B2M
Beta-2-microglobulin precursor [Contains: Beta-2-microglobulin form pI 5.3] [CDABP0092] [HDCMA22P]
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Whether accelerated aging develops over the course of chronic HIV infection or can be observed prior to significant immunosuppression on is unknown. We studied DNA methylation in blood to estimate cellular aging in persons living with HIV (PLWH) prior to the initiation of antiretroviral therapy. 378 antiretroviral therapy-naïve PLWH with CD4 T cell counts >500 cells/mm 3 enrolled in the Strategic Timing of Antiretroviral Therapy trial (Pulmonary Substudy) were compared to 34 HIV-negative controls. DNA methylation was performed using the Illumina MethylationEPIC BeadChip. Differentially methylated positions (DMPs) and regions (DMRs) in PLWH compared to controls were identified using a robust linear model. Methylation age was calculated using a previously described epigenetic clock. There were a total of 56,639 DMPs and 6,103 DMRs at a false discovery rate<0.1. The top 5 DMPs corresponded to genes NLRC5, VRK2, B2M, and GPR6 and were highly enriched for cancer-related pathways. PLWH had significantly higher methylation age compared to HIV-negative controls (p=0.001), with black race, low CD4, high CD8 T cell counts, and duration of HIV being risk factors for age acceleration. PLWH prior to the initiation of antiretroviral therapy and with preserved immune status show evidence of advanced methylation aging.
Keywords
- HIV
- aging
- epigenetics
- methylation
Our aim was to define the relationships between plasma biomarkers of kidney injury and intrarenal haemodynamic function (glomerular filtration rate [GFR], effective renal plasma flow [ERPF], renal vascular resistance [RVR]) in adults with type 1 diabetes (T1D). The study sample comprised patients with longstanding T1D (duration ≥50 years), among whom 44 were diabetic kidney disease (DKD) resistors (eGFR >60 mL/min/1.73 m and <30 mg/d urine albumin excretion) and 22 had DKD, in addition to 73 control participants. GFR and ERPF were measured, RVR was calculated, and afferent (R )/efferent (R ) areteriolar resistances were derived from Gomez equations. Plasma neutrophil gelatinase-associated lipocalin (NGAL), β2 microglobulin (B2M), osteopontin (OPN) and uromodulin (UMOD) were measured using immunoassay kits from Meso Scale Discovery. Plasma NGAL, B2M and OPN were higher and UMOD was lower in DKD patients vs DKD resistors and non-diabetic controls. In participants with T1D, plasma NGAL inversely correlated with GFR (r = -0.33; P = 0.006) and ERPF (r = -0.34; P = 0.006), and correlated positively with R (r = 0.26; P = 0.03) and RVR (r = 0.31; P = 0.01). In participants without T1D, NGAL and B2M inversely correlated with GFR (NGAL r = -0.18; P = 0.13 and B2M r = -0.49; P < 0.0001) and with ERPF (NGAL r = -0.19; P = 0.1 and B2M r = -0.42; P = 0.0003), and correlated positively with R (NGAL r = 0.19; P = 0.10 and B2M r = 0.3; P = 0.01) and with RVR (NGAL r = 0.20; P = 0.09 and B2M r = 0.34; P = 0.003). Differences were significant after adjusting for age, sex, HbA1c, SBP and LDL. There were statistical interactions between T1D status, B2M and intrarenal haemodynamic function (P < 0.05). Elevated NGAL relates to intrarenal haemodynamic dysfunction in T1D, whereas elevated NGAL and B2M relate to intrarenal haemodynamic dysfunction in adults without T1D. These data may define a diabetes-specific interplay between tubular injury and intrarenal haemodynamic dysfunction.
