Antioxidant Supplementation in Oxidative Stress-Related Diseases: What Have We Learned from Studies on Alpha-Tocopherol?

Oxidative stress has been proposed as a key contributor to lifestyle- and age-related diseases. Because free radicals play an important role in various processes such as immune responses and cellular signaling, the body possesses an arsenal of different enzymatic and non-enzymatic antioxidant defense mechanisms. Oxidative stress is, among others, the result of an imbalance between the production of various reactive oxygen species (ROS) and antioxidant defense mechanisms including vitamin E (α-tocopherol) as a non-enzymatic antioxidant. Dietary vitamins, such as vitamin C and E, can also be taken in as supplements. It has been postulated that increasing antioxidant levels through supplementation may delay and/or ameliorate outcomes of lifestyle- and age-related diseases that have been linked to oxidative stress. Although supported by many animal experiments and observational studies, randomized clinical trials in humans have failed to demonstrate any clinical benefit from antioxidant supplementation. Nevertheless, possible explanations for this discrepancy remain underreported. This review aims to provide an overview of recent developments and novel research techniques used to clarify the existing controversy on the benefits of antioxidant supplementation in health and disease, focusing on α-tocopherol as antioxidant. Based on the currently available literature, we propose that examining the difference between antioxidant activity and capacity, by considering the catabolism of antioxidants, will provide crucial knowledge on the preventative and therapeutical use of antioxidant supplementation in oxidative stress-related diseases

Within-person variation in serum thyrotropin concentration: main sources, potential underlying biological mechanisms, and clinical implications

Background: Individuals exhibit fluctuations in the concentration of serum thyroid-stimulating hormone (TSH) over time. The scale of these variations ranges from minutes to hours, and from months to years. The main factors contributing to the observed within-person fluctuations in serum TSH comprise pulsatile secretion, circadian rhythm, seasonality, and ageing. In clinical practice and clinical research however, such within-person biological variation in serum TSH concentrations is often not considered. The aim of this review is to present an overview of the main sources of within-person variation in TSH levels, as well as the potential underlying biological mechanisms, and the clinical implications.Summary: In euthyroid individuals, the circadian rhythm, with a nocturnal surge around 02:00-04:00 h and a nadir during daytime has the greatest impact on variations in serum TSH concentrations. Another source of within-person variation in TSH levels is seasonality, with generally higher levels during the cold winter months. Since TSH is secreted in a pulsatile manner, TSH levels also fluctuate over minutes. Furthermore, elevated TSH levels have been observed with ageing. Other factors that affect TSH levels include thyroid peroxidase (TPO)-antibody positivity, BMI, obesity, smoking, critical illness, and many xenobiotics, including environmental pollutants and drugs. Potential underlying biological mechanisms of within-person variation in TSH levels can be safely concluded from the ability of TSH to respond quickly to changes in cues from the internal or external environment in order to maintain homeostasis. Such cues include the biological clock, environmental temperature, and length of day. The observed increase in TSH level with ageing can be explained at a population level and at an organism level. In clinical practice, the season for thyroid testing can influence a patient's test result and it occurs frequently that subclinical hypothyroid patients normalize to euthyroid levels over time without intervention.Conclusions: Serum TSH concentrations vary over time within an individual, which is caused by multiple different internal and external factors. It is important to take the within-person variations in serum TSH concentrations into account when testing a patient in clinical practice, but also in performing clinical research.Diabetes mellitus: pathophysiological changes and therap

Relationships between 24-hour LH and testosterone concentrations and with other pituitary hormones in healthy older men

