The Leucocyte Telomere Length,GSTM1 and GSTT1 Null Genotypes and the Risk of Chronic Obstructive Pulmonary Disease

Simple SummaryChronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation and oxidative stress, both in the airways and blood, and in other organs. Elevated oxidative stress and inflammation have been reported to affect leucocyte telomere length (LTL). We explored the link between GSTM1 and GSTT1 gene polymorphisms, LTL and COPD risk. For GSTM1 and GSTT1, we genotyped 152 COPD patients and 131 non-affected controls, while for TL, we assessed 91 patients and 88 controls. There was a significant difference in GSTM1 null genotype frequency between the patients and controls (0.59 vs. 0.38, p ≤ 0.000), but such was not found for GSTT1 (p = 0.192). COPD patients carrying the GSTM1 null genotype had shorter telomeres compared to those carrying the non-null genotype (15,720 bp vs. 22,442 bp, p = 0.008); and in controls, the opposite occurred (31,354 bp vs. 17,800 bp, p = 0.020). According to our results GSTM1, but not GSTT1, null genotypes might play role in leucocyte telomere shortening, and thus be involved in the pathogenesis of COPD.AbstractChronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation and oxidative stress both in the airways and blood and other organs. Elevated oxidative stress and inflammation have been reported to affect leucocyte telomere length (LTL). Glutathione S-transferase (GST) enzymes are a large family of xenobiotic-metabolizing enzymes that utilize different ROS products. We aimed to explore the link between GSTM1 and GSTT1 gene polymorphisms, LTL and COPD risk. For GSTM1, we genotyped 152 COPD patients and 131 non-affected controls; for GSTT1, we genotyped 149 COPD patients and 130 controls. We were able to assess TL for 91 patients and 88 controls. There was a significant difference in the GSTM1 null genotype frequency between the patients and controls (0.59 vs. 0.38, p ≤ 0.000), but such was not found for GSTT1 (p = 0.192). When combining both polymorphisms, we obtained a significantly greater presence of at least one null genotype among patients (0.12 vs. 0.05, p = 0.027). An association between GSTT1 and LTL was not found. COPD patients carrying the GSTM1 null genotype had shorter telomeres compared to those carrying the non-null genotype (15,720 bp vs. 22,442 bp, p = 0.008); as for the controls, it was the opposite (31,354 bp vs. 17,800 bp, p = 0.020). The significance in both groups remained when combining GSTM1 and GSTT1 (COPD (at least one null) 16,409 bp vs. COPD (non-null) 22,092 bp, p = 0.029; control (at least one null) 29,666 bp vs. control (non-null) 16,370 bp, p = 0.027). The total glutathione level in GSTM1 non-null controls was higher compared to the null genotype (15.39 ng/mL vs. 5.53 ng/mL, p = 0.002). In COPD patients, we found no association (p = 0.301). In conclusion, according to our results, GSTM1, but not GSTT1, null genotypes might play a role in leucocyte telomere shortening, and thus be involved in the pathogenesis of COPD.     

Insulin resistance, oxidative stress, hypertension, and leukocyte telomere length in men from the Framingham Heart Study

Insulin resistance and oxidative stress are associated with accelerated telomere attrition in leukocytes. Both are also implicated in the biology of aging and in aging-related disorders, including hypertension. We explored the relations of leukocyte telomere length, expressed by terminal restriction fragment (TRF) length, with insulin resistance, oxidative stress and hypertension. We measured leukocyte TRF length in 327 Caucasian men with a mean age of 62.2 years (range 40-89 years) from the Offspring cohort of the Framingham Heart Study. TRF length was inversely correlated with age (r = -0.41, P < 0.0001) and age-adjusted TRF length was inversely correlated with the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) (r =-0.16, P = 0.007) and urinary 8-epi-PGF(2alpha) (r = -0.16, P = 0.005) - an index of systemic oxidative stress. Compared with their normotensive peers, hypertensive subjects exhibited shorter age-adjusted TRF length (hypertensives = 5.93 +/- 0.042 kb, normotensives = 6.07 +/- 0.040 kb, P = 0.025). Collectively, these observations suggest that hypertension, increased insulin resistance and oxidative stress are associated with shorter leukocyte telomere length and that shorter leukocyte telomere length in hypertensives is largely due to insulin resistance.     

