1.Pathophysiological implications of cellular senescence and prospects for novel anti-aging drugs.
Acta Physiologica Sinica 2023;75(6):847-863
Chronological aging is the leading risk factor for human diseases, while aging at the cellular level, namely cellular senescence, is the fundamental driving force of organismal aging. The impact of cellular senescence on various life processes, including normal physiology, organismal aging and the progress of various age-related pathologies, has been largely ignored for a long time. However, with recent advancement in relevant fields, cellular senescence has become the core of aging biology and geriatric medicine. Although senescent cells play important roles in physiological processes including tissue repair, wound healing, and embryonic development, they can also contribute to tissue dysfunction, organ degeneration and various pathological conditions during adulthood. Senescent cells exert paracrine effects on neighboring cells in tissue microenvironments by developing a senescence-associated secretory phenotype, thus maintaining long-term and active intercellular communications that ultimately results in multiple pathophysiological effects. This is regarded as one of the most important discoveries in life science of this century. Notably, selective elimination of senescent cells through inducing their apoptosis or specifically inhibiting the senescence-associated secretory phenotype has shown remarkable potential in preclinical and clinical interventions of aging and age-related diseases. This reinforces the belief that senescent cells are the key drug target to alleviate various aging syndromes. However, senescent cells exhibit heterogeneity in terms of form, function and tissue distribution, and even differ among species, which presents a challenge for the translation of significant research achievements to clinical practice in future. This article reviews and discusses the characteristics of senescent cells, current targeting strategies and future trends, providing useful and valuable references for the rapidly blooming aging biology and geriatric medicine.
Humans
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Adult
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Aged
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Cellular Senescence/genetics*
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Aging
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Apoptosis
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Cell Communication
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Wound Healing/physiology*
2.Decreased expression of DNA repair proteins Ku70 and Mre11 is associated with aging and may contribute to the cellular senescence.
Yeun Jin JU ; Kee Ho LEE ; Jeong Eun PARK ; Yong Su YI ; Mi Yong YUN ; Yong Ho HAM ; Tae Jin KIM ; Hyun Mi CHOI ; Gwi Jung HAN ; Jong Hoon LEE ; Juneyoung LEE ; Jong Seol HAN ; Kyung Mi LEE ; Gil Hong PARK
Experimental & Molecular Medicine 2006;38(6):686-693
The gradual loss of telomeric DNA can contribute to replicative senescence and thus, having longer telomeric DNA is generally considered to provide a longer lifespan. Maintenance and stabilization of telomeric DNA is assisted by binding of multiple DNA-binding proteins, including those involved in double strand break (DSB) repair. We reasoned that declining DSB repair capacity and increased telomere shortening in aged individuals may be associated with decreased expression of DSB repair proteins capable of telomere binding. Our data presented here show that among the DSB repair proteins tested, only the expression of Ku70 and Mre11 showed statistically significant age-dependent changes in human lymphocytes. Furthermore, we found that expressions of Ku70 and Mre11 are statistically correlated, which indicate that the function of Ku70 and Mre11 may be related. All the other DSB repair proteins tested, Sir2, TRF1 and Ku80, did not show any significant differences upon aging. In line with these data, people who live in the regional community (longevity group), which was found to have statistically longer average life span than the rest area, shows higher level of Ku70 expression than those living in the neighboring control community. Taken together, our data show, for the first time, that Ku70 and Mre11 may represent new biomarkers for aging and further suggest that maintenance of higher expression of Ku70 and Mre11 may be responsible for keeping longer life span observed in the longevity group.
Telomere/genetics
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Middle Aged
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Longevity
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Humans
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DNA-Binding Proteins/*metabolism
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DNA Repair/*genetics
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DNA/genetics
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Cell Aging/*physiology
;
CD4-Positive T-Lymphocytes/metabolism
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Antigens, Nuclear/*metabolism
;
Aging/*physiology
;
Aged, 80 and over
;
Aged
;
Adult
3.Loss of KDM4B impairs osteogenic differentiation of OMSCs and promotes oral bone aging.
