Редактирование: CD38 (раздел)

==Publications==

{{medline-entry
|title=Re-equilibration of imbalanced NAD metabolism ameliorates the impact of telomere dysfunction.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32935380
|abstract=Short telomeres are a principal defining feature of telomere biology disorders, such as dyskeratosis congenita (DC), for which there are no effective treatments. Here, we report that primary fibroblasts from DC patients and late generation telomerase knockout mice display lower nicotinamide adenine dinucleotide (NAD) levels, and an imbalance in the NAD metabolome that includes elevated [[CD38]] NADase and reduced poly(ADP-ribose) polymerase and [[SIRT1]] activities, respectively, affecting many associated biological pathways. Supplementation with the NAD precursor, nicotinamide riboside, and [[CD38]] inhibition improved NAD homeostasis, thereby alleviating telomere damage, defective mitochondrial biosynthesis and clearance, cell growth retardation, and cellular senescence of DC fibroblasts. These findings reveal a direct, underlying role of NAD dysregulation when telomeres are short and underscore its relevance to the pathophysiology and interventions of human telomere-driven diseases.

|keywords=* CD38 NADase
* NAD metabolism
* mitochondrial impairment
* replicative senescence
* telomere biology disorders
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604620
}}
{{medline-entry
|title=Macrophage Immunometabolism and Inflammaging: Roles of Mitochondrial Dysfunction, Cellular Senescence, [[CD38]], and NAD.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32774895
|abstract=Aging is a complex process that involves dysfunction on multiple levels, all of which seem to converge on inflammation. Macrophages are intimately involved in initiating and resolving inflammation, and their dysregulation with age is a primary contributor to inflammaging-a state of chronic, low-grade inflammation that develops during aging. Among the age-related changes that occur to macrophages are a heightened state of basal inflammation and diminished or hyperactive inflammatory responses, which seem to be driven by metabolic-dependent epigenetic changes. In this review article we provide a brief overview of mitochondrial functions and age-related changes that occur to macrophages, with an emphasis on how the inflammaging environment, senescence, and NAD decline can affect their metabolism, promote dysregulation, and contribute to inflammaging and age-related pathologies.

|keywords=* CD38
* NAD
* SASP
* aging
* immunometabolism
* inflammaging
* macrophage
* mitochondria
* monocyte
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409778
}}
{{medline-entry
|title=TNFRSF12A and [[CD38]] Contribute to a Vicious Circle for Chronic Obstructive Pulmonary Disease by Engaging Senescence Pathways.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32537452
|abstract=Pathogenesis of chronic obstructive pulmonary disease (COPD) is dependent on chronic inflammation and is hypothesized to represent organ-specific senescence phenotype. Identification of senescence-associated gene drivers for the development of COPD is warranted. By employing automated pipeline, we have compiled lists of the genes implicated in COPD ([i]N[/i] = 918) and of the genes changing their activity along with cell senescence ([i]N[/i] = 262), with a significant ([i]p[/i] < 7.06e ) overlap between these datasets ([i]N[/i] = 89). A mega-analysis and a partial mega-analysis were conducted for gene sets linked to senescence but not yet to COPD, in nine independent mRNA expression datasets comprised of tissue samples of COPD cases ([i]N[/i] = 171) and controls ([i]N[/i] = 256). Mega-analysis of expression has identified [i][[CD38]][/i] and [i]TNFRSF12A[/i] ([i]p[/i] < 2.12e ) as genes not yet explored in a context of senescence-COPD connection. Functional pathway enrichment analysis allowed to generate a model, which explains accelerated aging phenotypes previously observed in COPD patients. Presented results call for investigation of the role of TNFRSF12A/[[CD38]] balance in establishing a vicious cycle of unresolvable tissue remodeling in COPD lungs.

|keywords=* aging
* chronic inflammation
* lung
* network analysis
* senescence
* tissue remodeling
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268922
}}
{{medline-entry
|title=Aging alters acetylation status in skeletal and cardiac muscles.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32300965
|abstract=During aging, organs such as skeletal muscle and heart require sufficient NAD  both as a coenzyme for oxidative-reductive electron transfer and as a substrate for multiple signaling pathways. Sirtuins (SIRTs), a family of NAD -dependent deacetylase, play an important role in regulating mitochondrial homeostasis and antioxidant defense by deacetylating transcription factors and enzymes such as [[PGC]]-1α, p65, GCN5, and [[SOD2]]. However, age-related DNA damage and increased SASP activate PARP-1 and [[CD38]], the enzymes competing with SIRTs for NAD . Thus, it is important to know how aging alters intracellular NAD  status and NAD -depending enzyme expression in muscles. In this study, we report that the acetylation level of muscle protein pool, as well as major SIRTs target proteins ([[PGC]]-1α, GCN5, p65, and [[SOD2]]), was significantly increased in hindlimb and cardiac muscles of 24-month old mice compared with their 6-month old counterparts, despite the fact that most members of the SIRT family were upregulated with aging. Aging increased the protein content of PARP-1 and [[CD38]], whereas decreased NAD  levels in both skeletal and heart muscles. Aged muscles demonstrated clear signs of mitochondrial dysfunction, oxidative stress, and inflammation. Taken together, our data suggest that despite the upregulation of SIRTs, aged muscles suffered from NAD  deficit partly due to the competition of elevated [[CD38]] and PARP-1. The enhanced acetylation of several key proteins involved in broad cellular functions may contribute to the age-related muscle deterioration.

|keywords=* Aging
* CD38
* Deacetylation
* NAD 
* PARP
* SIRT
* Skeletal muscle
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286993
}}
{{medline-entry
|title=[[CD38]] in Neurodegeneration and Neuroinflammation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32085567
|abstract=Neurodegenerative diseases are characterized by neuronal degeneration as well as neuroinflammation. While [[CD38]] is strongly expressed in brain cells including neurons, astrocytes as well as microglial cells, the role played by [[CD38]] in neurodegeneration and neuroinflammation remains elusive. Yet, [[CD38]] expression increases as a consequence of aging which is otherwise the primary risk associated with neurodegenerative diseases, and several experimental data demonstrated that [[CD38]] knockout mice are protected from neurodegenerative and neuroinflammatory insults. Moreover, nicotinamide adenine dinucleotide, whose levels are tightly controlled by [[CD38]], is a recognized and potent neuroprotective agent, and NAD supplementation was found to be beneficial against neurodegenerative diseases. The aims of this review are to summarize the physiological role played by [[CD38]] in the brain, present the arguments indicating the involvement of [[CD38]] in neurodegeneration and neuroinflammation, and to discuss these observations in light of [[CD38]] complex biology.

|keywords=* ALS.
* Alzheimer’s disease
* CD38
* NAD
* Parkinson’s disease
* aging
* neurodegeneration
* neuroinflammation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072759
}}
{{medline-entry
|title=[[CD38]], a Receptor with Multifunctional Activities: From Modulatory Functions on Regulatory Cell Subsets and Extracellular Vesicles, to a Target for Therapeutic Strategies.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31783629
|abstract=[[CD38]] is a multifunctional cell surface protein endowed with receptor/enzymatic functions. The protein is generally expressed at low/intermediate levels on hematological tissues and some solid tumors, scoring the highest levels on plasma cells ([[PC]]) and [[PC]]-derived neoplasia. [[CD38]] was originally described as a receptor expressed by activated cells, mainly T lymphocytes, wherein it also regulates cell adhesion and cooperates in signal transduction mediated by major receptor complexes. Furthermore, [[CD38]] metabolizes extracellular NAD , generating ADPR and cyclic ADPR. This ecto-enzyme controls extra-cellular nucleotide homeostasis and intra-cellular calcium fluxes, stressing its relevance in multiple physiopathological conditions (infection, tumorigenesis and aging). In clinics, [[CD38]] was adopted as a cell activation marker and in the diagnostic/staging of leukemias. Quantitative surface [[CD38]] expression by multiple myeloma (MM) cells was the basic criterion used for therapeutic application of anti-[[CD38]] monoclonal antibodies (mAbs). Anti-[[CD38]] mAbs-mediated [[PC]] depletion in autoimmunity and organ transplants is currently under investigation. This review analyzes different aspects of [[CD38]]'s role in regulatory cell populations and how these effects are obtained. Characterizing [[CD38]] functional properties may widen the extension of therapeutic applications for anti-[[CD38]] mAbs. The availability of therapeutic mAbs with different effects on [[CD38]] enzymatic functions may be rapidly translated to immunotherapeutic strategies of cell immune defense.
|mesh-terms=* ADP-ribosyl Cyclase 1
* Aging
* Animals
* Antibodies, Monoclonal
* B-Lymphocytes, Regulatory
* Cell Line
* Extracellular Vesicles
* Humans
* Infections
* Membrane Glycoproteins
* Mice
* Neoplasms
* T-Lymphocytes, Regulatory
|keywords=* CD38
* adenosine
* immune-modulation
* regulatory cells
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953043
}}
{{medline-entry
|title=Age-related alterations in human gut [[CD4]] T cell phenotype, T helper cell frequencies, and functional responses to enteric bacteria.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31573727
|abstract=Intestinal lamina propria (LP) [[CD4]] T cells play critical roles in maintaining intestinal homeostasis and in immune responses to enteric microbes, yet little is known regarding whether they contribute to age-associated intestinal immune dysfunction. In this study, we evaluated the direct ex vivo frequency, activation/inhibitory phenotype, death profiles, and in vitro functional responses of human jejunum LP [[CD4]] T cells, including Th1, Th17, and Th22 subsets isolated from younger (<45 years) and older (>65years) persons. Expression of the co-inhibitory molecule CTLA-4 was significantly lower in older [[CD4]] T cells, whereas expression of HLA-DR, [[CD38]], CD57, and PD-1 were not significantly different between groups. Total [[CD4]] T cell frequencies were similar between age groups, but lower frequencies and numbers of Th17 cells were observed directly ex vivo in older samples. Older Th17 and Th1 cells proliferated to a lesser degree following in vitro exposure to bacterial antigens vs. their younger counterparts. Levels of spontaneous cell death were increased in older [[CD4]] T cells; however, cellular death profiles following activation did not differ based on age. Thus, small intestinal [[CD4]] T cells from older persons have altered phenotypic and functional profiles including reduced expression of a co-inhibitory molecule, increased spontaneous cell death, and both reduced frequencies and altered functional responses of specific Th cell subsets. These changes may contribute to altered intestinal homeostasis and loss of protective gut immunity with aging.
|mesh-terms=* Adolescent
* Adult
* Age Factors
* Aged
* Aged, 80 and over
* CD4-Positive T-Lymphocytes
* Female
* Gastrointestinal Microbiome
* Humans
* Interleukin-17
* Intestinal Mucosa
* Male
* Middle Aged
* Phenotype
* Th1 Cells
* Th17 Cells
* Young Adult
|keywords=* T helper cells
* aging
* gut
* human
|full-text-url=https://sci-hub.do/10.1002/JLB.5A0919-177RR
}}
{{medline-entry
|title=[[CD38]] Deficiency Alleviates D-Galactose-Induced Myocardial Cell Senescence Through NAD /Sirt1 Signaling Pathway.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31551807
|abstract=Our previous research showed that [[CD38]] played vital roles in Ang-II induced hypertrophy and high fat diet induced heart injury. However, the role of [[CD38]] in heart aging is still unknown. In the present study, we reported that [[CD38]] knockdown significantly protected cardiomyocytes from D-galactose (D-gal)-induced cellular senescence. Cellular senescence was evaluated by [i]β[/i]-galactosidase staining, the expressions of genes closely related to aging including p16 and p21, and the ROS production, MDA content and the expressions of oxidant stress related genes were examined by biochemical analysis, Western blot and QPCR. Our results showed that the expression of [[CD38]] was increased in H9c2 cells after D-gal treatment and the expressions of [[NAMPT]] and Sirt1 were downregulated in heart tissue from old mice. [[CD38]] knockdown significantly reduced the number of SA-[i]β[/i]-gal-positive cells and the expressions of p16 and p21 in H9c2 cells with or without D-gal treatment. The acetylation level of total protein was decreased in [[CD38]] knockdown group, but the expression of Sirt3 was increased in [[CD38]] knockdown group treated with D-gal. In addition, knockdown of [[CD38]] significantly attenuated D-gal induced ROS production, MDA content and [[NOX4]] expression in the cells. Inhibition Sirt1 partially reversed the effects of [[CD38]] knockdown on D-gal induced senescence and oxidative stress. Furthermore, NAD  supplementation reduced D-gal induced cellular senescence, ROS production and MDA content. The expression of [[SOD2]] was increased and the [[NOX4]] expression was decreased in H9c2 cells after NAD  supplementation. Taken together, our results demonstrated that [[CD38]] knockdown alleviated D-gal induced cell senescence and oxidative stress via NAD /Sirt1 signaling pathway.

