Aging is a pivotal risk factor for intervertebral disc degeneration(IVDD)and chronic low back pain(LBP).The restoration of aging nucleus pulposus cells(NPCs)to a youthful epigenetic state is crucial for IVDD treatment...Aging is a pivotal risk factor for intervertebral disc degeneration(IVDD)and chronic low back pain(LBP).The restoration of aging nucleus pulposus cells(NPCs)to a youthful epigenetic state is crucial for IVDD treatment,but remains a formidable challenge.Here,we proposed a strategy to partially reprogram and reinstate youthful epigenetics of senescent NPCs by delivering a plasmid carrier that expressed pluripotency-associated genes(Oct4,Klf4 and Sox2)in Cavin2-modified exosomes(OKS@M-Exo)for treatment of IVDD and alleviating LBP.The functional OKS@M-Exo efficaciously alleviated senescence markers(p16^(INK4a),p21^(CIP1)and p53),reduced DNA damage and H4K20me3 expression,as well as restored proliferation ability and metabolic balance in senescent NPCs,as validated through in vitro experiments.In a rat model of IVDD,OKS@M-Exo maintained intervertebral disc height,nucleus pulposus hydration and tissue structure,effectively ameliorated IVDD via decreasing the senescence markers.Additionally,OKS@MExo reduced nociceptive behavior and downregulated nociception markers,indicating its efficiency in alleviating LBP.The transcriptome sequencing analysis also demonstrated that OKS@M-Exo could decrease the expression of age-related pathways and restore cell proliferation.Collectively,reprogramming by the OKS@M-Exo to restore youthful epigenetics of senescent NPCs may hold promise as a therapeutic platform to treat IVDD.展开更多
Chronic pain affects over 30%of the global adult population,significantly impairing quality of life,physical function,and psychological well-being,while imposing a substantial personal and economic burden[1].As the gl...Chronic pain affects over 30%of the global adult population,significantly impairing quality of life,physical function,and psychological well-being,while imposing a substantial personal and economic burden[1].As the global population continues to age,there is an urgent and unmet need to effectively prevent,assess,and manage chronic pain in older adults.Although age-related changes in pain perception,processing,and coping mechanisms have been increasingly recognized over recent decades,many aspects of the relationship between aging and pain remain poorly understood.In addition,aging is associated with increased susceptibility to chronic pain conditions,particularly following peripheral nerve injury[2,3].However,the incomplete understanding of the mechanisms underlying pain in the aged population represents a major barrier to the development of effective medical treatment is often insufficient to provide complete pain relief[4,5].Targeted interventions for geriatric pain management are needed.Therefore,elucidating the impact of aging on the pathogenesis of chronic pain is urgently needed.展开更多
Bone marrow lesions(BML)are early signs of osteoarthritis(OA)and are strongly correlated with the deterioration of cartilage lesions.Single-cell RNA sequencing(scRNA-seq)analyses were performed on BM from non-BML and ...Bone marrow lesions(BML)are early signs of osteoarthritis(OA)and are strongly correlated with the deterioration of cartilage lesions.Single-cell RNA sequencing(scRNA-seq)analyses were performed on BM from non-BML and BML areas and articular cartilage from intact and damaged areas to explore BML landscape and BML-cartilage crosstalk.We revealed the immune landscape of BM in non-BML and BML,and the transition to pro-inflammatory states of clusters in BMLs,such as classical monocytes and nonclassical monocytes.Non-classical monocytes have high inflammation,OA gene signatures,and senescence scores,and are potential primary clusters promoting OA progression.Histological signs of OA related to the cellular landscape in damaged cartilage were identified,including PreFC exhaustion.The BM-cartilage crosstalk at the cell-cell interaction(CCIs)level and the TNF signal transmitted by non-classical monocytes are the critical CCIs in BML-induced cartilage damage,and PreFC is one of the primary receivers of the signal.We further validated the higher senescence level of non-classical monocyte and FC-2 in OA mice,compared with classical monocyte and PreFC,respectively.Transcription factor 7 like 2(TCF7L2)was identified as a shared transcription factor in the senescence of monocytes and chondrocytes,facilitating the development of the senescence-associated secretory phenotype(SASP).Therefore,senescent non-classical monocytes promote BMLs and inflammation and senescence of chondrocytes by modulating BML–cartilage crosstalk in OA,with TCF7L2 serving as a regulator.展开更多
In the ever-evolving landscape of cancer therapy,while cancer treatments such as chemotherapy,radiotherapy,and targeted therapy aim to eradicate malignant cells,they also inadvertently trigger cellular senescence in b...In the ever-evolving landscape of cancer therapy,while cancer treatments such as chemotherapy,radiotherapy,and targeted therapy aim to eradicate malignant cells,they also inadvertently trigger cellular senescence in both cancerous and microenvironmental tissues.Therapy-induced senescence(TIS)can act as a barrier against tumor growth by halting cell proliferation in the short term,but the long-term persistence of therapy-induced senescent(TISnt)cells may pose a significant challenge in cancer management.Their distinct characteristics,like senescence-associated secretory phenotype(SASP),metabolic dysregulation,and immune evasion,make them exhibit remarkable heterogeneity to orchestrate the tumor microenvironment(TME),resulting in therapy resistance.However,how these TISnt cells functioning differently in cancer progression,and the intricate mechanisms by which they remodel the senescence-associated immunosuppressive microenvironment present challenges for improving anticancer therapy.Therefore,this review summarizes the heterogeneous TISnt cell phenotypes contributing to an accumulated senescent state,outlines their multidimensional interactions in the senescent microenvironment,and discusses current senescence-targeting strategies.Building on the current understanding of TIS,we propose potential avenues for improving TIS-targeting methodologies in the context of head and neck cancer,a representative heterogeneous malignancy,which can substantially enhance the efficacy of the“one-two punch”sequential treatment approach for head and neck cancer.展开更多
Senescent macrophages have emerged as dynamic cells within the tumor microenvironment that significantly promote tumor progression through complex cellular and molecular functional alterations. This review explores th...Senescent macrophages have emerged as dynamic cells within the tumor microenvironment that significantly promote tumor progression through complex cellular and molecular functional alterations. This review explores the multifaceted roles of macrophage senescence in cancer, and establishes links between senescent macrophages and tumor progression from multiple perspectives, on the basis of the first comprehensive analysis of the molecular mechanisms and pathways involved. By systematically examining the diverse changes in senescent macrophages, this review integrates and analyzes their effects on tumors, thus offering a comprehensive and novel theoretical foundation, and practical insights for cancer treatment. Notably, by integrating current molecular research and therapeutic advancements, we summarize novel therapeutic strategies targeting senescent macrophages, including senolytics, senescence modulators, and cutting-edge immunotherapies, thereby highlighting the potential of senescent macrophages as a therapeutic target and introducing new opportunities for cancer treatment.展开更多