Peng DENG ; Insoon CHANG ; Jiongke WANG ; Amr A BADRELDIN ; Xiyao LI ; Bo YU ; Cun-Yu WANG
International Journal of Oral Science 2022;14(1):24-24
Aging of craniofacial skeleton significantly impairs the repair and regeneration of trauma-induced bony defects, and complicates dental treatment outcomes. Age-related alveolar bone loss could be attributed to decreased progenitor pool through senescence, imbalance in bone metabolism and bone-fat ratio. Mesenchymal stem cells isolated from oral bones (OMSCs) have distinct lineage propensities and characteristics compared to MSCs from long bones, and are more suited for craniofacial regeneration. However, the effect of epigenetic modifications regulating OMSC differentiation and senescence in aging has not yet been investigated. In this study, we found that the histone demethylase KDM4B plays an essential role in regulating the osteogenesis of OMSCs and oral bone aging. Loss of KDM4B in OMSCs leads to inhibition of osteogenesis. Moreover, KDM4B loss promoted adipogenesis and OMSC senescence which further impairs bone-fat balance in the mandible. Together, our data suggest that KDM4B may underpin the molecular mechanisms of OMSC fate determination and alveolar bone homeostasis in skeletal aging, and present as a promising therapeutic target for addressing craniofacial skeletal defects associated with age-related deteriorations.
Aging
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Cell Differentiation
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Facial Bones/physiology*
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Humans
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Jumonji Domain-Containing Histone Demethylases/genetics*
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Mesenchymal Stem Cells/cytology*
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Osteogenesis
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Osteoporosis
4.p41-Arc, a regulatory subunit of Arp2/3 complex, can induce premature senescence in the absence of p53 and Rb.
Un Jung YUN ; Sang Eun PARK ; Deug Y SHIN
Experimental & Molecular Medicine 2011;43(7):389-392
Cellular senescence is a tumor-suppressive process instigated by proliferation in the absence of telomere replication, by cellular stresses such as oncogene activation, or by activation of the tumor suppressor proteins, such as Rb or p53. This process is characterized by an irreversible cell cycle exit, a unique morphology, and expression of senescence-associated-beta-galactosidase (SA-beta-gal). Despite the potential biological importance of cellular senescence, little is known of the mechanisms leading to the senescent phenotype. p41-Arc has been known to be a putative regulatory component of the mammalian Arp2/3 complex, which is required for the formation of branched networks of actin filaments at the cell cortex. In this study, we demonstrate that p41-Arc can induce senescent phenotypes when it is overexpressed in human tumor cell line, SaOs-2, which is deficient in p53 and Rb tumor suppressor genes, implying that p41 can induce senescence in a p53-independent way. p41-Arc overexpression causes a change in actin filaments, accumulating actin filaments in nuclei. Therefore, these results imply that a change in actin filament can trigger an intrinsic senescence program in the absence of p53 and Rb tumor suppressor genes.
Actin Cytoskeleton/metabolism
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Actin-Related Protein 2-3 Complex/*metabolism
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*Cell Aging
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Cell Cycle Proteins/metabolism
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Cell Line, Tumor
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Cell Nucleus/metabolism
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Fibroblasts/physiology
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Humans
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Recombinant Proteins/genetics/*metabolism
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Retinoblastoma Protein/*deficiency/genetics
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Tumor Suppressor Protein p53/*deficiency/genetics
5.Gene expression characteristic in human auricular cartilage tissue engineering.
