Circulating cell-free DNA in health and disease - the relationship to health behaviours, ageing phenotypes and metabolomics.

Circulating cell-free DNA (cf-DNA) has emerged as a promising biomarker of ageing, tissue damage and cellular stress. However, less is known about health behaviours, ageing phenotypes and metabolic processes that lead to elevated cf-DNA levels. We sought to analyse the relationship of circulating cf-DNA level to age, sex, smoking, physical activity, vegetable consumption, ageing phenotypes (physical functioning, the number of diseases, frailty) and an extensive panel of biomarkers including blood and urine metabolites and inflammatory markers in three human cohorts (N = 5385; 17-82 years). The relationships were assessed using correlation statistics, and linear and penalised regressions (the Lasso), also stratified by sex.cf-DNA levels were significantly higher in men than in women, and especially in middle-aged men and women who smoke, and in older more frail individuals. Correlation statistics of biomarker data showed that cf-DNA level was higher with elevated inflammation (C-reactive protein, interleukin-6), and higher levels of homocysteine, and proportion of red blood cells and lower levels of ascorbic acid. Inflammation (C-reactive protein, glycoprotein acetylation), amino acids (isoleucine, leucine, tyrosine), and ketogenesis (3-hydroxybutyrate) were included in the cf-DNA level-related biomarker profiles in at least two of the cohorts.In conclusion, circulating cf-DNA level is different by sex, and related to health behaviour, health decline and metabolic processes common in health and disease. These results can inform future studies where epidemiological and biological pathways of cf-DNA are to be analysed in details, and for studies evaluating cf-DNA as a potential clinical marker.

Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction.

Cellular senescence has been shown to contribute to skin ageing. However, the role of melanocytes in the process is understudied. Our data show that melanocytes are the only epidermal cell type to express the senescence marker p16INK4A during human skin ageing. Aged melanocytes also display additional markers of senescence such as reduced HMGB1 and dysfunctional telomeres, without detectable telomere shortening. Additionally, senescent melanocyte SASP induces telomere dysfunction in paracrine manner and limits proliferation of surrounding cells via activation of CXCR3-dependent mitochondrial ROS. Finally, senescent melanocytes impair basal keratinocyte proliferation and contribute to epidermal atrophy in vitro using 3D human epidermal equivalents. Crucially, clearance of senescent melanocytes using the senolytic drug ABT737 or treatment with mitochondria-targeted antioxidant MitoQ suppressed this effect. In conclusion, our study provides proof-of-concept evidence that senescent melanocytes affect keratinocyte function and act as drivers of human skin ageing.

Reallocating sitting time to standing or stepping through isotemporal analysis: associations with markers of chronic low-grade inflammation.

Although high levels of sitting time are adversely related to health, it is unclear whether moving from sitting to standing provides a sufficient stimulus to elicit benefits upon markers of chronic low-grade inflammation in a population at high risk of type 2 diabetes (T2DM). Three hundred and seventy two participants (age = 66.8 ± 7.5years; body mass index (BMI) = 31.7 ± 5.5kg/m2; Male = 61%) were included. Sitting, standing and stepping was determined using the activPAL3TM device. Linear regression modelling employing an isotemporal substitution approach was used to quantify the association of theoretically substituting 60 minutes of sitting per day for standing or stepping on interleukin-6 (IL-6), C-reactive protein (CRP) and leptin. Reallocating 60 minutes of sitting time per day for standing was associated with a -4% (95% CI -7%, -1%) reduction in IL-6 (p = 0.048). Reallocating 60 minutes of sitting time for light stepping was also associated with lower IL-6 levels (-28% (-46%, -4%; p = 0.025)). Substituting sitting for moderate-to-vigorous (MVPA) stepping was associated with lower CRP (-41% (-75%, -8%; p = 0.032)), leptin (-24% (-34%, -12%; p ≤ 0.001)) and IL-6 (-16% (-28%, 10%; p = 0.036). Theoretically replacing 60 minutes of sitting per day with an equal amount of either standing or stepping yields beneficial associations upon markers of chronic-low grade inflammation.