|keywords=* CD38
* D-galactose
* NAD 
* heart senescence
* oxidative stress
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735286
}}
{{medline-entry
|title=Metabolism and biochemical properties of nicotinamide adenine dinucleotide (NAD) analogs, nicotinamide guanine dinucleotide (NGD) and nicotinamide hypoxanthine dinucleotide (NHD).
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31511627
|abstract=Nicotinamide adenine dinucleotide (NAD) is an important coenzyme that regulates various metabolic pathways, including glycolysis, β-oxidation, and oxidative phosphorylation. Additionally, NAD serves as a substrate for poly(ADP-ribose) polymerase (PARP), sirtuin, and NAD glycohydrolase, and it regulates DNA repair, gene expression, energy metabolism, and stress responses. Many studies have demonstrated that NAD metabolism is deeply involved in aging and aging-related diseases. Previously, we demonstrated that nicotinamide guanine dinucleotide (NGD) and nicotinamide hypoxanthine dinucleotide (NHD), which are analogs of NAD, are significantly increased in Nmnat3-overexpressing mice. However, there is insufficient knowledge about NGD and NHD in vivo. In the present study, we aimed to investigate the metabolism and biochemical properties of these NAD analogs. We demonstrated that endogenous NGD and NHD were found in various murine tissues, and their synthesis and degradation partially rely on Nmnat3 and [[CD38]]. We have also shown that NGD and NHD serve as coenzymes for alcohol dehydrogenase (ADH) in vitro, although their affinity is much lower than that of NAD. On the other hand, NGD and NHD cannot be used as substrates for [[SIRT1]], [[SIRT3]], and [[PARP1]]. These results reveal the basic metabolism of NGD and NHD and also highlight their biological function as coenzymes.
|mesh-terms=* Aging
* Animals
* Guanine Nucleotides
* Guanosine Triphosphate
* Inosine Triphosphate
* Mice
* NAD
* Poly(ADP-ribose) Polymerases
* Sirtuins

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739475
}}
{{medline-entry
|title=The Multi-faceted Ecto-enzyme [[CD38]]: Roles in Immunomodulation, Cancer, Aging, and Metabolic Diseases.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31214171
|abstract=[[CD38]] (Cluster of Differentiation 38) is a multifunctional ecto-enzyme that metabolizes NAD  and mediates nicotinamide dinucleotide (NAD ) and extracellular nucleotide homeostasis as well as intracellular calcium. [[CD38]] is also an emerging therapeutic target under conditions in which metabolism is altered including infection, aging, and tumorigenesis. We describe multiple enzymatic activities of [[CD38]], which may explain the breadth of biological roles observed for this enzyme. Of greatest significance is the role of [[CD38]] as an ecto-enzyme capable of modulating extracellular NAD  precursor availability: 1 to bacteria unable to perform de novo synthesis of NAD ; and 2 in aged parenchyma impacted by the accumulation of immune cells during the process of 'inflammaging'. We also discuss the paradoxical role of [[CD38]] as a modulator of intracellular NAD , particularly in tumor immunity. Finally, we provide a summary of therapeutic approaches to [[CD38]] inhibition and 'NAD  boosting' for treatment of metabolic dysfunction observed during aging and in tumor immunity. The present review summarizes the role of [[CD38]] in nicotinamide nucleotide homeostasis with special emphasis on the role of [[CD38]] as an immunomodulator and druggable target.
|mesh-terms=* ADP-ribosyl Cyclase 1
* Aging
* Animals
* Homeostasis
* Humans
* Immunity
* Immunomodulation
* Metabolic Diseases
* Neoplasms
|keywords=* CD38
* NAD 
* NADase
* aging
* cancer
* macrophages
* metabolism
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555258
}}
{{medline-entry
|title=Interacting NAD  and Cell Senescence Pathways Complicate Antiaging Therapies.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31140365
|abstract=During human aging, decrease of NAD  levels is associated with potentially reversible dysfunction in the liver, kidney, skeletal and cardiac muscle, endothelial cells, and neurons. At the same time, the number of senescent cells, associated with damage or stress that secretes proinflammatory factors (SASP or senescence-associated secretory phenotype), increases with age in many key tissues, including the kidneys, lungs, blood vessels, and brain. Senescent cells are believed to contribute to numerous age-associated pathologies and their elimination by senolytic regimens appears to help in numerous preclinical aging-associated disease models, including those for atherosclerosis, idiopathic pulmonary fibrosis, diabetes, and osteoarthritis. A recent report links these processes, such that decreased NAD  levels associated with aging may attenuate the SASP potentially reducing its pathological effect. Conversely, increasing NAD  levels by supplementation or genetic manipulation, which may benefit tissue homeostasis, also may worsen SASP and encourage tumorigenesis at least in mouse models of cancer. Taken together, these findings suggest a fundamental trade-off in treating aging-related diseases with drugs or supplements that increase NAD . Even more interesting is a report that senescent cells can induce [[CD38]] on macrophages and endothelial cells. In turn, increased [[CD38]] expression is believed to be the key modulator of lowered NAD  levels with aging in mammals. So, accumulation of senescent cells may itself be a root cause of decreased NAD , which in turn could promote dysfunction. On the contrary, the lower NAD  levels may attenuate SASP, decreasing the pathological influence of senescence. The elimination of most senescent cells by senolysis before initiating NAD  therapies may be beneficial and increase safety, and in the best-case scenario reduce the need for NAD  supplementation.
|mesh-terms=* Aging
* Animals
* Cellular Senescence
* Humans
* Inflammation
* NAD
|keywords=* NAD
* aging
* cancer
* senescence
|full-text-url=https://sci-hub.do/10.1089/rej.2019.2218
}}
{{medline-entry
|title=The NADase [[CD38]] is induced by factors secreted from senescent cells providing a potential link between senescence and age-related cellular NAD  decline.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30975470
|abstract=Tissue nicotinamide adenine dinucleotide (NAD ) decline has been implicated in aging. We have recently identified [[CD38]] as a central regulator involved in tissue NAD  decline during the aging process. [[CD38]] is an ecto-enzyme highly expressed in endothelial and inflammatory cells. To date, the mechanisms that regulate [[CD38]] expression in aging tissues characterized by the presence of senescent cells is not completely understood. Cellular senescence has been described as a hallmark of the aging process and these cells are known to secrete several factors including cytokines and chemokines through their senescent associated secretory phenotype (SASP). Here we investigated if the cellular senescence phenotype is involved in the regulation of [[CD38]] expression and its NADase activity. We observed that senescent cells do not have high expression of [[CD38]]. However, the SASP factors secreted by senescent cells induced [[CD38]] mRNA and protein expression and increased [[CD38]]-NADase activity in non-senescent cells such as endothelial cells or bone marrow derived macrophages. Our data suggest a link between cellular senescence and NAD  decline in which SASP-mediated upregulation of [[CD38]] can disrupt cellular NAD  homeostasis.
|mesh-terms=* ADP-ribosyl Cyclase 1
* Aging
* Animals
* Cells, Cultured
* Cellular Senescence
* Endothelial Cells
* Female
* Human Umbilical Vein Endothelial Cells
* Humans
* Macrophages
* Mice, Inbred C57BL
* Middle Aged
* NAD
|keywords=* Aging
* CD38
* Inflammaging
* NAD( )
* Senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486859
}}
{{medline-entry
|title=Measuring [[CD38]] Hydrolase and Cyclase Activities: 1,N -Ethenonicotinamide Adenine Dinucleotide (ε-NAD) and Nicotinamide Guanine Dinucleotide (NGD) Fluorescence-based Methods.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30112426
|abstract=[[CD38]] is a multifunctional enzyme involved in calcium signaling and Nicotinamide Adenine Dinucleotide (NAD ) metabolism. Through its major activity, the hydrolysis of NAD , [[CD38]] helps maintain the appropriate levels of this molecule for all NAD -dependent metabolic processes to occur. Due to current advances and studies relating NAD  decline and the development of multiple age-related conditions and diseases, [[CD38]] gained importance in both basic science and clinical settings. The discovery and development of strategies to modulate its function and, possibly, treat diseases and improve health span put [[CD38]] under the spotlights. Therefore, a consistent and reliable method to measure its activity and explore its use in medicine is required. We describe here the methods how our group measures both the hydrolase and cyclase activity of [[CD38]], utilizing a fluorescence-based enzymatic assay performed in a plate reader using 1,N -Ethenonicotinamide Adenine Dinucleotide (ε-NAD) and Nicotinamide Guanine Dinucleotide (NGD) as substrates, respectively.

|keywords=* Aging
* CD38
* Cyclase
* Hydrolase
* NAD 
* NADase
* NGD
* ε-NAD
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6089541
}}
{{medline-entry
|title=The Plasma NAD  Metabolome Is Dysregulated in "Normal" Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30124109
|abstract=Nicotinamide adenine dinucleotide (NAD ) is an essential pyridine nucleotide that serves as an electron carrier in cellular metabolism and plays a crucial role in the maintenance of balanced redox homeostasis. Quantification of NAD :NADH and NADP :NADPH ratios are pivotal to a wide variety of cellular processes, including intracellular secondary messenger signaling by [[CD38]] glycohydrolases, DNA repair by poly(adenosine diphosphate ribose) polymerase (PARP), epigenetic regulation of gene expression by NAD-dependent histone deacetylase enzymes known as sirtuins, and regulation of the oxidative pentose phosphate pathway. We quantified changes in the NAD  metabolome in plasma samples collected from consenting healthy human subjects across a wide age range (20-87 years) using liquid chromatography coupled to tandem mass spectrometry. Our data show a significant decline in the plasma levels of NAD , NADP , and other important metabolites such as nicotinic acid adenine dinucleotide (NAAD) with age. However, an age-related increase in the reduced form of NAD  and NADP -NADH and NADPH-and nicotinamide (NAM), N-methyl-nicotinamide (MeNAM), and the products of adenosine diphosphoribosylation, including adenosine diphosphate ribose (ADPR) was also reported. Whereas, plasma levels of nicotinic acid (NA), nicotinamide mononucleotide (NMN), and nicotinic acid mononucleotide (NAMN) showed no statistically significant changes across age groups. Taken together, our data cumulatively suggest that age-related impairments are associated with corresponding alterations in the extracellular plasma NAD  metabolome. Our future research will seek to elucidate the role of modulating NAD  metabolites in the treatment and prevention of age-related diseases.
|mesh-terms=* Aged
* Aging
* Body Mass Index
* Female
* Humans
* Least-Squares Analysis
* Male
* Metabolome
* Middle Aged
* NAD
* Regression Analysis
* Young Adult
|keywords=* NAD
* aging
* biomarker
* nicotinamide
* plasma
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6482912
}}
{{medline-entry
|title=Assays for NAD -Dependent Reactions and NAD  Metabolites.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30097862
|abstract=Nicotinamide adenine dinucleotide (NAD ) is an essential redox cofactor and signaling molecule that controls the activity of enzymes involved in metabolism, DNA repair, and cellular survival, such as the PARPs, [[CD38]], and the sirtuins. Here, we describe three methods for measuring the activity of these enzymes: the etheno-NAD  assay measures NAD  hydrolase activity using an NAD  analog to produce a fluorescent product that is measured in real time; the PNC1 assay converts a native product of NAD  hydrolysis, nicotinamide, into a quantitative fluorescent readout; and liquid chromatography tandem mass spectrometry (LC-MS/MS) is used to characterize the entire NAD  metabolome in a sample. These methods will enable new insights into the roles that NAD  and the enzymes that utilize it play in health and disease.
|mesh-terms=* Biological Assay
* Chromatography, Liquid
* Humans
* Hydrolysis
* NAD
* Niacinamide
* Sirtuins
* Tandem Mass Spectrometry
|keywords=* ADP-ribose
* ARTD
* Aging
* BST1
* CD38
* Epigenetics
* HDAC
* Mass spectrometry
* Metabolism
* Metabolomics
* NAD  nicotinamide
* PARP
* Sirtuin
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409209
}}
{{medline-entry
|title=Decreased NAD Activates [[STAT3]] and Integrin Pathways to Drive Epithelial-Mesenchymal Transition.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29980616
|abstract=Nicotinamide adenine dinucleotide (NAD) plays an essential role in all aspects of human life. NAD levels decrease as humans age, and supplementation with NAD precursors plays a protective role against aging and associated disease. Less is known about the effects of decreased NAD on cellular processes, which is the basis for understanding the relationship between cellular NAD levels and aging-associated disease. In the present study, cellular NAD levels were decreased by overexpression of [[CD38]], a NAD hydrolase, or by treating cells with FK866, an inhibitor of nicotinamide phosphoribosyltransferase (NAMPT). Quantitative proteomics revealed that declining NAD levels downregulated proteins associated with primary metabolism and suppressed cell growth in culture and nude mice. Decreased glutathione synthesis caused a 4-fold increase in cellular reactive oxygen species levels, and more importantly upregulated proteins related to movement and adhesion. In turn, this significantly changed cell morphology and caused cells to undergo epithelial to mesenchymal transition (EMT). Secretomic analysis also showed that decreased NAD triggered interleukin-6 and transforming growth factor beta (TGFβ) secretion, which activated integrin-β-catenin, TGFβ-MAPK, and inflammation signaling pathways to sustain the signaling required for EMT. We further revealed that decreased NAD inactivated sirtuin 1, resulting in increased signal transducer and activator of transcription 3 ([[STAT3]]) acetylation and phosphorylation, and [[STAT3]] activation. Repletion of nicotinamide or nicotinic acid inactivated [[STAT3]] and reversed EMT, as did [[STAT3]] inhibition. Taken together, these results indicate that decreased NAD activates multiple signaling pathways to promote EMT and suggests that age-dependent decreases in NAD may contribute to tumor progression. Consequently, repletion of NAD precursors has potential benefits for inhibiting cancer progression.
|mesh-terms=* ADP-ribosyl Cyclase 1
* Acrylamides
* Animals
* Cell Line
* Cell Proliferation
* Epithelial-Mesenchymal Transition
* Female
* Humans
* Integrins
* Mice, Nude
* NAD
* Oxidative Stress
* Piperidines
* Proteome
* Proteomics
* Reactive Oxygen Species
* STAT3 Transcription Factor
* Signal Transduction
|keywords=* Aging
* Cell adhesion
* Epithelial-Mesenchymal Transition
* Lung cancer
* Omics
* Phosphoproteome
* SILAC
* Secretome
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166677
}}
{{medline-entry
|title=Innate and adaptive immune dysregulation in critically ill ICU patients.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29976949
|abstract=This study aimed to evaluate whether ICU patients who developed persistent critical illness displayed an immune profile similar to an aged immune phenotype and any associations with patient outcomes. Twenty two critically ill ICU patients (27-76 years, 15 males), at day 5 of mechanical ventilation, and 22 healthy age-matched controls (27-77 years, 13 males) were recruited. Frequency and phenotype of innate and adaptive immune cells and telomere length in peripheral blood mononuclear cells (PBMCs) were measured. An elevated granulocyte count (p < 0.0001), increased numbers of immature granulocytes (p < 0.0001), increased CD16  monocytes (p = 0.003) and [[CD14]]  HLADR  monocytes (p = 0.004) and lower NK cell numbers (p = 0.007) were observed in ICU patients compared to controls. Critically ill patients also had lower numbers of total T lymphocytes (p = 0.03), naïve [[CD4]] T cells (p = 0.003) and [[PTK7]]  recent thymic emigrants (p = 0.002), and increased senescent [[CD28]]  CD57  [[CD4]] T cells (p = 0.02), but there was no difference in PBMC telomere length. Regulatory immune cell frequency was affected with reduced circulating [[CD19]] [[CD24]] [[CD38]]  regulatory B cells (p = 0.02). However, only a raised neutrophil:lymphocyte ratio and reduced frequency of [[CD14]]  HLADR  monocytes were associated with poor outcomes. We conclude that persistent critical illness results in changes to immune cell phenotype only some of which are similar to that seen in physiological ageing of the immune system.
|mesh-terms=* Adult
* Aged
* Aging
* Critical Illness
* Female
* Healthy Volunteers
* Humans
* Immunity, Cellular
* Intensive Care Units
* Leukocyte Count
* Leukocytes, Mononuclear
* Male
* Middle Aged
* Phenotype
* Telomere Homeostasis