Farah Wahida I ; Aminuddin BS ; Munirah S ; Chua KH ; Fuzina NH ; Isa MR ; Saim L ; Ruszymah BH
The Medical Journal of Malaysia 2004;59 Suppl B():190-191
This study was to assess collagen type II and collagen type I gene expression in tissue-engineered human auricular: cartilage formed via tissue engineering technique. Large-scale culture expansions were transformed into 3D in vitro construct and were implanted subcutaneously on the dorsal of athymic mice. After 8 weeks, explanted construct was processed in the same manner of native cartilage to facilitate cells for gene expression analysis. Isolated cells from in vivo construct demonstrated expression of type II collagen gene comparable to native cartilage. This study verified that tissue-engineered auricular cartilage expressed cartilage specific gene, collagen type II after in vivo maturation.
Actins/genetics
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Cartilage/transplantation
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Cell Aging/physiology
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Cells, Cultured
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Chondrocytes/*cytology
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Collagen Type I/*genetics
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Collagen Type II/*genetics
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Ear, External
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Fibroblasts/cytology
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Gene Expression/physiology
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Mice, Nude
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*Phenotype
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Reverse Transcriptase Polymerase Chain Reaction
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Tissue Engineering/*methods
6.Gene expression changes of urokinase plasminogen activator and urokinase receptor in rat testes at postnatal stages.
Dong-Hui HUANG ; Hu ZHAO ; Yong-Hong TIAN ; Hong-Gang LI ; Xiao-Fang DING ; Cheng-Liang XIONG
Asian Journal of Andrology 2007;9(5):679-683
AIMTo investigate the gene expression changes of urokinase plasminogen activator (uPA)/urokinase receptor (uPAR) in rat testes at postnatal stages and explore the effects of uPA/uPAR system on the rat spermatogenesis.
METHODSThe mRNAs of uPA and uPAR in rat testes were measured by using real-time quantitative polymerase chain reaction (PCR) at postnatal days 0, 5, 10, 15, 21, 28, 35, 42, 49 and 56, respectively.
RESULTSThe tendencies of uPA and uPAR mRNA expression were similar at most postnatal stages except for D(0). The expression of uPAR mRNA in rats testes was relatively higher than that of uPA at postnatal D(0), and both were decreased until D(21), increased obviously at postnatal D(28), reached a peak at postnatal D(35), then declined sharply at postnatal D(42) and retained at a low level afterwards.
CONCLUSIONThe uPA/uPAR system may be strongly linked to spermiation and spermatogenesis via regulating germ cell migration and proliferation, as well as promoting the spermiation and detached residual bodies from the mature spermatids.
Aging ; genetics ; Animals ; Animals, Newborn ; Gene Expression Regulation, Developmental ; Gene Expression Regulation, Enzymologic ; Male ; Polymerase Chain Reaction ; Rats ; Receptors, Cell Surface ; genetics ; Receptors, Urokinase Plasminogen Activator ; Spermatogenesis ; Spermatozoa ; enzymology ; physiology ; Testis ; growth & development ; physiology ; Urokinase-Type Plasminogen Activator ; genetics
7.Characterization of the Two Genes Differentially Expressed During Development in Human Fetal Astrocytes.
