Dopaminergic mediation in the brain aging and neurodegenerative diseases:a role of senescent cells

Aging is well known to be the main risk factor for the neurodegenerative pathologies,in particular,Parkinson’s disease（PD）and Alzheimer’s disease（AD）.In aging and in the diseases,similar changes in various hallmarks of neurodegeneration（lipofuscin accumulation,autophagia weakening,and disturbances in functions of mitochondriaand lysosomes） were shown （Tan et al., 2014）. Furthermore, dopami- nergic system （DAS） involvement in mechanisms of aging, PD, and AD were revealed （Martorana and Koch, 2014）.

Repurpose dasatinib and quercetin:Targeting senescent cells ameliorates postmenopausal osteoporosis and rejuvenates bone regeneration

Clinical therapies developed for estrogen-deficiency-driven postmenopausal osteoporosis(PMO)and related diseases,such as bone degeneration,show multiple adverse effects nowadays.Targeting senescent cells(SnCs)and the consequent senescence-associated secretory phenotype(SASP)with a combination of dasatinib and quercetin(DQ)is a recently developed novel therapy for multiple age-related diseases.Herein,we found that estrogen deficiency induced-bone loss was attributed to a pro-inflammatory microenvironment with SASP secretions and accelerated SnC accumulation,especially senescent mesenchymal stem cells(MSCs)characterized by exhaustion and dysfunction in middle aged rats.Systematically targeting SnCs with DQ strikingly ameliorated PMO and restored MSC function.Local administration of DQ and bone morphogenetic protein 2(BMP2)in combination promoted osteogenic differentiation of MSCs and rejuvenated osteoporotic bone regeneration.Our results repurposed DQ as an attractive therapy for treating PMO and related diseases.

A near-infrared fluorescent probe for fast and precise imaging of senescent cells and ovarian cancer cells via trackingβ-galactosidase

Aging-related diseases are gradually becoming a major problem with the rapid development of aged population in human society.Although many fluorescent probes have been employed to diagnosis senescence via imaging senescence-associatedβ-galactosidase(SA-β-Gal),which is proved to be closely associated with senescent cells,the similar catalytic effectiveness of enzymatic reaction of ovarian cancer-associatedβ-Gal(OA-β-Gal)will interfere with imaging accuracy.Herein,a near-infrared(NIR)hemicyanine based fluorescent probe HCyXA-βGal was designed for light-up imaging of live cells containingβ-Gal.With the organelle-targeting morpholinyl and positive charge moieties,HCyxA-βGal was successfully applicated to image the difference of enzymatic location in senescent cells and ovarian cancer cells.Furthermore,inspired by the fast response performance,fast and precise imaging of the two cell lines was realized via covering another dimension of fluorescence signal:time-dependent intensity.

Therapy-induced senescent tumor cells in cancer relapse

Cellular senescence is characterized by a generally irreversible cell cycle arrest and the secretion of bioactive factors known as the senescence-associated secretory phenotype(SASP).In an oncogenic context,senescence is considered a tumor suppressive mechanism as it prevents cell proliferation and inhibits the progression from pre-malignant to malignant disease.However,recent studies have demonstrated that senescent tumor cells,which could spontaneously exist within cancer tissues or arise in response to various cancer interventions(the so-called therapy-induced senescence,TIS),can acquire pro-tumorigenic properties and are capable of driving local and metastatic relapse.This highlights the complex and multifaceted nature of cellular senescence in cancer biology.Here,we summarize the current knowledge of the pathological function of therapy-induced senescent tumor cells and discuss possible mechanisms by which tumor cell senescence contributes to cancer relapse.We also discuss implications for future studies toward targeting these less appreciated cells.

Alpl prevents bone ageing sensitivity by specifically regulating senescence and differentiation in mesenchymal stem cells

Mutations in the liver/bone/kidney alkaline phosphatase(Alpl) gene cause hypophosphatasia(HPP) and early-onset bone dysplasia,suggesting that this gene is a key factor in human bone development. However, how and where Alpl acts in bone ageing is largely unknown. Here, we determined that ablation of Alpl induces prototypical premature bone ageing characteristics, including bone mass loss and marrow fat gain coupled with elevated expression of p16INK4A(p16) and p53 due to senescence and impaired differentiation in mesenchymal stem cells(MSCs). Mechanistically, Alpl deficiency in MSCs enhances ATP release and reduces ATP hydrolysis. Then, the excessive extracellular ATP is, in turn, internalized by MSCs and causes an elevation in the intracellular ATP level, which consequently inactivates the AMPKα pathway and contributes to the cell fate switch of MSCs. Reactivating AMPKα by metformin treatment successfully prevents premature bone ageing in Alpl+/-mice by improving the function of endogenous MSCs.These results identify a previously unknown role of Alpl in the regulation of ATP-mediated AMPKα alterations that maintain MSC stemness and prevent bone ageing and show that metformin offers a potential therapeutic option.

