Biomarkers of aging

Aging biomarkers are a combination of biological parameters to(i)assess age-related changes,(ii)track the physiological aging process,and(iii)predict the transition into a pathological status.Although a broad spectrum of aging biomarkers has been developed,their potential uses and limitations remain poorly characterized.An immediate goal of biomarkers is to help us answer the following three fundamental questions in aging research:How old are we?Why do we get old?And how can we age slower?This review aims to address this need.Here,we summarize our current knowledge of biomarkers developed for cellular,organ,and organismal levels of aging,comprising six pillars:physiological characteristics,medical imaging,histological features,cellular alterations,molecular changes,and secretory factors.To fulfill all these requisites,we propose that aging biomarkers should qualify for being specific,systemic,and clinically relevant.

Tellurium-driven maple leaf-shaped manganese nanotherapeutics reshape tumor microenvironment via chemical transition in situ to achieve highly efficient radioimmunotherapy of triple negative breast cancer

The therapeutic efficacy of radioimmunotherapy against triple negative breast cancer(TNBC)is largely limited by the complicated tumor microenvironment(TME)and its immunosuppressive state.Thus developing a strategy to reshape TME is expected to achieve highly efficient radioimmunotherapy.Therefore,we designed and synthesized a tellurium(Te)-driven maple leaf manganese carbonate nanotherapeutics(MnCO3@Te)by gas diffusion method,but also provided a chemical catalytic strategy in situ to augment ROS level and activate immune cells for improving cancer radioimmunotherapy.As expected,with the help of H2O2 in TEM,MnCO3@Te heterostructure with reversible Mn3+/Mn2+transition could catalyze the intracellular ROS overproduction to amplify radiotherapy.In addition,by virtue of the ability to scavenge H+in TME by carbonate group,MnCO3@Te directly promote the maturation of dendritic cells and macrophage M1 repolarization by stimulator of interferon genes(STING)pathway activation,resulting in remodeling immuno-microenvironment.As a result,MnCO3@Te synergized with radiotherapy and immune checkpoint blockade therapy effectively inhibited the breast cancer growth and lung metastasis in vivo.Collectively,these findings indicate that MnCO3@Te as an agonist,successfully overcome radioresistance and awaken immune systems,showing promising potential for solid tumor radioimmunotherapy.

Chemical screen identifies a geroprotective role of quercetin in premature aging

Aging increases the risk of various diseases. The main goal of aging research is to find therapies that attenuate aging and alleviate aging-related diseases. In this study, we screened a natural product library for geroprotective compounds using Werner syndrome (WS) human mesenchymal stem cells (hMSCs), a premature aging model that we recently established. Ten candidate compounds were identified and quercetin was investigated in detail due to its leading effects. Mechanistic studies revealed that quercetin alleviated senescence via the enhancement of cell proliferation and restoration of heterochromatin architecture in WS hMSCs. RNA-sequencing analysis revealed the transcriptional commonalities and differences in the geroprotective effects by quercetin and Vitamin C. Besides WS hMSCs, quercetin also attenuated cellular senescence in Hutchinson-Gilford progeria syndrome (HGPS) and physiological-aging hMSCs. Taken together, our study identifies quercetin as a geroprotective agent against accelerated and natural aging in hMSCs, providing a potential therapeutic intervention for treating age-associated disorders.

CRISPR/Cas9-mediated gene knockout reveals a guardian role of NF-κB/RelA in maintaining the homeostasis of human vascular cells

Vascular cell functionality is critical to blood vessel homeostasis. Constitutive NF-κB activation in vascular cells results in chronic vascular inflammation, leading to various cardiovascular diseases. However, how NF-κB regulates human blood vessel homeostasis remains largely elusive. Here, using CRISPR/Cas9-mediated gene editing, we generated RelA knockout human embryonic stem cells （hESCs） and differentiated them into various vascular cell derivatives to study how NF- KS modulates human vascular cells under basal and inflammatory conditions. Multi-dimensional phenotypic assessments and transcriptomic analyses revealed that RelA deficiency affected vascular cells via modulatinginflammation, survival, vasculogenesis, cell differentia- tion and extracellular matrix organization in a cell type- specific manner under basal condition, and that RelA protected vascular cells against apoptosis and modu- lated vascular inflammatory response upon tumor necrosis factor a （TNFa） stimulation. Lastly, further evaluation of gene expression patterns in IKBo knockout vascular cells demonstrated that IKBa acted largely independent of RelA signaling. Taken together, our data reveal a protective role of NF-κB/ReiA in modulating human blood vessel homeostasis and map the human vascular transcriptomic landscapes for the discovery of novel therapeutic targets.

