Aging and death are unavoidable in life. While immortality may be impossible, many people dream of living a long and healthy life. Throughout history, humans have searched for ways to stay young, but have not found an...Aging and death are unavoidable in life. While immortality may be impossible, many people dream of living a long and healthy life. Throughout history, humans have searched for ways to stay young, but have not found an effective way. This may be because the methods used do not target the causes of aging directly. To address this, we investigated how to delay aging using traditional Chinese medicine (TCM) and Western medicine approaches. In this article, we will explain the causes of aging in the context of TCM and Western medicine and suggest methods to delay it. By integrating TCM and Western medicine, I hope to help everyone age healthily and enjoy a long life.展开更多
Retinal degeneration is a debilitating ocular complication characterized by the progressive loss of photoreceptors and other retinal neurons,which are caused by a group of retinal diseases affecting various age groups...Retinal degeneration is a debilitating ocular complication characterized by the progressive loss of photoreceptors and other retinal neurons,which are caused by a group of retinal diseases affecting various age groups,and increasingly prevalent in the elderly.Age-related macular degeneration,diabetic retinopathy and glaucoma are among the most common complex degenerative retinal disorders,posing significant public health problems worldwide largely due to the aging society and the lack of effective therapeutics.Whilst pathoetiologies vary,if left untreated,loss of retinal neurons can result in an acquired degeneration and ultimately severe visual impairment.Irrespective of underlined etiology,loss of neurons and supporting cells including retinal pigment epithelium,microvascular endothelium,and glia,converges as the common endpoint of retinal degeneration and therefore discovery or repurposing of therapies to protect retinal neurons directly or indirectly are under intensive investigation.This review overviews recent developments of potential neuroprotectants including neuropeptides,exosomes,mitochondrial-derived peptides,complement inhibitors,senolytics,autophagy enhancers and antioxidants either still experimentally or in clinical trials.Effective treatments that possess direct or indirect neuroprotective properties would significantly lift the burden of visual handicap.展开更多
Given its state of stable proliferative inhibition,cellular senescence is primarily depicted as a critical mechanism by which organisms delay the progression of carcinogenesis.Cells undergoing senescence are often ass...Given its state of stable proliferative inhibition,cellular senescence is primarily depicted as a critical mechanism by which organisms delay the progression of carcinogenesis.Cells undergoing senescence are often associated with the alteration of a series of specific features and functions,such as metabolic shifts,stemness induction,and microenvironment remodeling.However,recent research has revealed more complexity associated with senescence,including adverse effects on both physiological and pathological processes.How organisms evade these harmful consequences and survive has become an urgent research issue.Several therapeutic strategies targeting senescence,including senolytics,senomorphics,immunotherapy,and function restoration,have achieved initial success in certain scenarios.In this review,we describe in detail the characteristic changes associated with cellular senescence and summarize currently available countermeasures.展开更多
Kidney fibrosis is the final common pathway of virtually all chronic kidney disease(CKD).However,despite great progress in recent years,no targeted antifibrotic therapies have been approved.Epidemiologic,clinical,and ...Kidney fibrosis is the final common pathway of virtually all chronic kidney disease(CKD).However,despite great progress in recent years,no targeted antifibrotic therapies have been approved.Epidemiologic,clinical,and molecular evidence suggest that aging is a major contributor to the increasing incidence of CKD.Senescent renal tubular cells,fibroblasts,endothelial cells,and podocytes have been detected in the kidneys of patients with CKD and animal models.Nonetheless,although accumulated evidence supports the essential role of cellular senescence in CKD,the mechanisms that promote cell senescence and how senescent cells contribute to CKD remain largely unknown.In this review,we summarize the features of the cellular senescence of the kidney and discuss the possible functions of senescent cells in the pathogenesis of kidney fibrosis.We also address whether pharmacological approaches targeting senescent cells can be used to retard the the progression of kidney fibrosis.展开更多