Rb1 protects endothelial cells from hydrogen peroxide-induced cell senescence by modulating redox status

Objectives Endothelial senescence has been proposed to be involved in endothelial dysfunction and atherogenesis. This study investigates the effects of ginsenoside Rbl, a major constituent of ginseng,on H2O2-induced endothelial senescence.Methods Primary human umbilical vein endothelial cells（HUVECs） senescence was induced by H2O2 as judged by senescence-associated P-galactosidase assay （SA-P-gal）.Fntracellur superoxide dismutase（S0D1） activity and malondialdehyde（MDA） level were determined by commercial kit.S0D1 mRNA and protein expression were analyzed by real time PCR and Western blot.Reactive oxygen species（ROS） were determined by flow cytometry.Results Rb1 was found to reverse endothelial senescence,as witnessed by a significant decrease of senescent cell numbers. Rbl could markedly increase intracellular SOD activity, decrease the MDA level,and suppress the generation of intracellular ROS in H2O2-treated HUVECs.Consistent with these findings,Rbl can effectively restore SOD1 mRNA and protein expression which decreased in H2O2 treated cells. Conclusions Our report demonstrates thatRbl can exert reversal effects on H2O2-induced cellular senescence through modulating cellular redox status.

Effect of senescence marker protein 30 on the proliferation and apoptosis of human lens epithelial cells SRA01/04

AIM： To study the effect of senescence marker protein 30（SMP30） on the proliferation and apoptosis of human lens epithelial cell（HLEC） SRA01/04.METHODS： SMP30 overexpression（OE） and knock down（KD） type cell lines were cultivated by using two groups regucalcin（RGN; SMP30） lentiviral vectors（LVRGN, LV-RGN-RNAi） and the respective negative control virus infect SRA01/04 cells. Western blot and real-time quantitative polymerase chain reaction（q-PCR） analysis were used to determine RGN overexpression and knock down efficiency. We use cell counting kit-8（CCK8） assay to measure cell viability and 5-bromodeoxyuridine（Brd U） assay to test cell proliferation. Cell cycle was measured by PI FACS assay and cell apoptosis was tested by Annexin V-APC assay through flow cytometry. We use Western blot to measure the content of caspase-3 in SRA01/04.RESULTS： We used PCR and Western blot techniques to determine the successful transfection of SMP30 OE and KD SRA01/04 cell lines. By CCK8, Brdu and PI FACS cell cycle assay, it was found that the SMP30 OE group promoted cell proliferation（P〈0.05） compared with the control group, and the KD group inhibited cell proliferation（P〈0.05）. The results of Annexin V-APC signal staining detection indicated that compared with respective control group, the cell apoptosis rate was higher in KD group（P〈0.05） but lower in OE group（P〈0.01）. The expression of caspase-3 was down-regulated in OE group through Western blot assay and up-regulated in KD group compared with respective control group. CONCLUSION： Proliferation of SRA01/04 was promoted by SMP30 OE and apoptosis was suppressed. Increasing the expression of SMP30 may protect HLEC SRA01/04 against apoptosis in cataract.

Measuring Telomere Length in Proliferating Cells by Flow-FISH Method

The purpose of present work is a measurement of telomere length dynamic in proliferating cells in vitro by modified flow-FISH method. This method is a combination of two modifications： telomere length measurement in differentiated cells by surface antigen and analysis of cells divisions＇ number by vital dye dilution. Lymphocytes were activated by anti-CD3 Abs with IL-2 presents and grown in vitro for 7 days. Cells division＇s number was measured by dilution of CFSE vital dye which cells were stained previously activation. For telomere length measurement we used flow-FISH method with Cy3 labeled telomere PNH probe. Using this method we evaluated the dynamic of telomere length in CD4＋ and CD8＋ T-cells after 7 days culturing in vitro and revealed the difference in telomere lengthening and shortening versus division rounds in cell subsets. In CD8＋ cells telomeres start lengthen on a second division with the maximum on 4th division round becoming more that 20% longer compared with undividing cells. In CD4＋ cells telomeres did not have any length peculiarities through all division rounds demonstrating different telomere regulation in subsets. This probably occurs due to the higher level ofhTERT protein expression in CD8＋ than CD4＋ cells do.