Inflammation,epigenetics,and metabolism converge to cell senescence and ageing:the regulation and intervention

Remarkable progress in ageing research has been achieved over the past decades.General perceptions and experimental evidence pinpoint that the decline of physical function often initiates by cell senescence and organ ageing.Epigenetic dynamics and immunometabolic reprogramming link to the alterations of cellular response to intrinsic and extrinsic stimuli,representing current hotspots as they not only(re-)shape the individual cell identity,but also involve in cell fate decision.This review focuses on the present findings and emerging concepts in epigenetic,inflammatory,and metabolic regulations and the consequences of the ageing process.Potential therapeutic interventions targeting cell senescence and regulatory mechanisms,using state-of-the-art techniques are also discussed.

Photodynamic therapy accelerates skin wound healing through promoting re-epithelialization

Background:Epidermal stem cells(EpSCs)that reside in cutaneous hair follicles and the basal layer of the epidermis are indispensable for wound healing and skin homeostasis.Little is known about the effects of photochemical activation on EpSC differentiation,proliferation and migration during wound healing.The present study aimed to determine the effects of photodynamic therapy(PDT)on wound healing in vivo and in vitro.Methods:We created mouse full-thickness skin resection models and applied 5-aminolevulinic acid(ALA)for PDT to the wound beds.Wound healing was analysed by gross evaluation and haematoxylin–eosin staining in vivo.In cultured EpSCs,protein expression was measured using flow cytometry and immunohistochemistry.Cell migration was examined using a scratch model;apoptosis and differentiation were measured using flow cytometry.Results:PDT accelerated wound closure by enhancing EpSC differentiation,proliferation and migration,thereby promoting re-epithelialization and angiogenesis.PDT inhibited inflammatory infiltration and expression of proinflammatory cytokines,whereas the secretion of growth factors was greater than in other groups.The proportion of transient amplifying cells was significantly greater in vivo and in vitro in the PDT groups.EpSC migration was markedly enhanced after ALAinduced PDT.Conclusions:Topical ALA-induced PDT stimulates wound healing by enhancing re-epithelialization,promoting angiogenesis as well as modulating skin homeostasis.This work provides a preliminary theoretical foundation for the clinical administration of topical ALA-induced PDT in skin wound healing.

Eosinophil-derived chemokine(hCCL 15/23,mCCL6)interacts with CCR1 to promote eosinophilic airway inflammation

Eosinophils are terminally differentiated cells derived from hematopoietic stem cells(HSCs)in the bone marrow.Several studies have confirmed the effective roles of eosinophils in asthmatic airway pathogenesis.However,their regulatory functions have not been well elucidated.Here,increased C-C chemokine ligand 6(CCL6)in asthmatic mice and the human orthologs CCL15 and CCL23 that are highly expressed in asthma patients are described,which are mainly derived from eosinophils.Using Cc/6 knockout mice,further studies revealed CCL6-dependent allergic airway inflammation and committed eosinophilia in the bone marrow following ovalbumin(OVA)challenge and identified a CCL6-CCR1 regulatory axis in hematopoietic stem cells(HSCs).Eosinophil differentiation and airway inflammation were remarkably decreased by the specific CCR1 antagonist BX471.Thus,the study identifies that the CCL6-CCR1 axis is involved in the crosstalk between eosinophils and HSCs during the development of allergic airway inflammation,which also reveals a potential therapeutic strategy for targeting G protein-coupled receptors(GPCRs)for future clinical treatment of asthma.

Nicotinamide adenine dinucleotide replenishment rescues colon degeneration in aged mice