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033948
}}
{{medline-entry
|title=Abnormalities of age-related T cell senescence in Parkinson's disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29807534
|abstract=A wealth of evidence implicates both central and peripheral immune changes as contributing to the pathogenesis of Parkinson's disease (PD). It is critical to better understand this aspect of PD given that it is a tractable target for disease-modifying therapy. Age-related changes are known to occur in the immune system (immunosenescence) and might be of particular relevance in PD given that its prevalence rises with increasing age. We therefore sought to investigate this with respect to T cell replicative senescence, a key immune component of human ageing. Peripheral blood mononuclear cells were extracted from blood samples from 41 patients with mild PD (Hoehn and Yahr stages 1-2, mean (SD) disease duration 4.3 (1.2) years) and 41 age- and gender-matched controls. Immunophenotyping was performed with flow cytometry using markers of T lymphocyte activation and senescence (CD3, [[CD4]], CD8, HLA-DR, [[CD38]], [[CD28]], [[CCR7]], [[CD4]]5RA, CD57, CD31). Cytomegalovirus (CMV) serology was measured given its proposed relevance in driving T cell senescence. Markers of replicative senescence in the CD8  population were strikingly reduced in PD cases versus controls (reduced CD57 expression (p = 0.005), reduced percentage of 'late differentiated' CD57 [[CD28]]  cells (p = 0.007) and 'TEMRA' cells (p = 0.042)), whilst expression of activation markers ([[CD28]]) was increased (p = 0.005). This was not driven by differences in CMV seropositivity. No significant changes were observed in the [[CD4]] population. This study demonstrates for the first time that the peripheral immune profile in PD is distinctly atypical for an older population, with a lack of the CD8  T cell replicative senescence which characterises normal ageing. This suggests that 'abnormal' immune ageing may contribute to the development of PD, and markers of T cell senescence warrant further investigation as potential biomarkers in this condition.
|mesh-terms=* Aged
* Aging
* Antigens, CD
* Case-Control Studies
* Cellular Senescence
* Cytomegalovirus
* Female
* Flow Cytometry
* Humans
* Immunoglobulin G
* Immunophenotyping
* Immunosenescence
* Leukocytes, Mononuclear
* Male
* Middle Aged
* Parkinson Disease
* Serology
* T-Lymphocytes
|keywords=* Immune markers
* Immunosenescence
* Parkinson’s disease
* T cells
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5972443
}}
{{medline-entry
|title=A Potent and Specific [[CD38]] Inhibitor Ameliorates Age-Related Metabolic Dysfunction by Reversing Tissue NAD  Decline.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29719225
|abstract=Aging is characterized by the development of metabolic dysfunction and frailty. Recent studies show that a reduction in nicotinamide adenine dinucleotide (NAD ) is a key factor for the development of age-associated metabolic decline. We recently demonstrated that the NADase [[CD38]] has a central role in age-related NAD  decline. Here we show that a highly potent and specific thiazoloquin(az)olin(on)e [[CD38]] inhibitor, 78c, reverses age-related NAD  decline and improves several physiological and metabolic parameters of aging, including glucose tolerance, muscle function, exercise capacity, and cardiac function in mouse models of natural and accelerated aging. The physiological effects of 78c depend on tissue NAD  levels and were reversed by inhibition of NAD  synthesis. 78c increased NAD  levels, resulting in activation of pro-longevity and health span-related factors, including sirtuins, AMPK, and PARPs. Furthermore, in animals treated with 78c we observed inhibition of pathways that negatively affect health span, such as mTOR-S6K and ERK, and attenuation of telomere-associated DNA damage, a marker of cellular aging. Together, our results detail a novel pharmacological strategy for prevention and/or reversal of age-related NAD  decline and subsequent metabolic dysfunction.
|mesh-terms=* ADP-ribosyl Cyclase 1
* Aging
* Animals
* Cellular Senescence
* DNA Damage
* Enzyme Inhibitors
* Glucose Intolerance
* Humans
* MAP Kinase Signaling System
* Mice
* NAD
* Physical Functional Performance
* Poly(ADP-ribose) Polymerases
* Protein Kinases
* Quinolines
* Sirtuins
* TOR Serine-Threonine Kinases
* Triazoles
|keywords=* CD38
* NAD( )
* SIRTUINS
* acetylation
* aging
* exercise capacity
* glucose
* progeroid
* skeletal muscle
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935140
}}
{{medline-entry
|title=Role of Nicotinamide Adenine Dinucleotide and Related Precursors as Therapeutic Targets for Age-Related Degenerative Diseases: Rationale, Biochemistry, Pharmacokinetics, and Outcomes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29634344
|abstract= Nicotinamide adenine dinucleotide (NAD ) is an essential pyridine nucleotide that serves as an essential cofactor and substrate for a number of critical cellular processes involved in oxidative phosphorylation and ATP production, DNA repair, epigenetically modulated gene expression, intracellular calcium signaling, and immunological functions. NAD  depletion may occur in response to either excessive DNA damage due to free radical or ultraviolet attack, resulting in significant poly(ADP-ribose) polymerase (PARP) activation and a high turnover and subsequent depletion of NAD , and/or chronic immune activation and inflammatory cytokine production resulting in accelerated [[CD38]] activity and decline in NAD  levels. Recent studies have shown that enhancing NAD  levels can profoundly reduce oxidative cell damage in catabolic tissue, including the brain. Therefore, promotion of intracellular NAD  anabolism represents a promising therapeutic strategy for age-associated degenerative diseases in general, and is essential to the effective realization of multiple benefits of healthy sirtuin activity. The kynurenine pathway represents the [i]de novo[/i] NAD  synthesis pathway in mammalian cells. NAD  can also be produced by the NAD  salvage pathway.   In this review, we describe and discuss recent insights regarding the efficacy and benefits of the NAD  precursors, nicotinamide (NAM), nicotinic acid (NA), nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN), in attenuating NAD  decline in degenerative disease states and physiological aging.   Results obtained in recent years have shown that NAD  precursors can play important protective roles in several diseases. However, in some cases, these precursors may vary in their ability to enhance NAD  synthesis [i]via[/i] their location in the NAD  anabolic pathway. Increased synthesis of NAD  promotes protective cell responses, further demonstrating that NAD  is a regulatory molecule associated with several biochemical pathways.   In the next few years, the refinement of personalized therapy for the use of NAD  precursors and improved detection methodologies allowing the administration of specific NAD  precursors in the context of patients' NAD  levels will lead to a better understanding of the therapeutic role of NAD  precursors in human diseases.
|mesh-terms=* Aging
* Animals
* Biomarkers
* Disease Susceptibility
* Gene Expression Regulation
* Gene Expression Regulation, Enzymologic
* Humans
* Metabolic Networks and Pathways
* Molecular Targeted Therapy
* NAD
* Neurodegenerative Diseases
* Oxidation-Reduction
* Signal Transduction
|keywords=* DNA damage
* NAD
* nicotinamide
* oxidative stress
* sirtuins
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277084
}}
{{medline-entry
|title=Hyper-Expression of PD-1 Is Associated with the Levels of Exhausted and Dysfunctional Phenotypes of Circulating CD161 TCR iVα7.2  Mucosal-Associated Invariant T Cells in Chronic Hepatitis B Virus Infection.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29616020
|abstract=Mucosal-associated invariant T (MAIT) cells, defined as CD161 TCR iVα7.2  T cells, play an important role in the innate defense against bacterial infections, and their functionality is impaired in chronic viral infections. Here, we investigated the frequency and functional role of MAIT cells in chronic hepatitis B virus (HBV) infection. The peripheral CD3 CD161 TCR iVα7.2  MAIT cells in chronic HBV-infected patients and healthy controls were phenotypically characterized based on CD57, PD-1, TIM-3, and CTLA-4, as well as HLA-DR and [[CD38]] expression. The frequency of MAIT cells was significantly decreased among chronic HBV-infected individuals as compared to controls. Expression of CD57, PD-1, CTLA-4, as well as HLA-DR and [[CD38]] on MAIT cells was significantly elevated in chronic HBV-infected individuals relative to controls. The percentage of T cell receptor (TCR) iVα7.2  CD161  MAIT cells did not correlate with HBV viral load but inversely with HLA-DR on [[CD4]]  T cells and MAIT cells and with CD57 on CD8  T cells suggesting that decrease of MAIT cells may not be attributed to direct infection by HBV but driven by HBV-induced chronic immune activation. The percentage and expression levels of PD-1 as well as CTLA-4 on MAIT cells inversely correlated with plasma HBV-DNA levels, which may suggest either a role for MAIT cells in the control of HBV infection or the effect of HBV replication in the liver on MAIT cell phenotype. We report that decrease of TCR iVα7.2  MAIT cells in the peripheral blood and their functions were seemingly impaired in chronic HBV-infected patients likely because of the increased expression of PD-1.
|mesh-terms=* Adult
* CD8-Positive T-Lymphocytes
* DNA, Viral
* Female
* Gene Expression Regulation
* Hepatitis B, Chronic
* Humans
* Male
* Middle Aged
* Mucous Membrane
* NK Cell Lectin-Like Receptor Subfamily B
* Programmed Cell Death 1 Receptor
* Receptors, Antigen, T-Cell, alpha-beta
|keywords=* CTLA-4
* HBV infection
* HLA-DR
* PD-1
* immune exhaustion
* immunosenescence
* mucosal-associated invariant T cells
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868455
}}
{{medline-entry
|title=The Pharmacology of [[CD38]]/NADase: An Emerging Target in Cancer and Diseases of Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29482842
|abstract=Recent reports indicate that intracellular NAD levels decline in tissues during chronological aging, and that therapies aimed at increasing cellular NAD levels could have beneficial effects in many age-related diseases. The protein [[CD38]] (cluster of differentiation 38) is a multifunctional enzyme that degrades NAD and modulates cellular NAD homeostasis. At the physiological level, [[CD38]] has been implicated in the regulation of metabolism and in the pathogenesis of multiple conditions including aging, obesity, diabetes, heart disease, asthma, and inflammation. Interestingly, many of these functions are mediated by [[CD38]] enzymatic activity. In addition, [[CD38]] has also been identified as a cell-surface marker in hematologic cancers such as multiple myeloma, and a cytotoxic anti-[[CD38]] antibody has been approved by the FDA for use in this disease. Although this is a remarkable development, killing [[CD38]]-positive tumor cells with cytotoxic anti-[[CD38]] antibodies is only one of the potential pharmacological uses of targeting [[CD38]]. The present review discusses the biology of the [[CD38]] enzyme and the current state of development of pharmacological tools aimed at [[CD38]], and explores how these agents may represent a novel approach for treating human conditions including cancer, metabolic disease, and diseases of aging.
|mesh-terms=* ADP-ribosyl Cyclase 1
* Aging
* Animals
* Antibodies
* Humans
* Molecular Targeted Therapy
* NAD
* NAD  Nucleosidase
* Neoplasms
* Small Molecule Libraries
|keywords=* CD38
* NAD( )
* NADase
* aging
* antibodies
* cancer and metabolism
* sirtuins
* small molecules
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885288
}}
{{medline-entry
|title=NAD  Deficiency Is a Common Central Pathological Factor of a Number of Diseases and Aging: Mechanisms and Therapeutic Implications.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29295624
|abstract=Increasing evidence has indicated critical roles of nicotinamide adenine dinucleotide, oxidized form (NAD ) in various biological functions. NAD  deficiency has been found in models of a number of diseases such as cerebral ischemia, myocardial ischemia, and diabetes, and in models of aging. Applications of NAD  or other approaches that can restore NAD  levels are highly protective in these models of diseases and aging. NAD  produces its beneficial effects by targeting at multiple pathological pathways, including attenuating mitochondrial alterations, DNA damage, and oxidative stress, by modulating such enzymes as sirtuins, glyceraldehyde-3-phosphate dehydrogenase, and AP endonuclease. These findings have suggested great therapeutic and nutritional potential of NAD  for diseases and senescence. Recent Advances: Approaches that can restore NAD  levels are highly protective in the models of such diseases as glaucoma. The NAD  deficiency in the diseases and aging results from not only poly(ADP-ribose) polymerase-1 (PARP-1) activation but also decreased nicotinamide phosphoribosyltransferase (Nampt) activity and increased [[CD38]] activity. Significant biological effects of extracellular NAD  have been found. Increasing evidence has suggested that NAD  deficiency is a common central pathological factor in a number of diseases and aging. Critical Issues and Future Directions: Future studies are required for solidly establishing the concept that "NAD  deficiency is a common central pathological factor in a number of disease and aging." It is also necessary to further investigate the mechanisms underlying the NAD  deficiency in the diseases and aging. Preclinical and clinical studies should be conducted to determine the therapeutic potential of NAD  for the diseases and aging.
|mesh-terms=* Aging
* Animals
* Brain Ischemia
* Diabetes Mellitus
* Humans
* Myocardial Ischemia
* NAD
* Signal Transduction
|keywords=* NAD
* aging
* cell death
* diseases
* tissue injury
|full-text-url=https://sci-hub.do/10.1089/ars.2017.7445
}}
{{medline-entry
|title=Reevaluation of immune activation in the era of cART and an aging HIV-infected population.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29046481
|abstract=Biological aging is associated with immune activation (IA) and declining immunity due to systemic inflammation. It is widely accepted that HIV infection causes persistent IA and premature immune senescence despite effective antiretroviral therapy and virologic suppression; however, the effects of combined HIV infection and aging are not well defined. Here, we assessed the relationship between markers of IA and inflammation during biological aging in HIV-infected and -uninfected populations. Antibody response to seasonal influenza vaccination was implemented as a measure of immune competence and relationships between IA, inflammation, and antibody responses were explored using statistical modeling appropriate for integrating high-dimensional data sets. Our results show that markers of IA, such as coexpression of HLA antigen D related (HLA-DR) and [[CD38]] on [[CD4]]  T cells, exhibit strong associations with HIV infection but not with biological age. Certain variables that showed a strong relationship with aging, such as declining naive and [[CD38]]  [[CD4]] and CD8  T cells, did so regardless of HIV infection. Interestingly, the variable of biological age was not identified in a predictive model as significantly impacting vaccine responses in either group, while distinct IA and inflammatory variables were closely associated with vaccine response in HIV-infected and -uninfected populations. These findings shed light on the most relevant and persistent immune defects during virological suppression with antiretroviral therapy.
|mesh-terms=* Age Factors
* Aging
* Antibodies, Viral
* Antibody Formation
* Biomarkers
* CD4-Positive T-Lymphocytes
* CD8-Positive T-Lymphocytes
* Cytokines
* HIV Infections
* HLA-DR Antigens
* Humans
* Immunity, Humoral
* Inflammation
* Influenza Vaccines
* Influenza, Human
* Lymphocyte Activation
* Nerve Tissue Proteins