Postprandial endothelial function, inflammation, and oxidative stress in obese children and adolescents

Most studies in adults suggest that acute glucose consumption induces a transient impairment in endothelial function. We hypothesized that obese youth would demonstrate reduced endothelial function and increased inflammation and oxidative stress following acute glucose ingestion and that transient elevations in plasma glucose would correlate with endothelial dysfunction, inflammation, and oxidative stress. Thirty-four obese (BMI ≥ 95th percentile) children and adolescents (age 12.4 ± 2.6 years; BMI = 37.9 ± 6.7 kg/m2; 50% females) underwent measurement of endothelial function (reactive hyperemic index (RHI)), glucose, insulin, C-reactive protein (CRP), interleukin-6 (IL-6), circulating oxidized low-density lipoprotein (oxLDL), and myeloperoxidase (MPO) in a fasting state and at 1- and 2-h following glucose ingestion. Repeated measures ANOVA with Tukey post-tests and Pearson correlations were performed. Glucose and insulin levels significantly increased at 1- and 2-h (all P values < 0.001). Compared to baseline, there were no statistically significant differences in 1- and 2-h RHI, CRP, IL-6, and oxLDL. However, MPO significantly decreased at the 1- (P < 0.05) and 2-h (P < 0.001) time points. At the 1-h time point, glucose level was significantly inversely correlated with RHI (r = -0.40, P < 0.05) and at the 2-h time point, glucose level was positively correlated with MPO (r = 0.40, P < 0.05). An acute oral glucose load does not reduce endothelial function or increase levels of inflammation or oxidative stress in obese youth. However, associations of postprandial hyperglycemia with endothelial function and oxidative stress may have implications for individuals with impaired glucose tolerance or frank type 2 diabetes.     

Leukocyte telomeres are longer in African Americans than in whites: the National Heart, Lung, and Blood Institute Family Heart Study and the Bogalusa Heart Study

Leukocyte telomere length (LTL) is ostensibly a bio-indicator of human aging. Here we report that African Americans have longer LTL than whites. We studied cross-sectionally 2453 individuals from the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study (age = 30–93 years) and the Bogalusa Heart Study (age = 19–37 years), comprising 1742 whites and 711 African Americans. We measured LTL by Southern blots of the terminal restriction fragments length. In 234 participants, telomere repeats were also measured by quantitative polymerase chain reaction (qPCR). Adjusted for age and body mass index (BMI), the respective leukocyte telomere lengths (mean ± SEM) were considerably longer in African Americans than in whites both in the Family Heart Study (7.004 ± 0.033 kb vs. 6.735 ± 0.024 kb, p  < 0.0001) and the Bogalusa Heart Study (7.923 ± 0.063 kb vs. 7.296 ± 0.039 kb, p  < 0.0001). We confirmed the racial effect on LTL by qPCR (3.038 ± 0.565 T/S units for African Americans vs. 2.714 ± 0.487 T/S units for whites, p  < 0.001). Cross-sectionally, sex- and BMI-adjusted LTL became shorter with age (range 19–93 years) at a steeper slope in African Americans than in whites (0.029 kb year⁻¹ vs. 0.020 kb year⁻¹, respectively, p  = 0.0001). We suggest that racial difference in LTL arises from a host of interacting biological factors, including replication rates of hematopoietic stem cells.     