Objective: To investigate the relationship between LH and testosterone (T), which characteristics associate with the strength of this relationship, and their interrelationships with GH, TSH, cortisol, and ACTH.Design: Hormones were measured in serum samples collected every 10 minutes during 24 hours from 20 healthy men, comprising 10 offspring of long-lived families and 10 control subjects, with a mean (SD) age of 65.6 (5.3) years. We performed cross-correlation analyses to assess the relative strength between 2 timeseries for all possible time shifts.Results: Mean (95% CI) maximal correlation was 0.21 (0.10-0.31) at lag time of 60 minutes between LH and total T concentrations. Results were comparable for calculated free, bioavailable, or secretion rates of T. Men with strong LH-T cross-correlations had, compared with men with no cross-correlation, lower fat mass (18.5 [14.9-19.7] vs. 22.3 [18.4-29.4] kg), waist circumference (93.6 [5.7] vs. 103.1 [12.0] cm), high-sensitivity C-reactive protein (0.7 [0.4-1.3] vs. 1.8 [0.8-12.3] mg/L), IL-6 (0.8 [0.6-1.0] vs. 1.2 [0.9-3.0] pg/mL), and 24-hour mean LH (4.3 [2.0] vs. 6.1 [1.5] U/L), and stronger LH-T feedforward synchrony (1.5 [0.3] vs. 1.9 [0.2]). Furthermore,T was positively cross-correlated withTSH (0.32 [0.21-0.43]), cortisol (0.26 [0.19-0.33]), and ACTH (0.26 [0.19-0.32]).Conclusions: LH is followed by T with a delay of 60 minutes in healthy older men. Men with a strong LH-T relationship had more favorable body composition, inflammatory markers, LH levels, and LH-T feedforward synchrony. We observed positive correlations between T and TSH, cortisol, and ACTH.Pathophysiology, epidemiology and therapy of agein

Both low circulating insulin-like growth factor-1 and high-density lipoprotein cholesterol are associated with hair loss in middle-aged women.

YesBackground: Multiple biomarkers have been associated with hair loss in women, but studies showed inconsistent results. Objective: We investigated the association between markers of cardiovascular disease risk (e.g., serum lipid levels and hypertension) and aging (e.g., 25-hydroxyvitamin D and insulin-like growth factor) with hair loss in a population of middle-aged women. Methods: In a random subgroup of 323 middle-aged women (mean age: 61.5 years) from the Leiden Longevity Study, hair loss was graded by three assessors using the Sinclair scale; women with a mean score higher than 1.5 were classified as cases with hair loss. Results: Every standard deviation increase in HDL cholesterol was associated with a 0.65 times lower risk (95% confidence interval [CI]: 0.46–0.91) of hair loss; for IGF-1 the risk was 0.68 times lower (95% CI: 0.48–0.97) per standard deviation increase, independent of the other studied variables. Women with both IGF-1 and HDL cholesterol levels below the median of the study population had a 3.47 times higher risk (95% CI: 1.30–9.25) of having hair loss. Limitations: The observational setting limits causal inference of the findings. Conclusion: Low HDL cholesterol and IGF-1 were associated with a higher risk of hair loss in women.This study was funded by the Innovation Oriented Research Program on Genomics (SenterNovem; IGE01014 and IGE5007), the Centre for Medical Systems Biology (CMSB), the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (05040202 and 050-060-810, NCHA), Unilever PLC and the European Union-funded Network of Excellence Lifespan (FP6 036894)

Differential and sex- and age-specific risks of cardiometabolic diseases with unrelated metabolic syndrome dimensions

ObjectiveThis study aimed to investigate whether independent dimensions of metabolic syndrome (MetS) components are associated differentially with incident cardiometabolic diseases. MethodsPrincipal components analysis was performed using the five MetS components from 153,073 unrelated European-ancestry participants (55% women) from the UK Biobank. The associations of the principal components (PCs) with incident type 2 diabetes mellitus (T2D), coronary artery disease (CAD), and (ischemic) stroke were analyzed using multivariable-adjusted Cox proportional hazards models in groups stratified by sex and baseline age. ResultsPC1 (40.5% explained variance; increased waist circumference with dyslipidemia) and PC2 (22.7% explained variance; hyperglycemia) were both associated with incident cardiometabolic disease. Hazard ratios (HR [95% CI]) for CAD and T2D were higher for PC1 than for PC2 (1.27 [95% CI: 1.25-1.29] vs. 1.06 [95% CI: 1.03-1.08] and 2.09 [95% CI: 2.03-2.16] vs. 1.39 [95% CI: 1.34-1.44], respectively). Furthermore, the association of PC1 with T2D was slightly higher for women than for men, and especially the HRs of PC1 with CAD and T2D attenuated with increasing age (p values for heterogeneity test among subgroups < 0.05). ConclusionsMetS can be dissected into two distinct presentations characterized by differential sex- and age-associated cardiometabolic disease risk, confirming the loss of information using the dichotomous MetS.Metabolic health: pathophysiological trajectories and therap