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846952
}}
{{medline-entry
|title=Altered marginal zone and innate-like B cells in aged senescence-accelerated SAMP8 mice with defective IgG1 responses.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28817118
|abstract=Aging has a strong impact on the activity of the immune system, enhancing susceptibility to pathogens and provoking a predominant pre-inflammatory status, whereas dampening responses to vaccines in humans and mice. Here, we demonstrate a loss of marginal zone B lymphocytes (MZ, [[CD19]] [[CD4]]5R CD21 CD23 ) and a decrease of naive B cells ([[CD19]] IgD ), whereas there is an enhancement of a [[CD19]] [[CD4]]5R  innate-like B cell population (B1REL) and the so-called aged B cell compartment (ABC, [[CD4]]5R CD21 CD23 [[CD5]] CD11b ) in aged senescence-accelerated (SAMP8) mice but not in aged senescence-resistant (SAMR1) mice. These changes in aged SAMP8 mice were associated with lower IgG isotype levels, displaying low variable gene usage repertoires of the immunoglobulin heavy chain (V ) diversity, with a diminution on IgG1-memory B cells (CD11b Gr1 CD138 IgM IgD [[CD19]] [[CD38]] IgG1 ), an increase in T follicular helper (T , [[CD4]] [[CXCR5]] PD1 ) cell numbers, and an altered MOMA-1 (metallophilic macrophages) band in primary follicles. LPS-mediated IgG1 responses were impaired in the B1REL and ABC cell compartments, both in vitro and in vivo. These data demonstrate the prominent changes to different B cell populations and in structural follicle organization that occur upon aging in SAMP8 mice. These novel results raise new questions regarding the importance of the cellular distribution in the B cell layers, and their effector functions needed to mount a coordinated and effective humoral response.
|mesh-terms=* Aging
* Animals
* Antigens, CD
* B-Lymphocytes
* Cell Death
* Cell Proliferation
* Gene Expression Regulation, Developmental
* IgG Deficiency
* Immunity, Humoral
* Immunity, Innate
* Immunoglobulin D
* Immunoglobulin G
* Immunoglobulin Heavy Chains
* Immunoglobulin M
* Immunologic Memory
* Lipopolysaccharides
* Mice, Inbred C57BL
* Mice, Transgenic
* Primary Cell Culture
* Signal Transduction
* Spleen
* T-Lymphocytes, Helper-Inducer

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596542
}}
{{medline-entry
|title=Age dependent differences in the kinetics of γδ T cells after influenza vaccination.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28700738
|abstract=Immunosenescence is a hallmark of the aging immune system and is considered the main cause of a reduced vaccine efficacy in the elderly. Although γδ T cells can become activated by recombinant influenza hemagglutinin, their age-related immunocompetence during a virus-induced immune response has so far not been investigated. In this study we evaluate the kinetics of γδ T cells after vaccination with the trivalent 2011/2012 northern hemisphere seasonal influenza vaccine. We applied multi-parametric flow cytometry to a cohort of 21 young (19-30 years) and 23 elderly (53-67 years) healthy individuals. Activated and proliferating γδ T cells, as identified by [[CD38]] and Ki67 expression, were quantified on the days 0, 3, 7, 10, 14, 17, and 21. We observed a significantly lower number of activated and proliferating γδ T cells at baseline and following vaccination in elderly as compared to young individuals. The kinetics changes of activated γδ T cells were much stronger in the young, while corresponding changes in the elderly occurred slower. In addition, we observed an association between day 21 HAI titers of influenza A and the frequencies of Ki67  γδ T cells at day 7 in the young. In conclusion, aging induces alterations of the γδ T cell response that might have negative implications for vaccination efficacy.
|mesh-terms=* ADP-ribosyl Cyclase 1
* Adult
* Aged
* Aging
* Female
* Humans
* Influenza Vaccines
* Influenza, Human
* Ki-67 Antigen
* Kinetics
* Male
* Middle Aged
* T-Lymphocytes
* Young Adult

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5507438
}}
{{medline-entry
|title=NAD and the aging process: Role in life, death and everything in between.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27825999
|abstract=Life as we know it cannot exist without the nucleotide nicotinamide adenine dinucleotide (NAD). From the simplest organism, such as bacteria, to the most complex multicellular organisms, NAD is a key cellular component. NAD is extremely abundant in most living cells and has traditionally been described to be a cofactor in electron transfer during oxidation-reduction reactions. In addition to participating in these reactions, NAD has also been shown to play a key role in cell signaling, regulating several pathways from intracellular calcium transients to the epigenetic status of chromatin. Thus, NAD is a molecule that provides an important link between signaling and metabolism, and serves as a key molecule in cellular metabolic sensoring pathways. Importantly, it has now been clearly demonstrated that cellular NAD levels decline during chronological aging. This decline appears to play a crucial role in the development of metabolic dysfunction and age-related diseases. In this review we will discuss the molecular mechanisms responsible for the decrease in NAD levels during aging. Since other reviews on this subject have been recently published, we will concentrate on presenting a critical appraisal of the current status of the literature and will highlight some controversial topics in the field. In particular, we will discuss the potential role of the NADase [[CD38]] as a driver of age-related NAD decline.
|mesh-terms=* ADP-ribosyl Cyclase 1
* Aging
* Animals
* Armadillo Domain Proteins
* Caloric Restriction
* Cyclic ADP-Ribose
* Cytoskeletal Proteins
* Humans
* Membrane Glycoproteins
* Mitochondria
* NAD
* NADP
* Oxidation-Reduction
* Poly(ADP-ribose) Polymerases
* Protein Processing, Post-Translational
* Signal Transduction
* Sirtuins
|keywords=* Aging
* CD38
* Mitochondrial function
* NAD( )
* PARP
* SIRTUINS
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5419884
}}
{{medline-entry
|title=Constitutive Expression of Inducible Cyclic Adenosine Monophosphate Early Repressor (ICER) in Cycling Quiescent Hematopoietic Cells: Implications for Aging Hematopoietic Stem Cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27822872
|abstract=Despite extensive insights on the interaction between hematopoietic stem cells (HSCs) and the supporting bone marrow (BM) stroma in hematopoietic homeostasis there remains unanswered questions on HSC regulation. We report on the mechanism by which HSCs attain cycling quiescence by addressing a role for inducible cyclic AMP early repressor (ICER). ICER negatively transcriptional regulators of cAMP activators such as [[CREM]] and CREB. These activators can be induced by hematopoietic stimulators such as cytokines. We isolated subsets of hematopoietic cells from ten healthy donors: [[CD34]] [[CD38]] /c-kit   (primitive progenitor), [[CD34]] [[CD38]] /c-kit  (mature progenitor) and [[CD34]] [[CD38]] /c-kit  (differentiated lineage-). The relative maturity of the progenitors were verified in long-term culture initiating assay. Immunoprecipitation indicated the highest level of ICER in the nuclear extracts of [[CD34]] /[[CD38]]  cells. Phospho (p)-[[CREM]] was also present suggesting a balance between ICER and p-[[CREM]] in HSC. ICER seems to be responsible for decrease in G1 transition, based on reduced Cdk4 protein, decreased proliferation and functional studies with propidium iodide. There were no marked changes in the cycling inhibitors, p15 and p-Rb, suggesting that ICER may act independently of other cycling inhibitors. The major effects of ICER were validated with BM mononuclear cells (BMNCs) in which ICER was ectopically expressed, and with BMNCs resistant to 5-fluorouracil- or cyclophosphamide. In total, this study ascribes a novel role for ICER in G1 checkpoint regulation in HSCs. These findings are relevant to gene therapy that require engineering of HSCs, age-related disorders that are associated with hematopoietic dysfunction and other hematological disorders.
|mesh-terms=* ADP-ribosyl Cyclase 1
* Aging
* Antigens, CD34
* Blotting, Western
* Cell Cycle
* Cell Differentiation
* Cells, Cultured
* Cyclic AMP Response Element Modulator
* Cyclophosphamide
* Fluorouracil
* Gene Expression
* Hematopoietic Stem Cells
* Humans
* Immunosuppressive Agents
* Proto-Oncogene Proteins c-kit
* Signal Transduction
|keywords=* Bone marrow
* Cell cycle
* Cytokines
* Hematopoietic stem cell
* Inducible cAMP early repressor
* Transcription factors
|full-text-url=https://sci-hub.do/10.1007/s12015-016-9701-5
}}
{{medline-entry
|title=Why NAD( ) Declines during Aging: It's Destroyed.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27304496
|abstract=NAD( ) is required not only for life but for a long life. In this issue, Camacho-Pereira et al. (2016) implicate [[CD38]] in the decline of NAD( ) during aging, with implications for combating age-related diseases.
|mesh-terms=* ADP-ribosyl Cyclase 1
* Aging
* Animals
* Mice
* Mitochondria
* Models, Biological
* NAD