Susceptibility of gastrointestinal dysmotility increases with age-associated colonic degeneration.A paucity of remedies reversing colonic degeneration per se hinders the fundamental relief of symptoms.Here we discovered the correlation between colon degeneration and altered nicotinamide adenine dinucleotide(NAD)level in aged mice.Compared to 3-month-old young controls,2-year-old mice showed a spectrum of degenerative colonic phenotypes and exhibited a significant elongated transit time and slowed stool frequency in the context of Lomotil-induced slow-transit constipation.Despite upregulated colonic tryptophan hydroxylases expression,serotonin release and expression of colon-predominant type IV serotonin receptor,reduced viability of interstitial cells of Cajal while enhanced aquaporins(Aqp1,3 and 11)led to a less colonic motility and increased luminal dehydration in aged mice.Notably,this colonic degeneration was accompanied with reduced key NAD^(+)-generating enzyme expression and lowered NAD^(+)/NADH ratio in aged colon.Three-month continuous administration of beta nicotinamide mononucleotide,a NAD^(+)precursor,elevated colonic NAD^(+)level and improved defecation in aged mice.In contrast,pharmacological inhibition of nicotinamide phosphoribosyltransferase,the rate-limiting enzyme for NAD^(+)biosynthesis,induced a reduction in colonic NAD content and impaired gastrointestinal function in young mice.Taken together,these findings suggest the beneficial effect of NAD^(+)in maintaining colonic homoeostasis and reactivating NAD^(+)biosynthesis may represent a promising strategy to counteract age-related gastrointestinal degeneration.

Differentiation of embryonic stem cells in adult bone marrow

Embryonic stem cells （ESCs） are a potential source of generating transplantable hematopoietic stem and progenitor cells,which in turn can serve as ＂seed＂ cells for hematopoietic regeneration.In this study,we aimed to gauge the ability of mouse ESCs directly differentiating into hematopoietic cells in adult bone marrow （BM）.To this end,we first derived a new mouse ESC line that constitutively expressed the green fluorescent protein （GFP） and then injected the ESCs into syngeneic BM via intra-tibia.The progeny of the transplanted ESCs were then analyzed at different time points after transplantation.Notably,however,most injected ESCs differentiated into non-hematopoietic cells in the BM whereas only a minority of the cells acquired hematopoietic cell surface markers.This study provides a strategy for evaluating the differentiation potential of ESCs in the BM micro-environment,thereby having important implications for the physiological maintenance and potential therapeutic applications of ESCs.

High-speed multimode fiber imaging system based on conditional generative adversarial network

The multimode fiber(MMF)has great potential to transmit high-resolution images with less invasive methods in endoscopy due to its large number of spatial modes and small core diameter.However,spatial modes crosstalk will inevitably occur in MMFs,which makes the received images become speckles.A conditional generative adversarial network(GAN)composed of a generator and a discriminator was utilized to reconstruct the received speckles.We conduct an MMF imaging experimental system of transmitting over 1 m MMF with a 50μm core.Compared with the conventional method of U-net,this conditional GAN could reconstruct images with fewer training datasets to achieve the same performance and shows higher feature extraction capability.

Hepatic microRNA-126 deficiency restrains liver regeneration through p53 pathway in mice

Dear Editor,Emerging evidences show close associations between miRNAs and liver regeneration.MiR-126 is known as a governor of vascular integrity and angiogenesis.MiR-126 is involved in the self-renewal of hematopoietic stem cells(HSCS)and leukemia stem cells.1,2 MiR-126 also plays a vital role in hepatocellular carcinogenesis,however,the functions of miR-126 in liver regeneration were still unclear.

DNA Damage Response in Hematopoietic Stem Cell Ageing

Maintenance of tissue-specific stem cells is vital for organ homeostasis and organismal longevity.Hematopoietic stem cells（HSCs） are the most primitive cell type in the hematopoietic system.They divide asymmetrically and give rise to daughter cells with HSC identity（selfrenewal） and progenitor progenies（differentiation）,which further proliferate and differentiate into full hematopoietic lineages.Mammalian ageing process is accompanied with abnormalities in the HSC self-renewal and differentiation.Transcriptional changes and epigenetic modulations have been implicated as the key regulators in HSC ageing process.The DNA damage response（DDR）in the cells involves an orchestrated signaling pathway,consisting of cell cycle regulation,cell death and senescence,transcriptional regulation,as well as chromatin remodeling.Recent studies employing DNA repair-deficient mouse models indicate that DDR could intrinsically and extrinsically regulate HSC maintenance and play important roles in tissue homeostasis of the hematopoietic system.In this review,we summarize the current understanding of how the DDR determines the HSC fates and finally contributes to organismal ageing.