Aging and cancer share overlapping characteristics,referred to as meta-hallmarks,which elucidate the convergent,antagonistic,or contradictory relationships between aging and cancer.Likewise,as a key characteristic of ...Aging and cancer share overlapping characteristics,referred to as meta-hallmarks,which elucidate the convergent,antagonistic,or contradictory relationships between aging and cancer.Likewise,as a key characteristic of aging,senescent cells share some meta-hallmarks with tumor cells.These hallmarks include apoptosis resistance,metabolic alterations,secretory phenotypes,epigenetic reprogramming,and immune surveillance,all of which play pivotal roles in both tumorigenesis and senescence.Moreover,senolytic drugs,which are a class of agents selectively designed to eliminate senescent cells,have emerged as promising therapeutic agents in oncology and aging-related diseases.Since the discovery of the first senolytic drug in 2015,a diverse array of such agents has been developed.Notably,most senolytic drugs are repurposed from existing anti-tumor therapies,leveraging their shared mechanisms with senescent cells and tumor cells.Thus,this review examines the similarities between senescent cells and tumor cells,providing a better understanding of the meta-hallmarks.Besides,we categorize existing senolytic drugs based upon meta-hallmarks and elucidate the potential molecular mechanisms underlying their effects.By integrating insights from cancer and senescence research,this work aims to inspire innovative strategies for senolytic drug discovery.展开更多
Acute kidney injury(AKI)affects more than 20%of hospitalized patients and is a significant contributor to morbidity and mortality,primarily due to ischemia-reperfusion injury(IRI),which is one of the leading causes of...Acute kidney injury(AKI)affects more than 20%of hospitalized patients and is a significant contributor to morbidity and mortality,primarily due to ischemia-reperfusion injury(IRI),which is one of the leading causes of AKI.IRI not only exacerbates the immediate impact of AKI but also facilitates its progression to chronic kidney disease(CKD)and,in cases of preexisting CKD,to end-stage renal disease(ESRD).One of the critical pathological processes associated with IRI-AKI is cellular senescence,characterized by an irreversible arrest in the cell cycle,morphological and chromatin organization changes,altered transcriptional and metabolic profiles,and the development of a hypersecretory phenotype known as the senescence-associated secretory phenotype(SASP).The SASP amplifies senescence signals in surrounding normal cells through senescence-related pathways,contributing to tissue damage,fibrosis,and chronic inflammation.This review provides an overview of the defining features of senescent cells and explores the fundamental mechanisms underlying senescent cell generation following IRI.We elucidate the pivotal roles of cellular senescence in the transition from IRI-AKI to chronic kidney injury.Furthermore,we discuss emerging therapies targeting cellular senescence,including senolytics and senomorphics,which have shown promising results in both preclinical and clinical settings.These therapies position cellular senescence as a crucial target for the treatment of IRI in the kidneys.Additionally,advancements in single-cell sequencing technology and artificial intelligence-assisted drug screening are expected to accelerate the discovery of novel senescent biomarkers and synotherapeutics,paving the way for optimized and personalized therapeutic interventions.展开更多
Cellular senescence,an irreversible state of cell cycle arrest characterized by phenotypic changes and a specific secretory profile,plays a dual role in liver health and disease.Under physiological conditions,senescen...Cellular senescence,an irreversible state of cell cycle arrest characterized by phenotypic changes and a specific secretory profile,plays a dual role in liver health and disease.Under physiological conditions,senescence aids organ repair and regeneration,but its accumulation due to aging or pathological stress significantly contributes to chronic liver diseases,including alcoholic liver disease,metabolic dysfunction-associated steatohepatitis,liver fibrosis,and hepatocellular carcinoma.Senescence is identified by a range of cellular and molecular changes,such as morphological alterations,expression of cell cycle inhibitors,senescence-associated β-galactosidase activity,and nuclear membrane changes.The onset of senescence in organ cells can affect the entire organism,primarily through the senescence-associated secretory phenotype,which has autocrine,paracrine,and endocrine effects on tissue microenvironments.The objective of this review is to offer a contemporary overview of the pathophysiological events involving hepatic senescent cells and to elucidate their role in the onset and progression of liver diseases,particularly through mechanisms like telomere shortening,genomic and mitochondrial DNA damage,and inflammation.Additionally,this review discusses the emerging senolytic therapies aimed at targeting senescent cells to delay or mitigate liver disease progression.The therapeutic potential of these interventions,alongside their safety and effectiveness,highlights the need for further research to refine these approaches and address unresolved problems in the field of hepatic cellular senescence.展开更多
