Xiaojuan Bai

Lack of independent relationship between age-related kidney function decline and carotid intima–media thickness in a healthy Chinese population

BACKGROUND Ageing-related decline in kidney function is an independent predictor for cardiovascular events and death. However, the underlying mechanism is not clear. The purpose of this study was to identify the associations between ageing-related decline in kidney function and carotid intima-media thickness (IMT) in a healthy Chinese population with normal kidney function and with no cardiovascular disease. Methods. In cross-sectional study, we examined 852 participants (aged 30-98 years, 392 men) free from cardiovascular disease and with an estimated glomerular filtration rate (eGFR) >60 ml/min/1.73 m(2). Kidney function was estimated by using two markers: eGFR, which was evaluated by the creatinine-based Modification of Diet in Renal Disease (MDRD) Study equation, and cystatin C (CYSC) level. Participants were categorized into quartiles (I-IV) of eGFR and CYSC with quartile I representing the best kidney function (the highest eGFR quartiles and lowest CYSC). Carotid IMT was analysed using M-mode ultrasonography, and elevated carotid IMT was defined as measures above the 75th percentile of the sample distribution (0.9 mm). RESULTS CYSC was significantly correlated with age in both males (r = 0.441, P < 0.001) and females (r = 0.634, P < 0.001). However, eGFR was only significantly related with age in females (r = -0.173, P < 0.001). CYSC was significantly associated with elevated carotid IMT in an unadjusted model in quartiles III and IV; the odds ratios (95% CI) were 3.64 (2.116-6.261) and 6.407 (3.786-10.84), respectively. However, this association was significantly attenuated by age adjustment and was lost after full adjustment of age and all other confounding variables including sex, body mass index, systolic blood pressure, diastolic blood pressure, triglyceride, total cholesterol, high-density lipoprotein, low-density lipoprotein, albumin, fasting blood glucose, log C-reactive protein, log interleukin-6 and fibrinogen. No significant association was found between quartiles of eGFR and higher IMT. CONCLUSIONS Ageing is a major factor contributing to decline in kidney function in a healthy population. There is no independent relationship between ageing-related decline in kidney function and atherosclerosis in a population with normal kidney function.

Apoptosis is involved in the senescence of endothelial cells induced by angiotensin II

Vascular endothelial cells have a finite cell lifespan and eventually enter an irreversible growth arrest, cellular senescence. The functional changes associated with cellular senescence are thought to contribute to human aging and age‐related cardiovascular disorders, e.g. atherosclerosis. In this study, induction of Angiotensin II (Ang II) promoted a growth arrest with phenotypic characteristics of cell senescence, such as enlarged cell shapes, increased senescence‐associated β‐galactosidase (SA‐β‐gal) positive staining cell, and depressed cell proliferation. Apoptotic changes were increased in senescent cells, with a small subset of the senescent cells showing aberrant morphology such as pronounced nuclear fragmentation or multiple micronuclei. The results suggest cell apoptosis is possibly an important factor in the process of pathologic and physiologic senescence of endothelial cells as well as vascular aging.

From autophagy to senescence and apoptosis in Angiotensin II-treated vascular endothelial cells.

The aim of this study was to explore if cell autophagy is activated by AngII before aging using human umbilical vascular endothelial cells (HUVECs). The ultrastructural analysis of HUVECs was performed to observe autophagosomes. The LC3‐II/LC3‐I ratio was determined by western blot assay. The β‐gal staining was used to identify cell senescence. The flow cytometry was performed to evaluate cell apoptosis. The BH3 domain analog ABT737 or Beclin‐1 knockdown by specific shRNA or valsartan was applied to investigate their effects on cell autophagy, senescence, and apoptosis induced by Ang II. Cell autophagy was initiated after Ang II treatment at 24 h. And cell senescence and apoptosis were observed in Ang II‐treated cells at 48 h. The significant interaction of Beclin‐1 and Bcl‐2 was detected at 48 h after Ang II treatment. Beclin‐1 was indispensable to Ang II‐induced autophagy, and its BH3 domain was required for the interaction with Bcl‐2 to attenuate autophagy. Pretreated with valsartan, cells were present with less autophagic, senescent, and apoptotic cells after Ang II stimulation. In conclusion, Ang II induced autophagy, senescence, and apoptosis of HUVECs progressively, and autophagy presented an early protective effect on vascular endothelial damage due to Ang II.