Neural tube defects and maternal biomarkers of folate, homocysteine, and glutathione metabolism

BACKGROUND: Alterations in maternal folate and homocysteine metabolism are associated with neural tube defects (NTDs). The role played by specific micronutrients and metabolites in the causal pathway leading to NTDs is not fully understood. METHODS: We conducted a case-control study to investigate the association between NTDs and maternal alterations in plasma micronutrients and metabolites in two metabolic pathways: methionine remethylation and glutathione transsulfuration. Biomarkers were measured in a population-based sample of women who had NTD-affected pregnancies (n = 43) and a control group of women who had a pregnancy unaffected by a birth defect (n = 160). We compared plasma concentrations of folate, vitamin B(12), vitamin B(6), methionine, S-adenosylmethionine (SAM), s-adenosylhomocysteine (SAH), adenosine, homocysteine, cysteine, and reduced and oxidized glutathione between cases and controls after adjusting for lifestyle and sociodemographic factors. RESULTS: Women with NTD-affected pregnancies had significantly higher plasma concentrations of SAH (29.12 vs. 23.13 nmol/liter, P = .0011), adenosine (0.323 vs. 0.255 mumol/liter; P = .0269), homocysteine (9.40 vs. 7.56 micromol/liter; P < .001), and oxidized glutathione (0.379 vs. 0.262 micromol/liter; P = .0001), but lower plasma SAM concentrations (78.99 vs. 83.16 nmol/liter; P = .0172) than controls. This metabolic profile is consistent with reduced methylation capacity and increased oxidative stress in women with affected pregnancies. CONCLUSIONS: Increased maternal oxidative stress and decreased methylation capacity may contribute to the occurrence of NTDs. Further analysis of relevant genetic and environmental factors is required to define the basis for these observed alterations.     

Polymorphisms in the NQO1, GSTT and GSTM genes are associated with coronary heart disease and biomarkers of oxidative stress

It was hypothesized that the presence of genetic polymorphisms that decrease activity of the detoxification enzymes glutathione-S-transferase (GST) and quinone oxido-reductase (NQO1) may contribute to heart disease and affect biomarkers of coronary health and oxidative stress. Sixty-seven patients with angiographically confirmed coronary heart disease (CHD) and 63 healthy controls were genotyped for polymorphisms in the GST isoforms Mu and Theta (GSTM and GSTT respectively) and NQO1. Participants' blood levels of homocysteine (Hcy), C-reactive protein (CRP), oxidized low density lipoprotein (LDL) and total antioxidant capacity (TAOX) were measured. TAOX levels were significantly lower in women than men (P < or = 0.001) and this finding was more marked in the control group (P < or = 0.001). Hcy levels were higher in CHD patients (P=0.003 vs. control) which was mostly attributed to female patients (P=0.034 case vs. control). GSTM polymorphisms were present with greater frequencies in CHD cases with the odds ratio (OR) for GSTM equal to 3.77 vs. control. CHD patients also have an increased incidence of both GSTM and GSTT null polymorphisms (OR=5.13). In contrast, NQO1 polymorphisms were protective in CHD patients (OR=0.18 vs. control), which when stratified for genotype was due to heterozygous individuals. Significantly higher C-reactive protein levels occurred in CHD patients with lower NQO1 activity (P=0.001), however, due to the large variations in CRP levels seen in CHD patients; the clinical importance of this difference is unclear. Smokers with the GSTM null polymorphism were more likely to have CHD than non-smokers expressing the GSTM null polymorphism (OR=3.54, P=0.079). We conclude that a lack of activity in the detoxification enzymes NQO1 and GSTM, and biomarker levels are strongly associated with coronary heart disease with sex as a mitigating factor.     

Race,Ethnicity, Psychosocial Factors,and Telomere Length in a Multicenter Setting

Background

Leukocyte telomere length(LTL) has been associated with age, self-reported race/ethnicity, gender, education, and psychosocial factors, including perceived stress, and depression. However, inconsistencies in associations of LTL with disease and other phenotypes exist across studies. Population characteristics, including race/ethnicity, laboratory methods, and statistical approaches in LTL have not been comprehensively studied and could explain inconsistent LTL associations.

Methods

LTL was measured using Southern Blot in 1510 participants from a multi-ethnic, multi-center study combining data from 3 centers with different population characteristics and laboratory processing methods. Main associations between LTL and psychosocial factors and LTL and race/ethnicity were evaluated and then compared across generalized estimating equations(GEE) and linear regression models. Statistical models were adjusted for factors typically associated with LTL(age, gender, cancer status) and also accounted for factors related to center differences, including laboratory methods(i.e., DNA extraction). Associations between LTL and psychosocial factors were also evaluated within race/ethnicity subgroups (Non-hispanic Whites, African Americans, and Hispanics).

