Transplanted adipose-derived stem cells delay D-galactose-induced aging in rats

To investigate the effects of allogeneically transplanted, adipose-derived stem cells in aging rats, in the present study, we established a rat model of subacute aging using continuous subcutaneous injections of D-galactose. Two weeks after the adipose-derived stem cells transplantations, serum superoxide dismutase activity was significantly increased, malondialdehyde content was significantly reduced, hJppocampal neuronal degeneration was ameliorated, the apoptotic index of hippocampal neurons was decreased, and leaming and memory function was significantly improved in the aging rats. These results indicate that allogeneic transplantation of adipose-derived stem cells may effectively delay D-galactose-induced aging.

Effects of Aging on the Proliferation and Differentiation Capacity of Human Periodontal Ligament Stem Cells

periodontal ligament stem cells; aging; proliferation; osteogenic differentiation Objective The aim of this study is to investigate the proliferation, differentiation and apoptosis of periodontal ligament stem cells （PDLSC） derived from different aged donors, and to evaluate the effects of aging on the biological characteristics of PDLSC. Methods Periodontal ligament tissues were obtained from 24 surgically extracted human premolars during orthodontics therapy. The specimens were divided into three groups according to the donor’s age. Group A： 18-20 years, group B： 30-35 years, group C： 45-50 years. PDLSC were isolated and cultured using a tissue-block-based enzymolytic method by limiting dilution assay. The colony forming efficiency of PDLSC for three experimental groups was determined. Senescence-Associated β-Galactosidase （SA-β-G） expression in the three groups was examined using β-galactosidase staining working solution. Cell cycle and apoptosis of the PDLSC were examined by the flow cytometry. Alkaline phosphatase （ALP） activity was evaluated by ALP staining. The expression of osteoplastic differentiation related genes Runt-related transcription factor-2 （Runx-2）, Collagen Type 1 （col-1）, and ALP of PDLSC were examined by quantitative real-time RT-PCR. Results The colony forming efficiency of PDLSC in Group A, B and C was 36.67%, 22.67% and 9.33%, respectively, which decreased with donors’ age （P〈0.05）. SA-β-G expression of the senescent PDLSC in group A, B and C were 4.14%, 16.39%, 50.38%, respectively （P〈0.05）. Cells in G2/S phase was 38.73%, 29.88%, 18.25% （P〈0.05）, and the apoptosis rate was 1.57%, 4.56%, 5.84% （P〈0.05）, in group A, B and C respectively. The ALP staining in the three groups decreased with the increase of donors’ ages, and the expression of Runx-2, col-1 and ALP decreased gradually from group A to group C （all P〈0.05）, which indicated the osteogenic differentiation capacity of PDLSC decreased while donor aging. Conclusion Human PDLSC could be successfully isolated from periodontal ligament tissues of different aged donors. However, the proliferation and osteogenic differentiation capacity of PDLSC decreased while donor aging.

Discovery of molecular associations among aging, stem cells, and cancer based on gene expression profiling

The emergence of a huge volume of "omics" data enables a computational approach to the investigation of the biology of cancer. The cancer informatics approach is a useful supplement to the traditional experimental approach. I reviewed several reports that used a bioinformatics approach to analyze the associations among aging, stem cells, and cancer by microarray gene expression profiling. The high expression of aging- or human embryonic stem cell-related molecules in cancer suggests that certain important mechanisms are commonly underlying aging, stem cells, and cancer. These mechanisms are involved in cell cycle regulation, metabolic process, DNA damage response, apoptosis, p53 signaling pathway, immune/inflammatory response, and other processes, suggesting that cancer is a developmental and evolutional disease that is strongly related to aging. Moreover, these mechanisms demonstrate that the initiation, proliferation, and metastasis of cancer are associated with the deregulation of stem cells. These findings provide insights into the biology of cancer. Certainly, the findings that are obtained by the informatics approach should be justified by experimental validation. This review also noted that next-generation sequencing data provide enriched sources for cancer informatics study.