MARK-AGE biomarkers of ageing.

Many candidate biomarkers of human ageing have been proposed in the scientific literature but in all cases their variability in cross-sectional studies is considerable, and therefore no single measurement has proven to serve a useful marker to determine, on its own, biological age. A plausible reason for this is the intrinsic multi-causal and multi-system nature of the ageing process. The recently completed MARK-AGE study was a large-scale integrated project supported by the European Commission. The major aim of this project was to conduct a population study comprising about 3200 subjects in order to identify a set of biomarkers of ageing which, as a combination of parameters with appropriate weighting, would measure biological age better than any marker in isolation.

Plant-rich mixed meals based on Palaeolithic diet principles have a dramatic impact on incretin, peptide YY and satiety response, but show little effect on glucose and insulin homeostasis: an acute-effects randomised study.

There is evidence for health benefits from 'Palaeolithic' diets; however, there are a few data on the acute effects of rationally designed Palaeolithic-type meals. In the present study, we used Palaeolithic diet principles to construct meals comprising readily available ingredients: fish and a variety of plants, selected to be rich in fibre and phyto-nutrients. We investigated the acute effects of two Palaeolithic-type meals (PAL 1 and PAL 2) and a reference meal based on WHO guidelines (REF), on blood glucose control, gut hormone responses and appetite regulation. Using a randomised cross-over trial design, healthy subjects were given three meals on separate occasions. PAL2 and REF were matched for energy, protein, fat and carbohydrates; PAL1 contained more protein and energy. Plasma glucose, insulin, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP) and peptide YY (PYY) concentrations were measured over a period of 180 min. Satiation was assessed using electronic visual analogue scale (EVAS) scores. GLP-1 and PYY concentrations were significantly increased across 180 min for both PAL1 (P= 0·001 and P< 0·001) and PAL2 (P= 0·011 and P= 0·003) compared with the REF. Concomitant EVAS scores showed increased satiety. By contrast, GIP concentration was significantly suppressed. Positive incremental AUC over 120 min for glucose and insulin did not differ between the meals. Consumption of meals based on Palaeolithic diet principles resulted in significant increases in incretin and anorectic gut hormones and increased perceived satiety. Surprisingly, this was independent of the energy or protein content of the meal and therefore suggests potential benefits for reduced risk of obesity.

Reactive oxygen species production and mitochondrial dysfunction in white blood cells are not valid biomarkers of ageing in the very old.

Reliable and valid biomarkers of ageing (BoA) are needed to understand mechanisms, test interventions and predict the timing of adverse health events associated with ageing. Since increased reactive oxygen species (ROS) production and mitochondrial dysfunction are consequences of cellular senescence and may contribute causally to the ageing of organisms, we focused on these parameters as candidate BoA. Superoxide levels, mitochondrial mass and mitochondrial membrane potential in human peripheral blood mononuclear cells (PBMCs) and subpopulations (lymphocytes and monocytes) were measured in participants from the Newcastle 85+ study, a population-based study of the very old (aged 85 years and older). The intra- and inter-assay precision expressed as coefficient of variation (CV) for all parameters was acceptable (3% to 12% and 5 to 22% respectively). All parameters were stable in the short-term (1 week interval) in a sample of control individuals in the PBMCs and lymphocyte subpopulation, however they were unstable in the monocyte subpopulation; this rendered monocytes unreliable for further analysis. There was a significant association between superoxide levels and mitochondrial mass (positive in lymphocytes, p = 0.01) and between superoxide levels and mitochondrial membrane potential (negative in PBMCs, p = 0.01; positive in lymphocytes, p = 0.05). There were also significant associations between superoxide levels and mitochondrial parameters with other markers of oxidative stress-induced cellular senescence (p≤0.04), however some were in the opposite direction to expected. No associations were found between the measured parameters and age-related outcomes, including cognitive impairment, disability, co-morbidity and survival - questioning the validity of these parameters as candidate BoA in the very old.