Alzheimer’s disease(AD)is one of the most common neurodegenerative disorders,characterized by the accumulation of Aβand abnormal tau hyperphosphorylation.Despite substantial efforts in development of drugs targetin...Alzheimer’s disease(AD)is one of the most common neurodegenerative disorders,characterized by the accumulation of Aβand abnormal tau hyperphosphorylation.Despite substantial efforts in development of drugs targeting Aβand tau pathologies,effective therapeutic strategies for AD remain elusive.Recent attention has been paid to the significant role of cellular senescence in AD progression.Mounting evidence suggests that interventions targeting cellular senescence hold promise in improving cognitive function and ameliorating hallmark pathologies in AD.This narrative review provides a comprehensive summary and discussion of the physiological roles,characteristics,biomarkers,and commonly employed in vivo and in vitro models of cellular senescence,with a particular focus on various cell types in the brain,including astrocytes,microglia,oligodendrocyte precursor cells,neurons,and endothelial cells.The review further delves into factors influencing cellular senescence in AD and emphasizes the significance of targeting cellular senescence as a promising approach for AD treatment,which includes the utilization of senolytics and senomorphics.展开更多
Cellular senescence is a status of irreversible growth arrest,which can be triggered by the p53/p21cip1 and p16INK4/Rb pathways via intrinsic and external factors.Senescent cells are typically enlarged and flattened,a...Cellular senescence is a status of irreversible growth arrest,which can be triggered by the p53/p21cip1 and p16INK4/Rb pathways via intrinsic and external factors.Senescent cells are typically enlarged and flattened,and characterized by numerous molecular features.The latter consists of increased surfaceome,increased resid-ual lysosomal activity at pH 6.0(manifested by increased activity of senescence-associated beta-galactosidase[SA-𝛽-gal]),senescence-associated mitochondrial dysfunction,cytoplasmic chromatin fragment,nuclear lamin b1 exclusion,telomere-associated foci,and the senescence-associated secretory phenotype.These features vary depending on the stressor leading to senescence and the type of senescence.Cellular senescence plays pivotal roles in organismal aging and in the pathogenesis of aging-related diseases.Interestingly,senescence can also both promote and inhibit wound healing processes.We recently report that senescence as a programmed pro-cess contributes to normal lung development.Lung senescence is also observed in Down Syndrome,as well as in premature infants with bronchopulmonary dysplasia and in a hyperoxia-induced rodent model of this disease.Furthermore,this senescence results in neonatal lung injury.In this review,we briefly discuss the molecular features of senescence.We then focus on the emerging role of senescence in normal lung development and in the pathogenesis of bronchopulmonary dysplasia as well as putative signaling pathways driving senescence.Finally,we discuss potential therapeutic approaches targeting senescent cells to prevent perinatal lung diseases.展开更多
Traumatic brain injury(TBI)and stroke pose major health challenges,impacting millions of individuals globally.Once considered solely acute events,these neurological conditions are now recognized as enduring pathologic...Traumatic brain injury(TBI)and stroke pose major health challenges,impacting millions of individuals globally.Once considered solely acute events,these neurological conditions are now recognized as enduring pathological processes with long-term consequences,including an increased susceptibility to neurodegeneration.However,effective strategies to counteract their devastating consequences are still lacking.Cellular senescence,marked by irreversible cell-cycle arrest,is emerging as a crucial factor in various neurodegenerative diseases.Recent research further reveals that cellular senescence may be a potential driver for secondary neurodegeneration following brain injury.Herein,we synthesize emerging evidence that TBI and stroke drive the accumulation of senescent cells in the brain.The rationale for targeting senescent cells as a therapeutic approach to combat neurodegeneration following TBI/stroke is outlined.From a translational perspective,we emphasize current knowledge and future directions of senolytic therapy for these neurological conditions.展开更多