Bibliometrics of stem cell effects on aging in the last decade based on the Web of Science database

Objective:To summarize the recent 10 years of related literature on stem cell effect on aging and explore the research results and hot topics.Methods:Based on the core databaseof Web of Science,all relevant literature from January 1,2012,to December 31,2021,was screened,and CiteSpace 6.1.R2 software was used to show the intrinsic value of literature.The number of publications,research institutions,research countries,co-cited literature,and keywords was analyzed and visualized.Results:In the past 10 years,the total number of articles published showed an upward trend.The number of articles published by relevant countries was 3,911,and the United States had the most significant number of articles published and the highest centrality.The research institutions were mainly universities,supplemented by research centers,and the quality of articles published by famous foreign universities in this field was high.The most co-cited literature is“Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan”by Darren J Baker,which clarifies the feasibility of cell therapy for aging.The high-frequency keywords are stem cell,senescence,expression,etc.,and the most central ones are cancer cell,migration and DNA repair,etc.In addition,emergent words and clustering show that research hotspots are mainly in the aging mechanism.There are many research entry points,and the pathogenesis and development of senescence,therapeutic targets of ion channels in senescent cells,and their effects on exosomes are the main focus of current research.Conclusion:Literature through the analysis of 10 years of research literature summary suggests that stem cell function in aging still needs further study;the United States is in the leading position in this regard,and the research results also show that research institutions dominate in the developed countries,North America and Europe in the increasing number of papers at the same time,and China should pay attention to the quality of the post,in order to make more progress.The literature of some high-quality scholars can be used as a reference to expand our thinking.The aging mechanism still needs to be many follow-upstudies to clarify the pathway and target in the treatment of more refined Alzheimer’s disease and other age-related diseases need to delve into.Subsequent scholars should study the specific role of stem cells in treating aging;in recent years,hot words,such as exosomes,oxidative stress,etc.,can be used as the thinking of the follow-up study and contribute to the development of the field.

Cancer stem cells in Helicobacter pylori infection and aging: Implications for gastric carcinogenesis

AIM: To demonstrated the combined effects of aging and carcinogen treatment on cancer stem/stem-like cells(CSCs) of gastric mucosa in an animal model. METHODS: In this study we investigated the effects of aging and Helicobacter pylori(H. pylori) inflammation as a model for inflammation induced carcinogenesis in human and rat gastric mucosa samples. In aging studies, we compared 4-mo old(young) with 22 mo(aged) old Fischer-344 rats. For human studies, gastric biop-sies and resection specimens representing normal mucosa or different stages of H. pylori gastritis and gastric adenocarcinomas were used for determining the expression of stem cell markers CD166, ALDH1 and LGR5. In addition we performed immunofluorescent double labeling for B-catenin and Lgr5 in both rat and human gastric tissues to examine the status of Wnt signaling in these cells. RESULTS: CSC markers ALDH1, LGR5, and CD166 were expressed in very low levels in normal human gastric mucosa or young rat gastric mucosa. In contrast, level of expression for all three markers significantly increased in H. pylori gastritis and gastric adenocarcinomas as well as in normal gastric mucosa in aged rats. We also observed cytoplasmic B-catenin staining in both aged rat and human H. pylori inflamed gastric mucosa, which were found to be colocalized with Lgr5 immunoreactive cells. The increased number of ALDH1, CD166 and LGR5 positive cells in H. pylori gastritis indicates that increased number of stem-like cells in gastric mucosa is an early event, and may constitute an important step in the progression to neoplasia. CONCLUSION: Our observation of the age-related increase in cancer stem/stem-like cells in the gastric mucosa may explain the increased incidence of gastric cancer during aging. Combination of aging and H. pylori infection may have additive effects in progression to neoplasia.

Effect of aging on stem cells

Pluripotent stem cells have the remarkable self-renewal ability and are capable of differentiating into multiple diverse cells. There is increasing evidence that the aging process can have adverse effects on stem cells. As stem cells age, their renewal ability deteriorates and their ability to differentiate into the various cell types is altered. Accordingly, it is suggested aging-induced deterioration of stem cell functions may play a key role in the pathophysiology of the various aging-associated disorders. Understanding the role of the aging process in deterioration of stem cell function is crucial, not only in understanding the pathophysiology of agingassociated disorders, but also in future development of novel effective stem cell-based therapies to treat agingassociated diseases. This review article first focuses on the basis of the various aging disease-related stem cell dysfunction. It then addresses the several concepts on the potential mechanism that causes aging-related stem cell dysfunction. It also briefly discusses the current potential therapies under development for aging-associated stem cell defects.