Intervertebral disc degeneration(IVDD)is a leading cause of chronic lower back pain,affecting a significant portion of the global population.Traditional treatments,including drug administration and surgery,focus prima...Intervertebral disc degeneration(IVDD)is a leading cause of chronic lower back pain,affecting a significant portion of the global population.Traditional treatments,including drug administration and surgery,focus primarily on symptom relief but fail to address the underlying pathological mechanisms of IVDD,Extracellular matrix(ECM)degradation is closely related to the senescence of nucleus pulposus cells(NPCs)caused by highly levels of inflammation,overproduction of reactive oxygen species(ROS),DNA damage,low levels of autophagy,and the acidic microenvironment in the disc.This review explores the pathogenesis of IVDD mediated by NPC senescence,summarizes recent advances in biological therapy,and highlights the latest developments in antisenescent biomaterials.These biomaterials have the potential to delay disc degeneration by clearing senescent cells,inhibiting oxidative stress and inflammation,activating autophagy,and modulating the acidic microenvironment of the disc.A deeper understanding of the molecular mechanisms underlying IVDD,coupled with the design of more effective antisenescent biomaterials,offers promising avenues for optimizing therapeutic outcomes and improving patients'quality of life.展开更多
BACKGROUND Pancreatic cancer,a formidable gastrointestinal neoplasm,is characterized by its insidious onset,rapid progression,and resistance to treatment,which often lead to a grim prognosis.While the complex pathogen...BACKGROUND Pancreatic cancer,a formidable gastrointestinal neoplasm,is characterized by its insidious onset,rapid progression,and resistance to treatment,which often lead to a grim prognosis.While the complex pathogenesis of pancreatic cancer is well recognized,recent attention has focused on the oncogenic roles of senescent tumor-associated fibroblasts.However,their precise role in pancreatic cancer remains unknown.Resveratrol is a natural polyphenol known for its multifaceted biological actions,including antioxidative and neuroprotective properties,as well as its potential to inhibit tumor proliferation and migration.Our current investigation builds on prior research and reveals the remarkable ability of resveratrol to inhibit pancreatic cancer proliferation and metastasis.AIM To explore the potential of resveratrol in inhibiting pancreatic cancer by targeting senescent tumor-associated fibroblasts.METHODS Immunofluorescence staining of pancreatic cancer tissues revealed prominent coexpression ofα-SMA and p16.HP-1 expression was determined using immunohistochemistry.Cells were treated with the senescence-inducing factors known as 3CKs.Long-term growth assays confirmed that 3CKs significantly decreased the CAF growth rate.Western blotting was conducted to assess the expression levels of p16 and p21.Immunofluorescence was performed to assess LaminB1 expression.Quantitative real-time polymerase chain reaction was used to measure the levels of several senescence-associated secretory phenotype factors,including IL-4,IL-6,IL-8,IL-13,MMP-2,MMP-9,CXCL1,and CXCL12.A scratch assay was used to assess the migratory capacity of the cells,whereas Transwell assays were used to evaluate their invasive potential.RESULTS Specifically,we identified the presence of senescent tumor-associated fibroblasts within pancreatic cancer tissues,linking their abundance to cancer progression.Intriguingly,Resveratrol effectively eradicated these fibroblasts and hindered their senescence,which consequently impeded pancreatic cancer progression.CONCLUSION This groundbreaking discovery reinforces Resveratrol's stature as a potential antitumor agent and positions senescent tumor-associated fibroblasts as pivotal contenders in future therapeutic strategies against pancreatic cancer.展开更多
Aging-related diseases are gradually becoming a major problem with the rapid development of aged population in human society.Although many fluorescent probes have been employed to diagnosis senescence via imaging sene...Aging-related diseases are gradually becoming a major problem with the rapid development of aged population in human society.Although many fluorescent probes have been employed to diagnosis senescence via imaging senescence-associatedβ-galactosidase(SA-β-Gal),which is proved to be closely associated with senescent cells,the similar catalytic effectiveness of enzymatic reaction of ovarian cancer-associatedβ-Gal(OA-β-Gal)will interfere with imaging accuracy.Herein,a near-infrared(NIR)hemicyanine based fluorescent probe HCyXA-βGal was designed for light-up imaging of live cells containingβ-Gal.With the organelle-targeting morpholinyl and positive charge moieties,HCyxA-βGal was successfully applicated to image the difference of enzymatic location in senescent cells and ovarian cancer cells.Furthermore,inspired by the fast response performance,fast and precise imaging of the two cell lines was realized via covering another dimension of fluorescence signal:time-dependent intensity.展开更多
Aging is well known to be the main risk factor for the neurodegenerative pathologies,in particular,Parkinson’s disease（PD）and Alzheimer’s disease（AD）.In aging and in the diseases,similar changes in various hallm...Aging is well known to be the main risk factor for the neurodegenerative pathologies,in particular,Parkinson’s disease（PD）and Alzheimer’s disease（AD）.In aging and in the diseases,similar changes in various hallmarks of neurodegeneration（lipofuscin accumulation,autophagia weakening,and disturbances in functions of mitochondriaand lysosomes） were shown （Tan et al., 2014）. Furthermore, dopami- nergic system （DAS） involvement in mechanisms of aging, PD, and AD were revealed （Martorana and Koch, 2014）.展开更多
Mesenchymal stem/stromal cells(MSCs)have various properties that make them promising candidates for stem cell-based therapies in clinical settings.These include self-renewal,multilineage differentiation,and immunoregu...Mesenchymal stem/stromal cells(MSCs)have various properties that make them promising candidates for stem cell-based therapies in clinical settings.These include self-renewal,multilineage differentiation,and immunoregulation.However,recent studies have confirmed that aging is a vital factor that limits their function and therapeutic properties as standardized clinical products.Understanding the features of senescence and exploration of cell rejuvenation methods are necessary to develop effective strategies that can overcome the shortage and instability of MSCs.This review will summarize the current knowledge on characteristics and functional changes of aged MSCs.Additionally,it will highlight cell rejuvenation strategies such as molecular regulation,noncoding RNA modifications,and microenvironment controls that may enhance the therapeutic potential of MSCs in clinical settings.展开更多