Chronic wounds(e.g.diabetic wounds,pressure wounds,vascular ulcers,etc.)do not usually heal in a timely and orderly manner but rather last for years and may lead to irreversible adverse events,resulting in a substanti...Chronic wounds(e.g.diabetic wounds,pressure wounds,vascular ulcers,etc.)do not usually heal in a timely and orderly manner but rather last for years and may lead to irreversible adverse events,resulting in a substantial financial burden for patients and society.Recently,a large amount of evidence has proven that cellular senescence has a crucial influence on chronic nonhealing wounds.As a defensive mechanism,cell senescence is a manner of cell-cycle arrest with increased secretory phenotype to resist death,preventing cells from stress-induced damage in cancer and noncancer diseases.A growing amount of research has advanced the perception of cell senescence in various chronic wounds and focuses on pathological and physiological processes and therapies targeting senescent cells.However,previous reviews have failed to sum up novel understandings of senescence in chronic wounds and emerging strategies targeting senescence.Herein,we discuss the characteristics and mechanisms of cellular senescence and the link between senescence and chronic wounds as well as some novel antisenescence strategies targeting other diseases that may be applied for chronic wounds.展开更多
Cellular senescence(CS)is a state of stable cell cycle arrest characterized by the production and secretion of inflammatory molecules.Early studies described oncogene-induced senescence(OIS)as a barrier to tumorigenes...Cellular senescence(CS)is a state of stable cell cycle arrest characterized by the production and secretion of inflammatory molecules.Early studies described oncogene-induced senescence(OIS)as a barrier to tumorigenesis,such that the therapeutic induction of CS might represent a rational anti-cancer strategy.Indeed,the validity of this approach has been borne out by the development and approval of the cyclin-dependent kinase(CDK)inhibitor palbociclib for the treatment of breast cancer.Apart from tumors,senescent cells have also been shown to accumulate during natural mammalian aging,where they produce detrimental effects on the physiology of surrounding tissues.Thus,pharmacological senescent cell depletion has been proposed as an approach to delay age-related functional decline;this has been formally demonstrated in animal models.In this review article,we describe the current mechanistic understanding of cellular senescence at the molecular level and how it informs the development of new therapeutic strategies to combat cancer and aging.展开更多
Significant cellular senescence has been observed in cartilage harvested from patients with osteoarthritis(OA).In this study,we aim to develop a senescence-relevant OA-like cartilage model for developing disease-modif...Significant cellular senescence has been observed in cartilage harvested from patients with osteoarthritis(OA).In this study,we aim to develop a senescence-relevant OA-like cartilage model for developing disease-modifying OA drugs(DMOADs).Spe-cifically,human bone marrow-derived mesenchymal stromal cells(MSCs)were expanded in vitro up to passage 10(P10-MSCs).Following their senescent phenotype formation,P10-MSCs were subjected to pellet culture in chondrogenic medium.Results from qRT-PCR,histology,and immunostaining indicated that cartilage generated from P10-MSCs displayed both senescent and OA-like phenotypes without using other OA-inducing agents,when compared to that from normal passage 4(P4)-MSCs.Interestingly,the same gene expression differences observed between P4-MSCs and P10-MSC-derived cartilage tissues were also observed between the preserved and damaged OA cartilage regions taken from human samples,as demonstrated by RNA sequencing data and other analysis methods.Lastly,the utility of this senescence-initiated OA-like cartilage model in drug development was assessed by testing several potential DMOADs and senolytics.The results suggest that pre-existing cellular senescence can induce the generation of OA-like changes in cartilage.The P4-and P10-MSCs derived cartilage models also represent a novel platform for predicting the efficacy and toxicity of potential DMOADs on both preserved and damaged cartilage in humans.展开更多
文摘Aging and death are unavoidable in life. While immortality may be impossible, many people dream of living a long and healthy life. Throughout history, humans have searched for ways to stay young, but have not found an effective way. This may be because the methods used do not target the causes of aging directly. To address this, we investigated how to delay aging using traditional Chinese medicine (TCM) and Western medicine approaches. In this article, we will explain the causes of aging in the context of TCM and Western medicine and suggest methods to delay it. By integrating TCM and Western medicine, I hope to help everyone age healthily and enjoy a long life.