MeSH Terms
- Aged
- Aged, 80 and over
- Biomarkers
- Canada
- Case-Control Studies
- Cross-Sectional Studies
- Diabetes Mellitus, Type 1
- Diabetic Nephropathies
- Disease Progression
- Female
- Glomerular Filtration Rate
- Hemodynamics
- Humans
- Kidney
- Lipocalin-2
- Longevity
- Male
- Middle Aged
- Predictive Value of Tests
- Prognosis
- Regional Blood Flow
- Vascular Resistance
- beta 2-Microglobulin
Keywords
- biomarkers
- diabetic kidney disease
- type 1 diabetes
To examine the association between serum β2-microglobulin (B2M) levels and frailty in an elderly Chinese population. A population-based cohort study. We used data on 1,663 elderly participants (aged 70-84 years) from the aging arm of the Rugao Longevity and Ageing study, a population-based observational two-arm cohort study conducted in Rugao, China. The serum B2M was measured with chemiluminescence immunoassay by a technician in the biochemistry laboratory of the Rugao People's Hospital. Information on the frailty index and phenotype was collected. The mean B2M levels and frailty index were 1.8 mg/L and 0.16, respectively; 188 (11.3%) participants were classified as frail (frailty phenotype). For a standard deviation increase in B2M, the adjusted odds ratio for frailty phenotype was 1.20 (95% CI: 1.05, 1.39; [i]P[/i]=0.009) and the standardized coefficient for frailty index was 0.07 (95% CI: 0.02, 0.11; [i]P[/i]=0.004). Relative to the lowest quartile, the highest B2M quartile had a greater risk of prevalent frailty with adjusted odds ratios of 1.68 (95% CI: 1.04, 2.71; [i]P[/i]=0.034) for frailty phenotype and 1.51 (95% CI: 1.01, 2.27; [i]P[/i]=0.044) for frailty index (≥0.25). In addition, estimated glomerular filtration rate (based on B2M) or chronic kidney disease (estimated glomerular filtration rate <60 mL/min/1.73 m ) was significantly associated with frailty phenotype and index. B2M was significantly associated with both frailty phenotype and index in elderly Chinese population. The findings underscore the promising kidney relevant biomarkers for identifying vulnerable elderly Chinese population.
MeSH Terms
- Aged
- Aged, 80 and over
- Asian Continental Ancestry Group
- Biomarkers
- China
- Cohort Studies
- Female
- Frail Elderly
- Frailty
- Glomerular Filtration Rate
- Humans
- Longevity
- Male
- Odds Ratio
- Phenotype
- Prevalence
- Renal Insufficiency, Chronic
- Risk
- beta 2-Microglobulin
Keywords
- biomarker
- elderly
- frailty index
- frailty phenotype
- kidney
Studies in chronic kidney disease populations suggest that the non-glomerular filtration rate (GFR) determinants of serum levels of the low-molecular-weight protein filtration markers cystatin C, β -microglobulin (B2M), and beta-trace protein (BTP) are less affected by age, sex, and ethnicity than those of creatinine. Cross-sectional study. Predominantly elderly participants selected from the Age, Gene/Environment Susceptibility Kidney Study (AGES-Kidney; N=683; mean [SD] age, 79 [4] years; GFR, 62 [17]mL/min/1.73 m ) and from the Multi-Ethnic Study of Atherosclerosis Kidney Study (MESA-Kidney; N=273; mean [SD] age, 70.5 [9] years; GFR, 73 [19]mL/min/1.73 m ). Demographic and clinical factors hypothesized to be associated with conditions affecting non-GFR determinants of the filtration markers. Measured GFRs and estimated GFRs (eGFRs) based on creatinine, cystatin C, B2M, and BTP levels (eGFR eGFR , eGFR , and eGFR , respectively). Residual associations of factors with eGFR after accounting for measured GFR as the parameter of interest. eGFR , eGFR , and eGFR had significantly less strong residual associations with age and sex than eGFR in both AGES-Kidney and MESA-Kidney and were not associated with ethnicity (black vs white) in MESA-Kidney. After adjusting for age, sex, and ethnicity, residual associations with most clinical factors were smaller than observed with age and sex. eGFR and eGFR , but not eGFR , had significant residual associations with C-reactive protein levels in both studies. Small sample size may limit power to detect associations. Participants may be healthier than the general population. Similar to previous studies in chronic kidney disease, in community-dwelling elders, cystatin C, B2M, and BTP levels are less affected than creatinine level by age and sex and are not affected by ethnicity. Both cystatin C and B2M levels may be affected by inflammation. These findings are important for the development and use of GFR estimating equations based on low-molecular-weight serum proteins throughout the range in GFRs.