Results

Beyond adjustment for age, gender, and cancer status, additional adjustments for DNA extraction and clustering by center were needed given their effects on LTL measurements. In adjusted GEE models, longer LTL was associated with African American race (Beta(β)(standard error(SE)) = 0.09(0.04), p-value = 0.04) and Hispanic ethnicity (β(SE) = 0.06(0.01), p-value = 0.02) compared to Non-Hispanic Whites. Longer LTL was also associated with less than a high school education compared to having greater than a high school education (β(SE) = 0.06(0.02), p-value = 0.04). LTL was inversely related to perceived stress (β(SE) = -0.02(0.003), p<0.001). In subgroup analyses, there was a negative association with LTL in African Americans with a high school education versus those with greater than a high school education(β(SE) = -0.11(0.03), p-value<0.001).

Conclusions

Laboratory methods and population characteristics that differ by center can influence telomere length associations in multicenter settings, but these effects could be addressed through statistical adjustments. Proper evaluation of potential sources of bias can allow for combined multicenter analyses and may resolve some inconsistencies in reporting of LTL associations. Further, biologic effects on LTL may differ under certain psychosocial and racial/ethnic circumstances and could impact future health disparity studies.     

Telomeres,cardiovascular aging,and potential intervention for cellular senescence

A consistent association has been observed between leukocyte telomere length (LTL) and atherosclerosis, but the mechanisms underlying these associations are still not well understood. Premature biology aging was evident in atherosclerotic plaques, characterized by reduced cell proliferation, irreversible growth arrest and apoptosis, and telomere attrition. As atherosclerosis is a state of chronic low-grade inflammation and increased oxidative stress, shortened LTL in patients with atherosclerosis might stem from the two sources, one is an accelerated rate in hematopoietic stem cells (HSCs) replication to replace leukocytes consumed in the inflammatory process, and another is the increase in the loss of telomere repeats per replication. Thus, diminished HSC reserves at birth and age-dependent telomere attrition afterward are mirrored in shortened LTL during the adulthood. In addition, the inter-individual variation of LTL in the general population can be partly explained by genetic factors regulating telomere maintenance and the rate of HSCs replication. Atherosclerosis is an aging-related disease, and practically all humans develop atherosclerosis if they live long enough. Here we overview the potential roles of LTL dynamics in the imbalance between injurious oxidative stress/inflammation and endothelial repair during the pathogenesis of age-related atherosclerosis, and discuss the possibility that preventing accelerated cellular senescence is a potential target in prevention of atherosclerosis.     

CRP is related to higher leptin levels in minority peripubertal females regardless of adiposity levels

Overweight is related to higher levels of C-reactive protein (CRP) and leptin, which have been independently associated with increased risk for diabetes, cardiovascular disease, and the metabolic syndrome. Elevated CRP may trigger leptin resistance by inhibiting the binding of leptin to its receptors. We cross-sectionally examined the relationship between CRP, leptin, BMI z-score, percent body fat (%BF) assessed by air plethysmography (BodPod), and insulin sensitivity (SI) and acute insulin response (AIRg) measured by intravenous glucose tolerance test in 51 Latina and African-American females (77% Latina), mean age 9.2 (±0.9) years, at either Tanner Pubertal Stage (TPS) 1 (n = 25) or TPS 2 (n = 26). Females at TPS 2 had higher BMI z-scores, %BF (23% ± 10.1 vs. 30% ± 10.0, P = 0.02), AIRg (976.7 ± 735.2 vs. 1555.3 ± 1,223 μIU/ml, P = 0.05), fasting insulin (11.0 ± 10.8 vs. 17.2 ± 13.6 μlU/ml, P = 0.00) and leptin levels (11.0 ± 7.1 vs. 19.6 ± 10.9 ng/ml, P < 0.001) than those at TPS 1. There were no ethnic differences in any of the measured variables. CRP was positively correlated with BMI z-score (P = 0.001), %BF (P = 0.006), fasting insulin and AIRg (P = 0.02), and fasting leptin (P = 0.00), and negatively correlated with SI (P = 0.05). A linear regression model showed that CRP independently explained 10% (P = 0.00) of the variance in leptin after adjusting %BF, TPS, ethnicity, habitual physical activity and SI. Hence, low-grade inflammation may contribute to prolonged leptin exposure and leptin resistance, even in healthy children.     