Spatiotemporal transformable nano-assembly for on-demand drug delivery to enhance anti-tumor immunotherapy

Induction of tumor cell senescence has become a promising strategy for anti-tumor immunotherapy,but fibrotic matrix severely blocks senescence inducers penetration and immune cells infiltration.Herein,we designed a cancer-associated fibroblasts(CAFs)triggered structure-transformable nano-assembly(HSD-P@V),which can directionally deliver valsartan(Val,CAFs regulator)and doxorubicin(DOX,senescence inducer)to the specific targets.In detail,DOX is conjugated with hyaluronic acid(HA)via diselenide bonds(Se-Se)to form HSD micelles,while CAFs-sensitive peptide is grafted onto the HSD to form a hydrophilic polymer,which is coated on Val nanocrystals(VNs)surface for improving the stability and achieving responsive release.Once arriving at tumor microenvironment and touching CAFs,HSD-P@V disintegrates into VNs and HSD micelles due to sensitive peptide detachment.VNs can degrade the extracellularmatrix,leading to the enhanced penetration of HSD.HSD targets tumor cells,releases DOX to induce senescence,and recruits effector immune cells.Furthermore,senescent cells are cleared by the recruited immune cells to finish the integrated anti-tumor therapy.In vitro and in vivo results show that the nanoassembly remarkably inhibits tumor growth as well as lungmetastasis,and extends tumorbearing mice survival.This work provides a promising paradigm of programmed delivering multi-site nanomedicine for cancer immunotherapy.

Mechanisms of neuroplasticity and brain degeneration: strategies for protection during the aging process

Aging is a dynamic and progressive process that begins at conception and continues until death.This process leads to a decrease in homeostasis and morphological,biochemical and psychological changes,increasing the individual’s vulnerability to various diseases.The growth in the number of aging populations has increased the prevalence of chronic degenerative diseases,impairment of the central nervous system and dementias,such as Alzheimer’s disease,whose main risk factor is age,leading to an increase of the number of individuals who need daily support for life activities.Some theories about aging suggest it is caused by an increase of cellular senescence and reactive oxygen species,which leads to inflammation,oxidation,cell membrane damage and consequently neuronal death.Also,mitochondrial mutations,which are generated throughout the aging process,can lead to changes in energy production,deficiencies in electron transport and apoptosis induction that can result in decreased function.Additionally,increasing cellular senescence and the release of proinflammatory cytokines can cause irreversible damage to neuronal cells.Recent reports point to the importance of changing lifestyle by increasing physical exercise,improving nutrition and environmental enrichment to activate neuroprotective defense mechanisms.Therefore,this review aims to address the latest information about the different mechanisms related to neuroplasticity and neuronal death and to provide strategies that can improve neuroprotection and decrease the neurodegeneration caused by aging and environmental stressors.

Determining the in vitro Anti-Aging Effect of the Characteristic Components from Eucommia ulmoides

To evaluate the potential anti-aging ability of Eucommia ulmoides,four characteristic components(chlorogenic acid,geniposidic acid,aucubin,quercetin)were selected to assess their effects on H_(2)O_(2)-induced oxidative damage model of human umbilical vein endothelial cell(HUVEC).Oxidative damage indexes,inflammatory factors,cell cycle,cell apoptosis,cell senescence,and their related proteins were analyzed by methyl thiazolyl tetrazolium(MTT)assay,enzyme-linked immunosorbent assay(ELISA),propidium iodide(PI)staining,annexin V-FITC/PI double staining,SAβ-galactosidase staining,and western blotting(WB).The results showed that H_(2)O_(2)-induced cell growth inhibition rate decreased as supplementation with characteristic components when compared to H_(2)O_(2) group.Meanwhile,the contents of antioxidant indexes(reactive oxygen species,lactate dehydrogenase,molondialdehyde,superoxide dismutase,glutathione),inflammatory factors(nuclear factor kappa-B,intercellular cell adhesion molecule-1,vascular cell adhesion protein 1),and functional factors(NO,Endothelin-1)in characteristic components treated groups improved if comparison with H_(2)O_(2) group,suggesting the characteristic components of E.ulmoides could alleviate H_(2)O_(2)-induced oxidative damage.Moreover,cell cycle,cell apoptosis,cell senescence,and their related proteins under characteristic components treatment exhibited a better effect than under H_(2)O_(2) treatment,implying the characteristic components could participate in anti-aging via multiple pathways.These results manifested that the characteristic components of E.ulmoides posses the capacity of anti-aging,which provided a basis for investigating the anti-aging ability of E.ulmoides itself.