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5088772
}}
{{medline-entry
|title=[[CD38]] Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an [[SIRT3]]-Dependent Mechanism.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27304511
|abstract=Nicotinamide adenine dinucleotide (NAD) levels decrease during aging and are involved in age-related metabolic decline. To date, the mechanism responsible for the age-related reduction in NAD has not been elucidated. Here we demonstrate that expression and activity of the NADase [[CD38]] increase with aging and that [[CD38]] is required for the age-related NAD decline and mitochondrial dysfunction via a pathway mediated at least in part by regulation of [[SIRT3]] activity. We also identified [[CD38]] as the main enzyme involved in the degradation of the NAD precursor nicotinamide mononucleotide (NMN) in vivo, indicating that [[CD38]] has a key role in the modulation of NAD-replacement therapy for aging and metabolic diseases.
|mesh-terms=* ADP-ribosyl Cyclase 1
* Aging
* Animals
* Diet, High-Fat
* Mammals
* Mice, Inbred C57BL
* Mice, Knockout
* Mitochondria
* NAD
* NAD  Nucleosidase
* Niacinamide
* Organ Specificity
* RNA, Messenger
* Sirtuin 3
|keywords=* CD38
* NAD( )
* aging
* glucose intolerance
* mitochondrial function
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4911708
}}
{{medline-entry
|title=Immunity in young adult survivors of childhood leukemia is similar to the elderly rather than age-matched controls: Role of cytomegalovirus.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27129782
|abstract=Many treatment complications that occur late in childhood cancer survivors resemble age-related comorbidities observed in the elderly. An immune phenotype characterized by increased immune activation, systemic inflammation, and accumulation of late-differentiated memory CD57( ) CD28(-) T cells has been associated with comorbidities in the elderly. Here, we explored if this phenotype was present in young adult leukemia survivors following an average of 19 years from chemotherapy and/or radiotherapy completion, and compared this with that in age-matched controls. We found that markers of systemic inflammation-IL-6 and human C-reactive protein and immune activation-[[CD38]] and HLA-DR on T cells, soluble CD (sCD)163 from monocytes and macrophages-were increased in survivors compared to controls. T-cell responses specific to cytomegalovirus (CMV) were also increased in survivors compared to controls while CMV IgG levels in survivors were comparable to levels measured in the elderly (>50years) and correlated with IL-6, human C-reactive protein, sCD163, and CD57( ) CD28(-) memory T cells. Immune activation and inflammation markers correlated poorly with prior chemotherapy and radiotherapy exposure. These data suggest that CMV infection/reactivation is strongly correlated with the immunological phenotype seen in young childhood leukemia survivors and these changes may be associated with the early onset of age-related comorbidities in this group.
|mesh-terms=* Adolescent
* Adult
* Age Factors
* Aged
* Antibodies, Viral
* Biomarkers
* Case-Control Studies
* Cytomegalovirus
* Cytomegalovirus Infections
* Female
* Humans
* Immunity
* Immunocompromised Host
* Immunoglobulin G
* Inflammation
* Leukemia
* Lymphocyte Activation
* Male
* Middle Aged
* Odds Ratio
* Risk Factors
* Survivors
* T-Lymphocyte Subsets
* Young Adult
|keywords=* Childhood cancer survivors
* Cytomegalovirus
* Immune activation
* Immunologic aging
* Systemic inflammation
|full-text-url=https://sci-hub.do/10.1002/eji.201646356
}}
{{medline-entry
|title=Aging of immune system: Immune signature from peripheral blood lymphocyte subsets in 1068 healthy adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26886066
|abstract=Aging is a major risk factor for several conditions including neurodegenerative, cardiovascular diseases and cancer. Functional impairments in cellular pathways controlling genomic stability, and immune control have been identified. Biomarker of immune senescence is needed to improve vaccine response and to develop therapy to improve immune control. To identify phenotypic signature of circulating immune cells with aging, we enrolled 1068 Chinese healthy volunteers ranging from 18 to 80 years old. The decreased naïve CD4  and CD8  T cells, increased memory CD4  or CD8  T cells, loss of [[CD28]] expression on T cells and reverse trend of [[CD38]] and HLA-DR, were significant for aging of immune system. Conversely, the absolute counts and percentage of NK cells and CD19 B cells maintained stable in aging individuals. The Chinese reference ranges of absolute counts and percentage of peripheral lymphocyte in this study might be useful for future clinical evaluation.
|mesh-terms=* Adolescent
* Adult
* Aged
* Aged, 80 and over
* Aging
* B-Lymphocytes
* Female
* Healthy Volunteers
* Humans
* Killer Cells, Natural
* Lymphocyte Activation
* Lymphocyte Count
* Lymphocyte Subsets
* Male
* Middle Aged
* Reference Values
* Young Adult
|keywords=* aging
* flow cytometry
* lymphocyte subsets
* reference range
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4931839
}}
{{medline-entry
|title=Peripheral loss of CD8( ) CD161(  ) TCRVα7·2( ) mucosal-associated invariant T cells in chronic hepatitis C virus-infected patients.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26681320
|abstract=Mucosal-associated invariant T (MAIT) cells play an important role in innate host defence. MAIT cells appear to undergo exhaustion and are functionally weakened in chronic viral infections. However, their role in chronic hepatitis C virus (HCV) infection remains unclear. We investigated the frequency of CD8( ) CD161(  ) TCR Vα7.2( ) MAIT cells in a cross-sectional cohort of chronic HCV-infected patients (n = 25) and healthy controls (n = 25). Peripheral blood mononuclear cells were investigated for circulating MAIT cell frequency, liver-homing ([[CCR5]] and CD103), biomarkers of immune exhaustion (PD-1, TIM-3 and CTLA-4), chronic immune activation ([[CD38]] and HLA-DR), and immunosenescence (CD57) by flow cytometry. The frequency of MAIT cells was significantly decreased, and increased signs of immune exhaustion and chronic immune activation were clearly evident on MAIT cells of HCV-infected patients. Decrease of [[CCR5]] on circulating MAIT cells is suggestive of their peripheral loss in chronic HCV-infected patients. MAIT cells also showed significantly increased levels of HLA-DR, [[CD38]], PD-1, TIM-3 and CTLA-4, besides CD57 in chronic HCV disease. Immune exhaustion and senescence of CD8( ) CD161(  ) TCR Vα7.2( ) MAIT cells could contribute to diminished innate defence attributes likely facilitating viral persistence and HCV disease progression.
|mesh-terms=* ADP-ribosyl Cyclase 1
* Adult
* Antigens, CD
* Biomarkers
* CD57 Antigens
* CD8-Positive T-Lymphocytes
* CTLA-4 Antigen
* Case-Control Studies
* Cohort Studies
* Cross-Sectional Studies
* Female
* Flow Cytometry
* HLA-DR Antigens
* Hepatitis A Virus Cellular Receptor 2
* Hepatitis C, Chronic
* Humans
* Immunity, Innate
* Immunosenescence
* Integrin alpha Chains
* Lymphocyte Count
* Male
* Membrane Proteins
* Middle Aged
* NK Cell Lectin-Like Receptor Subfamily B
* Programmed Cell Death 1 Receptor
* Receptors, Antigen, T-Cell, alpha-beta
* Receptors, CCR5
* Viral Load
* Young Adult
|keywords=* CD38
* HCV infection
* MAIT cells
* PD-1
* TCRVα7.2
* exhaustion
|full-text-url=https://sci-hub.do/10.1111/eci.12581
}}
{{medline-entry
|title=Probiotics Reduce Inflammation in Antiretroviral Treated, HIV-Infected Individuals: Results of the "Probio-HIV" Clinical Trial.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26376436
|abstract=HIV infection results in damage to the gastrointestinal (GI) tract, microbial translocation and immune activation. These are not completely normalized with combined antiretroviral therapy (cART). Moreover, increate morbidity and mortality of cART-treated HIV-infected individuals is associated with inflammation. In order to enhance GI tract immunity, we recruited and treated 20 HIV-infected humans with cART supplemented with probiotics and followed inflammation and immunological parameters (clinical trial number NCT02164344). 11 HIV seronegative subjects were included as control group. The enumeration of [[CD4]] , CD8 , [[CD38]]  and HLA-DR  lymphocytes were evaluated on peripheral blood; HIV-RNA levels, sCD14, d-dimer, C-reactive protein (CRP) high sensitivity C-reactive protein (hsCRP), IL-6 and Lipopolysaccharide Binding Protein ([[LBP]]) were assayed on plasma. We observe that cART does not normalize the levels of immune activation in HIV positive patients anyway inflammation and markers of microbial translocation were significantly reduced with probiotic supplementation. Patients show a clear and statistically significant reduction in the levels of immune activation on [[CD4]] T-lymphocytes, for both markers [[CD38]] and HLA-DR and their simultaneous expression, [[LBP]] and hsCRP plasma levels after probiotic diet supplementation settling to values comparable to controls. Supplementing cART with probiotics in HIV-infected individuals may improve GI tract immunity and there by mitigate inflammatory sequelae, ultimately improving prognosis. ClinicalTrials.gov NCT02164344.
|mesh-terms=* Adult
* Aged
* Aging
* Anti-HIV Agents
* CD4-Positive T-Lymphocytes
* Combined Modality Therapy
* Dysbiosis
* Female
* Gastrointestinal Microbiome
* HIV Infections
* Humans
* Inflammation
* Longitudinal Studies
* Male
* Middle Aged
* Probiotics

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573418
}}
{{medline-entry
|title=Concurrent loss of co-stimulatory molecules and functional cytokine secretion attributes leads to proliferative senescence of CD8( ) T cells in HIV/TB co-infection.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26071876
|abstract=The role of T-cell immunosenescence and functional CD8( ) T-cell responses in HIV/TB co-infection is unclear. We examined and correlated surrogate markers of HIV disease progression with immune activation, immunosenescence and differentiation using T-cell pools of HIV/TB co-infected, HIV-infected and healthy controls. Our investigations showed increased plasma viremia and reduced CD4/CD8 T-cell ratio in HIV/TB co-infected subjects relative to HIV-infected, and also a closer association with changes in the expression of [[CD38]], a cyclic ADP ribose hydrolase and CD57, which were consistently expressed on late-senescent CD8( ) T cells. Up-regulation of CD57 and [[CD38]] were directly proportional to lack of co-stimulatory markers on CD8( ) T cells, besides diminished expression of CD127 (IL-7Rα) on CD57( )CD4( ) T cells. Notably, intracellular IFN-γ, perforin and granzyme B levels in HIV-specific CD8( ) T cells of HIV/TB co-infected subjects were diminished. Intracellular CD57 levels in HIV gag p24-specific CD8( ) T cells were significantly increased in HIV/TB co-infection. We suggest that HIV-TB co-infection contributes to senescence associated with chronic immune activation, which could be due to functional insufficiency of CD8( ) T cells. 
|mesh-terms=* ADP-ribosyl Cyclase 1
* Adult
* CD4-CD8 Ratio
* CD57 Antigens
* CD8-Positive T-Lymphocytes
* Cell Differentiation
* Cell Proliferation
* Cellular Senescence
* Coinfection
* Disease Progression
* Female
* Granzymes
* HIV Infections
* HLA-DR alpha-Chains
* Humans
* Immunosenescence
* Interferon-gamma
* Interleukin-7 Receptor alpha Subunit
* Lymphocyte Activation
* Male
* Membrane Glycoproteins
* Perforin
* Tuberculosis, Pulmonary
|keywords=* Co-stimulation
* HIV/TB co-infection
* Immune activation
* Immunosenescence
* T-cell activation
|full-text-url=https://sci-hub.do/10.1016/j.cellimm.2015.05.005
}}
{{medline-entry
|title=Mapping NAD( ) metabolism in the brain of ageing Wistar rats: potential targets for influencing brain senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24337988
|abstract=Over the last decade, the importance of NAD( ) has expanded beyond its role as an essential cofactor for energy metabolism. NAD( ) has emerged as a major signalling molecule that serves as the sole substrate for several enzymatic reactions including the DNA repair enzyme, poly(ADP-ribose) polymerase (PARP), NAD-dependent protein deacetylases or [[CD38]], and transcriptional factors by a new class of histone deacetylases known as sirtuins. NAD( ) levels are regulated by the metabolic status and cellular stress caused by oxidative stress and DNA damage. Since a detailed study of NAD( ) metabolism in the healthy ageing mammalian brain is nascent, we examined the effect of ageing on intracellular NAD( ) metabolism in different brain regions in female Wistar rats in young (3 months), middle aged (12 months) and older adults (24 months). Our results are the first to show a significant decline in intracellular NAD( ) levels and NAD:NADH ratio with ageing in the CNS, occurring in parallel to an increase in lipid peroxidation and protein oxidation (o- and m-tyrosine) and a decline in total antioxidant capacity. Hyperphosphorylation of [[H2AX]] levels was also observed together with increased PARP-1 and PARP-2 expression, and [[CD38]] activity, concomitantly with reduced NAD( ) and ATP levels and [[SIRT1]] function in the cortex, brainstem, hippocampus and cerebellum. Reduced activity of mitochondrial complex I-IV and impaired maximum mitochondrial respiration rate were also observed in the ageing rat brain. Among the multiple physiological pathways associated with NAD( ) catabolism, our discovery of [[CD38]] as the major regulator of cellular NAD( ) levels in rat neurons indicates that [[CD38]] is a promising therapeutic target for the treatment of age-related neurodegenerative diseases. 
|mesh-terms=* ADP-ribosyl Cyclase
* ADP-ribosyl Cyclase 1
* Adenosine Diphosphate Ribose
* Adenosine Triphosphate
* Aging
* Animals
* Brain
* DNA Damage
* Electron Transport
* Female
* Gene Knockdown Techniques
* Lipid Peroxidation
* Membrane Glycoproteins
* Mitochondria
* NAD
* Oxidative Stress
* Poly(ADP-ribose) Polymerases
* Protein Carbonylation
* RNA, Small Interfering
* Rats
* Rats, Wistar
* Sirtuin 1
* Tissue Distribution

|full-text-url=https://sci-hub.do/10.1007/s10522-013-9489-5
}}
{{medline-entry
|title=Accelerated aging in HIV/AIDS: novel biomarkers of senescent human CD8  T cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23717651
|abstract=Clinical evaluation of immune reconstitution and health status during HIV-1 infection and anti-retroviral therapy (ART) is largely based on CD4  T cell counts and viral load, measures that fail to take into account the CD8  T cell subset, known to show features of accelerated aging in HIV disease. Here, we compare adenosine deaminase ([[ADA]]), glucose uptake receptor 1 (GLUT1), and leucine-rich repeat neuronal 3 ([[LRRN3]]) to [[CD38]] expression and telomerase activity, two strong predictors of HIV disease progression. Our analysis revealed that reduced [[ADA]], telomerase activity and [[LRRN3]] gene expression were significantly associated with high [[CD38]] and HLA-DR in CD8  T cells, with % [[ADA]]  cells being the most robust predictor of CD8  T cell activation. Our results suggest that [[ADA]], [[LRRN3]] and telomerase activity in CD8  T cells may serve as novel, clinically relevant biomarkers of immune status in HIV-1 infection, specifically by demonstrating the degree to which CD8  T cells have progressed to the end stage of replicative senescence. Since chronological aging itself leads to the accumulation of senescent CD8  T cells, the prolonged survival and resultant increased age of the HIV  population may synergize with the chronic immune activation to exacerbate both immune decline and age-associated pathologies. The identification and future validation of these new biomarkers may lead to fresh immune-based HIV treatments.
|mesh-terms=* Aging
* Base Sequence
* Biomarkers
* CD8-Positive T-Lymphocytes
* Cellular Senescence
* DNA Primers
* Flow Cytometry
* HIV Infections
* Humans
* Middle Aged
* Real-Time Polymerase Chain Reaction