Angiotensin II induces endothelial cell senescence via the activation of mitogen-activated protein kinases

Vascular endothelial cells have a finite cell lifespan and eventually enter an irreversible growth arrest, cellular senescence. The functional changes associated with cellular senescence are thought to contribute to human aging and age‐related cardiovascular disorders, for example, atherosclerosis. Angiotensin II (Ang II), a principal effector of the renin‐angiotensin system (RAS), an important signaling molecule involved in atherogenic stimuli, is known to promote aging and cellular senescence. In the present study, induction of Ang II promoted a growth arrest with phenotypic characteristics of cell senescence, such as enlarged cell shapes, increased senescence‐associated ß‐galactosidase (SA‐ß‐gal) positive staining cells, and depressed cell proliferation. Ang II drastically decreased the expression level of Bcl‐2, in part via the activation of extracellular signal‐regulated kinase (ERK). Our results suggest that Ang II can induce HUVEC senescence; one of its molecular mechanisms is a probability that the mitogen‐activated protein kinase (MAPK) signal pathway is involved in the process of pathological and physiological senescence of endothelial cells as well as vascular aging. Copyright

Select aging biomarkers based on telomere length and chronological age to build a biological age equation

The purpose of this study is to build a biological age (BA) equation combining telomere length with chronological age (CA) and associated aging biomarkers. In total, 139 healthy volunteers were recruited from a Chinese Han cohort in Beijing. A genetic index, renal function indices, cardiovascular function indices, brain function indices, and oxidative stress and inflammation indices (C-reactive protein [CRP]) were measured and analyzed. A BA equation was proposed based on selected parameters, with terminal telomere restriction fragment (TRF) and CA as the two principal components. The selected aging markers included mitral annulus peak E anterior wall (MVEA), intima-media thickness (IMT), cystatin C (CYSC), D-dimer (DD), and digital symbol test (DST). The BA equation was: BA = −2.281TRF + 26.321CYSC + 0.025DD − 104.419MVEA + 34.863IMT − 0.265DST + 0.305CA + 26.346. To conclude, telomere length and CA as double benchmarks may be a new method to build a BA.

Associations Between Bone Mineral Density and Subclinical Atherosclerosis: A Cross-Sectional Study of a Chinese Population

CONTEXT The significance of associations between bone mineral density (BMD) and atherosclerosis in the Asian population is less clear. OBJECTIVE The aim of this study was to explore the population-level associations between BMD and subclinical atherosclerosis. DESIGN AND SETTING This was a community-based cross-sectional study conducted in Shenyang, China. PARTICIPANTS A total of 385 Chinese women and men aged 37-87 years were studied. MAIN OUTCOME MEASURES The BMD was measured at the total hip and lumbar spine using dual-energy x-ray absorptiometry. The ankle-brachial index (ABI), pulse wave velocity (PWV), and carotid intima-media thickness (CIMT) were measured to assess atherosclerosis. Multiple regression analysis was applied to study the associations. Multicolinearity was examined using the variance inflation factor, condition index, and variance proportions. Factor analysis and principal component regression were used to remove the problem of multicolinearity. RESULTS The differences of ABI, PWV, and CIMT among the normal BMD, osteopenia, and osteoporosis groups were not found. Total hip BMD was correlated with ABI in women after adjustment for age (r = 0.156). Sex-specific regression models included adjustment for age, body mass index, cigarette smoking, alcohol consumption, menopausal status (women), systolic blood pressure, diastolic blood pressure, triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, fasting blood glucose, serum uric acid, estimated glomerular filtration rate, high-sensitivity C-reactive protein, and fibrinogen. Total hip BMD was associated with ABI in women after adjustment for age (per SD decrease in ABI: -0.130 g/cm(2), P = .022), but the association was borderline significant after full adjustment (P = .045). Total hip BMD and lumbar spine BMD were not associated with ABI, PWV, and CIMT after full adjustment in participants without a fracture history. The risk of osteoporosis was not associated with ABI, PWV, and CIMT. CONCLUSIONS Low BMD is not associated with subclinical atherosclerosis as assessed by ABI, PWV, and CIMT.