Race/ethnicity and telomere length in the Multi-Ethnic Study of Atherosclerosis

Telomere length has emerged as a marker of exposure to oxidative stress and aging. Race/ethnic differences in telomere length have been infrequently investigated. Leukocyte telomere length (LTL) was assessed 981 white, black and Hispanic men and women aged 45–84 years participating in the Multi-Ethnic Study of Atherosclerosis. Direct measurement and questionnaire were used to assess covariates. Linear regression was used to estimate associations of LTL with race/ethnicity and age after adjustment for sex, income, education, smoking, physical activity, diet and body mass index. On average blacks and Hispanics had shorter telomeres than whites [adjusted mean differences (standard error) in T/S ratio compared to whites: −0.041 (0.018) for blacks and −0.044 (0.018) for Hispanics]. Blacks and Hispanics showed greater differences in telomere length associated with age than whites (adjusted mean differences in T / S ratio per 1 year increase in age −0.0018, −0.0047 and −0.0055 in whites, blacks and Hispanics respectively). Differences in age associations were more pronounced and only statistically significant in women. Race/ethnic differences in LTL may reflect the cumulative burden of differential exposure to oxidative stress (and its predictors) over the lifecourse.     

Association of Insulin Resistance,Arterial Stiffness and Telomere Length in Adults Free of Cardiovascular Diseases

Background

Chronic inflammation and oxidative stress might be considered the key mechanisms of aging. Insulin resistance (IR) is a phenomenon related to inflammatory and oxidative stress. We tested the hypothesis that IR may be associated with cellular senescence, as measured by leukocyte telomere length (LTL), and arterial stiffness (core feature of arterial aging), as measured by carotid-femoral pulse wave velocity (c-f PWV).

Methods

The study group included 303 subjects, mean age 51.8 ±13.3 years, free of known cardiovascular diseases and regular drug consumption. For each patient, blood pressure was measured, blood samples were available for biochemical parameters, and LTL was analyzed by real time q PCR. C-f PWV was measured with the help of SphygmoCor. SAS 9.1 was used for statistical analysis.

Results

Through multiple linear regression analysis, c-f PWV is independently and positively associated with age (p = 0.0001) and the homeostasis model assessment of insulin resistance (HOMA-IR; p = 0.0001) and independently negatively associated with LTL (p = 0.0378). HOMA-IR seems to have a stronger influence than SBP on arterial stiffness. In all subjects, age, HOMA-IR, LTL, and SBP predicted 32% of the variance in c-f PWV. LTL was inversely associated with HOMA-IR (p = 0.0001) and age (p = 0.0001). In all subjects, HOMA-IR, age, sex, and SBP predicted 16% of the variance in LTL.

Conclusions

These data suggest that IR is associated with cell senescence and arterial aging and could, therefore, become the main target in preventing accelerated arterial aging, besides blood pressure control. Research in telomere biology may reveal new ways of estimating cardiovascular aging and risk.     

Sex differences in leucocyte telomere length in a free‐living mammal

Mounting evidence suggests that average telomere length reflects previous stress and predicts subsequent survival across vertebrate species. In humans, leucocyte telomere length (LTL) is consistently shorter during adulthood in males than in females, although the causes of this sex difference and its generality to other mammals remain unknown. Here, we measured LTL in a cross‐sectional sample of free‐living Soay sheep and found shorter telomeres in males than in females in later adulthood (>3 years of age), but not in early life. This observation was not related to sex differences in growth or parasite burden, but we did find evidence for reduced LTL associated with increased horn growth in early life in males. Variation in LTL was independent of variation in the proportions of different leucocyte cell types, which are known to differ in telomere length. Our results provide the first evidence of sex differences in LTL from a wild mammal, but longitudinal studies are now required to determine whether telomere attrition rates or selective disappearance are responsible for these observed differences.     