Preventing aging with stem cell rejuvenation:Feasible or infeasible?

Characterized by dysfunction of tissues, organs, organ systems and the whole organism, aging results fromthe reduced function of effective stem cell populations. Recent advances in aging research have demonstrated that old tissue stem cells can be rejuvenated for the purpose of maintaining the old-organ function by youthful re-calibration of the environment where stem cells reside. Biochemical cues regulating tissue stem cell function include molecular signaling pathways that interact between stem cells themselves and their niches. Historically, plasma fractions have been shown to contain factors capable of controlling age phenotypes; subsequently, signaling pathways involved in the aging process have been identified. Consequently, modulation of signaling pathways such as Notch/Delta, Wnt, transforming growth factor-β, JAK/STAT, mammalian target of rapamycin and p38 mitogen-activated protein kinase has demonstrated potential to rejuvenate stem cell function leading to organismic rejuvenation. Several synthetic agents and natural sources, such as phytochemicals and flavonoids, have been proposed to rejuvenate old stem cells by targeting these pathways. However, several concerns still remain to achieve effective organismic rejuvenation in clinical settings, such as possible carcinogenic actions; thus, further research is still required.

Effect of aging on behaviour of mesenchymal stem cells

Organs whose source is the mesoderm lineage contain a subpopulation of stem cells that are able to differentiate among mesodermal derivatives (chondrocytes, osteocytes, adipocytes). This subpopulation of adult stem cells, called “mesenchymal stem cells” or “mesenchymal stromal cells (MSCs)”, contributes directly to the homeostatic maintenance of their organs;hence, their senescence could be very deleterious for human bodily functions. MSCs are easily isolated and amenable their expansion in vitro because of the research demanding to test them in many diverse clinical indications. All of these works are shown by the rapidly expanding literature that includes many in vivo animal models. We do not have an in-depth understanding of mechanisms that induce cellular senescence, and to further clarify the consequences of the senescence process in MSCs, some hints may be derived from the study of cellular behaviour in vivo and in vitro, autophagy, mitochondrial stress and exosomal activity. In this particular work, we decided to review these biological features in the literature on MSC senescence over the last three years.

How mesenchymal stem cells transform into adipocytes:Overview of the current understanding of adipogenic differentiation

Mesenchymal stem cells(MSCs)are stem/progenitor cells capable of self-renewal and differentiation into osteoblasts,chondrocytes and adipocytes.The transformation of multipotent MSCs to adipocytes mainly involves two subsequent steps from MSCs to preadipocytes and further preadipocytes into adipocytes,in which the process MSCs are precisely controlled to commit to the adipogenic lineage and then mature into adipocytes.Previous studies have shown that the master transcription factors C/enhancer-binding protein alpha and peroxisome proliferation activator receptor gamma play vital roles in adipogenesis.However,the mechanism underlying the adipogenic differentiation of MSCs is not fully understood.Here,the current knowledge of adipogenic differentiation in MSCs is reviewed,focusing on signaling pathways,noncoding RNAs and epigenetic effects on DNA methylation and acetylation during MSC differentiation.Finally,the relationship between maladipogenic differentiation and diseases is briefly discussed.We hope that this review can broaden and deepen our understanding of how MSCs turn into adipocytes.

Extracellular vesicles from human urine-derived stem cells delay aging through the transfer of PLAU and TIMP1

Aging increases the risks of various diseases and the vulnerability to death.Cellular senescence is a hallmark of aging that contributes greatly to aging and aging-related diseases.This study demonstrates that extracellular vesicles from human urine-derived stem cells(USC-EVs)efficiently inhibit cellular senescence in vitro and in vivo.The intravenous injection of USC-EVs improves cognitive function,increases physical fitness and bone quality,and alleviates aging-related structural changes in different organs of senescence-accelerated mice and natural aging mice.The anti-aging effects of USC-EVs are not obviously affected by the USC donors’ages,genders,or health status.Proteomic analysis reveals that USC-EVs are enriched with plasminogen activator urokinase(PLAU)and tissue inhibitor of metalloproteinases 1(TIMP1).These two proteins contribute importantly to the anti-senescent effects of USC-EVs associated with the inhibition of matrix metalloproteinases,cyclin-dependent kinase inhibitor 2A(P16INK4a),and cyclin-dependent kinase inhibitor 1A(P21cip1).These findings suggest a great potential of autologous USC-EVs as a promising anti-aging agent by transferring PLAU and TIMP1 proteins.