Sedentary time and markers of chronic low-grade inflammation in a high risk population.

BACKGROUND: Sedentary behaviour has been identified as a distinct risk factor for several health outcomes. Nevertheless, little research has been conducted into the underlying mechanisms driving these observations. This study aimed to investigate the association of objectively measured sedentary time and breaks in sedentary time with markers of chronic low-grade inflammation and adiposity in a population at a high risk of type 2 diabetes mellitus. METHODS: This study reports data from an ongoing diabetes prevention programme conducted in Leicestershire, UK. High risk individuals were recruited from 10 primary care practices. Sedentary time (<25 counts per 15 s) was measured using Actigraph GT3X accelerometers (15 s epochs). A break was considered as any interruption in sedentary time (≥25 counts per 15 s). Biochemical outcomes included interleukin-6 (IL-6), C-reactive protein (CRP), leptin, adiponectin and leptin:adiponectin ratio (LAR). A sensitivity analysis investigated whether results were affected by removing participants with a CRP level >10 mg/L, as this can be indicative of acute inflammation. RESULTS: 558 participants (age = 63.6±7.7 years; male = 64.7%) had complete adipokine and accelerometer data. Following adjustment for various confounders, sedentary time was detrimentally associated with CRP (ß = 0.176±0.057, p = 0.002), IL-6 (ß = 0.242±0.056, p = <0.001), leptin (ß = 0.146±0.043, p = <0.001) and LAR (ß = 0.208±0.052, p = <0.001). Associations were attenuated after further adjustment for moderate-to-vigorous physical activity (MVPA) with only IL-6 (ß = 0.231±0.073, p = 0.002) remaining significant; this result was unaffected after further adjustment for body mass index and glycosylated haemoglobin (HbA1c). Similarly, breaks in sedentary time were significantly inversely associated with IL-6 (ß = -0.094±0.047, p = 0.045) and leptin (ß = -0.075±0.037, p = 0.039); however, these associations were attenuated after adjustment for accelerometer derived variables. Excluding individuals with a CRP level >10 mg/L consistently attenuated the significant associations across all markers of inflammation. CONCLUSION: These novel findings from a high risk population recruited through primary care suggest that sedentary behaviour may influence markers associated with inflammation, independent of MVPA, glycaemia and adiposity.

Effect of short-term reduced physical activity on cardiovascular risk factors in active lean and overweight middle-aged men.

OBJECTIVES: An experimental reduction in physical activity is a useful tool for exploring the health benefits of physical activity. This study investigated whether similarly-active overweight men show a more pronounced response to reduced physical activity than their lean counterparts because of their atherogenic phenotype (i.e., greater abdominal adiposity). METHODS: From 115 active men aged 45-64years, we recruited nine active lean (waist circumference <84cm) and nine active central overweight men (waist circumference >94cm). Fasting blood samples and responses to an oral glucose tolerance test (OGTT) were measured at baseline and following one week of reduced physical activity to simulate sedentary levels (removal of structured exercise and reduced habitual physical activity). RESULTS: Glucose and insulin areas under the curve (AUC), CRP, ALT, TAG were all higher in the overweight group and remained so throughout (P<0.05). Insulin and glucose AUC responses to an OGTT, as well as fasting triglyceride (TAG) concentrations, increased in both groups as a result of the intervention (P<0.05). There was no change in interleukin-6, C-reactive protein (CRP), Tumour Necrosis Factor-α, soluble intracellular adhesion molecule 1, or alanine transaminase (ALT). CONCLUSION: One-week of reduced activity similarly-impaired glucose control and increased fasting TAG in both lean and overweight men. Importantly, in spite of very similar (high) levels of habitual physical activity, central overweight men displayed a poorer profile for various inflammatory and metabolic outcomes (CRP, ALT, TAG, glucose AUC and insulin AUC).