文摘Retinal degeneration is a debilitating ocular complication characterized by the progressive loss of photoreceptors and other retinal neurons,which are caused by a group of retinal diseases affecting various age groups,and increasingly prevalent in the elderly.Age-related macular degeneration,diabetic retinopathy and glaucoma are among the most common complex degenerative retinal disorders,posing significant public health problems worldwide largely due to the aging society and the lack of effective therapeutics.Whilst pathoetiologies vary,if left untreated,loss of retinal neurons can result in an acquired degeneration and ultimately severe visual impairment.Irrespective of underlined etiology,loss of neurons and supporting cells including retinal pigment epithelium,microvascular endothelium,and glia,converges as the common endpoint of retinal degeneration and therefore discovery or repurposing of therapies to protect retinal neurons directly or indirectly are under intensive investigation.This review overviews recent developments of potential neuroprotectants including neuropeptides,exosomes,mitochondrial-derived peptides,complement inhibitors,senolytics,autophagy enhancers and antioxidants either still experimentally or in clinical trials.Effective treatments that possess direct or indirect neuroprotective properties would significantly lift the burden of visual handicap.
文摘Given its state of stable proliferative inhibition,cellular senescence is primarily depicted as a critical mechanism by which organisms delay the progression of carcinogenesis.Cells undergoing senescence are often associated with the alteration of a series of specific features and functions,such as metabolic shifts,stemness induction,and microenvironment remodeling.However,recent research has revealed more complexity associated with senescence,including adverse effects on both physiological and pathological processes.How organisms evade these harmful consequences and survive has become an urgent research issue.Several therapeutic strategies targeting senescence,including senolytics,senomorphics,immunotherapy,and function restoration,have achieved initial success in certain scenarios.In this review,we describe in detail the characteristic changes associated with cellular senescence and summarize currently available countermeasures.
基金supported by grants from National High Level Hospital Clinical Research Funding(Scientific Research Fund of Peking University First Hospital,No.2023IR16State Key Laboratory of Vascular Homeostasis and Remodeling,Peking University,No.24QZ003)+2 种基金the National Natural Science Foundation of China(Nos.82090023 and 82330019)to Dr.Jing Niethe grants from Science/Technology Project of Sichuan Province(No.2024NSFSC1727)the 1.3.5 project for disciplines of excellence from West China Hospital of Sichuan University(No.ZYGD23015)to Dr.Ping Fu.
文摘Kidney fibrosis is the final common pathway of virtually all chronic kidney disease(CKD).However,despite great progress in recent years,no targeted antifibrotic therapies have been approved.Epidemiologic,clinical,and molecular evidence suggest that aging is a major contributor to the increasing incidence of CKD.Senescent renal tubular cells,fibroblasts,endothelial cells,and podocytes have been detected in the kidneys of patients with CKD and animal models.Nonetheless,although accumulated evidence supports the essential role of cellular senescence in CKD,the mechanisms that promote cell senescence and how senescent cells contribute to CKD remain largely unknown.In this review,we summarize the features of the cellular senescence of the kidney and discuss the possible functions of senescent cells in the pathogenesis of kidney fibrosis.We also address whether pharmacological approaches targeting senescent cells can be used to retard the the progression of kidney fibrosis.
基金supported in part by grants from National Natural Science Foundation of China(Grant Nos.82403746,82172649,and 82373193)China Postdoctoral Science Foundation(Grant No.2024M762256)+2 种基金the Postdoctoral Research Fund of West China Hospital,Sichuan University(Grant No.2024HXBH088)Natural Science Foundation of Sichuan Province(Grant Nos.2025ZNSFSC1716 and 2024NSFSC0627,China)Postdoctoral Fellowship Program of CPSF(Grant No.GZC20241174,China).