Review of Major Theories of Skin Aging

Here we aim to describe each factor that leads to skin aging and describe their mechanisms. A PubMed database searches (from January 2004 to March 2014) using aging and skin as searched terms. There are substantial evidences showing that aging is associated with damage from free radicals represented by various reactive oxygen species (ROS). Mitochondria are producers and also targets of oxidative stress. The cycle of mitochondrial dysfunction can trigger the aging process. In the cellular senescence and telomeres theory, the diploid cells exhibit a limited proliferation potential. After a finite number of divisions, they enter a state of senescence with a stop replication in cell proliferation. It is suggested that aging is associated mainly with hyper-regulation of apoptosis. Obesity presumably accelerates the process of aging, which is aggravated by smoking. And the influence of the environment, called solar UV irradiation is of considerable importance to skin aging. There are several mechanisms that trigger the natural aging process and contribute to age-related changes, including oxidative stress theory of free radicals, the mitochondrial dysfunction, telomere shortening, UV radiation and other mechanisms that taken together or alone may or not accelerate the change in skin.

Salidroside Ameliorates Vascular Endothelial Cell Senescence through Downregulation of KLF4

Salidroside is extensively used as a herbal medicine worldwide, and it has been shown to protect against disruption of endothelial homeostasis and act as an anti-aging agent. The present study aimed to investigate the ameliorative effects of salidroside on homocysteine (Hcy)-induced cell senescence in human umbilical vein endothelial cells (HUVECs) that were mediated via inhibition of Krüppel-like factor 4 (KLF4). An endothelial cell senescence model was induced by Hcy. The cell viability, activities of telomerase and lactate dehydrogenase (LDH), and the level of reactive oxygen species were determined using commercial kits. The expression levels of KLF4, p53 and p21 were determined via western blot analysis, whereas the mRNA expression levels of KLF4 were detected by reverse transcription-quantitative PCR. Small interfering RNA-mediated knockdown of KLF4 was found to reverse Hcy-induced cell senescence. Hcy treatment led to an accelerated cell senescence, as evidenced by decreases in both cell viability and telomerase activity, whereas increases were noted in the leakage of LDH and the level of reactive oxygen species, in addition to an up-regulation of the protein levels of p53 and p21, and up-regulation of KLF4 at both the mRNA and protein level. Treatment with salidroside ameliorated Hcy-induced cell senescence in a dose-dependent manner. Taken together, these results suggested that Hcy may induce cell senescence through upregulation of KLF4, and this may be reversed by treatment with salidroside. Therefore, salidroside was shown to inhibit Hcy-induced cell senescence through KLF4 inhibition.

Conditionally Reprogrammed Human Normal Airway Epithelial Cells at ALI: A Physiological Model for Emerging Viruses

Cancer cell lines have been used widely in cancer biology, and as biological or functional cell systems in many biomedical research fields. These cells are usually defective for many normal activities or functions due to significant genetic and epigenetic changes. Normal primary cell yields and viability from any original tissue specimens are usually relatively low or highly variable. These normal cells cease after a few passages or population doublings due to very limited proliferative capacity. Animal models(ferret, mouse, etc.) are often used to study virus-host interaction. However, viruses usually need to be adapted to the animals by several passages due to tropism restrictions including viral receptors and intracellular restrictions. Here we summarize applications of conditionally reprogrammed cells(CRCs), long-term cultures of normal airway epithelial cells from human nose to lung generated by conditional cell reprogramming(CR) technology, as an ex vivo model in studies of emerging viruses. CR allows to robustly propagate cells from non-invasive or minimally invasive specimens, for example, nasal or endobronchial brushing. This process is rapid(2 days) and conditional. The CRCs maintain their differentiation potential and lineage functions, and have been used for studies of adenovirus, rhinovirus, respiratory syncytial virus, influenza viruses, parvovirus, and SARS-CoV. The CRCs can be easily used for airliquid interface(ALI) polarized 3 D cultures, and these coupled CRC/ALI cultures mimic physiological conditions and are suitable for studies of viral entry including receptor binding and internalization, innate immune responses, viral replications, and drug discovery as an ex vivo model for emerging viruses.