Stress-related thinking predicts the cortisol awakening response and somatic symptoms in healthy adults.

OBJECTIVE: Perseverative cognition (i.e., worry, stress-related thinking) may prolong stress-related physiological activation. However, its role within the context of the written emotional disclosure paradigm has not been examined. This study explored: (1) the effects of stress-related thinking on the cortisol awakening response and upper respiratory infection symptoms and; (2) the efficacy of two expressive writing interventions on these health outcomes. METHODS: Participants were randomly assigned to write about their most stressful life experience (using the Guided Disclosure Protocol; n=39) or positive life experiences (n=42) or plans for the day (n=41) for 20 min on 3 consecutive days. Participants reported the extent to which they thought about their assigned writing topic during the study and in the past (event-related thought). Cortisol was measured at 0, 15, 30 and 45 min after awakening on 2 consecutive days at baseline and 4 weeks post-intervention. Upper respiratory infection (URI) symptoms were assessed at baseline, at 4 weeks and at 6 months. RESULTS: Results showed that the writing interventions had no beneficial effects on any of the outcome measures. However, a significant interaction was found between event-related thought and condition on the cortisol awakening response at 1 month follow-up and URI symptoms at 6 months. Among participants who wrote about stressful/traumatic events, higher stress-related thinking during the study predicted increased cortisol levels and URI symptoms compared to participants who reported low stress-related thinking. DISCUSSION: These findings are broadly consistent with Brosschot et al.'s (2006) perseverative cognition hypothesis and highlight the importance of ruminative thinking in understanding stress-health processes.

Conduit vessel stiffness in British south Asians of Indian descent relates to 25-hydroxyvitamin D status.

BACKGROUND: South Asians migrating to Northern latitudes are more susceptible to premature cardiovascular disease (CVD) than expected for given levels of blood pressure. Vitamin D deficiency is common in this group and may play an important role mediating vascular wall senescence in response to central pressure effects. METHODS: A cross-sectional association study. South Asian and White European participants were randomly recruited from a population-based diabetes-screening programme. Carotid-femoral pulse wave velocity (cfPWV), biochemistry (25-hydroxyvitamin D, fasting glucose), anthropometrics, resting blood pressure and a physical activity measure (International Physical Activity Questionnaire) were measured under controlled conditions. PARTICIPANTS: One hundred and thirty-two and 125 age-matched South Asians and White Europeans not taking vitamin D supplementation with a risk factor for diabetes but no overt CVD. RESULTS: Age (mean south Asian: 55.7 vs. White European: 56.0 years), mean arterial pressure (MAP) and calculated CVD risk were similar in both groups. Unadjusted (cf)PWV (m/s) was higher (9.32 vs. 8.68 P = 0.001) and 25-hydroxyvitamin D (nmol/l) lower in (21.29 vs. 52.5 P < 0.001) south Asians. 25-Hydroxyvitamin D independently associated with cfPWV in multivariate modelling adjusted for age, MAP, sex, glucose, heart rate, vasoactive medication and south Asian ethnicity (R = 0.73, P = 0.004). 25-Hydroxyvitamin D but not physical activity was negatively correlated with cfPWV independent of south Asian ethnicity. CONCLUSION: Aortic stiffness is increased in British Indo-Asians without vascular disease despite conventional risk profiles, which are comparable to age-matched white Europeans. This effect may be mediated by a greater pressure-dependent increase in stiffness in individuals with vitamin D insufficiency.

An investigation into the relationship between sleep-disordered breathing, the metabolic syndrome, cardiovascular risk profiles, and inflammation between South Asians and Caucasians residing in the United Kingdom.