文摘Aging and cancer share overlapping characteristics,referred to as meta-hallmarks,which elucidate the convergent,antagonistic,or contradictory relationships between aging and cancer.Likewise,as a key characteristic of aging,senescent cells share some meta-hallmarks with tumor cells.These hallmarks include apoptosis resistance,metabolic alterations,secretory phenotypes,epigenetic reprogramming,and immune surveillance,all of which play pivotal roles in both tumorigenesis and senescence.Moreover,senolytic drugs,which are a class of agents selectively designed to eliminate senescent cells,have emerged as promising therapeutic agents in oncology and aging-related diseases.Since the discovery of the first senolytic drug in 2015,a diverse array of such agents has been developed.Notably,most senolytic drugs are repurposed from existing anti-tumor therapies,leveraging their shared mechanisms with senescent cells and tumor cells.Thus,this review examines the similarities between senescent cells and tumor cells,providing a better understanding of the meta-hallmarks.Besides,we categorize existing senolytic drugs based upon meta-hallmarks and elucidate the potential molecular mechanisms underlying their effects.By integrating insights from cancer and senescence research,this work aims to inspire innovative strategies for senolytic drug discovery.
基金This study was funded by the National Natural Science Foundation of China(Nos.82270709 and 82130021)the National Key R&D Program of China(Nos.2022YFC2502500 and 2022YFC2502502)+2 种基金the Michigan Medicine-PKUHSC Joint Institute for Translational and Clinical Research(No.BMU2022JI002)the Capital’s Funds for Health Improvement and Research(No.CFH2022-1-4071)the High Quality Clinical Research Project of Peking University First Hospital(No.2022CR83).
文摘Acute kidney injury(AKI)affects more than 20%of hospitalized patients and is a significant contributor to morbidity and mortality,primarily due to ischemia-reperfusion injury(IRI),which is one of the leading causes of AKI.IRI not only exacerbates the immediate impact of AKI but also facilitates its progression to chronic kidney disease(CKD)and,in cases of preexisting CKD,to end-stage renal disease(ESRD).One of the critical pathological processes associated with IRI-AKI is cellular senescence,characterized by an irreversible arrest in the cell cycle,morphological and chromatin organization changes,altered transcriptional and metabolic profiles,and the development of a hypersecretory phenotype known as the senescence-associated secretory phenotype(SASP).The SASP amplifies senescence signals in surrounding normal cells through senescence-related pathways,contributing to tissue damage,fibrosis,and chronic inflammation.This review provides an overview of the defining features of senescent cells and explores the fundamental mechanisms underlying senescent cell generation following IRI.We elucidate the pivotal roles of cellular senescence in the transition from IRI-AKI to chronic kidney injury.Furthermore,we discuss emerging therapies targeting cellular senescence,including senolytics and senomorphics,which have shown promising results in both preclinical and clinical settings.These therapies position cellular senescence as a crucial target for the treatment of IRI in the kidneys.Additionally,advancements in single-cell sequencing technology and artificial intelligence-assisted drug screening are expected to accelerate the discovery of novel senescent biomarkers and synotherapeutics,paving the way for optimized and personalized therapeutic interventions.
基金funded by grants from the National Nat-ural Science Foundation of China(Nos.82325007 and 82370620)the National Key Research and Develop-ment Program of China(No.2021YFA1100502).
文摘Cellular senescence,an irreversible state of cell cycle arrest characterized by phenotypic changes and a specific secretory profile,plays a dual role in liver health and disease.Under physiological conditions,senescence aids organ repair and regeneration,but its accumulation due to aging or pathological stress significantly contributes to chronic liver diseases,including alcoholic liver disease,metabolic dysfunction-associated steatohepatitis,liver fibrosis,and hepatocellular carcinoma.Senescence is identified by a range of cellular and molecular changes,such as morphological alterations,expression of cell cycle inhibitors,senescence-associated β-galactosidase activity,and nuclear membrane changes.The onset of senescence in organ cells can affect the entire organism,primarily through the senescence-associated secretory phenotype,which has autocrine,paracrine,and endocrine effects on tissue microenvironments.The objective of this review is to offer a contemporary overview of the pathophysiological events involving hepatic senescent cells and to elucidate their role in the onset and progression of liver diseases,particularly through mechanisms like telomere shortening,genomic and mitochondrial DNA damage,and inflammation.Additionally,this review discusses the emerging senolytic therapies aimed at targeting senescent cells to delay or mitigate liver disease progression.The therapeutic potential of these interventions,alongside their safety and effectiveness,highlights the need for further research to refine these approaches and address unresolved problems in the field of hepatic cellular senescence.