Evaluation of Biological Aging Process – A Population-Based Study of Healthy People in China

Background: Although there have been cross-sectional and longitudinal studies examining biological age (BA) with chronological age (CA)-related changes in physical, physiological, biochemical, and hormonal variables, few studies have performed echocardiographic evaluation of the cardiovascular system and inflammatory biomarkers. Furthermore, little is known about biomarkers of aging and BA score (BAS) for healthy people in China. Objectives: The purpose of this study was to identify the biomarkers of healthy aging and to establish BAS for healthy people in China. Methods: We examined 2,876 men and women aged 30–98 years old in three Chinese cities, and 852 healthy subjects were assessed with 108 physical, morphological, physiological and biochemical variables. After excluding binary variables, variables that had a correlation coefficient with CA of ≤0.25 and redundant variables, eight variables including CA, arterial pulse pressure (PP), intima-media thickness (IMT), end diastolic velocity (EDV), ratio of peak velocity of early filling to atrial filling (E/A), mitral valve annulus lateral wall of peak velocity of early filling (MVEL), cystatin C (CYSC), and fibrinogen (FIB) were selected as candidate biomarkers of aging based on a factor-weighted BAS composite for predicting BA. Results: The BAS equation was 0.248 (CA) + 0.195 (IMT) – 0.196 (EDV) – 0.167 (E/A) – 0.166 (MVEL) + 0.188 (PP) + 0.182 (FIB) + 0.193 (CYSC). Individual BAS were significantly correlated with CA (r = 0.893, p < 0.001). Biological aging rate predicted by BAS was accelerated with increases in CA, and peaked when healthy men and women reached ≧75 years of age. Conclusions: Our data suggest that BAS is superior to CA in assessing the rate of aging in healthy Chinese people. The cardiovascular variables play a crucial role in the evaluation of biological aging. Biological aging rate appears to be age specific.

The correlation between peripheral leukocyte telomere length and indicators of cardiovascular aging.

OBJECTIVES To investigate the relationship between telomere length in peripheral blood white cells and cardiovascular function in a healthy, aging Han Chinese population. METHODS In 2012, peripheral blood leukocytes were obtained from 139 healthy individuals in Beijing, China, and telomere restriction fragment (TRF) length was assayed using a digoxigenin-labeled hybridization probe in Southern blot assays. Indicators of cardiovascular function were also evaluated, including electrocardiograms (ECG), (RR, P, PR, QRS, ST and T intervals); blood pressure (BP), (SBP, DBP, PP, PPI); cardiovascular ultrasound (left ventricular ejection fraction, LVEF); mitral early and late diastolic peak flow velocity (MVE and MVA); and lipid indices (TC, TG, HDL, LDL, LCI). The relationships of these cardiovascular indictors to telomere length were evaluated. RESULTS No correlations were found between telomere length and ECG, BP or lipid indices even after adjustment for age. Correlations were found between TFR length and some cardiovascular ultrasound indictors (D, MVEA, MVEDT, MVES, MVEL, MVEI, IMT), but these were not seen after adjusting for age. CONCLUSIONS We did not find that leukocyte TFR length was associated with cardiovascular ultrasound indictors, ECG, BP, or lipid indices in this population of healthy Han Chinese individuals. Telomere length may serve as a genetic factor in biological aging.