Sung Soo LEE ; Hee Seok SEO ; Sun Ju CHOI ; Hyun Sook PARK ; Ji Yong LEE ; Kyung Ho LEE ; Joo Young PARK
Yonsei Medical Journal 2003;44(6):1059-1068
Astrocytes are ubiquitous in the brain and have multiple functions. It is becoming clear that they play an important role in monitoring the neuromicroenvironment, information processing, and signaling in the central nervous system (CNS) in normal conditions and that they respond to CNS injuries. During the development of the CNS, astrocytes play a key role as a substrate for neuronal migration and axonal growth. To identify genes that could participate in astrocyte maturation, we used the differential display reverse transcription-PCR (DDRT-PCR) method. Human fetal astrocytes were cultured and total RNAs were isolated at intervals of 5 days for 50 days. Using 24 primer combinations, we identified a set of 18 candidate cDNAs deriving from the excised DDRT-PCR bands. DNA sequencing revealed 16 genes that have been described already. We found that RTP, TG, hTM-alpha, SPARC, TRIP7, and RPL7 genes were expressed increasingly, while HMGCR, RPL27a, NACA, NPM, and TARBP2 genes were expressed decreasingly, according to their culture stages. We also found two unidentified genes, A3 and C8, which were expressed differently in culture stages; the former was expressed decreasingly and the latter increasingly. These two genes were found in the same amount in genomic DNA from various human cells such as astrocytes, astrocytoma, trophoblasts and lymphocytes. The A3 gene was found only in human genomic DNA, but not in rat (ATr5), mouse (RAW264.7), or monkey (Vero) cells, whereas the C8 gene was found in human genomic DNA and monkey cells, but not in rat or mouse cells. We analysed these two genes for identification. There was > 92% nucleotide sequence identity between the A3 gene (3, 626 bp) and the Homo sapiens general transcription factor 3 (GTF3), and > 96% nucleotide sequence identity between the C8 gene (2, 401 bp) and the transmembrane receptor Unc5h2. These findings suggest that these two genes may participate in some functional roles within the cells.
Animals
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Astrocytes/*physiology
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Cell Aging/genetics
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Cells, Cultured
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Cercopithecus aethiops
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Embryo and Fetal Development
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Fetus/*physiology
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*Gene Expression
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Gene Expression Profiling
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Human
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Mice
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Rats
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Reverse Transcriptase Polymerase Chain Reaction
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Support, Non-U.S. Gov't
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Vero Cells
8.Mutant Huntingtin Causes a Selective Decrease in the Expression of Synaptic Vesicle Protein 2C.
Chaohua PENG ; Gaochun ZHU ; Xiangqian LIU ; He LI
Neuroscience Bulletin 2018;34(5):747-758
Huntington's disease (HD) is a neurodegenerative disease caused by a polyglutamine expansion in the huntingtin (Htt) protein. Mutant Htt causes synaptic transmission dysfunctions by interfering in the expression of synaptic proteins, leading to early HD symptoms. Synaptic vesicle proteins 2 (SV2s), a family of synaptic vesicle proteins including 3 members, SV2A, SV2B, and SV2C, plays important roles in synaptic physiology. Here, we investigated whether the expression of SV2s is affected by mutant Htt in the brains of HD transgenic (TG) mice and Neuro2a mouse neuroblastoma cells (N2a cells) expressing mutant Htt. Western blot analysis showed that the protein levels of SV2A and SV2B were not significantly changed in the brains of HD TG mice expressing mutant Htt with 82 glutamine repeats. However, in the TG mouse brain there was a dramatic decrease in the protein level of SV2C, which has a restricted distribution pattern in regions particularly vulnerable in HD. Immunostaining revealed that the immunoreactivity of SV2C was progressively weakened in the basal ganglia and hippocampus of TG mice. RT-PCR demonstrated that the mRNA level of SV2C progressively declined in the TG mouse brain without detectable changes in the mRNA levels of SV2A and SV2B, indicating that mutant Htt selectively inhibits the transcriptional expression of SV2C. Furthermore, we found that only SV2C expression was progressively inhibited in N2a cells expressing a mutant Htt containing 120 glutamine repeats. These findings suggest that the synaptic dysfunction in HD results from the mutant Htt-mediated inhibition of SV2C transcriptional expression. These data also imply that the restricted distribution and decreased expression of SV2C contribute to the brain region-selective pathology of HD.
Aging
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metabolism
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Animals
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Brain
;
metabolism
;
pathology
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Cell Line, Tumor
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Gene Expression
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physiology
;
Huntingtin Protein
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genetics
;
metabolism
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Membrane Glycoproteins
;
metabolism
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Mice
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Mice, Transgenic
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Mutation
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Nerve Tissue Proteins
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metabolism
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RNA, Messenger
;
metabolism
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Transcription, Genetic
;
physiology
9.Knockdown of Moesin Expression Accelerates Cellular Senescence of Human Dermal Microvascular Endothelial Cells.