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3661524
}}
{{medline-entry
|title=Aging is associated with chronic innate immune activation and dysregulation of monocyte phenotype and function.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/22708967
|abstract=Chronic inflammation in older individuals is thought to contribute to inflammatory, age-related diseases. Human monocytes are comprised of three subsets (classical, intermediate and nonclassical subsets), and despite being critical regulators of inflammation, the effect of age on the functionality of monocyte subsets remains to be fully defined. In a cross-sectional study involving 91 healthy male (aged 20-84 years, median 52.4) and 55 female (aged 20-82 years, median 48.3) individuals, we found age was associated with an increased proportion of intermediate and nonclassical monocytes (P = 0.002 and 0.04, respectively) and altered phenotype of specific monocyte subsets (e.g. increased expression of CD11b and decreased expression of [[CD38]], CD62L and CD115). Plasma levels of the innate immune activation markers [[CXCL10]], neopterin (P < 0.001 for both) and sCD163 (P = 0.003) were significantly increased with age. Whilst similar age-related changes were observed in both sexes, monocytes from women were phenotypically different to men [e.g. lower proportion of nonclassical monocytes (P = 0.002) and higher CD115 and CD62L but lower [[CD38]] expression] and women exhibited higher levels of [[CXCL10]] (P = 0.012) and sCD163 (P < 0.001) but lower sCD14 levels (P < 0.001). Monocytes from older individuals exhibit impaired phagocytosis (P < 0.05) but contain shortened telomeres (P < 0.001) and significantly higher intracellular levels of [[TNF]] both at baseline and following [[TLR4]] stimulation (P < 0.05 for both), suggesting a dysregulation of monocyte function in the aged. These data show that aging is associated with chronic innate immune activation and significant changes in monocyte function, which may have implications for the development of age-related diseases.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Aging
* Chronic Disease
* Female
* Humans
* Immunity, Innate
* Inflammation
* Male
* Middle Aged
* Monocytes
* Phenotype
* Young Adult

|full-text-url=https://sci-hub.do/10.1111/j.1474-9726.2012.00851.x
}}
{{medline-entry
|title=Circulating human B and plasma cells. Age-associated changes in counts and detailed characterization of circulating normal CD138- and CD138  plasma cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/20081059
|abstract=Generation of B and plasma cells involves several organs with a necessary cell trafficking between them. A detailed phenotypic characterization of four circulating B-cell subsets (immature-, naïve-, memory- B-lymphocytes and plasma cells) of 106 healthy adults was realized by multiparametric flow cytometry. We show that CD10, [[CD27]] and [[CD38]] is the minimal combination of subsetting markers allowing unequivocal identification of immature (CD10( )[[CD27]](-)[[CD38]]( ), 6 /-6 cells/microL), naïve (CD10(-)[[CD27]](-)[[CD38]](-), 125 /-90 cells/microL), memory B lymphocytes (CD10(-)[[CD27]]( )[[CD38]](-), 58 /-42 cells/microL), and plasma cells (CD10(-)[[CD27]](  )[[CD38]](  ), 2.1 /-2.1 cells/microL) within circulating CD19( ) cells. From these four subsets, only memory B lymphocytes and plasma cells decreased with age, both in relative and absolute counts. Circulating plasma cells split into CD138(-) (57 /-12%) and CD138( ) (43 /-12%) cells, the latter displaying a more mature phenotypic profile: absence of surface immunoglobulin, lower CD45 positivity and higher amounts of cytoplasmic immunoglobulin, [[CD38]] and [[CD27]]. Unlike B lymphocytes, both populations of plasma cells are KI-67( ) and show weak [[CXCR4]] expression.
|mesh-terms=* Adult
* Age Factors
* Aged
* Aged, 80 and over
* Aging
* B-Lymphocyte Subsets
* Female
* Flow Cytometry
* Humans
* Immunophenotyping
* Lymphocyte Count
* Male
* Middle Aged
* Plasma Cells
* Syndecan-1
* Young Adult

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2878802
}}
{{medline-entry
|title=Immunophenotypic analysis of bone marrow B lymphocyte precursors (hématogones) by flow cytometry.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/19967915
|abstract=The aims of this flow cytometry study were to quantify B lymphoid precursors known as hématogones across age and clinical conditions and to study the immunophenotypic profile of these benign immature B cells. A total of 406 consecutive marrow specimens were analyzed for hématogones using 4-color flow cytometry during a 19 month period (60% males and 40% females). The age range was 3 months to 89 years. Hématogones were present in 80% of the specimens. Morphologic analysis of the smears from each patient showed small numbers of hématogones (<13% of total cellularity). The B cell population was defined by [[CD19]]   CD45 bright positivity, coexpression of other B lineage markers: CD20, [[CD22]], CD10, CD29, [[CD38]] and [[CD58]] in addition to HLA-DR and [[CD34]]. In our study we found a significant decline in hématogones with increasing age but a broad range was found at all ages. Marrow from some adults contained relatively high numbers. Diagnosis in these patients included cytopenias, infections, and neoplastic diseases. Distinction of hématogones is critical for disease management particularly after therapy of paediatric B acute lymphoblastic leukaemia to monitor for minimal residual disease.
|mesh-terms=* Adolescent
* Adult
* Aged
* Aged, 80 and over
* Aging
* Antigens, CD
* Child
* Child, Preschool
* Female
* Flow Cytometry
* Humans
* Immunophenotyping
* Infant
* Male
* Middle Aged
* Precursor Cells, B-Lymphoid
* Prospective Studies
* Young Adult


}}
{{medline-entry
|title=Age and stress related phenotypical changes in bone marrow [[CD34]]  cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/18836945
|abstract=Phenotypical changes in the human bone marrow (BM) due to age and stress have not so far been properly addressed in the literature. In the present study, we compared [[CD34]]( ) BM cells between older and young volunteers. The influence of stress on [[CD34]]( ) cell phenotype in older patients was investigated in an age-matched group with acute myocardial infarction (AMI). Cytokines thought to influence BM [[CD34]]( ) cell homeostasis were also analysed. BM mononuclear cells of 10 older volunteers and of 7 young volunteers (18-25 years), as well as 22 AMI patients, were analysed by flow cytometry for the following markers: [[CD34]], [[CD38]], CD117 (c-kit) and CD133. Blood samples were analysed for [[CRP]], IL-6, MCP-1, IL-8, MMP-9, TIMP-1 and TNFalpha by ELISA methods. Significantly higher numbers of [[CD34]]( ) [[CD38]](-) cells (both absolute and relative) were observed in older volunteers than in young volunteers and AMI patients. Higher numbers of immature progenitors, namely [[CD34]]( )[[CD38]](-) cells and [[CD34]]( )[[CD38]](-)CD117( )CD133( ) cells, were observed among older volunteers compared to the other groups. However, the relative number of [[CD34]]( ) cells lacking [[CD38]] expression or expressing CD133 was higher in the old volunteers and AMI patients. None of the circulating factors investigated correlated with any of the cell population yields. In this study, we found that the absolute and relative numbers of BM [[CD34]]( )[[CD38]](-) progenitor cells increase with age. The increment is attenuated in patients with AMI.
|mesh-terms=* ADP-ribosyl Cyclase 1
* Acute-Phase Proteins
* Adolescent
* Adult
* Age Distribution
* Aged
* Aging
* Antigens, CD34
* Bone Marrow Cells
* C-Reactive Protein
* Cell Count
* Cytokines
* Female
* Flow Cytometry
* Humans
* Male
* Middle Aged
* Myocardial Infarction
* Phenotype
* Stress, Physiological

|full-text-url=https://sci-hub.do/10.1080/00365510802419447
}}
{{medline-entry
|title=Regulation of SIRT 1 mediated NAD dependent deacetylation: a novel role for the multifunctional enzyme [[CD38]].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/16935261
|abstract=The SIRT 1 enzyme is a NAD dependent deacetylase implicated in ageing, cell protection, and energy metabolism in mammalian cells. How the endogenous activity of SIRT 1 is modulated is not known. The enzyme [[CD38]] is a multifunctional enzyme capable of synthesis of the second messenger, cADPR, NAADP, and ADPR. However, the major enzymatic activity of [[CD38]] is the hydrolysis of NAD. Of particular interest is the fact that [[CD38]] is present on the inner nuclear membrane. Here, we investigate the modulation of the SIRT 1 activity by [[CD38]]. We propose that by modulating availability of NAD to the [[SIRT1]] enzyme, [[CD38]] may regulate [[SIRT1]] enzymatic activity. We observed that in [[CD38]] knockout mice, tissue levels of NAD are significantly increased. We also observed that incubation of purified recombinant [[SIRT1]] enzyme with [[CD38]] or nuclear extracts of wild-type mice led to a significant inhibition of its activity. In contrast, incubation of [[SIRT1]] with cellular extract from [[CD38]] knockout mice was without effect. Furthermore, the endogenous activity of [[SIRT1]] was several time higher in nuclear extracts from [[CD38]] knockout mice when compared to wild-type nuclear extracts. Finally, the in vivo deacetylation of the [[SIRT1]] substrate P53 is increased in [[CD38]] knockout mice tissue. Our data support the novel concept that nuclear [[CD38]] is a major regulator of cellular/nuclear NAD level, and [[SIRT1]] activity. These findings have strong implications for understanding the basic mechanisms that modulate intracellular NAD levels, energy homeostasis, as well as ageing and cellular protection modulated by the SIRT enzymes.
|mesh-terms=* ADP-ribosyl Cyclase 1
* Acetylation
* Aging
* Animals
* Calcium
* Cell Nucleus
* Gene Expression Regulation
* Homeostasis
* Liver
* Mice
* Mice, Knockout
* NAD
* Nuclear Envelope
* Recombinant Proteins
* Sirtuin 1
* Sirtuins

|full-text-url=https://sci-hub.do/10.1016/j.bbrc.2006.08.066
}}
{{medline-entry
|title=Age dependency and mutual relations in T and B lymphocyte abnormalities in common variable immunodeficiency patients.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/16412063
|abstract=Common variable immunodeficiency (CVID) is primary hypogammaglobulinaemia with an unknown aetiopathogenesis. Although various abnormalities of T and B cells have been described, their pathogenetic roles are unclear. We determined T and B lymphocyte subsets known to be abnormal in CVID in order to disclose possible relations between numerical abnormalities in those cells. Markers associated with B cell development (CD21, [[CD27]], IgM, IgD) were determined on B lymphocytes (CD19 ); T lymphocyte development (CD45RA, CD45RO, CD62L) and activation markers (CD25, [[CD27]], [[CD28]], CD29, [[CD38]], CD57, HLA-DR) were determined on CD4  and CD8  T lymphocytes in 42 CVID patients and in 33 healthy controls. Abnormalities in CD4  T lymphocyte activation markers (increase in CD29, HLA-DR, CD45RO, decrease in [[CD27]], CD62L, CD45RA) were observed particularly in patients with a decreased number of memory ([[CD27]] ) and mature (CD21 ) B cells (group Ia according to the Freiburg group's classification), while abnormalities observed in CD8  cells (increase in [[CD27]] and [[CD28]] and decrease in HLA-DR, CD57 and [[CD38]]) did not depend upon grouping patients together according to B lymphocyte developmental subpopulations. We observed correlations between immature B cells (IgM  CD21-) and expression of [[CD27]], CD62L, CD45RA, CD45RO and HLA-DR on CD4  T cells in CVID patients but not in the control group. The expression of [[CD27]] and CD45RA on CD4  T lymphocytes, such as the percentage of IgD  [[CD27]]- and IgD  [[CD27]]  cells in B lymphocytes, showed age dependency to be more significant than in the control group. Our study demonstrates that T and B lymphocyte abnormalities in CVID are partially related to each other. Some of those abnormalities are not definite, but may evolve with age of the patient.
|mesh-terms=* Adult
* Aging
* Antigens, CD
* Antigens, Differentiation, B-Lymphocyte
* Antigens, Differentiation, T-Lymphocyte
* B-Lymphocyte Subsets
* B-Lymphocytes
* Biomarkers
* CD4-Positive T-Lymphocytes
* CD8-Positive T-Lymphocytes
* Common Variable Immunodeficiency
* Female
* Flow Cytometry
* Humans
* Immunoglobulin D
* Immunoglobulin M
* Lymphocyte Activation
* Male
* Middle Aged
* T-Lymphocytes

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1809591
}}
{{medline-entry
|title=The [[CD38]]-independent ADP-ribosyl cyclase from mouse brain synaptosomes: a comparative study of neonate and adult brain.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/16411897
|abstract=cADPR (cADP-ribose), a metabolite of NAD , is known to modulate intracellular calcium levels and to be involved in calcium-dependent processes, including synaptic transmission, plasticity and neuronal excitability. However, the enzyme that is responsible for producing cADPR in the cytoplasm of neural cells, and particularly at the synaptic terminals of neurons, remains unknown. In the present study, we show that endogenous concentrations of cADPR are much higher in embryonic and neonate mouse brain compared with the adult tissue. We also demonstrate, by comparing wild-type and Cd38-/- tissues, that brain cADPR content is independent of the presence of [[CD38]] (the best characterized mammalian ADP-ribosyl cyclase) not only in adult but also in developing tissues. We show that Cd38-/- synaptosome preparations contain high ADP-ribosyl cyclase activities, which are more important in neonates than in adults, in line with the levels of endogenous cyclic nucleotide. By using an HPLC method and adapting the cycling assay developed initially to study endogenous cADPR, we accurately examined the properties of the synaptosomal ADP-ribosyl cyclase. This intracellular enzyme has an estimated K(m) for NAD  of 21 microM, a broad optimal pH at 6.0-7.0, and the concentration of free calcium has no major effect on its cADPR production. It binds NGD  (nicotinamide-guanine dinucleotide), which inhibits its NAD -metabolizing activities (K(i)=24 microM), despite its incapacity to cyclize this analogue. Interestingly, it is fully inhibited by low (micromolar) concentrations of zinc. We propose that this novel mammalian ADP-ribosyl cyclase regulates the production of cADPR and therefore calcium levels within brain synaptic terminals. In addition, this enzyme might be a potential target of neurotoxic Zn2 .
|mesh-terms=* ADP-ribosyl Cyclase
* ADP-ribosyl Cyclase 1
* Aging
* Animals
* Animals, Newborn
* Brain
* Cyclic ADP-Ribose
* Guanine Nucleotides
* Hydrogen-Ion Concentration
* Kinetics
* Mice
* Mice, Knockout
* NAD
* Synaptosomes
* Zinc