BACKGROUND: The aim of this study was to determine the prevalence of sleep-disordered breathing (SDB) in a South Asian and a Caucasian population and to compare the cardiovascular risk factors in those with SDB within these ethnic groups and determine if SDB is independently associated with the metabolic syndrome and markers of inflammation. METHODS: A total of 1,598 participants within a U.K. multiethnic population underwent an oral glucose tolerance test, completed the Berlin Sleep Questionnaire, and provided anthropometric data and fasting bloods. Metabolic syndrome was classified according to National Cholesterol Education Program Adult Treatment Panel III criteria. RESULTS: The prevalence of SDB was 28.3% and did not differ between the two ethnic groups. South Asians with SDB had a higher body fat percentage (38.4±10% vs. 35.6±9%, P=0.016), glycosylated hemoglobin (5.6±0.5% vs. 5.6±0.5%, P=0.001) and lower high-density lipoprotein cholesterol (1.21±0.23 mmol/L vs. 1.29±0.34 mmol/L, P=0.002) compared to Caucasians with SDB, who were older (59.6±8.6 years vs. 50.4±10.3 years, P<0.001) and had higher systolic blood pressure (139.8±18.5 mmHg vs. 131.7±18.6 mmHg, P<0.001). SDB was associated with metabolic syndrome after adjustment for age, gender, ethnicity, and waist circumference (odds ratio=1.54, 95% confidence interval 1.12-2.09, P=0.01). There was no independent association between SDB and markers of inflammation. CONCLUSION: The relationship between SDB and metabolic syndrome is not driven via the inflammatory pathway. The prevalence of SDB is significantly higher in those with metabolic syndrome although these South Asians had a greater cardiovascular disease (CVD) risk profile the relationship is independent of ethnicity. Routine screening for SDB within primary/secondary care may have a role in the prevention of CVD and type 2 diabetes mellitus.

Self-reported sitting time and markers of inflammation, insulin resistance, and adiposity.

BACKGROUND: Sedentary behavior is emerging as an independent risk factor for chronic disease; however, potential mechanisms underpinning these observations are not well understood. PURPOSE: This study aimed to investigate the association of self-reported weekday sitting time with biomarkers linked to chronic low-grade inflammation, insulin resistance, and adiposity. METHODS: This study reports data from individuals attending a diabetes screening program, United Kingdom, 2004-2007; analysis was conducted in 2010. Sitting time and physical activity were measured using the International Physical Activity Questionnaire; biochemical outcomes included fasting and 2-hour postchallenge glucose, fasting insulin, C-reactive protein (CRP), leptin, adiponectin, and interleukin-6 (IL-6). RESULTS: This study included 505 (female=46%; South-Asian ethnicity=19%, aged 59±10 years, BMI=29.5±4.7) individuals with valid sitting data. Increased sitting time was positively associated with fasting insulin, leptin, leptin/adiponectin ratio, CRP, and IL-6 in women, but not men, after adjustment for age, ethnicity, social deprivation, and smoking and medication status; interaction analysis revealed that the gender-specific differences were significant. The associations for women remained significant after additional adjustment for total moderate- to vigorous-intensity physical activity; however all associations were attenuated when further adjusted for BMI. There was no association between sitting time and glycemic status. CONCLUSIONS: Total self-reported weekday sitting time was associated with biomarkers linked to chronic low-grade inflammation and poor metabolic health in women, but not men, independent of physical activity.

Assessment of a large panel of candidate biomarkers of ageing in the Newcastle 85+ study.