Heat stress occurs frequently in energy-saving sunlight greenhouses(ESSG) at the late growth stage. Three-year delayed cultivation(DC) of the Red Globe cultivar of Vitis vinifera L. was used to clarify the physiologic...Heat stress occurs frequently in energy-saving sunlight greenhouses(ESSG) at the late growth stage. Three-year delayed cultivation(DC) of the Red Globe cultivar of Vitis vinifera L. was used to clarify the physiological mechanisms of short-term heat stress on PSII and subsequent recovery from heat stress. By November, the photosynthetic function had declined and the fall in transpiration rate(E) with heating time increased the possibility of heat damage. In July, the most obvious increase was in the relative variable fluorescence at J point at 40°C, and in November it changed to K point. The 5 min of heat treatment resulted in a significant increase of the relative variable fluorescence at 0.3 ms(W), and after 10 min of heat treatment, the number of reactive centres per excited cross section(RC/CS), probability that a trapped exciton moves an electron into the electron transport chain beyond Q–(at t=0)(Ψ) and quantum yield of electron transport at t=0(φ) decreased significantly(P<0.05), suggesting that the reaction centre, donor and acceptor side of photosystem II(PSII) were all significantly inhibited(P<0.05) and that the thermal stability of the photosynthetic mechanism was reduced. The inhibition of energy fluxes for senescent leaves in November was earlier and more pronounced than that for healthy leaves, which did not recover from heat stress of more than 15 min after 2 h recovery at room temperature.展开更多
Cellular senescence is the results of aging and age-related diseases,and the development of anti-aging methods may improve health and extend longevity.The natural flavonol fisetin has been shown to antagonize senescen...Cellular senescence is the results of aging and age-related diseases,and the development of anti-aging methods may improve health and extend longevity.The natural flavonol fisetin has been shown to antagonize senescence in vitro and increases longevity in vivo,but has poor water solubility and limited bioavailability.In this study,a food-grade and senescent cell-targeted delivery system for fisetin was developed based on whey protein isolate-galactooligosaccharides(WPI-GOS)Maillard conjugate,which could recognize senescence associatedβ-galactosidase in senescent cells.The fisetin nanoparticles possessed a high encapsulation efficiency,excellent dispersibility in water,good storage stability and well biocompatibility.Moreover,they could effectively accumulate and retain in senescent cells with excellent senescent cell-targeting efficacy,and inhibit the oxidative stress-induced cellular senescence in vitro.Thus,this novel nanoparticle system based on WPI-GOS Maillard conjugate showed promise to deliver hydrophobic bioactive ingredients like fisetin to senescent cells to improve their bioavailability and anti-senescence effect.展开更多
Cellular senescence is characterized by a generally irreversible cell cycle arrest and the secretion of bioactive factors known as the senescence-associated secretory phenotype(SASP).In an oncogenic context,senescence...Cellular senescence is characterized by a generally irreversible cell cycle arrest and the secretion of bioactive factors known as the senescence-associated secretory phenotype(SASP).In an oncogenic context,senescence is considered a tumor suppressive mechanism as it prevents cell proliferation and inhibits the progression from pre-malignant to malignant disease.However,recent studies have demonstrated that senescent tumor cells,which could spontaneously exist within cancer tissues or arise in response to various cancer interventions(the so-called therapy-induced senescence,TIS),can acquire pro-tumorigenic properties and are capable of driving local and metastatic relapse.This highlights the complex and multifaceted nature of cellular senescence in cancer biology.Here,we summarize the current knowledge of the pathological function of therapy-induced senescent tumor cells and discuss possible mechanisms by which tumor cell senescence contributes to cancer relapse.We also discuss implications for future studies toward targeting these less appreciated cells.展开更多
Regulatory changes in senescent cells could potentially affect the composition of extracellular vehicles(EVs),specifically altering their size and cargo.As a result,the released senescent EVs contain an unpredictable ...Regulatory changes in senescent cells could potentially affect the composition of extracellular vehicles(EVs),specifically altering their size and cargo.As a result,the released senescent EVs contain an unpredictable cocktail of growth factors and cytokines.These biomolecules have dual effects,potentially guiding the induction of senescence in affected cells and promoting an inflammation-related“domino effect”within the cellular environment,ultimately leading to tissue inflammaging.展开更多
Breast cancer is the predominant form of carcinoma among women worldwide,with 70%of advanced patients developing bone metastases,with a high mortality rate.In this sense,the bone marrow(BM)mesenchymal stem/stromal cel...Breast cancer is the predominant form of carcinoma among women worldwide,with 70%of advanced patients developing bone metastases,with a high mortality rate.In this sense,the bone marrow(BM)mesenchymal stem/stromal cells(MSCs)are critical for BM/bone homeostasis,and failures in their functionality,transform the BM into a premetastatic niche(PMN).We previously found that BM-MSCs from advanced breast cancer patients(BCPs,infiltrative ductal carcinoma,stage III-B)have an abnormal profile.This work aims to study some of the metabolic and molecular mechanisms underlying MSCs shift from a normal to an abnormal profile in this group of patients.A comparative analysis was undertaken,which included self-renewal capacity,morphology,proliferation capacity,cell cycle,reactive oxygen species(ROS)levels,and senescence-associatedβ‑galactosidase(SA‑β‑gal)staining of BMderived MSCs isolated from 14 BCPs and 9 healthy volunteers(HVs).Additionally,the expression and activity of the telomerase subunit TERT,as well as telomere length,were measured.Expression levels of pluripotency,osteogenic,and osteoclastogenic genes(OCT-4,SOX-2,M-CAM,RUNX-2,BMP-2,CCL-2,M-CSF,and IL-6)were also determined.The results showed that MSCs from BCPs had reduced,self-renewal and proliferation capacity.These cells also exhibited inhibited cell cycle progression and phenotypic changes,such as an enlarged and flattened appearance.Additionally,there was an increase in ROS and senescence levels and a decrease in the functional capacity of TERT to preserve telomere length.We also found an increase in pro-inflammatory/pro-osteoclastogenic gene expression and a decrease in pluripotency gene expression.We conclude that these changes could be responsible for the abnormal functional profile that MSCs show in this group of patients.展开更多
Objective： To determine whether balloon catheter denudation can induce vascular smooth muscle cells （VSMCs） to senescence, and whether this senescence can result in inflammation activity. Methods： Twelve male Chin...Objective： To determine whether balloon catheter denudation can induce vascular smooth muscle cells （VSMCs） to senescence, and whether this senescence can result in inflammation activity. Methods： Twelve male Chinese white rabbits were denuded of the carotid arteries or VSMCs. Acidic β-galactosidase activity of carotid arteries or VSMCs was detected. Transfection and chloramphenicol acetyltransferase （CAT） assay for iNOS gene and nitrite （NO2^-） assay were undertaken. Reverse transcription-polymerase chain reaction （RT-PCR） was used to evaluate inflammation cytokines mRNA expression. Measurement of NF-kB activity was detected by electrophoretic mobility shift assay （EMSA）. MMP-9, ICAM-1, P-p65, and IkBα expressions were analyzed by Western blotting. Results： After denudation VSMCs from denuded arteries showed an accumulation of significantly more senescence-associated β-galactosidase （SA-β-Gal） positive ceils and greater iNOS activity. Transcriptional activity of iNOS was highly expressed. The mRNA expressions of IL-1β, ICAM-1,MMP-9, TNF-α and the iNOS enzyme were significantly increased in injuring-induced senescence SMCs. However, the TNF-α or IL-1β-induced the protein production （ICAM-1 and MMP-9） was prevented by PDTC and MG132, which are inhibitors of NF-kB activation. Also, activation of NF-kB and cytokine-induced degradation of IKBα in the denuded VSMC were significantly affected. Conclusion： Intraluminal injury to the artery may lead to the emergence of senescent VSMC. Inflammation activity in SMCs is closely related to the senescence and the activation of NF-kB is involved.展开更多