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1422756
}}
{{medline-entry
|title=[[CD27]]( ) (memory) B cell decrease and apoptosis-resistant [[CD27]](-) (naive) B cell increase in aged humans: implications for age-related peripheral B cell developmental disturbances.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/15724062
|abstract=To investigate age-related alterations in human humoral immunity, we analyzed the quantity and quality of peripheral B cell subsets, [[CD27]]-negative ([[CD27]](-)) and [[CD27]]-positive ([[CD27]]( )) B cells, by flow cytometry analysis in 54 aged individuals (mean age  /- SE, 74.6  /- 0.7 years) and 30 young individuals (mean age  /- SE, 26.1  /- 0.5 years). [[CD27]](-) and [[CD27]]( ) B cells are regarded as naive and memory B cells, respectively. [[CD38]], Ki-67, CD95 and bcl-2 were used as activation, proliferation and apoptotic markers. Susceptibility to apoptosis was evaluated by cell size and annexin-V binding in culture cells. The percentage of [[CD27]]( ) B cells was significantly lower in aged (mean, 19.2%) individuals than that in young individuals (mean, 28.2%). The opposite was true for [[CD27]](-) B cells (mean, 80.8% in aged and 71.8% in young) (P < 0.01). The absolute number of [[CD27]]( ) B cells in aged individuals was significantly less than the number of [[CD27]](-) B cells. The [[CD27]]( ) B cells from aged individuals showed little susceptibility to apoptosis, although CD95 expression on the [[CD27]]( ) B cells was significantly higher in the aged individuals than in the young individuals (P < 0.05). The [[CD38]] and bcl-2 expression on the [[CD27]](-) B cells was significantly higher in the aged individuals than in the young individuals (P < 0.05). In addition, the [[CD27]](-) B cells from the aged individuals showed a decreased susceptibility to apoptosis compared with that of the young individuals. These findings suggested that human aging leads to both quantitative and qualitative alterations in the peripheral B cell developmental system, including memory and naive B cell balance and their surface phenotypes.
|mesh-terms=* ADP-ribosyl Cyclase
* ADP-ribosyl Cyclase 1
* Adult
* Aged
* Aged, 80 and over
* Aging
* Antigens, CD
* Apoptosis
* B-Lymphocytes
* Cell Differentiation
* Female
* Humans
* Immunologic Memory
* Male
* Membrane Glycoproteins
* Proto-Oncogene Proteins c-bcl-2
* Tumor Necrosis Factor Receptor Superfamily, Member 7
* fas Receptor

|full-text-url=https://sci-hub.do/10.1093/intimm/dxh218
}}
{{medline-entry
|title=Immunophenotyping of blood lymphocytes at birth, during childhood, and during adulthood in HIV-1-uninfected Ethiopians.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/14697749
|abstract=To obtain more insight into blood lymphocyte subpopulations of Ethiopians, we studied the immunologic profile of children and neonates and compared these data with those obtained from adults. Peripheral blood mononuclear cells (PBMCs) and cord blood mononuclear cells (CBMCs) were collected from 137 HIV-1-uninfected subjects aged 0 (cord blood) up to 40 years. Lymphocyte subsets (T, B, and NK cells, [[CD4]]  and CD8  T cells) were determined and T cell activation ([[CD38]] and HLA-DR) and differentiation ([[CD4]]5RO and CD27) markers were measured on [[CD4]]  and CD8  T cells. The absolute number and percentage values of most lymphocyte subpopulations differed substantially with age. Neonates and children were found to have significantly higher [[CD4]]  T cell counts compared to adults. The median absolute [[CD4]] count at birth was comparable to those reported for Caucasians. At birth 97% of the [[CD4]]  T cells were naîve and this proportion significantly declined to 14.2% during adulthood. In addition, activation of both [[CD4]]  and CD8  T cells, as determined by the double expression of HLA-DR and [[CD38]], was observed in children under the age of 16 and adults, but not in neonates. A more differentiated phenotype (CD27-) was observed in adults compared to children for both [[CD4]]  and CD8  T cells. The immune alterations including the remarkably low [[CD4]] count with highly depleted naîve phenotype and a persistently activated immune system seen in adult Ethiopians are not apparent at birth, but rather develop over time.
|mesh-terms=* ADP-ribosyl Cyclase
* ADP-ribosyl Cyclase 1
* Adolescent
* Adult
* Aging
* Antigens, CD
* B-Lymphocytes
* CD3 Complex
* CD4-CD8 Ratio
* CD4-Positive T-Lymphocytes
* CD56 Antigen
* CD8-Positive T-Lymphocytes
* Child
* Child, Preschool
* Cohort Studies
* Ethiopia
* Flow Cytometry
* HLA-DR Antigens
* Humans
* Immunophenotyping
* Infant, Newborn
* Killer Cells, Natural
* Leukocyte Count
* Lymphocyte Activation
* Lymphocyte Subsets
* Membrane Glycoproteins
* Receptors, IgG

|full-text-url=https://sci-hub.do/10.1016/j.clim.2003.08.008
}}
{{medline-entry
|title=Germinal center B cells in Peyer's patches of aged mice exhibit a normal activation phenotype and highly mutated IgM genes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/12633935
|abstract=Systemic and mucosal humoral immune responses have been reported to exhibit an age related decline. However, differences in primary and memory responses at mucosal sites in aged mice have been noted. In an effort to begin characterizing deficiencies in the mucosal system of aged mice, we examined the B cell compartment of gut associated Peyer's patch lymphoid tissue. To our surprise, we found that germinal center ([[GC]]) B cells from aged B6D2F1 mice (24-26 months) were present at similar frequencies and exhibited a normal activation phenotype such as upregulation of B7.1, B7.2 and [[CD44]], and downregulation of CD23, CD62L and [[CD38]] as that observed in younger mice (2.5-4 months). As expected, Peyer's patch [[GC]] B cells from aged mice expressing V(H)X24 genes displayed higher somatic mutation frequencies compared with younger mice. However, this was particularly striking in IgM sequences where high mutational loads suggested we were sampling memory cells. It is conceivable that B-cells expressing these genes reflect the presence of a mucosal memory compartment in aged mice that either retains flexibility in effector function or is committed to the secretion of IgM antibody.
|mesh-terms=* Aging
* Animals
* B-Lymphocytes
* Base Sequence
* Germinal Center
* Immunoglobulin M
* Immunoglobulin Variable Region
* Immunologic Memory
* Mice
* Mice, Inbred Strains
* Molecular Sequence Data
* Peyer's Patches
* Phenotype
* Somatic Hypermutation, Immunoglobulin

|full-text-url=https://sci-hub.do/10.1016/s0047-6374(02)00115-x
}}
{{medline-entry
|title=[[CD38]] expression by hematopoietic stem cells of newborn and juvenile mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/12529675
|abstract=While investigators in a number of laboratories have documented that the hematopoietic stem cells (HSCs) of fetal and adult mice are [[CD38]] , no information is available about [[CD38]] expression by HSCs of newborn and juvenile mice. We used a murine transplantation model to examine HSC [[CD38]] expression. First, we observed that all HSCs from newborn bone marrow are [[CD38]]-. Next, it was determined that the majority of HSCs in the bone marrow of 5-week-old mice are [[CD38]]-, with a minority being [[CD38]] . These observations indicated that the [[CD38]]  subpopulation of HSC appears before the age of 5 weeks and expands during adolescence. However, the majority of HSCs of 5-week-old mice became [[CD38]]  following injection of 5-fluorouracil, indicating that activation of juvenile stem cells enhances [[CD38]] expression. These observations may have implications for [[CD38]] expression by HSCs from human umbilical cord blood and bone marrow of young children in steady state and under pathological conditions.
|mesh-terms=* ADP-ribosyl Cyclase
* ADP-ribosyl Cyclase 1
* Aging
* Animals
* Animals, Genetically Modified
* Animals, Newborn
* Antigens, CD
* Antigens, CD34
* Antigens, Ly
* Bone Marrow Transplantation
* Cell Differentiation
* Female
* Gene Expression Regulation, Developmental
* Hematopoietic Stem Cells
* Membrane Glycoproteins
* Mice
* Mice, Inbred C57BL
* Tissue Donors
* Whole-Body Irradiation

|full-text-url=https://sci-hub.do/10.1038/sj.leu.2402785
}}
{{medline-entry
|title=Changing patterns of cell surface mono (ADP-ribosyl) transferase antigen ART2.2 on resting versus cytopathically-activated T cells in NOD/Lt mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/11508269
|abstract=ART2.2 is a mouse T-cell surface ectoenzyme [mono (ADP-ribosyl) transferase] shed upon strong activation. We analysed temporal changes in ART2.2 expression in unmanipulated and cyclophosphamide-treated NOD/Lt mice compared with diabetes-resistant control strains. We used NAD, the ART2.2 substrate, to test whether ART-mediated ADP-ribosylation could retard diabetogenic activation of islet-reactive T cells in vitro. ART2.2 and [[CD38]], another NAD-utilizing enzyme, were measured by flow cytometry. ADP-ribosylation from ethano-NAD was followed by flow cytometry using a reagent specific for etheno-ADP ribose. Although mature NOD [[CD4]]   and C D8   T cells expressed ART2.2, this expression was delayed in young NOD mice when compared with control strains. This ontological delay at 3 weeks of age correlated with an early burst of CD25 expression unique to NOD splenic T cells. This pattern was reproduced in cyclophosphamide-accelerated diabetes in young NOD/Lt males, wherein a retarded repopulation of ART2.2 T cells in spleen and islets correlated with development of heavy insulitis and diabetes. NAD inhibited anti-CD3 induced activation of splenic T cells in vitro and also retarded killing of beta-cell targets by NOD islet-reactive CD8 effectors in vitro at concentrations equal to or greater than 1 micromol/l. Evidence suggested that [[CD38]] on B lymphocytes competes with ART2.2 for substrate needed by B lymphocytes for ADP ribosylation. ART2.2 on T cells may not simply mark the resting state, but could also contribute to it via ADP-ribosylation.
|mesh-terms=* ADP Ribose Transferases
* ADP-ribosyl Cyclase
* ADP-ribosyl Cyclase 1
* Aging
* Animals
* Antigens, CD
* Antigens, Differentiation
* Cell Membrane
* Cyclophosphamide
* Diabetes Mellitus, Type 1
* Flow Cytometry
* Gene Expression Regulation, Developmental
* Gene Expression Regulation, Enzymologic
* Gene Rearrangement, T-Lymphocyte
* Islets of Langerhans
* Lymphocyte Activation
* Male
* Membrane Glycoproteins
* Mice
* Mice, Inbred BALB C
* Mice, Inbred C57BL
* Mice, Inbred CBA
* Mice, Inbred NOD
* Mice, Inbred Strains
* Mice, Transgenic
* NAD  Nucleosidase
* Spleen
* T-Lymphocytes

|full-text-url=https://sci-hub.do/10.1007/s001250100559
}}
{{medline-entry
|title=Ontogeny, distribution and function of [[CD38]]-expressing B lymphocytes in mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/11298353
|abstract=Analysis of expression of [[CD38]], CD45R (B220), IgM and IgD on splenic B lymphocytes from mice of different ages demonstrated [[CD38]] on both immature (B220( ), BCR(-)) and mature (B220( ), BCR( )) B lymphocytes. Similarly, [[CD38]] is expressed as early as B220 on the surface of progenitor B cells in the bone marrow. In spite of expressing of [[CD38]] and IgM, neonatal B cells, in contrast to the adult, failed to proliferate to either anti-[[CD38]] or anti-IgM cross-linking when IL-4 was present. They did, however, respond to LPS and anti-[[CD40]], and by 2 weeks of age they began to respond to anti-[[CD38]] and anti-IgM, reaching adult B cell levels by 4 weeks. Although the distribution of [[CD38]] on adult B cells from most different lymphoid compartments was broadly similar, significantly higher levels of [[CD38]] were expressed on peritoneal B lymphocytes. A detailed analysis, using IgM / IgD ratio and staining with anti-[[CD5]] confirmed that B1 lymphocytes were expressing a high level of [[CD38]]. Interestingly, both immature B cells and peritoneal B1 lymphocytes were unresponsive to anti-[[CD38]]. However, they were activated by LPS or anti-[[CD40]].
|mesh-terms=* ADP-ribosyl Cyclase
* ADP-ribosyl Cyclase 1
* Aging
* Animals
* Antibodies
* Antigens, CD
* Antigens, Differentiation
* B-Lymphocytes
* Bone Marrow Cells
* CD40 Antigens
* Cell Differentiation
* Cell Division
* Female
* Flow Cytometry
* Immunoglobulin D
* Immunoglobulin M
* Lipopolysaccharides
* Lymphocyte Activation
* Membrane Glycoproteins
* Mice
* Mice, Inbred BALB C
* Mice, Inbred C3H
* Mice, Inbred C57BL
* NAD  Nucleosidase
* Peritoneal Cavity
* Peyer's Patches
* Receptor Aggregation
* Spleen
* Stem Cells