MeSH Terms
- Age Factors
- Aged
- Aged, 80 and over
- Aging
- Biomarkers
- Creatinine
- Cross-Sectional Studies
- Cystatin C
- Female
- Glomerular Filtration Rate
- Humans
- Intramolecular Oxidoreductases
- Lipocalins
- Male
- Predictive Value of Tests
- Renal Insufficiency, Chronic
- Sex Factors
- United States
- beta 2-Microglobulin
Keywords
- Filtration markers
- GFR estimation
- beta-trace protein (BTP)
- biomarker
- creatinine
- cystatin C
- elderly
- glomerular filtration rate (GFR)
- kidney function
- β(2)-microglobulin (B2M)
To investigate whether higher serum β -microglobulin (B2M) levels, a kidney function marker, are associated with prevalent and incident frailty in community-dwelling older women. Cross-sectional and longitudinal analyses of a prospective cohort. Population-based cohort study in Tokyo, Japan. Community-dwelling women aged 75 and older with adequate data for assessing frailty status (N = 1,191) and a subset of participants without baseline frailty but with repeated frailty assessment at 2 and 4 years of follow-up. The primary predictor was B2M level. Outcomes were prevalent and incident frailty during the 4-year follow-up period. Frailty was defined as presence of three of the five Fried criteria: weight loss, exhaustion, weakness, slowness, and low physical activity. Adjusted odds ratios for the main confounders were obtained using logistic regression. Discrete-time Cox proportional hazards models were used to determine the risk of developing frailty. The study included 241 (20.2%) women with prevalent frailty at baseline and 139 (21.1%) with incident frailty during the 4-year follow-up. On multivariate analysis adjusted for multiple potential confounders, the odds of prevalent frailty were 2.5 times as great with B2M levels of 1.9 to 2.1 mg/L as with levels less than 1.6 mg/L and 2.0 times as great with B2M levels of 2.2 mg/L or more. In the unadjusted model, B2M levels of 1.9 to 2.1 mg/L were associated with a greater incidence of frailty than B2M levels of less than 1.6 mg/L (hazard ratio = 1.72, 95% confidence interval = 1.04-2.86). In the multivariate analysis adjusted for potential confounders, no significant association was noted between the highest B2M quartile and incident frailty. Higher B2M levels were independently associated with greater frailty at baseline in older adults but only slightly associated with greater risk of incident frailty over 4 years of follow-up.
MeSH Terms
- Aged
- Biomarkers
- Cross-Sectional Studies
- Female
- Frail Elderly
- Geriatric Assessment
- Humans
- Incidence
- Japan
- Longitudinal Studies
- Prevalence
- Risk Factors
- beta 2-Microglobulin
Keywords
- aging
- beta-2-microglobulin
- epidemiology
- frailty
- kidney function
Heterochronic parabiosis rejuvenates the performance of old tissue stem cells at some expense to the young, but whether this is through shared circulation or shared organs is unclear. Here we show that heterochronic blood exchange between young and old mice without sharing other organs, affects tissues within a few days, and leads to different outcomes than heterochronic parabiosis. Investigating muscle, liver and brain hippocampus, in the presence or absence of muscle injury, we find that, in many cases, the inhibitory effects of old blood are more pronounced than the benefits of young, and that peripheral tissue injury compounds the negative effects. We also explore mechanistic explanations, including the role of B2M and TGF-beta. We conclude that, compared with heterochronic parabiosis, heterochronic blood exchange in small animals is less invasive and enables better-controlled studies with more immediate translation to therapies for humans.
MeSH Terms
- Aging
- Animals
- Blood Transfusion
- Cellular Senescence
- Male
- Mice
- Mice, Inbred C57BL
- Physical Endurance
- Rejuvenation
- Stem Cells
Aging drives cognitive and regenerative impairments in the adult brain, increasing susceptibility to neurodegenerative disorders in healthy individuals. Experiments using heterochronic parabiosis, in which the circulatory systems of young and old animals are joined, indicate that circulating pro-aging factors in old blood drive aging phenotypes in the brain. Here we identify β2-microglobulin (B2M), a component of major histocompatibility complex class 1 (MHC I) molecules, as a circulating factor that negatively regulates cognitive and regenerative function in the adult hippocampus in an age-dependent manner. B2M is elevated in the blood of aging humans and mice, and it is increased within the hippocampus of aged mice and young heterochronic parabionts. Exogenous B2M injected systemically, or locally in the hippocampus, impairs hippocampal-dependent cognitive function and neurogenesis in young mice. The negative effects of B2M and heterochronic parabiosis are, in part, mitigated in the hippocampus of young transporter associated with antigen processing 1 (Tap1)-deficient mice with reduced cell surface expression of MHC I. The absence of endogenous B2M expression abrogates age-related cognitive decline and enhances neurogenesis in aged mice. Our data indicate that systemic B2M accumulation in aging blood promotes age-related cognitive dysfunction and impairs neurogenesis, in part via MHC I, suggesting that B2M may be targeted therapeutically in old age.