Sensitive and specific biomarkers of ageing are needed to evaluate interventions to extend health span. However, there is growing evidence that information provided by candidate biomarkers may change with age itself. Little is yet known about the value of candidate biomarkers in those over 85 years, currently the fastest growing population sub-group in many countries. This study assessed a large panel of candidate biomarkers in a cohort of 85 years old by studying comparative associations with health status. Using a cross-sectional sample of 852 individuals aged 85, we performed uni- and multi-variable analyses of associations between 74 candidate biomarkers and 4 health-status measures: viz. multi-morbidity, cognitive impairment, disability and proximity to death as measured by mortality within 1.5 years. We defined as most informative any measures that were significantly associated with at least two of the health-status measures in multivariable analyses in this age group. 10 out of 74 tested candidates fulfilled this criterion, while several proposed biomarkers of ageing, notably inflammation and immune risk markers and telomere length, did not. As future data accrues on health outcomes within the cohort, it will become possible also to evaluate the predictive value of these and others of the candidate biomarkers.

Behavioral neurocardiac training in hypertension: a randomized, controlled trial.

It is not established whether behavioral interventions add benefit to pharmacological therapy for hypertension. We hypothesized that behavioral neurocardiac training (BNT) with heart rate variability biofeedback would reduce blood pressure further by modifying vagal heart rate modulation during reactivity and recovery from standardized cognitive tasks ("mental stress"). This randomized, controlled trial enrolled 65 patients with uncomplicated hypertension to BNT or active control (autogenic relaxation), with six 1-hour sessions over 2 months with home practice. Outcomes were analyzed with linear mixed models that adjusted for antihypertensive drugs. BNT reduced daytime and 24-hour systolic blood pressures (-2.4+/-0.9 mm Hg, P=0.009, and -2.1+/-0.9 mm Hg, P=0.03, respectively) and pulse pressures (-1.7+/-0.6 mm Hg, P=0.004, and -1.4+/-0.6 mm Hg, P=0.02, respectively). No effect was observed for controls (P>0.10 for all indices). BNT also increased RR-high-frequency power (0.15 to 0.40 Hz; P=0.01) and RR interval (P<0.001) during cognitive tasks. Among controls, high-frequency power was unchanged (P=0.29), and RR interval decreased (P=0.03). Neither intervention altered spontaneous baroreflex sensitivity (P>0.10). In contrast to relaxation therapy, BNT with heart rate variability biofeedback modestly lowers ambulatory blood pressure during wakefulness, and it augments tonic vagal heart rate modulation. It is unknown whether efficacy of this treatment can be improved with biofeedback of baroreflex gain. BNT, alone or as an adjunct to drug therapy, may represent a promising new intervention for hypertension.

Correspondence of continuous interstitial glucose measurement against arterialised and capillary glucose following an oral glucose tolerance test in healthy volunteers.

The aim of the present study was to validate the Glucoday continuous interstitial ambulatory glucose-monitoring device (AGD) against plasma glucose measured from arterialised venous (AV) and glucose from capillary whole blood (finger prick, FP) in non-diabetic subjects in response to an oral glucose tolerance test. Fifteen healthy overweight men (age 30-49 years, BMI 26-31 kg/m2) participated. Glucose levels were measured before, during and after consumption of an oral 75 g glucose load using twelve FP samples and forty-four 1 ml AV blood samples during 180 min. Interstitial glucose was measured via the AGD. Three venous samples for fasting insulin were taken to estimate insulin resistance. Profiles of AGD, AV and FP glucose were generated for each participant. Glucose values for each minute of the measurement period were interpolated using a locally weighted scatterplot smoother. Data were compared using Bland-Altman plots that showed good correspondence between all pairs of measurements. Concordance between the three methods was 0.8771 (Kendall's W, n 15, P < 0.001). Concordance was greater between AV and FP (W = 0.9696) than AGD and AV (W = 0.8770) or AGD and FP (W = 0.8764). Analysis of time to peak glucose indicated that AGD measures lagged approximately 15 min behind FP and AV measures. Percent body fat was significantly correlated with time to peak glucose levels for each measure, while BMI and estimated insulin resistance (homeostatic model assessment, HOMA) were not. In conclusion, AGD shows good correspondence with FP and AV glucose measures in response to a glucose load with a 15 min time lag. Taking this into account, AGD has potential application in nutrition and behaviour studies.