Exercise Against Aging:Darwinian Natural Selection Among Fit and Unfit Cells Inside Human Body

Exercise inevitably induces damages and triggers a brief inflammation in challenged tissues of the human body.Nevertheless,regular exercise is associated with improved physical fitness and lower all-cause mortality among adults in a dose-dependent manner.The paradox between destructive nature of exercise and its anti-aging benefit can be best explained by decreasing aged cell population of the human body in a Darwinian natural selection fashion,resulting in tissue renewal.In this concept,the unfit-to-fit cell ratio of a multicellular system increases during growth(expansion of cell population and size)and decreases after exercise challenges.Inflammation serves as an innate mechanism to recognize cells in danger and triggers clearance mechanism to eliminate unhealthy cells followed by regeneration.A recent finding of decreased p16INK4a+senescent cells together with CD68+macrophage infiltration in human skeletal muscle after resistance exercise supports this concept.The senescent cells are mostly stem cells located in capillaries surrounding myofibers,functioning to replace short-lived endothelial cells.They can be found in young men aged 20-25 years.In this context,exercise controls weight gain(i.e.cell number and size)and decrease senescent cell proportion in capillaries of the human body,providing benefits in physical fitness and increasing life expectancy.

Bazi Bushen alleviates reproductive aging in aged male mice

Bazi Bushen(BZBS),a traditional Chinese medicine(TCM),has demonstrated therapeutic efficacy in testicular dysfunction within D-galactose and NaNO_(2)mouse models.This study aimed to ascertain if BZBS could also mitigate the decline in testicular function associated with natural aging.Therefore,male aged mice were employed to evaluate the preventive effects of BZBS on male reproductive aging.This was achieved by assessing sex hormone production,testicular histomorphology,and spermatogenesis.Relative to the untreated aged control group,BZBS administration elevated the levels of sex hormones and spermatocyte populations and preserved normal testicular structure in aged mice.Notably,spermatogenesis was maintained.Further analyses,including malondialdehyde(MDA)assays and real-time PCR,indicated that BZBS diminished testicular oxidative stress and the inflammatory burden.Corroborating these findings,mice treated with BZBS exhibited reductions in the populations of senescent and apoptotic cells within the seminiferous tubules,suggesting alleviated cellular damage.In contrast,we observed that rapamycin,a drug known for its longevity benefits,induced excessive testicular apoptosis and did not decrease lipid peroxidation.Collectively,our results highlight BZBS’s promising clinical potential in counteracting male reproductive aging,underlining its mechanisms of action.

Endothelial Cell Senescence and Age-Related Vascular Diseases

Advanced age is an independent risk factor for ageing-related complex diseases, such as coronary artery disease, stroke, and hypertension, which are common but life threatening and related to the ageing-associated vascular dysfunction. On the other hand, patients with progeria syndromes suffer from serious atherosclerosis, suggesting that the impaired vascular functions may be critical to organismal ageing, or vice versa. However, it remains largely unknown how vascular cells, particularly endothelial cell, become senescent and how the senescence impairs the vascular functions and contributes to the age-related vascular diseases over time. Here, we review the recent progress on the characteristics of vascular ageing and endothelial cell senescence in vitro and in vivo, evaluate how genetic and envi- ronmental factors as well as autophagy and stem cell influence endothelial cell senescence and how the senescence contributes to the age- related vascular phenotypes, such as atherosclerosis and increased vascular stiffness, and explore the possibility whether we can delay the age-related vascular diseases through the control of vascular ageing.