The aim of the present study was to investigate the effect of one capsule of the micro-immunotherapy medicine (MIM) 2LMISEN®compared to vehicle, in a neuronal aging model. Senescence and apoptosis of hippocamp...The aim of the present study was to investigate the effect of one capsule of the micro-immunotherapy medicine (MIM) 2LMISEN®compared to vehicle, in a neuronal aging model. Senescence and apoptosis of hippocampal neurons were evaluated by measuring p16INK4a and caspase 3 levels, respectively. The data presented is a single observation. Mice hippocampal neuron cultures were treated with MIM (11 mM) or vehicle (11 mM) from 22 days in vitro (DIV) until 27 DIV. After incubation, hippocampal neuron cultures were fixed at 15 (control condition), 22, 25 and 27 DIV and then incubated with primary antibodies p16INK4a, MAP2 and Caspase 3. Quantification of p16INK4a and Caspase 3-positive neurons was done using Developer software. We found that vehicle had no effect on p16INK4a expression, whereas MIM was able to decrease p16INK4a levels at 22, 25 and 27 DIV in a statistically significant manner. The MIM had no significative effect on Caspase 3 expression. Our preliminary results showed that the MIM capsule significantly reduced neuronal senescence and not apoptosis.展开更多
Background: Mature red blood cells lack protein synthesis and are unable to restore inactivated enzymes, damaged cytoskeleton and membrane proteins. An oxidation breakdown of band 3 is probably part of the mechanism l...Background: Mature red blood cells lack protein synthesis and are unable to restore inactivated enzymes, damaged cytoskeleton and membrane proteins. An oxidation breakdown of band 3 is probably part of the mechanism leading to the generation of a senescent cell antigen. This specific signal serves for the clearance of RBCs by inducing the binding of autologous IgG and C3, leading to phagocytosis. In addition, phosphatidilserin molecules appear in the outer membrane and the CD47 expression diminishes. Methods: Erythrocytes of different ages from whole blood were studied by flow cytometry analysing light scatter proprieties, binding of autologous IgG, C3 complement deposits, externalization of phosphatidylserine and CD47 expression. Dot-plot analysis based on forward scatter versus side scatter parameters showed two RBCs populations of different sizes and density. RBCs were further incubated with Alexa 488 IgG, APC-anti-C3, PE-annexin-V and PE-CD47. The comparison of the values obtained for the different variables studied in SeRBC and YRBC populations was carried out by the Student t-test for matched samples or by the Wilcoxon test (after verification of the normality assumption). Results: The percentage of IgG and C3 positive cells was significantly higher in senescent red blood cells population. The fraction of annexin-V positive RBCs was also larger in SeRBCs while the CD47 expression was lower in this population. Conclusions: These results indicate that flow cytometry allow differenciation of erythrocytes populations of different ages, turning this tool into an useful alternative option to study erythrocyte aging process. These findings will contribute to a better understanding of the process and mechanisms involved in erythrocyte senescence process.展开更多
Osteoarthritis(OA),the most prevalent joint disease of late life,is closely linked to cellular senescence.Previously,we found that the senescence of fibroblast-like synoviocytes(FLS)played an essential role in the deg...Osteoarthritis(OA),the most prevalent joint disease of late life,is closely linked to cellular senescence.Previously,we found that the senescence of fibroblast-like synoviocytes(FLS)played an essential role in the degradation of cartilage.In this work,single-cell sequencing data further demon-strated that cartilage acidic protein 1(CRTAC1)is a critical secreted factor of senescent FLS,which sup-presses mitophagy and induces mitochondrial dysfunction by regulating SIRT3 expression.In vivo,deletion of SIRT3 in chondrocytes accelerated cartilage degradation and aggravated the progression of OA.Oppositely,intra-articular injection of adeno-associated virus expressing SIRT3 effectively alleviated OA progression in mice.Mechanistically,we demonstrated that elevated CRTAC1 could bind with NRF2 in chondrocytes,which subsequently suppresses the transcription of SIRT3 in vitro.In addition,SIRT3 reduction could promote the acetylation of FOXO3a and result in mitochondrial dysfunction,which finally contributes to the degradation of chondrocytes.To conclude,this work revealed the critical role and underlying mechanism of senescent FLSs-derived CRTAC1 in OA progression,which provided a po-tential strategy for the OA therapy.展开更多
Background:Senescent human skin primary fibroblast(FB)models have been established for studying aging-related,proliferative,and inflammatory skin diseases.The aim of this study was to compare the transcriptome charact...Background:Senescent human skin primary fibroblast(FB)models have been established for studying aging-related,proliferative,and inflammatory skin diseases.The aim of this study was to compare the transcriptome characteristics of human primary dermal FBs from children and the elderly with four senescence models.Methods:Human skin primary FBs were obtained from healthy children(FB-C)and elderly donors(FB-E).Senescence models were generated by ultraviolet B irradiation(FB-UVB),D-galactose stimulation(FB-D-gal),atazanavir treatment(FB-ATV),and replication exhaustion induction(FB-P30).Flow cytometry,immunofluorescence staining,real-time quantitative polymerase chain reaction,co-culturing with immune cells,and bulk RNA sequencing were used for systematic comparisons of the models.Results:In comparison with FB-C,FB-E showed elevated expression of senescence-related genes related to the skin barrier and extracellular matrix,proinflammatory factors,chemokines,oxidative stress,and complement factors.In comparison with FB-E,FB-UVB and FB-ATV showed higher levels of senescence and expression of the genes related to the senescence-associated secretory phenotype(SASP),and their shaped immune microenvironment highly facilitated the activation of downstream immune cells,including T cells,macrophages,and natural killer cells.FB-P30 was most similar to FB-E in terms of general transcriptome features,such as FB migration and proliferation,and aging-related characteristics.FB-D-gal showed the lowest expression levels of senescence-related genes.In comparisons with the single-cell RNA sequencing results,FB-E showed almost complete simulation of the transcriptional spectrum of FBs in elderly patients with atopic dermatitis,followed by FB-P30 and FB-UVB.FB-E and FB-P30 showed higher similarity with the FBs in keloids.Conclusions:Each senescent FB model exhibited different characteristics.In addition to showing upregulated expression of natural senescence features,FB-UVB and FB-ATV showed high expression levels of senescence-related genes,including those involved in the SASP,and FB-P30 showed the greatest similarity with FB-E.However,D-galactose-stimulated FBs did not clearly present aging characteristics.展开更多
基金supported by the Ministry of Science and Technology of China(2020YFA0908900)National Natural Science Foundation of China(21935011 and 82072490)+1 种基金Shenzhen Science and Technology Innovation Commission(KQTD20200820113012029 and KJZD20230923114612025)Guangdong Provincial Key Laboratory of Advanced Biomaterials(2022B1212010003).