Extracellular vesicles derived from mesenchymal stem cells:the wine in Hebe's hands to treat skin aging

Owing to its constant exposure to the external environment and various stimuli,skin ranks among the organs most vulnerable to manifestations of aging.Preventing and delaying skin aging has become one of the prominent research subjects in recent years.Mesenchymal stem celis(MsCs)are multipotent stem cells derived from mesoderm with high self-renewal ability and multilineage differentiation potential.MSC-derived extracellular vesicles(MSC-EVs)are nanoscale biological vesicles that facilitate intercellular communication and regulate biological behavior.Recent studies have shown that MSC-EVs have potential applications in anti-aging therapy due to their anti-inflammatory,anti-oxidative stress,and wound healing promoting abilities.This review presents the latest progress of MSC-EVs in delaying skin aging.It mainly includes the MSC-EVs promoting the proliferation and migration of keratinocytes and fibroblasts,reducing the expression of matrix metalloproteinases,resisting oxidative stress,and regulating inflammation.We then briefly discuss the recently discovered treatment methods of MSc-EVs in the field of skin anti-aging.Moreover,the advantages and limitations of EV-based treatments are also presented.

Auditory Dysfunction in Aging: Prospects for Stem Cell Therapy

Age-related hearing loss is the most common cause of adult auditory dysfunction. It is characterized by bilateral, progressive auditory deterioration associated with the aging process. There currently are limited options for the treatment as hearing aids or cochlear implants. To establish novel strategies for the treatment of this entity, it is crucial to elucidate the mechanisms of age-related hearing loss. Its etiology is believed to be multifactorial including both intrinsic and extrinsic factors. Oxidative damage, as seen in other aging organs systems, may play an essential role in the pathogenesis of the age-related hearing loss. Studies on animal models and human temporal bones have indicated a close relationship between degeneration of the cochlear lateral wall and hearing loss. Additional therapies that may prove beneficial in the treatment of age-related hearing loss include stem cell therapy, which we intend to review in this manuscript.

Overview of Hematopoietic Stem Cells in Systemic Cancer Treatment, Aging, Pregnancy, and Radiation Hormesis

Background: The unavoidable links between the benefits of conventional systemic treatment of cancer and the side effects such as lymphopenia. Objective: To analyze this phenomenon in view of the newly discovered trophic function of circulating hematopoietic stem cells (HSC) and their lymphocyte descendants. Method: We used population statistics and recent current research involving natural aging and preliminary aging with cancer, its cytotoxic therapy, eclampsia at pregnancy, and radiation hormesis. Results: In contrast to immune-defense interpretations of these health conditions, the trophic influence of HSC and morphogenic lymphocytes on natural tissue renewal and regeneration after sublethal injuries eliminates the majority of covered inconsistencies, which are inherent to the dominating idea of cellular immunity. Conclusion: Our examination led to the feeding influence of lymphopoiesis on tumor progression, an indirect mechanism of tumor growth control by systemic therapy via either destruction of trophic cells, or by competitive distraction from malignant tissue via reparation of sublethal injuries in normal tissues. Analyses also involved similarities of the mechanisms of systemic chemotherapy and total body/half body radiotherapy in low doses, as well as the futility of the theoretical opposition of the radiation hormesis phenomenon to the linear non-threshold model, dominant in radiobiology.