基金supported by the National Natural Science Foundation of China(32300959 and 32100918)the China Postdoctoral Science Foundation(2021M690060 and 2022T150227)+1 种基金Guangzhou Scientific Research Grant(SL2024A04J00578)the SCNU Young Faculty Development Program(22KJ04).
文摘Alzheimer’s disease(AD)is one of the most common neurodegenerative disorders,characterized by the accumulation of Aβand abnormal tau hyperphosphorylation.Despite substantial efforts in development of drugs targeting Aβand tau pathologies,effective therapeutic strategies for AD remain elusive.Recent attention has been paid to the significant role of cellular senescence in AD progression.Mounting evidence suggests that interventions targeting cellular senescence hold promise in improving cognitive function and ameliorating hallmark pathologies in AD.This narrative review provides a comprehensive summary and discussion of the physiological roles,characteristics,biomarkers,and commonly employed in vivo and in vitro models of cellular senescence,with a particular focus on various cell types in the brain,including astrocytes,microglia,oligodendrocyte precursor cells,neurons,and endothelial cells.The review further delves into factors influencing cellular senescence in AD and emphasizes the significance of targeting cellular senescence as a promising approach for AD treatment,which includes the utilization of senolytics and senomorphics.
基金supported by an NIH R01 R01HL166327Institutional Development Award(IDeA)from the NIGMS of NIH un-der grant No.P20GM103652the Rhode Island Foundation grant No.14699_20231340(HY),and the Warren Alpert Foundation of Brown University(PAD).
文摘Cellular senescence is a status of irreversible growth arrest,which can be triggered by the p53/p21cip1 and p16INK4/Rb pathways via intrinsic and external factors.Senescent cells are typically enlarged and flattened,and characterized by numerous molecular features.The latter consists of increased surfaceome,increased resid-ual lysosomal activity at pH 6.0(manifested by increased activity of senescence-associated beta-galactosidase[SA-𝛽-gal]),senescence-associated mitochondrial dysfunction,cytoplasmic chromatin fragment,nuclear lamin b1 exclusion,telomere-associated foci,and the senescence-associated secretory phenotype.These features vary depending on the stressor leading to senescence and the type of senescence.Cellular senescence plays pivotal roles in organismal aging and in the pathogenesis of aging-related diseases.Interestingly,senescence can also both promote and inhibit wound healing processes.We recently report that senescence as a programmed pro-cess contributes to normal lung development.Lung senescence is also observed in Down Syndrome,as well as in premature infants with bronchopulmonary dysplasia and in a hyperoxia-induced rodent model of this disease.Furthermore,this senescence results in neonatal lung injury.In this review,we briefly discuss the molecular features of senescence.We then focus on the emerging role of senescence in normal lung development and in the pathogenesis of bronchopulmonary dysplasia as well as putative signaling pathways driving senescence.Finally,we discuss potential therapeutic approaches targeting senescent cells to prevent perinatal lung diseases.
基金supported by the National Institute on Aging of the National Institutes of Health under Award Number R01AG081874-01(QZ),R01AG082207(QZ),R41AG081124-01(PX).