文摘Aging is a pivotal risk factor for intervertebral disc degeneration(IVDD)and chronic low back pain(LBP).The restoration of aging nucleus pulposus cells(NPCs)to a youthful epigenetic state is crucial for IVDD treatment,but remains a formidable challenge.Here,we proposed a strategy to partially reprogram and reinstate youthful epigenetics of senescent NPCs by delivering a plasmid carrier that expressed pluripotency-associated genes(Oct4,Klf4 and Sox2)in Cavin2-modified exosomes(OKS@M-Exo)for treatment of IVDD and alleviating LBP.The functional OKS@M-Exo efficaciously alleviated senescence markers(p16^(INK4a),p21^(CIP1)and p53),reduced DNA damage and H4K20me3 expression,as well as restored proliferation ability and metabolic balance in senescent NPCs,as validated through in vitro experiments.In a rat model of IVDD,OKS@M-Exo maintained intervertebral disc height,nucleus pulposus hydration and tissue structure,effectively ameliorated IVDD via decreasing the senescence markers.Additionally,OKS@MExo reduced nociceptive behavior and downregulated nociception markers,indicating its efficiency in alleviating LBP.The transcriptome sequencing analysis also demonstrated that OKS@M-Exo could decrease the expression of age-related pathways and restore cell proliferation.Collectively,reprogramming by the OKS@M-Exo to restore youthful epigenetics of senescent NPCs may hold promise as a therapeutic platform to treat IVDD.
基金supported by the National Natural Science Foundation of China(82171229 and 82471232).
文摘Chronic pain affects over 30%of the global adult population,significantly impairing quality of life,physical function,and psychological well-being,while imposing a substantial personal and economic burden[1].As the global population continues to age,there is an urgent and unmet need to effectively prevent,assess,and manage chronic pain in older adults.Although age-related changes in pain perception,processing,and coping mechanisms have been increasingly recognized over recent decades,many aspects of the relationship between aging and pain remain poorly understood.In addition,aging is associated with increased susceptibility to chronic pain conditions,particularly following peripheral nerve injury[2,3].However,the incomplete understanding of the mechanisms underlying pain in the aged population represents a major barrier to the development of effective medical treatment is often insufficient to provide complete pain relief[4,5].Targeted interventions for geriatric pain management are needed.Therefore,elucidating the impact of aging on the pathogenesis of chronic pain is urgently needed.
基金supported by the Nature Science Foundation of Zhejiang Province(grant no.LD22C060002)National Science Foundation of China(grant no.82274547,82474240)+2 种基金Zhejiang Provincial Medical and Health Science and Technology Fund(grant no.2024KY1223)Research Project of Zhejiang Chinese Medical University(grant no.2023JKZKTS34)Project of Chunyan Special Fund for Chinese Medicine Development of Zhejiang Chinese Medical University(grant no.CY202305)。
文摘Bone marrow lesions(BML)are early signs of osteoarthritis(OA)and are strongly correlated with the deterioration of cartilage lesions.Single-cell RNA sequencing(scRNA-seq)analyses were performed on BM from non-BML and BML areas and articular cartilage from intact and damaged areas to explore BML landscape and BML-cartilage crosstalk.We revealed the immune landscape of BM in non-BML and BML,and the transition to pro-inflammatory states of clusters in BMLs,such as classical monocytes and nonclassical monocytes.Non-classical monocytes have high inflammation,OA gene signatures,and senescence scores,and are potential primary clusters promoting OA progression.Histological signs of OA related to the cellular landscape in damaged cartilage were identified,including PreFC exhaustion.The BM-cartilage crosstalk at the cell-cell interaction(CCIs)level and the TNF signal transmitted by non-classical monocytes are the critical CCIs in BML-induced cartilage damage,and PreFC is one of the primary receivers of the signal.We further validated the higher senescence level of non-classical monocyte and FC-2 in OA mice,compared with classical monocyte and PreFC,respectively.Transcription factor 7 like 2(TCF7L2)was identified as a shared transcription factor in the senescence of monocytes and chondrocytes,facilitating the development of the senescence-associated secretory phenotype(SASP).Therefore,senescent non-classical monocytes promote BMLs and inflammation and senescence of chondrocytes by modulating BML–cartilage crosstalk in OA,with TCF7L2 serving as a regulator.
基金supported by Noncommunicable Chronic Diseases-National Scienceand Technology Major Project(No.2023ZD0503000)National Natural ScienceFoundation of China(No.82301095,82301094)+1 种基金Sichuan Science and Technology Program(No.2025ZNSFSC0548,2024YFFK0373)the Research Funding fromWest China Hospital of Stomatology,Sichuan University(No.RD-03-202410)。
文摘In the ever-evolving landscape of cancer therapy,while cancer treatments such as chemotherapy,radiotherapy,and targeted therapy aim to eradicate malignant cells,they also inadvertently trigger cellular senescence in both cancerous and microenvironmental tissues.Therapy-induced senescence(TIS)can act as a barrier against tumor growth by halting cell proliferation in the short term,but the long-term persistence of therapy-induced senescent(TISnt)cells may pose a significant challenge in cancer management.Their distinct characteristics,like senescence-associated secretory phenotype(SASP),metabolic dysregulation,and immune evasion,make them exhibit remarkable heterogeneity to orchestrate the tumor microenvironment(TME),resulting in therapy resistance.However,how these TISnt cells functioning differently in cancer progression,and the intricate mechanisms by which they remodel the senescence-associated immunosuppressive microenvironment present challenges for improving anticancer therapy.Therefore,this review summarizes the heterogeneous TISnt cell phenotypes contributing to an accumulated senescent state,outlines their multidimensional interactions in the senescent microenvironment,and discusses current senescence-targeting strategies.Building on the current understanding of TIS,we propose potential avenues for improving TIS-targeting methodologies in the context of head and neck cancer,a representative heterogeneous malignancy,which can substantially enhance the efficacy of the“one-two punch”sequential treatment approach for head and neck cancer.
基金supported by grants from the Postdoctoral Science Foundation of China (Grant No. 2020M672072)。
文摘Senescent macrophages have emerged as dynamic cells within the tumor microenvironment that significantly promote tumor progression through complex cellular and molecular functional alterations. This review explores the multifaceted roles of macrophage senescence in cancer, and establishes links between senescent macrophages and tumor progression from multiple perspectives, on the basis of the first comprehensive analysis of the molecular mechanisms and pathways involved. By systematically examining the diverse changes in senescent macrophages, this review integrates and analyzes their effects on tumors, thus offering a comprehensive and novel theoretical foundation, and practical insights for cancer treatment. Notably, by integrating current molecular research and therapeutic advancements, we summarize novel therapeutic strategies targeting senescent macrophages, including senolytics, senescence modulators, and cutting-edge immunotherapies, thereby highlighting the potential of senescent macrophages as a therapeutic target and introducing new opportunities for cancer treatment.