Mediterranean Diet,Telomere Maintenance and Health Status among Elderly

Leukocyte telomere length (LTL) and rate of telomere shortening are known biomarkers of aging while, numerous studies showed that Mediterranean diet (MD) may boost longevity. We studied association between telomere length, telomerase activity and different adherence to MD and its effects on healthy status. The study was conducted in 217 elderly subjects stratified according Mediterranean diet score (MDS) in low adherence (MDS≤3), medium adherence (MDS 4–5) and high adherence (MDS≥6) groups. LTL was measured by quantitative polymerase chain reaction and telomerase activity by a PCR-ELISA protocol. High adherence group showed longer LTL (p = 0.003) and higher telomerase activity (p = 0.013) compared to others. Linear regression analysis including age, gender, smoking habit and MDS showed that MDS was independently associated with LTL (p = 0.024) and telomerase activity levels (p = 0.006). Telomerase activity was independently associated with LTL (p = 0.007) and negatively modulated by inflammation and oxidative stress. Indeed, telomerase levels were associated with healthy status independently of multiple covariates (p = 0.048). These results support a novel role of MD in promoting health-span suggesting that telomere maintenance, rather than LTL variability is the major determinant of healthy status among elderly.     

Exercise training blunts oxidative stress in sickle cell trait carriers

The aim of this study was to analyze the effects of exercise training on oxidative stress in sickle cell trait carriers. Plasma levels of oxidative stress [advanced oxidation protein products (AOPP), protein carbonyl, malondialdehyde (MDA), and nitrotyrosine], antioxidant markers [catalase, glutathione peroxidase (GPX), and superoxide dismutase (SOD)], and nitrite and nitrate (NOx) were assessed at baseline, immediately following a maximal exercise test (T(ex)), and during recovery (T(1h), T(2h), T(24h)) in trained (T: 8 h/wk minimum) and untrained (U: no regular physical activity) sickle cell trait (SCT) carriers or control (CON) subjects (T-SCT, n = 10; U-SCT, n = 8; T-CON, n = 11; and U-CON, n = 11; age: 23.5 ± 2.2 yr). The trained subjects had higher SOD activities (7.6 ± 5.4 vs. 5.2 ± 2.1 U/ml, P = 0.016) and lower levels of AOPP (142 ± 102 vs. 177 ± 102 μM, P = 0.028) and protein carbonyl (82.1 ± 26.0 vs. 107.3 ± 30.6 nm/ml, P = 0.010) than the untrained subjects in response to exercise. In response to exercise, U-SCT had a higher level of AOPP (224 ± 130 vs. 174 ± 121 μM, P = 0.012), nitrotyrosine (127 ± 29.1 vs.70.6 ± 46.6 nM, P = 0.003), and protein carbonyl (114 ± 34.0 vs. 86.9 ± 26.8 nm/ml, P = 0.006) compared with T-SCT. T-SCT had a higher SOD activity (8.50 ± 7.2 vs. 4.30 ± 2.5 U/ml, P = 0.002) and NOx (28.8 ± 11.4 vs. 14.6 ± 7.0 μmol·l(-1)·min(-1), P = 0.003) in response to exercise than U-SCT. Our data indicate that the overall oxidative stress and nitric oxide response is improved in exercise-trained SCT carriers compared with their untrained counterparts. These results suggest that physical activity could be a viable method of controlling the oxidative stress. This could have a beneficial impact because of its involvement in endothelial dysfunction and subsequent vascular impairment in hemoglobin S carriers.     