文摘Traumatic brain injury(TBI)and stroke pose major health challenges,impacting millions of individuals globally.Once considered solely acute events,these neurological conditions are now recognized as enduring pathological processes with long-term consequences,including an increased susceptibility to neurodegeneration.However,effective strategies to counteract their devastating consequences are still lacking.Cellular senescence,marked by irreversible cell-cycle arrest,is emerging as a crucial factor in various neurodegenerative diseases.Recent research further reveals that cellular senescence may be a potential driver for secondary neurodegeneration following brain injury.Herein,we synthesize emerging evidence that TBI and stroke drive the accumulation of senescent cells in the brain.The rationale for targeting senescent cells as a therapeutic approach to combat neurodegeneration following TBI/stroke is outlined.From a translational perspective,we emphasize current knowledge and future directions of senolytic therapy for these neurological conditions.
基金supported by the Science and Technology Innovation Project of Guangdong Province(No.2018KJYZ005)the Natural Science Foundation of Guangdong Province(No.2020A151501107)+1 种基金the Natural Science Foundation of Tibet Autonomous Region(No.XZ2017ZR-ZY021)the Guangdong Province Key FieldR&DProgramme Project(No.2020B1111150001).
文摘Chronic wounds(e.g.diabetic wounds,pressure wounds,vascular ulcers,etc.)do not usually heal in a timely and orderly manner but rather last for years and may lead to irreversible adverse events,resulting in a substantial financial burden for patients and society.Recently,a large amount of evidence has proven that cellular senescence has a crucial influence on chronic nonhealing wounds.As a defensive mechanism,cell senescence is a manner of cell-cycle arrest with increased secretory phenotype to resist death,preventing cells from stress-induced damage in cancer and noncancer diseases.A growing amount of research has advanced the perception of cell senescence in various chronic wounds and focuses on pathological and physiological processes and therapies targeting senescent cells.However,previous reviews have failed to sum up novel understandings of senescence in chronic wounds and emerging strategies targeting senescence.Herein,we discuss the characteristics and mechanisms of cellular senescence and the link between senescence and chronic wounds as well as some novel antisenescence strategies targeting other diseases that may be applied for chronic wounds.
基金This work was supported by the National Institute of Health(R01-CA233205 to X.F.W.).
文摘Cellular senescence(CS)is a state of stable cell cycle arrest characterized by the production and secretion of inflammatory molecules.Early studies described oncogene-induced senescence(OIS)as a barrier to tumorigenesis,such that the therapeutic induction of CS might represent a rational anti-cancer strategy.Indeed,the validity of this approach has been borne out by the development and approval of the cyclin-dependent kinase(CDK)inhibitor palbociclib for the treatment of breast cancer.Apart from tumors,senescent cells have also been shown to accumulate during natural mammalian aging,where they produce detrimental effects on the physiology of surrounding tissues.Thus,pharmacological senescent cell depletion has been proposed as an approach to delay age-related functional decline;this has been formally demonstrated in animal models.In this review article,we describe the current mechanistic understanding of cellular senescence at the molecular level and how it informs the development of new therapeutic strategies to combat cancer and aging.
文摘Significant cellular senescence has been observed in cartilage harvested from patients with osteoarthritis(OA).In this study,we aim to develop a senescence-relevant OA-like cartilage model for developing disease-modifying OA drugs(DMOADs).Spe-cifically,human bone marrow-derived mesenchymal stromal cells(MSCs)were expanded in vitro up to passage 10(P10-MSCs).Following their senescent phenotype formation,P10-MSCs were subjected to pellet culture in chondrogenic medium.Results from qRT-PCR,histology,and immunostaining indicated that cartilage generated from P10-MSCs displayed both senescent and OA-like phenotypes without using other OA-inducing agents,when compared to that from normal passage 4(P4)-MSCs.Interestingly,the same gene expression differences observed between P4-MSCs and P10-MSC-derived cartilage tissues were also observed between the preserved and damaged OA cartilage regions taken from human samples,as demonstrated by RNA sequencing data and other analysis methods.Lastly,the utility of this senescence-initiated OA-like cartilage model in drug development was assessed by testing several potential DMOADs and senolytics.The results suggest that pre-existing cellular senescence can induce the generation of OA-like changes in cartilage.The P4-and P10-MSCs derived cartilage models also represent a novel platform for predicting the efficacy and toxicity of potential DMOADs on both preserved and damaged cartilage in humans.