基金supported by the National Natural Science Foundation of China(81902306 and 82174406)the Shanghai Municipal Health Commission Traditional Chinese Medicine Research Project(2024QN012)+1 种基金the Shanghai Science and Technology Committee(22Y11923200 and 22ZR1453000)the Shanghai University of Traditional Chinese Medicine Science and Technology Development Project(23KFL023)。
文摘Intervertebral disc degeneration(IVDD)is a leading cause of chronic lower back pain,affecting a significant portion of the global population.Traditional treatments,including drug administration and surgery,focus primarily on symptom relief but fail to address the underlying pathological mechanisms of IVDD,Extracellular matrix(ECM)degradation is closely related to the senescence of nucleus pulposus cells(NPCs)caused by highly levels of inflammation,overproduction of reactive oxygen species(ROS),DNA damage,low levels of autophagy,and the acidic microenvironment in the disc.This review explores the pathogenesis of IVDD mediated by NPC senescence,summarizes recent advances in biological therapy,and highlights the latest developments in antisenescent biomaterials.These biomaterials have the potential to delay disc degeneration by clearing senescent cells,inhibiting oxidative stress and inflammation,activating autophagy,and modulating the acidic microenvironment of the disc.A deeper understanding of the molecular mechanisms underlying IVDD,coupled with the design of more effective antisenescent biomaterials,offers promising avenues for optimizing therapeutic outcomes and improving patients'quality of life.
文摘BACKGROUND Pancreatic cancer,a formidable gastrointestinal neoplasm,is characterized by its insidious onset,rapid progression,and resistance to treatment,which often lead to a grim prognosis.While the complex pathogenesis of pancreatic cancer is well recognized,recent attention has focused on the oncogenic roles of senescent tumor-associated fibroblasts.However,their precise role in pancreatic cancer remains unknown.Resveratrol is a natural polyphenol known for its multifaceted biological actions,including antioxidative and neuroprotective properties,as well as its potential to inhibit tumor proliferation and migration.Our current investigation builds on prior research and reveals the remarkable ability of resveratrol to inhibit pancreatic cancer proliferation and metastasis.AIM To explore the potential of resveratrol in inhibiting pancreatic cancer by targeting senescent tumor-associated fibroblasts.METHODS Immunofluorescence staining of pancreatic cancer tissues revealed prominent coexpression ofα-SMA and p16.HP-1 expression was determined using immunohistochemistry.Cells were treated with the senescence-inducing factors known as 3CKs.Long-term growth assays confirmed that 3CKs significantly decreased the CAF growth rate.Western blotting was conducted to assess the expression levels of p16 and p21.Immunofluorescence was performed to assess LaminB1 expression.Quantitative real-time polymerase chain reaction was used to measure the levels of several senescence-associated secretory phenotype factors,including IL-4,IL-6,IL-8,IL-13,MMP-2,MMP-9,CXCL1,and CXCL12.A scratch assay was used to assess the migratory capacity of the cells,whereas Transwell assays were used to evaluate their invasive potential.RESULTS Specifically,we identified the presence of senescent tumor-associated fibroblasts within pancreatic cancer tissues,linking their abundance to cancer progression.Intriguingly,Resveratrol effectively eradicated these fibroblasts and hindered their senescence,which consequently impeded pancreatic cancer progression.CONCLUSION This groundbreaking discovery reinforces Resveratrol's stature as a potential antitumor agent and positions senescent tumor-associated fibroblasts as pivotal contenders in future therapeutic strategies against pancreatic cancer.
基金supported by National Natural Science Foundation of China(Nos.22122803 and 21788102)the National Natural Science Foundation of Jiangsu Province(No.BK20220644).
文摘Aging-related diseases are gradually becoming a major problem with the rapid development of aged population in human society.Although many fluorescent probes have been employed to diagnosis senescence via imaging senescence-associatedβ-galactosidase(SA-β-Gal),which is proved to be closely associated with senescent cells,the similar catalytic effectiveness of enzymatic reaction of ovarian cancer-associatedβ-Gal(OA-β-Gal)will interfere with imaging accuracy.Herein,a near-infrared(NIR)hemicyanine based fluorescent probe HCyXA-βGal was designed for light-up imaging of live cells containingβ-Gal.With the organelle-targeting morpholinyl and positive charge moieties,HCyxA-βGal was successfully applicated to image the difference of enzymatic location in senescent cells and ovarian cancer cells.Furthermore,inspired by the fast response performance,fast and precise imaging of the two cell lines was realized via covering another dimension of fluorescence signal:time-dependent intensity.
文摘Aging is well known to be the main risk factor for the neurodegenerative pathologies,in particular,Parkinson’s disease（PD）and Alzheimer’s disease（AD）.In aging and in the diseases,similar changes in various hallmarks of neurodegeneration（lipofuscin accumulation,autophagia weakening,and disturbances in functions of mitochondriaand lysosomes） were shown （Tan et al., 2014）. Furthermore, dopami- nergic system （DAS） involvement in mechanisms of aging, PD, and AD were revealed （Martorana and Koch, 2014）.
基金Supported by the National Natural Science Foundation of China,Nos.81500207,81670458,and 81470393Shanghai Municipal Health and Family Planning Commission,No.ZY(2018-2020)-FWTX-2007+4 种基金Shanghai Key Medical Discipline for Critical Care Medicine,No.2017zz02017the National Key Research and Development Program of China,No.2017YFA0105600Major Program of Development Fund for Shanghai Zhangjiang National Innovtaion Demonstration Zone,No.ZJ2018-ZD-004the Science and Technology Commission of Shanghai Municipality,No.17431906600and the Top-level Clinical Discipline Project of Shanghai Pudong,No.PWYgf2018-05.
文摘Mesenchymal stem/stromal cells(MSCs)have various properties that make them promising candidates for stem cell-based therapies in clinical settings.These include self-renewal,multilineage differentiation,and immunoregulation.However,recent studies have confirmed that aging is a vital factor that limits their function and therapeutic properties as standardized clinical products.Understanding the features of senescence and exploration of cell rejuvenation methods are necessary to develop effective strategies that can overcome the shortage and instability of MSCs.This review will summarize the current knowledge on characteristics and functional changes of aged MSCs.Additionally,it will highlight cell rejuvenation strategies such as molecular regulation,noncoding RNA modifications,and microenvironment controls that may enhance the therapeutic potential of MSCs in clinical settings.