An Intensive Mind and Body Therapeutic Program Leads to Alteration in Gene Expression Critical to Aging Process in Peripheral Blood Stem Cells

Objective: Waiting to look young is not a new idea;the search for effective treatments prolonging youthfulness has been going on over many decades. Many scientific evidences have been suggestive of intensive or prolonged mind and body therapies (MBT) improving overall wellness and have anti-aging effects. However, the genetic basis of MBT-induced anti-aging and youthfulness are largely unknown. It is also known that aging adversely affects hematopoiesis in human through controlling compromised hematopoietic stem cells (HSC) and peripheral blood mononuclear cells (PBMNC’s). In this paper, we focus on evaluating changes in the expression levels of a critical panel of genes that regulates aging in PBMNC’s isolated from participants from MBT program. Design: Here, we have investigated the effects of a short intensive MBT program on aging related gene expression changes in the peripheral blood stem cells using affymetrix DNA microarray platform. A total of 108 people selected form many ethnicities were enrolled in the study;38 men and 70 women (aged 18 - 90) randomly assigned for the study. PBMNC’s were collected from the volunteers before and after the completion of the MBT program and evaluated for meditation by examining gene expression patterns in peripheral blood stem cells. Results: Critical pathways known to regulate aging process such as pro-inflammatory TNF alpha/NF-kB, IL-12 signaling pathway, hypoxic HIF-1-alpha, key regulator of programmed cell death, C-MYC, and P38 MAPK (mitogen-activated protein kinase) signaling pathway found to be dysregulated in the cohorts compared to subjects prior to MBT program. Furthermore, GATA-2 and Bmi1, key regulators of hemtopoiesis and adult stem cells numbers, went up in the mediated group. Additionally, key pro-inflammatory mediators IFN? and STAT-2 went down in the mediated group. Conclusion: MBT augments critical genes in PMBC which upregulate hematopoiesis and stem cell numbers and also controls genes that regulate age-related complications.

Multifaceted role of microRNAs in gastric cancer stem cells: Mechanisms and potential biomarkers

MicroRNAs(miRNAs)have received much attention in the past decade as potential key epigenomic regulators of tumors and cancer stem cells(CSCs).The abnormal expression of miRNAs is responsible for different phenotypes of gastric cancer stem cells(GCSCs).Some specific miRNAs could be used as promising biomarkers and therapeutic targets for the identification of GCSCs.This review summarizes the coding process and biological functions of miRNAs and demon-strates their role and efficacy in gastric cancer(GC)metastasis,drug resistance,and apoptosis,especially in the regulatory mechanism of GCSCs.It shows that the overexpression of onco-miRNAs and silencing of tumor-suppressor miRNAs can play a role in promoting or inhibiting tumor metastasis,apart from the initial formation of GC.It also discusses the epigenetic regulation and potential clinical applications of miRNAs as well as the role of CSCs in the pathogenesis of GC.We believe that this review may help in designing novel therapeutic approaches for GC.

Exploring the mechanism of Bazi Bushen capsule in delaying the senescence of mesenchymal stem cells by network pharmacology method and verifying it in vitro

OBJECTIVE To explore the key mechanism of Bazi Bushen capsule(BZBS)in delaying the senescence of mesenchymal stem cells(MSCs)through network pharmacology and in vitro experiments.METHODS Network pharmacology was used to predict the mechanism targets of BZBS in delaying MSCs senescence.A MSCs senescence model induced by D-galactose(D-gal)was used to investigate the effect and mechanism of BZBS on MSCs senescence in vitro.RESULTS Network pharmacology analy⁃sis showed that BZSB could delay MSCs senes⁃cence.The experiment showed that BZBS could significantly improve the survival activity of the aged MSCs.It significantly reduced the positive rate ofβ-galactosidase staining and p16,p21 expression in aged MSCs,enhanced the ability of adipogenic differentiation and osteogenic differentiation,and increased expression of Nanog,OCT4 and SOX2 in senescent MSCs.CONCLU⁃SIONS Network pharmacology and in vitro cell experiments verified that BZBS could delay MSCs senescence.