Ju Hee LEE ; Jung Hoan YOO ; Sang Ho OH ; Kyu Yeop LEE ; Kwang Hoon LEE
Yonsei Medical Journal 2010;51(3):438-447
PURPOSE: Endothelial cells maintain the homeostasis of blood, which consists of plasma and cellular components, and regulate the interaction between blood and the surrounding tissues. They also have essential roles in vascular permeability, the circulation, coagulation, inflammation, wound healing, and tissue growth. The senescence of endothelial cells is closely related to the aging of the adjacent tissues and to age-related vascular disease. Recently, the expression of moesin was found to be decreased in elderly human dermal microvascular endothelial cells (HDMECs), and an association between moesin and senescence has been suggested. This study examined the functional role of moesin in cellular senescence. MATERIALS AND METHODS: To study the effects of decreased moesin expression on cellular senescence and metabolism, HDMECs were transfected with short hairpin-RNA (shRNA) lentivirus to silence moesin gene expression. In addition, specimens from young and old human skin were stained with anti-moesin and anti-p16 antibodies as an in vivo study. RESULTS: Using shRNAl-entivirus, moesin knock-down HDMECs developed characteristics associated with aging and expressed senescence associated-beta-galactosidase during early passages. They also showed increased p16 expression, decreased metabolic activity, and cell growth retardation. Human skin tissue from elderly persons showed decreased moesin expression and increased p16 expression. CONCLUSION: These findings suggest that there is a functional association between moesin expression and cellular senescence. Further study of the functional mechanism of moesin in the cytoskeleton and cellular senescence is needed. In addition, this study provides a useful model for developing anti-aging treatments.
Aged, 80 and over
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Antigens, CD31/metabolism
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Blotting, Western
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Cell Aging/genetics/*physiology
;
Cell Line
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Child
;
Endothelial Cells/*cytology/*metabolism
;
Humans
;
Immunohistochemistry
;
Microfilament Proteins/genetics/*physiology
;
Microscopy, Phase-Contrast
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Microvessels/*cytology
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RNA, Small Interfering/genetics/physiology
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Reverse Transcriptase Polymerase Chain Reaction
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Skin/*blood supply
10.Study on the dynamic changing profiles of telomeric restricted fragment length among sex balanced different age groups.
Lu-lu GE ; Chao LIU ; Li-yang TAO
Journal of Forensic Medicine 2003;19(4):201-203
OBJECTIVE:
In human, both in vivo and in vitro, telomere shortening appears to be a major component of cell senescence and aging. The detailed telomere shortening status and mechanism in peripheral blood cell is needed to be further characterized.
METHODS:
One hundred and twenty three peripheral blood samples were collected from healthy individuals of different age groups and the mean telomeric restricted fragment (TRF) was measured using Southern Blotting with Dig labeled probe. The samples of different groups were homogenized in sex components as indicated by chi 2 test of sex ratio of different test groups (P > 0.05).
RESULTS:
The average length of TRF is shortening with aging and distinguished shortening dynamic profiles could be observed. Further analysis showed that there might be a shortening peak near the age of 5.
CONCLUSION
There are distinguished dynamics profiles of telomere shortening among different age groups. Thus, the results indicate that it might be possible to infer individual age by telomeric restricted fragment length assay.
Adolescent
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Adult
;
Aged
;
Aging/genetics*
;
Blood Cells
;
Blotting, Southern/methods*
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Cell Division
;
Cells, Cultured
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Cellular Senescence
;
Child
;
Child, Preschool
;
DNA/genetics*
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DNA Replication
;
Female
;
Forensic Medicine
;
Humans
;
Male
;
Middle Aged
;
Repetitive Sequences, Nucleic Acid
;
Telomere/physiology*