mesenchymal stem cell (HF-MSC) proliferation, decreases cellular senescence and apoptosis, and enhances induced pluripotent stem cell generation. Whether PBX1 attenuates HF-MSC senescence and apoptosis by alleviating DNA damage or by enhancing DNA repair remains unknown. In this study, we aimed to determine the effects of PBX1 on the intrinsic ROS or extrinsic H2O2-induced cellular senescence of HF-MSCs. To this end, we generated HF-MSCs overexpressing either PBX1, or poly (ADP-ribose) polymerase 1, or both. Our results showed that PBX1 overexpression attenuates HF-MSC senescence and apoptosis by alleviating reactive oxygen species (ROS)-mediated DNA damage instead of enhancing DNA repair. This is the first study to report that PBX1 attenuates stem cell senescence and apoptosis by alleviating DNA damage. It provides new insight into the mechanism of stem cell senescence and lays the foundation for the development of strategies for age-related disease prevention and treatment, and in particular, hair follicle repair and regeneration.

scholarly journals Persistence of a novel regeneration-associated transitional cell state in pulmonary fibrosis

2019 ◽  
Author(s):  
Yoshihiko Kobayashi ◽  
Aleksandra Tata ◽  
Arvind Konkimalla ◽  
Hiroaki Katsura ◽  
Rebecca F. Lee ◽  
...  
Keyword(s):  
Dna Damage ◽  
Stem Cell ◽  
Cell Differentiation ◽  
Pulmonary Fibrosis ◽  
Stem Cell Differentiation ◽  
Lineage Tracing ◽  
Cell Senescence ◽  
Alveolar Type ◽  
Transitional State

AbstractStem cell senescence is often seen as an age associated pathological state in which cells acquire an abnormal and irreversible state. Here, we show that alveolar stem cell differentiation during lung regeneration involves a unique previously uncharacterized transitional state that exhibits cardinal features normally associated with cell senescence. Specifically, using organoid cultures, multiple in vivo injury models coupled with single cell transcriptomics and lineage tracing analysis, we find that alveolar stem cell differentiation involves a novel, pre-alveolar type-1 transitional state (PATS) en route to their terminal maturation. PATS can be distinguished based on their unique transcriptional signatures, including enrichment for TP53, TGFβ, and DNA damage repair signaling, and cellular senescence in both in vivo and ex vivo regenerating tissues. Significantly, PATS undergo extensive cell stretching, which makes them vulnerable to DNA damage, a feature commonly associated with most degenerative lung diseases. Importantly, we find enrichment of PATS-like state in human fibrotic lung tissues, suggesting that persistence of such transitional states underlies the pathogenesis of pulmonary fibrosis. Our study thus redefines senescence as a state that can occur as part of a normal tissue maintenance program, and can be derailed in human disease, notably fibrosis.

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