Increased urinary excretion of 8-iso-prostaglandin F2alpha in patients with HFE-related hemochromatosis: a case-control study

The hypothesis according to which iron overload could be harmful has been extensively and controversially discussed in the literature. One underlying pathological mechanism may be elevated oxidative stress. Thus, we studied the correlation between hemochromatosis and an established marker of oxidative stress, 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha, iPF2alpha-III, 15-F2t-IsoP). We enrolled 21 patients with hemochromatosis, positive for the homozygous C282Y mutation in the HFE gene, and 21 healthy controls frequency-matched by age and gender in a case-control study design. The objective was to show that iron overload in HFE-related hemochromatosis is associated with increased oxidative stress assessed through 8-iso-PGF(2alpha) urinary excretion, and that oxidative stress is impacted by iron-removal treatment (phlebotomy). Study parameters were transferrin saturation, 8-iso-PGF(2alpha) urine excretion, transferrin, ferritin, serum iron, and vitamins A and E for all participants. Iron concentration in the liver and non-transferrin-bound iron were measured in patients only. We found a significant difference in 8-iso-PGF2alpha in patients (245 [interquartile range 157-348] pg/mg creatinine) compared with controls (128 [106-191] pg/mg creatinine, P = 0.002). Vitamin A was significantly reduced in cases (0.34 [0.25-1.83] microg/ml compared to 3.00 [2.11-3.39] microg/ml, P < 0.001), while vitamin E did not show a significant difference in cases (14.7 [11.5-18.1] microg/ml) compared with controls (14.9 [13.1-19.2] microg/ml, P = 0.52). After phlebotomy treatment and normalization of the iron parameters in the hemochromatosis group, serum vitamin A levels were significantly increased (1.36 [1.08-1.97] microg/ml, P = 0.035 vs. baseline, P < 0.001 vs. controls) and 8-iso-PGF2alpha urinary excretion was lowered to control levels (146 [117-198] pg/mg creatinine, P = 0.38 vs. controls). In our study, HFE-related hemochromatosis was associated with increased oxidative stress and hypovitaminemia A in C282Y homozygotes. The increased oxidative stress was reversible by normalization of the iron load by phlebotomy. Thus, phlebotomy is an effective and adequate means for reducing oxidative stress in these patients.     

Blood parameters indicative of oxidative stress are associated with symptom expression in chronic fatigue syndrome

Full blood counts, ESR, CRP, haematinics and markers for oxidative stress were measured for 33 patients diagnosed with chronic fatigue syndrome (CFS) and 27 age and sex matched controls. All participants also completed symptom questionnaires. CFS patients had increases in malondialdehyde (P <0.006), methaemoglobin (P <0.02), mean erythrocyte volume (P <0.02) and 2,3-diphosphoglycerate (P <0.04) compared with controls. Multiple regression analysis found methaemoglobin to be the principal component that differentiated between CFS patients and control subjects. Methaemoglobin was found to be the major component associated with variation in symptom expression in CFS patients (R(2) = 0.99, P <0.00001), which included fatigue, musculoskeletal symptoms, pain and sleep disturbance. Variation in levels of malondialdehyde and 2,3-diphosphoglycerate were associated with variations in cognitive symptoms and sleep disturbance (R(2) = 0.99, P <0.00001). These data suggest that oxidative stress due to excess free radical formation is a contributor to the pathology of CFS and was associated with symptom presentation.     

Cumulative inflammatory load is associated with short leukocyte telomere length in the Health, Aging and Body Composition Study

Background

Leukocyte telomere length (LTL) is an emerging marker of biological age. Chronic inflammatory activity is commonly proposed as a promoter of biological aging in general, and of leukocyte telomere shortening in particular. In addition, senescent cells with critically short telomeres produce pro-inflammatory factors. However, in spite of the proposed causal links between inflammatory activity and LTL, there is little clinical evidence in support of their covariation and interaction.

Methodology/Principal Findings

To address this issue, we examined if individuals with high levels of the systemic inflammatory markers interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP) had increased odds for short LTL. Our sample included 1,962 high-functioning adults who participated in the Health, Aging and Body Composition Study (age range: 70–79 years). Logistic regression analyses indicated that individuals with high levels of either IL-6 or TNF-α had significantly higher odds for short LTL. Furthermore, individuals with high levels of both IL-6 and TNF-α had significantly higher odds for short LTL compared with those who had neither high (OR = 0.52, CI = 0.37–0.72), only IL-6 high (OR = 0.57, CI = 0.39–0.83) or only TNF-α high (OR = 0.67, CI = 0.46–0.99), adjusting for a wide variety of established risk factors and potential confounds. In contrast, CRP was not associated with LTL.