基金supported by the National Natural Science Foundation of China(31660585)the Experimental Station for Scientific Observation of Fruit Trees in the Northwest of China(10218020)the earmarked fund for China Agriculture Research System(CARS-30-21)
文摘Heat stress occurs frequently in energy-saving sunlight greenhouses(ESSG) at the late growth stage. Three-year delayed cultivation(DC) of the Red Globe cultivar of Vitis vinifera L. was used to clarify the physiological mechanisms of short-term heat stress on PSII and subsequent recovery from heat stress. By November, the photosynthetic function had declined and the fall in transpiration rate(E) with heating time increased the possibility of heat damage. In July, the most obvious increase was in the relative variable fluorescence at J point at 40°C, and in November it changed to K point. The 5 min of heat treatment resulted in a significant increase of the relative variable fluorescence at 0.3 ms(W), and after 10 min of heat treatment, the number of reactive centres per excited cross section(RC/CS), probability that a trapped exciton moves an electron into the electron transport chain beyond Q–(at t=0)(Ψ) and quantum yield of electron transport at t=0(φ) decreased significantly(P<0.05), suggesting that the reaction centre, donor and acceptor side of photosystem II(PSII) were all significantly inhibited(P<0.05) and that the thermal stability of the photosynthetic mechanism was reduced. The inhibition of energy fluxes for senescent leaves in November was earlier and more pronounced than that for healthy leaves, which did not recover from heat stress of more than 15 min after 2 h recovery at room temperature.
基金supported by Dalian Youth Science and Technology Star Project(2020RQ121)the National Science Fund for Distinguished Young Scholars of China(31925031)+1 种基金Doctoral Scientific Research Foundation of Liaoning Province(2020-BS-211)Liaoning Province Education Administration(J2020101)。
文摘Cellular senescence is the results of aging and age-related diseases,and the development of anti-aging methods may improve health and extend longevity.The natural flavonol fisetin has been shown to antagonize senescence in vitro and increases longevity in vivo,but has poor water solubility and limited bioavailability.In this study,a food-grade and senescent cell-targeted delivery system for fisetin was developed based on whey protein isolate-galactooligosaccharides(WPI-GOS)Maillard conjugate,which could recognize senescence associatedβ-galactosidase in senescent cells.The fisetin nanoparticles possessed a high encapsulation efficiency,excellent dispersibility in water,good storage stability and well biocompatibility.Moreover,they could effectively accumulate and retain in senescent cells with excellent senescent cell-targeting efficacy,and inhibit the oxidative stress-induced cellular senescence in vitro.Thus,this novel nanoparticle system based on WPI-GOS Maillard conjugate showed promise to deliver hydrophobic bioactive ingredients like fisetin to senescent cells to improve their bioavailability and anti-senescence effect.
基金supported by the National Natural Science Foundation of China(grant number:82372820)。
文摘Cellular senescence is characterized by a generally irreversible cell cycle arrest and the secretion of bioactive factors known as the senescence-associated secretory phenotype(SASP).In an oncogenic context,senescence is considered a tumor suppressive mechanism as it prevents cell proliferation and inhibits the progression from pre-malignant to malignant disease.However,recent studies have demonstrated that senescent tumor cells,which could spontaneously exist within cancer tissues or arise in response to various cancer interventions(the so-called therapy-induced senescence,TIS),can acquire pro-tumorigenic properties and are capable of driving local and metastatic relapse.This highlights the complex and multifaceted nature of cellular senescence in cancer biology.Here,we summarize the current knowledge of the pathological function of therapy-induced senescent tumor cells and discuss possible mechanisms by which tumor cell senescence contributes to cancer relapse.We also discuss implications for future studies toward targeting these less appreciated cells.
文摘Regulatory changes in senescent cells could potentially affect the composition of extracellular vehicles(EVs),specifically altering their size and cargo.As a result,the released senescent EVs contain an unpredictable cocktail of growth factors and cytokines.These biomolecules have dual effects,potentially guiding the induction of senescence in affected cells and promoting an inflammation-related“domino effect”within the cellular environment,ultimately leading to tissue inflammaging.
基金Supported by the FONCYT,Argentina(PICT 2016-#1093)CONICET,Argentina(PIP2014-2016,#300)Fundación Florencio Fiorini(Subsidio 2021-2022),Argentina.
文摘Breast cancer is the predominant form of carcinoma among women worldwide,with 70%of advanced patients developing bone metastases,with a high mortality rate.In this sense,the bone marrow(BM)mesenchymal stem/stromal cells(MSCs)are critical for BM/bone homeostasis,and failures in their functionality,transform the BM into a premetastatic niche(PMN).We previously found that BM-MSCs from advanced breast cancer patients(BCPs,infiltrative ductal carcinoma,stage III-B)have an abnormal profile.This work aims to study some of the metabolic and molecular mechanisms underlying MSCs shift from a normal to an abnormal profile in this group of patients.A comparative analysis was undertaken,which included self-renewal capacity,morphology,proliferation capacity,cell cycle,reactive oxygen species(ROS)levels,and senescence-associatedβ‑galactosidase(SA‑β‑gal)staining of BMderived MSCs isolated from 14 BCPs and 9 healthy volunteers(HVs).Additionally,the expression and activity of the telomerase subunit TERT,as well as telomere length,were measured.Expression levels of pluripotency,osteogenic,and osteoclastogenic genes(OCT-4,SOX-2,M-CAM,RUNX-2,BMP-2,CCL-2,M-CSF,and IL-6)were also determined.The results showed that MSCs from BCPs had reduced,self-renewal and proliferation capacity.These cells also exhibited inhibited cell cycle progression and phenotypic changes,such as an enlarged and flattened appearance.Additionally,there was an increase in ROS and senescence levels and a decrease in the functional capacity of TERT to preserve telomere length.We also found an increase in pro-inflammatory/pro-osteoclastogenic gene expression and a decrease in pluripotency gene expression.We conclude that these changes could be responsible for the abnormal functional profile that MSCs show in this group of patients.
文摘Objective： To determine whether balloon catheter denudation can induce vascular smooth muscle cells （VSMCs） to senescence, and whether this senescence can result in inflammation activity. Methods： Twelve male Chinese white rabbits were denuded of the carotid arteries or VSMCs. Acidic β-galactosidase activity of carotid arteries or VSMCs was detected. Transfection and chloramphenicol acetyltransferase （CAT） assay for iNOS gene and nitrite （NO2^-） assay were undertaken. Reverse transcription-polymerase chain reaction （RT-PCR） was used to evaluate inflammation cytokines mRNA expression. Measurement of NF-kB activity was detected by electrophoretic mobility shift assay （EMSA）. MMP-9, ICAM-1, P-p65, and IkBα expressions were analyzed by Western blotting. Results： After denudation VSMCs from denuded arteries showed an accumulation of significantly more senescence-associated β-galactosidase （SA-β-Gal） positive ceils and greater iNOS activity. Transcriptional activity of iNOS was highly expressed. The mRNA expressions of IL-1β, ICAM-1,MMP-9, TNF-α and the iNOS enzyme were significantly increased in injuring-induced senescence SMCs. However, the TNF-α or IL-1β-induced the protein production （ICAM-1 and MMP-9） was prevented by PDTC and MG132, which are inhibitors of NF-kB activation. Also, activation of NF-kB and cytokine-induced degradation of IKBα in the denuded VSMC were significantly affected. Conclusion： Intraluminal injury to the artery may lead to the emergence of senescent VSMC. Inflammation activity in SMCs is closely related to the senescence and the activation of NF-kB is involved.