MeSH Terms
- ATP Binding Cassette Transporter, Subfamily B, Member 2
- ATP-Binding Cassette Transporters
- Adult
- Aged
- Aged, 80 and over
- Aging
- Animals
- Cognition
- Humans
- Major Histocompatibility Complex
- Mice
- Mice, Inbred C57BL
- Middle Aged
- Neurogenesis
- beta 2-Microglobulin
Stem cell function declines with age largely due to the biochemical imbalances in their tissue niches, and this work demonstrates that aging imposes an elevation in transforming growth factor β (TGF-β) signaling in the neurogenic niche of the hippocampus, analogous to the previously demonstrated changes in the myogenic niche of skeletal muscle with age. Exploring the hypothesis that youthful calibration of key signaling pathways may enhance regeneration of multiple old tissues, we found that systemically attenuating TGF-β signaling with a single drug simultaneously enhanced neurogenesis and muscle regeneration in the same old mice, findings further substantiated via genetic perturbations. At the levels of cellular mechanism, our results establish that the age-specific increase in TGF-β1 in the stem cell niches of aged hippocampus involves microglia and that such an increase is pro-inflammatory both in brain and muscle, as assayed by the elevated expression of β2 microglobulin (B2M), a component of MHC class I molecules. These findings suggest that at high levels typical of aged tissues, TGF-β1 promotes inflammation instead of its canonical role in attenuating immune responses. In agreement with this conclusion, inhibition of TGF-β1 signaling normalized B2M to young levels in both studied tissues.
MeSH Terms
- Aging
- Animals
- Blotting, Western
- Female
- Hippocampus
- Immunohistochemistry
- Male
- Mice
- Mice, Inbred C57BL
- Muscle Development
- Neural Stem Cells
- Neurogenesis
- Polymerase Chain Reaction
- Rats
- Rats, Inbred F344
- Stem Cell Niche
- Transforming Growth Factor beta
Keywords
- Gerotarget
- TGF-β signaling
- aging
- myogenesis
- neurogenesis
- stem cell microenvironment
Various enzymatic urinary activities have been proposed to assess renal proximal tubule damage in children, including neonates. Nevertheless comprehensive knowledge on the developmental aspects of physiological enzymuria is limited, particularly with regard to lysosomal and brush border enzymuria. Urinary activities of two lysosomal enzymes, N-acetyl-beta-D-glucosaminidase (NAG) and beta-galactosidase (GAL), and of two brush border enzymes, alanine aminopeptidase (AAG) and gamma-glutamyltransferase (GGT) were comparatively investigated in normal prematures (n = 28), term neonates (n = 52), infants aged less than 2 years (n = 19) and children (n = 33), and compared to urinary excretion of beta 2-microglobulin (B2M). Enzymatic activities were assayed using either spectrophotometrical (NAG, AAP, GGT) fluorimetrical (GAL) or radioimmunological (B2M) methods, and were related to urinary creatinine excretion. Developmental profiles of both the studied lysosomal enzymes and of B2M were similarly characterized with significantly decreasing values from prematures (NAG 9.29 /- 1.44, GAL 2.26 /- 0.26 IU/mmol creatinine, indicated as mean /- SEM) to term neonates (6,94 /- 0.58 and 1.76 /- 0.15 IU/mmol creatinine, respectively) and older infants and children. Lysosomal enzymatic urinary activities correlated linearly with a coefficient of r = 0.75, (p < 0.05), while correlations between each lysosomal enzymatic activity and B2M urinary excretion were weaker.(ABSTRACT TRUNCATED AT 250 WORDS)
MeSH Terms
- Acetylglucosaminidase
- Adolescent
- Aging
- Aminopeptidases
- CD13 Antigens
- Child
- Child, Preschool
- Creatinine
- Enzymes
- Female
- Humans
- Infant
- Infant, Newborn
- Infant, Premature
- Lysosomes
- Male
- Microvilli
- beta 2-Microglobulin
- gamma-Glutamyltransferase
Two hundred-one patients (97 leukaemias, 18 lymphoproliferative disorders, 86 solid tumors) were studied for B2M by radioimmune technique. Serum levels were high in all cases, excepting for ALL which presented normal values in 81% of the patients. The follow-up of the microprotein was carried out in 17 patients with acute leukaemias. The data obtained seem to suggest that subjects with high serum levels of B2M at the beginning of the disease do not respond favourably to chemotherapy.
MeSH Terms
- Acute Disease
- Adolescent
- Adult
- Aged
- Aging
- Beta-Globulins
- Chronic Disease
- Female
- Humans
- Leukemia
- Lymphoma
- Male
- Middle Aged
- Neoplasms
- Prognosis
- beta 2-Microglobulin