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270030
}}
{{medline-entry
|title=Granulocyte colony-stimulating factor-mobilized peripheral blood CD34  cells from children contain the same levels of long-term culture-initiating cells producing the same numbers of colony-forming cells as those from adults, but display greater in vitro monocyte/macrophage potential.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/11260087
|abstract=Autologous peripheral blood progenitor cell (PBPC) transplantation is now commonly used in children. The ontogenic differences in haematopoiesis published in recent years suggest differences in the categories of mobilized PBPCs between children and adults. We investigated the frequency and distribution of mature progenitor cells (colony-forming cells, CFCs) and primitive progenitor cells [CD34  [[CD38]]- and CD34  Thy-1  cells, long-term culture-initiating cells (LTC-ICs)] in children and adults mobilized using granulocyte colony-stimulating factor alone. We found similar proportions of granulocyte colony-forming units (CFU-G) and/or macrophage CFUs (CFU-M), mixed lineage CFUs (CFU-Mix) and megakarocyte CFUs (CFU-Mk), CD34  [[CD38]]- and CD34  Thy-1  cells, and LTC-ICs (16.5  /- 3.5 vs. 10.65  /- 5 per 104 CD34  cells), which produced the same number of CFCs (5  /- 1 vs. 6  /- 1 CFCs/LTC-ICs) in PB CD34  cells from children and adults. However, we noted a higher proportion of erythroid blast-forming units (BFU-E) in PB CD34  cells from adults (x 1.5, P = 0.003). Using cord blood as a third ageing point, we observed an inverse age-related propensity for commitment to the monocyte/macrophage lineage that was still found after normalizing the data per body weight and processed blood mass. This ontogeny-related programming was detected from the LTC-IC level, which produced 1.7 times more CFU-M in children than in adults (P = 0.048). These subtle differences in commitment between children and adults, shown here for the first time, are of interest for the in vitro manipulation of PBPCs and, in particular, for application in adoptive immunotherapy in children.
|mesh-terms=* Adult
* Aging
* Antigens, CD34
* Cell Count
* Cell Lineage
* Child
* Erythroblasts
* Fetal Blood
* Granulocyte Colony-Stimulating Factor
* Granulocytes
* Hematopoietic Stem Cell Mobilization
* Hematopoietic Stem Cell Transplantation
* Hematopoietic Stem Cells
* Humans
* Immunotherapy, Adoptive
* Macrophages
* Monocytes
* Thy-1 Antigens

|full-text-url=https://sci-hub.do/10.1046/j.1365-2141.2001.02604.x
}}
{{medline-entry
|title=Age-associated changes in the cellular composition of the human adenoid.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/9105431
|abstract=Histological investigations suggest that the size and number of lymphoid follicles of the adenoids and tonsils decrease during ageing. The mechanisms underlying the histological changes are unknown. The authors have analysed the frequency of lymphocyte subpopulations in the adenoids by flow cytometry. The proportion of B lymphocytes decreased and the proportion of T lymphocytes of all mononuclear cells increased with age. Of all B lymphocytes the proportion of [[CD38]] , surface IgD- B lymphocytes representing the germinal centre cell phenotype, decreased and the proportion of [[CD38]]-, IgD- B lymphocytes representing the mature B lymphocyte phenotype, increased with age. The expression of CD23, a cell surface molecule associated with activation of follicular mantle IgD  B lymphocytes, did not change with increasing age. The results imply that the involution of the adenoid is associated with a decreased germinal centre reaction and relative accumulation of mature B cells in the adenoidal tissue, as analysed by three-colour flow cytometry.
|mesh-terms=* Adenoids
* Adolescent
* Adult
* Aging
* B-Lymphocyte Subsets
* Child
* Child, Preschool
* Female
* Humans
* Hyperplasia
* Immunophenotyping
* Infant
* Male
* Otitis Media
* Sinusitis
* T-Lymphocyte Subsets

|full-text-url=https://sci-hub.do/10.1046/j.1365-3083.1997.d01-417.x
}}
{{medline-entry
|title=Expansion of cytotoxic CD8  [[CD2]]8- T cells in healthy ageing people, including centenarians.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/8881749
|abstract=Ageing is associated with complex remodelling in the phenotypic and functional profiles of T lymphocytes. We investigated whether expression of [[CD2]]8 antigen on T cells is conserved throughout adulthood and ageing in humans. For this purpose we analysed T cells obtained from peripheral blood of 102 healthy people of ages ranging from 20 to 105 years. We found an age-related increase of [[CD2]]8- T cells in percentage and absolute number, predominantly among CD8  T cells. [[CD2]]8- T cells from aged donors analysed by flow cytometry appeared as resting cells (not expressing [[CD2]]5, [[CD38]], [[CD69]], CD71, DR), bearing markers of cytotoxic activity (CD 11b and CD 57) and with a phenotype compatible with 'memory' cells (up-regulated [[CD2]] and CD11a; CD62L absent). At the functional level, freshly isolated purified [[CD2]]8- CD8  T cells showed high anti-CD3 redirected cytotoxic activity against Fc-bearing P815 cells. The same activity tested on freshly isolated bulk T lymphocytes was significantly augmented with age. We found a positive correlation between age, number of CD8  [[CD2]]8- T cells and anti-CD3 redirected cytotoxicity by freshly isolated T cells. These data suggest that an activation of unknown nature within the cytotoxic arm of the immune system occurs with age. We speculate that these cytotoxic T lymphocytes (CTL) in vivo may constitute armed effector cells for immediate killing of targets bearing peptides from pathogens of intracellular origin.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Aging
* CD28 Antigens
* CD3 Complex
* CD8-Positive T-Lymphocytes
* Cell Separation
* Cytotoxicity, Immunologic
* Flow Cytometry
* Humans
* Lymphocyte Count
* Middle Aged

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1456634
}}
{{medline-entry
|title=Age-related changes in human blood lymphocyte subpopulations. II. Varying kinetics of percentage and absolute count measurements.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/7905366
|abstract=A reference range for lymphocyte populations, with particular emphasis on T lymphocyte subsets, was obtained for normal individuals covering age cohorts from birth through adulthood. This report confirms and extends findings from a developmental reference range published earlier (1). Absolute numbers of WBC, lymphocytes, and T, B, and NK subsets decline significantly during childhood. However, differences in the rate of decline of certain lymphocyte subsets leads to discordance between absolute numbers and percentages. Those lymphocyte subsets which decline less rapidly with age than the total lymphocyte count will show an increase in percentage, whereas those which decline more rapidly will show further declines in percentage values. T cell percentages were seen to increase over time whereas B cell percentages decline. Markers of immaturity such as [[CD4]]5RA on [[CD4]] cells and [[CD38]] on CD8 cells declined in both percentages and absolute numbers. Activation markers, such as HLA-DR on CD8 cells and [[IL2]]-R on CD3 cells, increased in percentages with time but changed inconsistently in cell number from infancy to adulthood. These findings extend the lymphocyte references range to markers thought to be informative in various disease states, including HIV infection.
|mesh-terms=* Adolescent
* Adult
* Aging
* Antigens, Differentiation, T-Lymphocyte
* CD4-Positive T-Lymphocytes
* CD8 Antigens
* Child
* Child, Preschool
* Female
* Humans
* Immunophenotyping
* Infant
* Infant, Newborn
* Leukocyte Common Antigens
* Leukocyte Count
* Male
* Middle Aged
* T-Lymphocyte Subsets

|full-text-url=https://sci-hub.do/10.1006/clin.1994.1023
}}
{{medline-entry
|title=T cell activation in pediatric AIDS pathogenesis: three-color immunophenotyping.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/7511081
|abstract=Immune activation is an important component of HIV disease in adults that may reflect a protective host response and/or be a component of immunopathogenesis. The goals of this study were to gain understanding of T cell activation in pediatric HIV disease, to assess the usefulness of T cell activation markers as surrogates for disease progression and/or early identification of infection in infants at risk, and to determine any advantages of three- compared to two-color flow cytometric immunophenotyping for the above assessments. We examined the expression of cell-surface activation antigens on the [[CD4]] and CD8 T cells of 26 HIV-infected and 40 HIV-seronegative age-matched control children. Compared with controls, HIV-infected children showed a slight but not significant decrease in the proportion of [[CD4]] cells that coexpressed [[CD4]]5RA and L-selectin (mean of 83 vs 75% for < 2 years of age, 76 vs 62% for 2-3 years, 64 vs 56% for > or = 4 years). [[CD4]] cells coexpressing [[CD38]] and HLA-DR were significantly increased in HIV  children (mean of 2 vs 6% for < 2 years of age, 3 vs 11% for 2-3 years, 2 vs 8% for > or = 4 years). There was a striking and significant increase in the proportion of CD8 cells coexpressing [[CD38]] and HLA-DR (mean of 5 vs. 25% for < 2 years, 10 vs 41% for 2-3 years, 6 vs 31% for > or = 4 years); this double positive population of CD8 cells included cells that were approximately 1 log brighter for the expression of [[CD38]] than for that of [[CD38]] single-positive cells. There was a significant reduction in [[CD4]]5RA  CD8 cells (means of 92 vs 71% for < 2 years of age, 88 vs 50% for 2-3 years, 80 vs 57% for > or = 4 years) and an increase in CD57  CD8 cells (mean of 4 vs 8% for < 2 years of age, 8 vs 22% for 2-3 years, 19 vs 31% for > or = 4 years) in HIV  children. The inclusion of CD3 as an anchor marker for CD8 cell subsets to limit the analysis to CD3  CD8 cells did not substantially alter the data nor enhance the differences between infected and control children compared with the analysis of all CD8 cells.(ABSTRACT TRUNCATED AT 400 WORDS)
|mesh-terms=* Acquired Immunodeficiency Syndrome
* Aging
* Antigens, CD
* Antigens, Differentiation, T-Lymphocyte
* CD3 Complex
* CD4 Antigens
* CD57 Antigens
* CD8 Antigens
* Child
* Child, Preschool
* HIV Infections
* HLA-DR Antigens
* Humans
* Immunophenotyping
* Infant
* Lymphocyte Activation
* T-Lymphocyte Subsets
* T-Lymphocytes

|full-text-url=https://sci-hub.do/10.1006/clin.1994.1046
}}
{{medline-entry
|title=B-cell differentiation following autologous, conventional, or T-cell depleted bone marrow transplantation: a recapitulation of normal B-cell ontogeny.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/1698484
|abstract=The circulating lymphocytes of 88 consecutive patients following autologous, conventional, or T-cell depleted bone marrow transplantation were serially analyzed for B-cell surface antigen expression and function. In the majority of patients, except for those who developed chronic graft-versus-host disease, the number of circulating CD20  B cell normalized by the fourth posttransplant month. The earliest detectable B cells normally expressed HLA-DR, [[CD19]], surface immunoglobulin (slg), CD21, Leu-8, and lacked expression of CD10 (CALLA). In addition, the circulating B cells expressed CD1c, [[CD38]], [[CD5]], and CD23 for the first year following transplant, antigens that are normally expressed on a small percentage of circulating B cells in normal adults, but highly expressed on cord blood B cells. Similar to cord blood B cells, patient B cells isolated during the first year following transplant, proliferated normally to Staphylococcus aureus Cowan strain I (SAC), and produced IgM, but minimal or no IgG when stimulated with pokeweed mitogen and SAC, unlike normal adult B cells that produce both. The similar phenotype and function of posttransplant and cord blood B cells, and their similar rate of decline in patients and normal children adds further evidence to support the hypothesis that B-cell differentiation posttransplant is recapitulating normal B-cell ontogeny.
|mesh-terms=* Adult
* Aging
* Antigens, CD
* Antigens, CD20
* Antigens, Differentiation, B-Lymphocyte
* B-Lymphocytes
* Bone Marrow Transplantation
* Cell Differentiation
* Child
* Child, Preschool
* Graft vs Host Disease
* HLA-DR Antigens
* Humans
* Immunoglobulin G
* Immunoglobulin M
* Immunophenotyping
* Infant, Newborn
* Leukocyte Count
* Lymphocyte Activation
* Staphylococcus aureus
* T-Lymphocytes


}}
{{medline-entry
|title=Age-related changes in the expression of T cell activation antigens following phytohaemagglutinin stimulation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/1307243
|abstract=The role of accessory cells (AC) in the temporal expression of several key T-cell-activation-associated antigens has been studied in healthy aged subjects. Compared to responses seen in young adults, phytohaemagglutinin (PHA) induced weak proliferation in peripheral blood mononuclear cells from the aged and lower numbers of T cells expressing CD71, CD25, [[CD38]] or HLA-DR. T cell responses to the monoclonal antibody OKT3, however, were normal. Whereas HLA-DR  T cell numbers could be increased by raising the AC content (up to 50%) in cultures comprising purified T cells and graded numbers of autologous AC, CD25  T cell numbers remained largely unaltered. Co-stimulation with PHA   phorbol myristate acetate in the absence of AC restored both proliferation and CD25 expression in the aged. These results indicate that T cells from the healthy aged show selective deficiencies in their capacity to respond to mitogenic stimuli and suggest that impaired PHA responsiveness is due, at least in part, to defective AC-derived signals.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Antigen-Presenting Cells
* Antigens, CD
* Cell Division
* Female
* HLA-DR Antigens
* Humans
* Interleukin-2
* Lymphocyte Activation
* Male
* Monocytes
* Muromonab-CD3
* Phytohemagglutinins
* T-Lymphocyte Subsets
* Tetradecanoylphorbol Acetate


}}