文摘The aim of the present study was to investigate the effect of one capsule of the micro-immunotherapy medicine (MIM) 2LMISEN®compared to vehicle, in a neuronal aging model. Senescence and apoptosis of hippocampal neurons were evaluated by measuring p16INK4a and caspase 3 levels, respectively. The data presented is a single observation. Mice hippocampal neuron cultures were treated with MIM (11 mM) or vehicle (11 mM) from 22 days in vitro (DIV) until 27 DIV. After incubation, hippocampal neuron cultures were fixed at 15 (control condition), 22, 25 and 27 DIV and then incubated with primary antibodies p16INK4a, MAP2 and Caspase 3. Quantification of p16INK4a and Caspase 3-positive neurons was done using Developer software. We found that vehicle had no effect on p16INK4a expression, whereas MIM was able to decrease p16INK4a levels at 22, 25 and 27 DIV in a statistically significant manner. The MIM had no significative effect on Caspase 3 expression. Our preliminary results showed that the MIM capsule significantly reduced neuronal senescence and not apoptosis.
文摘Background: Mature red blood cells lack protein synthesis and are unable to restore inactivated enzymes, damaged cytoskeleton and membrane proteins. An oxidation breakdown of band 3 is probably part of the mechanism leading to the generation of a senescent cell antigen. This specific signal serves for the clearance of RBCs by inducing the binding of autologous IgG and C3, leading to phagocytosis. In addition, phosphatidilserin molecules appear in the outer membrane and the CD47 expression diminishes. Methods: Erythrocytes of different ages from whole blood were studied by flow cytometry analysing light scatter proprieties, binding of autologous IgG, C3 complement deposits, externalization of phosphatidylserine and CD47 expression. Dot-plot analysis based on forward scatter versus side scatter parameters showed two RBCs populations of different sizes and density. RBCs were further incubated with Alexa 488 IgG, APC-anti-C3, PE-annexin-V and PE-CD47. The comparison of the values obtained for the different variables studied in SeRBC and YRBC populations was carried out by the Student t-test for matched samples or by the Wilcoxon test (after verification of the normality assumption). Results: The percentage of IgG and C3 positive cells was significantly higher in senescent red blood cells population. The fraction of annexin-V positive RBCs was also larger in SeRBCs while the CD47 expression was lower in this population. Conclusions: These results indicate that flow cytometry allow differenciation of erythrocytes populations of different ages, turning this tool into an useful alternative option to study erythrocyte aging process. These findings will contribute to a better understanding of the process and mechanisms involved in erythrocyte senescence process.
基金supported by research grants from the National Major Research plan of NSFC(92368201)National Natural Science Foundation of China(82272530 and 82372459)+4 种基金Jiangsu Province Medical Innovation Center of Orthopedic Surgery(CXZX202214,China)China Postdoctoral Science Foundation(2024T170409)Excellent Postdoctoral Program of Jiangsu Province(2022ZB688,China)Youth Thousand Talents Program of China(13004001)The Research Team Start-up Funds of Nanjing University(14912203,China).
文摘Osteoarthritis(OA),the most prevalent joint disease of late life,is closely linked to cellular senescence.Previously,we found that the senescence of fibroblast-like synoviocytes(FLS)played an essential role in the degradation of cartilage.In this work,single-cell sequencing data further demon-strated that cartilage acidic protein 1(CRTAC1)is a critical secreted factor of senescent FLS,which sup-presses mitophagy and induces mitochondrial dysfunction by regulating SIRT3 expression.In vivo,deletion of SIRT3 in chondrocytes accelerated cartilage degradation and aggravated the progression of OA.Oppositely,intra-articular injection of adeno-associated virus expressing SIRT3 effectively alleviated OA progression in mice.Mechanistically,we demonstrated that elevated CRTAC1 could bind with NRF2 in chondrocytes,which subsequently suppresses the transcription of SIRT3 in vitro.In addition,SIRT3 reduction could promote the acetylation of FOXO3a and result in mitochondrial dysfunction,which finally contributes to the degradation of chondrocytes.To conclude,this work revealed the critical role and underlying mechanism of senescent FLSs-derived CRTAC1 in OA progression,which provided a po-tential strategy for the OA therapy.
基金supported by grants from the National Key R&D Program of China(No.2022YFC3601800)National Natural Science Foundation of China(Nos.82103735,82373489,and 82273542)CAMS Innovation Fund for Medical Sciences(Nos.CIFMS,2021-I2M-1-059,2022-I2M-C&T-B-096).
文摘Background:Senescent human skin primary fibroblast(FB)models have been established for studying aging-related,proliferative,and inflammatory skin diseases.The aim of this study was to compare the transcriptome characteristics of human primary dermal FBs from children and the elderly with four senescence models.Methods:Human skin primary FBs were obtained from healthy children(FB-C)and elderly donors(FB-E).Senescence models were generated by ultraviolet B irradiation(FB-UVB),D-galactose stimulation(FB-D-gal),atazanavir treatment(FB-ATV),and replication exhaustion induction(FB-P30).Flow cytometry,immunofluorescence staining,real-time quantitative polymerase chain reaction,co-culturing with immune cells,and bulk RNA sequencing were used for systematic comparisons of the models.Results:In comparison with FB-C,FB-E showed elevated expression of senescence-related genes related to the skin barrier and extracellular matrix,proinflammatory factors,chemokines,oxidative stress,and complement factors.In comparison with FB-E,FB-UVB and FB-ATV showed higher levels of senescence and expression of the genes related to the senescence-associated secretory phenotype(SASP),and their shaped immune microenvironment highly facilitated the activation of downstream immune cells,including T cells,macrophages,and natural killer cells.FB-P30 was most similar to FB-E in terms of general transcriptome features,such as FB migration and proliferation,and aging-related characteristics.FB-D-gal showed the lowest expression levels of senescence-related genes.In comparisons with the single-cell RNA sequencing results,FB-E showed almost complete simulation of the transcriptional spectrum of FBs in elderly patients with atopic dermatitis,followed by FB-P30 and FB-UVB.FB-E and FB-P30 showed higher similarity with the FBs in keloids.Conclusions:Each senescent FB model exhibited different characteristics.In addition to showing upregulated expression of natural senescence features,FB-UVB and FB-ATV showed high expression levels of senescence-related genes,including those involved in the SASP,and FB-P30 showed the greatest similarity with FB-E.However,D-galactose-stimulated FBs did not clearly present aging characteristics.