Conclusions/Significance

Results suggest that cumulative inflammatory load, as indexed by the combination of high levels of IL-6 and TNF-α, is associated with increased odds for short LTL. In contrast, high levels of CRP were not accompanied by short LTL in this cohort of older adults. These data provide the first large-scale demonstration of links between inflammatory markers and LTL in an older population.     

Plasma levels of soluble CD36, platelet activation, inflammation, and oxidative stress are increased in type 2 diabetic patients

Inflammation, oxidative stress, and platelet activation are involved in type 2 diabetes and its complications. Soluble CD36 (sCD36) has been proposed to early identify diabetics at risk of accelerated atherothrombosis. We aimed at characterizing the platelet contribution to sCD36 in diabetes, by correlating its concentration with the extent of platelet-mediated inflammation and in vivo lipid peroxidation and investigating the effects of low-dose aspirin on these processes. A cross-sectional comparison of sCD36, soluble CD40L (sCD40L) reflecting platelet-mediated inflammation, urinary 11-dehydro-TxB(2), and 8-iso-PGF(2α), in vivo markers of platelet activation and lipid peroxidation, was performed among 200 diabetic patients (94 of them on aspirin 100mg/day) and 47 healthy controls. sCD36 levels (median [IQR]: 0.72 [0.31-1.47] vs 0.26 [0.2-0.37], P=0.003) and urinary 11-dehydro-TxB(2) levels (666 [293-1336] vs 279 [160-396], P≤0.0001) were significantly higher in diabetic patients not on aspirin (n=106) than in healthy subjects. These variables were significantly lower in aspirin-treated diabetics than untreated patients (P<0.0001). Among patients not on aspirin, those with long-standing diabetes (>1 year) had significantly higher sCD36 levels in comparison to patients with diabetes duration <1 year (1.01 [0.62-1.86] vs 0.44 [0.22-1.21], P=0.001). sCD36 linearly correlated with sCD40L (rho=0.447; P=0.0001). On multiple regression analysis, 11-dehydro-TxB(2) (β=0.360; SEM=0.0001, P=0.001), 8-iso-PGF(2α) (β=0.469; SEM=0.0001, P<0.0001), and diabetes duration (β=0.244; SEM=0.207, P=0.017) independently predicted sCD36 levels. sCD36, platelet activation, inflammation, and oxidative stress are increased in type 2 diabetes. Future studies are needed to elucidate if the incomplete down-regulation of sCD36 by low-dose aspirin implies that sCD36 may be derived from tissues other than platelets or if additional antiplatelet strategies in diabetes are necessary to interrupt CD36-dependent platelet activation.     

Leukocyte Telomere Length in Young Adults Born Preterm: Support for Accelerated Biological Ageing

Background

Subjects born preterm have an increased risk for age-associated diseases, such as cardiovascular disease in later life, but the underlying causes are largely unknown. Shorter leukocyte telomere length (LTL), a marker of biological age, is associated with increased risk of cardiovascular disease.

Objectives

To compare LTL between subjects born preterm and at term and to assess if LTL is associated with other putative cardiovascular risk factors at young adult age.

Methods

We measured mean LTL in 470 young adults. LTL was measured using a quantitative PCR assay and expressed as T/S ratio. We analyzed the influence of gestational age on LTL and compared LTL between subjects born preterm (n = 186) and at term (n = 284). Additionally, we analyzed the correlation between LTL and potential risk factors of cardiovascular disease.

Results

Gestational age was positively associated with LTL (r = 0.11, p = 0.02). Subjects born preterm had shorter LTL (mean (SD) T/S ratio = 3.12 (0.44)) than subjects born at term (mean (SD) T/S ratio = 3.25 (0.46)), p = 0.003). The difference remained significant after adjustment for gender and size at birth (p = 0.001). There was no association of LTL with any one of the putative risk factors analyzed.

Conclusions

Young adults born preterm have shorter LTL than young adults born at term. Although we found no correlation between LTL and risk for CVD at this young adult age, this biological ageing indicator may contribute to CVD and other adult onset diseases at a later age in those born preterm.