Active middle-aged men have lower fasting inflammatory markers but the postprandial inflammatory response is minimal and unaffected by physical activity status.

Physical activity modifies some postprandial responses such as glycemic control, although it is unclear whether this translates into lower postprandial inflammation. Our objective in this study was to determine whether postprandial inflammatory markers are lower in active compared with sedentary middle-aged men. Thirteen active and twelve sedentary middle-aged men consumed a mixed meal on one occasion. Blood was taken via a cannula before and up to 8 h after the meal and with a single-use needle before and 8 h after the meal. Active men had lower fasted IL-6 (0.6 +/- 0.2 vs. 1.2 +/- 0.3 pg/ml; P = 0.004) and C-reactive protein (1.3 +/- 0.3 vs. 2.9 +/- 0.6 mg/l; P = 0.04) concentrations than sedentary men. Cannula blood IL-6 concentrations increased by 3.49 pg/ml in the 8 h following the meal (P < 0.001); however, this increase was minimal (0.36 pg/ml) in blood taken via a single-use needle from the contralateral arm (P = 0.013). The sedentary group had larger glucose (P = 0.034), insulin (P = 0.013), and triacylglycerol (P = 0.057) responses to the meal. These results provide further evidence that physical activity is associated with lower inflammatory marker concentrations in a fasted state and a lower postprandial metabolic response to a meal. However, this does not translate into lower postprandial inflammatory markers since the only evidence of postprandial inflammation (a large increase in serum IL-6) was actually due to the cannula used for blood sampling.

Acute consumption of fish oil improves postprandial VLDL profiles in healthy men aged 50-65 years.

Dietary supplementation with fish oil induces beneficial changes in the size and concentration of plasma lipoproteins, although the underlying mechanism is unclear. We have investigated the effect of increasing the amount of fish oil in a single meal on the size and concentration of VLDL, LDL and HDL particles during the postprandial period. Healthy men aged 58 (sd 5) years (n 11) consumed isoenergetic, mixed macronutrient test meals containing either 0.3 g (reference, REF) or 2.2 g (high fish oil, HFO) fish oil in a randomised order, and blood samples were collected over the following 6 h. Plasma lipoprotein size and concentration were measured by NMR spectroscopy. There was a significant interaction effect of time and meal composition on the VLDL, but not on the LDL or HDL, concentration (P = 0.036) and particle size (P = 0.005). Consuming the HFO meal significantly increased the VLDL concentration (P < 0.05) and reduced VLDL particle size (P < 0.05) when compared with the REF meal and baseline. LDL particle size decreased slightly during the postprandial period, but there was no difference between the meals. There was no effect of time or meal composition in the LDL concentration. The HDL concentration decreased and size increased slightly during the postprandial period, but there were no significant differences between the meals. Increased consumption of fish oil induces acute changes in the VLDL, but not in the LDL or HDL, metabolism.

Walking and inflammatory markers in individuals screened for type 2 diabetes.

OBJECTIVE: To investigate the association of walking activity with inflammatory markers and fasting insulin in a bi-ethnic population screened for type 2 diabetes in Leicester, United Kingdom, between 2005 and 2006. METHOD: Physical activity, adipocytokine, high-sensitivity C-reactive protein and fasting insulin measurements were available for 400 individuals screened for type 2 diabetes. Of the 400 participants, 56% were diagnosed with normal glucose control, 36% with prediabetes and 8% with diabetes. RESULTS: Multivariate statistical analysis showed that those who reported walking for at least 30 min on at least 5 days/week had lower levels of C-reactive protein, interleukin-6, and tumor necrosis factor-alpha compared to those who reported lower walking activity levels, after adjustment for other modes of moderate-to-vigorous intensity physical activity, age, ethnicity, sex, social deprivation and smoking status. Further adjustment for waist circumference attenuated the association of walking with tumor necrosis factor-alpha. CONCLUSION: Walking activity, independent of other forms of physical activity, is associated with lower levels of circulating pro-inflammatory markers.