The Relationship between Age-Related Kidney Dysfunction and Framingham Risk Score in Healthy People in China

BACKGROUND Aging process reduces kidney function, glomerular filtration rate (GFR) and/or creatinine clearance rate (Ccr), and also significantly increases the risk level for cardiovascular diseases. The classical Framingham risk equation provides a method for predicting cardiovascular risk, but it does not include the kidney function indexes. In this study, we investigated the relationship between age-related kidney function and Framingham risk score (FRS) in healthy Chinese people, and validated to assess the risk factor by GFR/Ccr. METHODS This community-based cross-sectional study recruited 505 healthy subjects (age from 35 to 93 yr.) with both gender is during September 2007 to June 2008 in Shenyang. Framingham risk equation was used to evaluate cardiovascular risk factors and generate FRS. GFR and Ccr were calculated with Cockcroft-Gault (CG) equation (GFR(CG)), abbreviated Modification of Diet in Renal Disease Study (MDRD) equation (GFR(MDRD1)) and modified MDRD equation (GFR(MDRD2)). All data were sorted according to FRS (low, moderate and high) risk levels, and five different age groups (≤44 yr; 45-54 yr; 55-64 yr; 65-74 yr and ≥75 yr). The ANOVA, correlation, partial correlation between GFR/Ccr and FRS, as well as other risk factors were analyzed with SPSS16.0 statistical package. RESULTS As the FRS level increased, GFR(CG), GFR(MDRD1), GFR(MDRD2) and Ccr decreased about 10 to 30% (low>moderate> high risk group, p<0.01). While the subjects were getting older, GFR(CG), GFR(MDRD1), GFR(MDRD2) and Ccr showed significant reduction (P<0.001). Ccr decreased about 50% from the young to oldest group (p<0.001). There was a significantly inverse correlation between FRS and GFR with Ccr having the Pearson correlation coefficient -0.586 (GFR(CG), P<0.001), - 0.449 (GFR(MDRD1) and GFR(MDRD2), P<0.001), -0.459 (Ccr, P<0.001). However, the relationship between FRS and Ccr was lost after controlling for age and other confounding variables. CONCLUSION In healthy population, we found inverse correlations between Framingham risk score and GFR, Ccr and GFR were independently related to the FRS with similar correlation coefficient among three equations. With the increase of FRS, the GFR and Ccr decrease. Aging is the major factor of GFR and Ccr reduction in the healthy population. We suggest that GFR/Ccr could be used as risk indexes for cardiovascular diseases.

The association of serum cathepsin B concentration with age-related cardiovascular-renal subclinical state in a healthy Chinese population.

CONTEXT Cathepsin B (CTSB) is an important enzyme for many physiological and pathological processes, and its activity increases with age. Here, we explored the association between serum CTSB and aging-related subclinical cardiovascular and renal status in a healthy Chinese population. METHODS The study included 369 healthy individuals aged 36-87 years. Cardiovascular structure and function were assessed by the left ventricular ejection fraction, the early-diastolic peak flow velocity to late-diastolic peak flow velocity ratio at the mitral leaflet tips, carotid intima-media thickness (IMT), the diameter of the bilateral common carotid artery (D), and blood systolic peak (SPV) and end diastolic velocities, which were measured by M-mode ultrasonography. Serum CTSB, insulin-like growth factor-1 (IGF-1), 1, 25-dihydroxy vitamin D3, and parathyroid hormone (PTH) were measured by enzyme-linked immunosorbent assay. RESULTS In men, serum CTSB was significantly related to IMT and IMT/D in the unadjusted model, and these associations were lost after age adjustment. In women, serum CTSB remained significantly associated with serum creatinine (SCr) (p=0.009), estimated glomerular filtration rate (p=0.048) and IMT/D (p=0.017) following full adjustment. PTH was independently associated with SCr. IGF-1 was significantly associated with SPV in women. CTSB was correlated with metabolic and endocrine biomarkers. CONCLUSION Serum CTSB was associated with aging-related cardiovascular-renal parameters even in healthy people. Measurement of serum CTSB alone or in combination with metabolic and endocrine biomarkers can provide valuable information for predicting cardiovascular-renal function in healthy people, especially in elderly women.