Evaluating role of bone marrow-derived stem cells in dry age-related macular degeneration using multifocal electroretinogram and fundus autofluorescence imaging

AIM：To evaluate the role of bone marrow-derived stem cells in the treatment of advanced dry age-related macular degeneration（AMD）using multifocal electroretinogram（mf-ERG）and fundus autofluorescence imaging.METHODS：Thirty patients（60 eyes）with bilateral central geographic atrophy（GA）were recruited.Worse eye of each patient received autologous bone marrow-derived hematopoietic stem cells（BM-HSCs）（group 1）and the fellow eye with better visual acuity served as control（group2）.The effect of stem cell therapy was determined in terms of visual acuity,amplitude and implicit time in mf-ERG and size of GA on fundus autofluorescence imaging.These tests were performed at presentation and first,third and sixth month follow up.Adverse events（if any）were also monitored.RESULTS：At 6mo follow-up there was no statistically significant improvement in median log MAR best corrected visual acuity（BCVA）in either group.Mf-ERG revealed significant improvement in amplitude and implicit time in the intervention group.A significant decrease was also noted in greatest linear dimension（GLD）of GA in the eyes receiving stem cells[6.78±2.60 mm at baseline to 6.56±2.59 mm at 6mo（P=0.021）].However,no such improvement was noted in the control group.CONCLUSION：Electrophysiological and anatomical improvement in the intervention group sheds light on the therapeutic role of BM-HSCs.Further studies are required to determine the stage of disease at which the maximal benefit can be achieved and to standardize the dose andfrequency of stem cell injection.

Epigenetic regulation of mesenchymal stem cell aging through histone modifications

Stem cell senescence and exhaustion,a hallmark of aging,lead to declines in tissue repair and regeneration in aged individuals.Emerging evidence has revealed that epigenetic regulation plays critical roles in the self-renew,lineage-commitment,survival,and function of stem cells.Moreover,epigenetic alterations are considered important drivers of stem cell dysfunction during aging.In this review,we focused on current knowledge of the histone modifications in the aging of mesenchymal stem cells(MSCs).The aberrant epigenetic modifications on histones,including methylation and acetylation,have been found in aging MSCs.By disturbing the expression of specific genes,these epigenetic modifications affect the self-renew,survival,and differentiation of MSCs.A set of epigenetic enzymes that write or erase these modifications are critical in regulating the aging of MSCs.Furthermore,we discussed the rejuvenation strategies based on epigenetics to prevent stem cell aging and/or rejuvenate senescent MSCs.

Apoptotic vesicles rejuvenate mesenchymal stem cells via Rab7-mediated autolysosome formation and alleviate bone loss in aging mice

Aging skeletons display decreased bone mass,increased marrow adiposity,and impaired bone marrow mesenchymal stem cells(MSCs).Apoptosis is a programmed cell death process that generates a large number of apoptotic vesicles(apoVs).Dysregulated apoptosis has been closely linked to senescence-associated diseases.However,whether apoVs mediate agingrelated bone loss is not clear.In this study,we showed that young MSC-derived apoVs effectively rejuvenated the nuclear abnormalities of aged bone marrow MSCs and restored their impaired self-renewal,osteo-/adipo-genic lineage differentiation capacities via activating autophagy.Mechanistically,apoptotic young MSCs generated and enriched a high level of Ras-related protein 7(Rab7)into apoVs.Subsequently,recipient aged MSCs reused apoV-derived Rab7 to restore autolysosomes formation,thereby contributing to autophagy flux activation and MSC rejuvenation.Moreover,systemic infusion of young MSC-derived apoVs enhanced bone mass,reduced marrow adiposity,and recused the impairment of recipient MSCs in aged mice.Our findings reveal the role of apoVs in rejuvenating aging-MSCs via restoring autolysosome formation and provide a potential approach for treating age-related bone loss.

Epigenetics and chromatin plasticity in embryonic stem cells

The study of embryonic stem cells is in the spotlight in many laboratories that study the structure and function of chromatin and epigenetic processes. The key properties of embryonic stem cells are their capacity for selfrenewal and their pluripotency. Pluripotent stem cells are able to differentiate into the cells of all three germ layers, and because of this property they represent a promising therapeutic tool in the treatment of diseases such as Parkinson's disease and diabetes, or in the healing of lesions after heart attack. As the basic nuclear unit, chromatin is responsible for the regulation of the functional status of cells, including pluripotency and differentiation. Therefore, in this review we discuss the functional changes in chromatin during differentiation and the correlation between epigenetics events and the differentiation potential of embryonic stem cells. In particular we focus on post-translational histone modification, DNA methylation and the heterochromatin protein HP1 and its unique function in mouse and human embryonic stem cells.