Membrane dynamics of ATG4B and LC3 in autophagosome formation

The biogenesis of autophagosomes provides the basis for macroautophagy to capture and degrade intracellular cargoes.Binding of the autophagy-related protein ATG8/LC3 to autophagic membranes is essential to autophagosome formation,which involves the specific and dynamic processing of ATG8/LC3 by cysteine protease ATG4.However,to date,the mechanism whereby ATG4 is recruited to the membranes,the interaction of ATG4 and ATG8/LC3 on the membranes,and its role in the growth of phagophore are not completely understood.Here,we used fluorescence recovery after photobleaching to monitor the turnover of GFP-tagged ATG4B and LC3B in living animal cells.The data show that ATG4B localizes to early autophagic membranes in an LC3B-dependent manner.During autophagy,ATG4B and LC3B undergo rapid cytosol/isolation membrane exchange but not at the cytosol/completed autophagosome.In addition,ATG4B activity controls the efficiency of autophagosome formation by impacting the membrane binding/dissociation of LC3B.These data suggest that ATG4 and LC3 play interdependent roles in the formation of autophagosomes.

Effects of telomere length on leukemogenesis

Dear Editor,Most cancer cells maintain the length of their telomeres via telomerase(Günes and Rudolph,2013;Kim et al.,1994).However,in some cancers,telomeres are maintained not by telomerase but by alternative lengthening of telomeres(Bryan et al.,1997).Telomerase activity appears to be reduced in some bone marrow(BM)diseases,including chronic myeloid leukemia,acute myeloid leukemia(AML),and myeloproliferative neoplasms(MPN),leading to shortened telomeres that correlate with leukemogenesis(Bouillon et al.,2018;Engelhardt et al.,2000;Shay et al.,1996).Our current study aimed to determine the definitive roles of telomeres and telomerase in leukemogenesis.

L1 drives HSC aging and affects prognosis of chronic myelomonocytic leukemia

Dear Editor,Telomere attrition is one of the hallmark of aging.Lategeneration Terc knockout mice exhibit impaired hematopoiesis,1 while the underling mechanisms remain poorly understood.Retrotransposon long interspersed element-1(L1)is the only human retrotransposable elements capable of autonomous retrotransposition,and evolutionarily inactive.Recent studies reported that L1 is derepressed during the aging process with redistribution and reorganization of the heterochromatin.2 Considering that telomere shortening can cause chromosome instability and rearrangements,3 we speculate that L1 may play a role in impaired hematopoiesis in telomere dysfunctional mice.

Inflamm-aging of hematopoietic stem cells

Hematopoietic stem cells(HSCs)are responsible for generating all blood cells throughout life.Apart from the role of HSCs in maintaining the homeostasis of blood cell production process,they must respond quickly to hematopoietic challenges,such as infection or blood loss.HSCs can be directly/indirectly activated and engage in blood formation for the acute needs in response to inflammation.Recent findings highlight the emerging role of inflammation signaling on HSC fate decision and shaping the hematopoietic system during aging.Here,we summarize recent studies identifying the changes in inflammation and their role in modulation of HSC function and discuss the interaction between inflammation and HSC biology in the contexts of aging and hematological malignancy.

CircZFR promotes colorectal cancer progression via stabilizing BCLAF1 and regulating the miR-3127-5p/RTKN2 axis

Aberrant expression of circular RNAs(circ RNAs)is frequently linked to colorectal cancer(CRC).Here,we identified circ ZFR as a promising biomarker for CRC diagnosis and prognosis.Circ ZFR was upregulated in CRC tissues and serum exosomes and its level was linked to cancer incidence,advanced-stages,and metastasis.In both in vitro and in vivo settings,circ ZFR promoted the growth and spread while suppressing apoptosis of CRC.Exosomes with circ ZFR overexpression promoted the proliferation and migration of cocultured CRC cells.Mechanistically,epithelial splicing regulatory protein 1(ESRP1)in CRC cells may enhance the production of circ ZFR.BCL2-associated transcription factor 1(BCLAF1)bound to circ ZFR,which prevented its ubiquitinated degradation.Additionally,circ ZFR sponged mi R-3127-5p to boost rhotekin 2(RTKN2)expression.Our TCP1-CD-QDs nanocarrier was able to carry and deliver circ ZFR si RNA(si-circ ZFR)to the vasculature of CRC tissues and cells,which inhibited the growth of tumors in patient-derived xenograft(PDX)models.Taken together,our results show that circ ZFR is an oncogenic circ RNA,which promotes the development and spread of CRC in a BCLAF1 and mi R-3127-5p-dependent manner.Circ ZFR is a possible serum biopsy marker for the diagnosis and a desirable target for further treatment of CRC.