A meal enriched with soy isoflavones increases nitric oxide-mediated vasodilation in healthy postmenopausal women.

Evidence from infusion studies suggests that soy isoflavones influence nitric oxide-dependent vasorelaxation. It is uncertain whether orally consumed isoflavones have similar effects. Healthy postmenopausal women (n = 22) consumed 2 low-fat test meals in random order 1 wk apart, with 80 mg isoflavones (ISO) or without isoflavones (CON). Endothelium-dependent vasodilation, assessed by brachial artery flow-mediated dilatation (FMD), was measured in fasting subjects, and 4 and 6 h following the test meal, in addition to blood pressure and pulse wave analysis to derive the peripheral augmentation index (pAIx). Blood samples were taken after fasting, and 5 and 7 h following the test meal for serum isoflavone, plasma 8-isoprostane F(2alpha), nitric oxide metabolites (NOx), glucose, and triacylglycerol analysis. Serum genistein and daidzein concentrations (geometric mean, 95% CI) reached 1.49 (1.20-1.84) micromol/L and 0.95 (0.70-1.30) micromol/L, respectively, following ISO (7 h). FMD and plasma NOx concentrations were greater following ISO compared with CON, indicating better postprandial endothelial function. FMD values (%, mean +/- SD) were: CON, 5.49 +/- 2.32, 4.35 +/- 2.32, 4.40 +/- 2.26; ISO, 5.38 +/- 1.91, 5.08 +/- 1.74, 6.11 +/- 2.60, at baseline, 4 h, and 6 h, respectively (P < 0.01). Plasma NOx concentrations (micromol/L, mean +/- SD) were: CON, 20.0 +/- 5.1, 16.8 +/- 5.1, 23.1 +/- 6.0; ISO, 18.6 +/- 6.3, 19.5 +/- 5.1, 21.3 +/- 10.1, at baseline, 5 h, and 7 h, respectively (P < 0.005). Treatment did not affect pAIx, blood pressure, or plasma 8-isoprostane F(2alpha) concentrations. In conclusion, consuming an isoflavone-enriched low-fat meal acutely increases endothelium-dependent vasodilation in postmenopausal women. Regular consumption of soy isoflavones may protect against endothelial dysfunction.

Low-dose docosahexaenoic acid lowers diastolic blood pressure in middle-aged men and women.

The intake of (n-3) long-chain PUFA is associated with a decreased risk of fatal myocardial infarction. Whether this effect is attributable to the effects of docosahexaenoic acid [22:6(n-3) (DHA)] on vascular function, particularly at intakes <1 g/d, is unknown. We report a randomized, double-blind, crossover, placebo controlled trial of 0.7 g DHA/d as a purified algal derived triacylglycerol (1.5 g/d) vs. placebo (1.5 g olive oil/d) on vascular function and biochemical indices of endothelial dysfunction in 38 healthy men and women, aged 40-65 y. Each treatment phase lasted 3 mo, separated by a 4 mo washout period. Supplementation increased the proportion of DHA in erythrocytes lipids by 58%, compared with placebo. Arterial compliance and endothelium independent and dependent responses, plasma concentrations of C-reactive protein, soluble thrombomodulin, E-selectin, von Willebrand factor antigen, and urinary microalbumin and isoprostane excretion were unaffected by treatment. Diastolic blood pressure decreased by 3.3 mm Hg (95% CI -6.1 to -0.6; P = 0.01). Heart rate tended to be 2.1 beats/min lower after DHA treatment than after the placebo period (P = 0.15). The results indicate that a moderate increase in the daily intake of DHA to approximately 0.7 g DHA lowers diastolic BP but does not influence indices of endothelial function or arterial stiffness in the short term.