Endothelium-specific SIRT1 overexpression inhibits hyperglycemia-induced upregulation of vascular cell senescence

The rapidly increasing prevalence of diabetes mellitus worldwide is one of the most serious and challenging health problems in the 21st century. Mammalian sirtuin 1 （SIRT1） has been shown to decrease high-glucose-induced endothelial cell senescence in vitro and prevent hyperglycemia-induced vascular dysfunction. However, a role for SIRTI in prevention of hyperglyce- mia-induced vascular cell senescence in vivo remains unclear. We used endothelium-specific SIRT1 transgenic （SIRT1-Tg） mice and wild-type （WT） mice to construct a 40-week streptozotocin （STZ）-induced diabetic mouse model. In this mode, 42.9% of wild-type （WT） mice and 38.5% of SIRT1-Tg mice were successfully established as diabetic. Forty weeks of hyper- glycemia induced significant vascular cell senescence in aortas of mice, as indicated by upregulation of expression of senes- cence-associated markers including p53, p21 and plasminogen activator inhibitor-1 （PAI-1）. However, SIRT1-Tg diabetic mice displayed dramatically decreased expression of p53, p21 and PAI-I compared with diabetic WT mice. Moreover, man- ganese superoxide dismutase expression （MnSOD） was significantly downregulated in the aortas of diabetic WT mice, but was preserved in diabetic SIRT1-Tg mice. Furthermore, expression of the oxidative stress adaptor p66Shc was significantly de- creased in aortas of SIRT1-Tg diabetic mice compared with WT diabetic mice. Overall, these findings suggest that SIRT 1-mediated inhibition of hyperglycemia-induced vascular cell senescence is mediated at least partly through the reduction of oxidative stress.

Guilu Erxian Glue(龟鹿二仙胶)Inhibits Chemotherapy-Induced Bone Marrow Hematopoietic Stem Cell Senescence in Mice May via p16INK4a-Rb Signaling Pathway

Objective To evaluate the effect of Guilu Erxian Glue(龟鹿二仙胶,GEG)on cyclophosphamide(CTX)-induced bone marrow hematopoietic stem cells(HSCs)senescence in mice and explore the underlying mechanism.Methods The H22 liver cancer ascites lump model was established in male Kunming mice by injecting intraperitoneally(i.p.)with 5×10^6/mL H22 cells per mouse.Fifty tumor-bearing mice were divided into the control,model,pifithrin-α,GEG,and GEG+pifithrin-αgroups using a random number table,10 mice in each group.CTX(100 mg/kg i.p.)was administrated to mice from day 1 to day 3(d1–d3)continuously except for the control group.The mice in the pifithrin-α,GEG and GEG+pifithrin-αgroups were treated with pifithrin-α(2.2 mg/(kg·d)i.p.)for 6 consecutive days(d4–d9),GEG(9.5 g/(kg·d)i.p.)for 9 consecutive days(d1–d9),and GEG plus pifithrin-α,respectively.HSCs were collected after 9-d drug treatment.The anti-aging effect of GEG was studied by cell viability,cell cycle,andβ-galactosidase(β-gal)assays.The mRNA and protein expressions of cyclin-dependent kinase 2(CDK2),CDK4,inhibitor of cyclin-dependent kinase 4a encoding the tumor suppressor protein p16^(p16^INK4a),p21^Cip1/Waf1,p53,and phosphorylated retinoblastoma(pRb)were evaluated by quantitative real-time reverse transcription-polymerase chain reaction and semi-quantitative Western blot,respectively.Results Compared with the model group,GEG increased cell viability as well as proliferation(P<0.05 or P<0.01)and reducedβ-gal expression.Furthermore,GEG significantly decreased the expressions of p16^INK4a,p53 and p21^Cip1/Waf1 proteins,and increased the expressions of CDK2,CDK4 and pRb proteins compared with the model group(P<0.05 or P<0.01).Conclusion GEG can alleviate CTX-induced HSCs senescence in mice,and the p16^INK4a-Rb signaling pathway might be the underlying mechanism.

An updated review on activated PI3 kinase delta syndrome(APDS)

Activated Phosphoinositide 3-kinase d syndrome(APDS)is a newly recognised primary immunodeficiency disease.It has currently been a hot topic of clinical research and new data are emerging regarding its pathogenesis,clinical manifestations and treatment.Patients with APDS syndrome have significant autoimmune manifestations and lymphoproliferation.It is important to differentiate APDS from the usual polygenic CVID in view of the availability of targeted therapy like mTOR inhibitors such as Rapamycin and selective PI3Kd inhibitors.We provide a comprehensive review on this interesting disorder focusing light on its etiology,genetic research and emerging therapy.