Genetically determined higher TSH is associated with a lower risk of diabetes mellitus in individuals with low BMI

Context: Thyroid status is hypothesized to be causally related with the risk of diabetes mellitus (DM), but previous results were conflicting possibly because of a complex interaction between thyrotropin (TSH), body mass index (BMI) and DM.Objective: This work aims to investigate the causal association between thyroid status with DM and glucose homeostasis and to what extent this association is dependent on BMI.Methods: A mendelian randomization study was conducted of European-ancestry participants from the UK Biobank population. The present study involved 408895 individuals (mean age 57.4 years [SD 8.0], 45.9% men), of whom 19773 had DM. Genetic variants for circulatory TSH, free thyroxine (fT4) concentrations and BMI to calculate weighted genetic risk scores. The main outcome measures included self-reported DM-stratified analyses by BMI. Analyses were repeated for nonfasting glucose and glycated hemoglobin A(1c) (HbA(1c)) among individuals without DM.Results: Genetically determined TSH and fT4 levels were not associated with risk of DM in the total UK Biobank population. However, in analyses stratified on genetically determined BMI, genetically determined higher TSH, and not fT4, was associated with a lower risk for DM only in the low BMI group (odds ratio 0.91; 95% CI, 0.85-0.98 in low BMI; P value for interaction = .06). Similar results were observed for glucose and HbA(1c) among individuals without DM.Conclusion: TSH, but not fT4, is a potential causal risk factor for DM in individuals with genetically determined low BMI highlighting potential protective effects of TSH only in low-risk populations.Pathophysiology, epidemiology and therapy of agein

Diet-derived circulating antioxidants and risk of coronary heart disease a Mendelian randomization study

BACKGROUND Previously, observational studies have identified associations between higher levels of dietary-derived antioxidants and lower risk of coronary heart disease (CHD), whereas randomized clinical trials showed no reduction in CHD risk following antioxidant supplementation.OBJECTIVES The purpose of this study was to investigate possible causal associations between dietary-derived circulating antioxidants and primary CHD risk using 2-sample Mendelian randomization (MR).METHODS Single-nucleotide polymorphisms for circulating antioxidants (vitamins E and C, retinol, 13-carotene, and lycopene), assessed as absolute levels and metabolites, were retrieved from the published data and were used as genetic instrumental variables. Summary statistics for gene-CHD associations were obtained from 3 databases: the CARDIoGRAMplusC4D consortium (60,801 cases; 123,504 control subjects), UK Biobank (25,306 cases; 462,011 control subjects), and FinnGen study (7,123 cases; 89,376 control subjects). For each exposure, MR analyses were performed per outcome database and were subsequently meta-analyzed.RESULTS Among an analytic sample of 768,121 individuals (93,230 cases), genetically predicted circulating antioxidants were not causally associated with CHD risk. For absolute antioxidants, the odds ratio for CHD ranged between 0.94 (95% confidence interval [CI]: 0.63 to 1.41) for retinol and 1.03 (95% CI: 0.97 to 1.10) for 13-carotene per unit increase in ln-transformed antioxidant values. For metabolites, the odds ratio ranged between 0.93 (95% CI: 0.82 to 1.06) for g-tocopherol and 1.01 (95% CI: 0.95 to 1.08) for ascorbate per 10-fold increase in metabolite levels.CONCLUSIONS Evidence from our study did not support a protective effect of genetic predisposition to high dietaryderived antioxidant levels on CHD risk. Therefore, it is unlikely that taking antioxidants to increase blood antioxidants levels will have a clinical benefit for the prevention of primary CHD. (C) 2021 by the American College of Cardiology Foundation.Clinical epidemiolog

Diet-derived antioxidants do not decrease risk of ischemic stroke: a Mendelian randomization study in 1 million people

Background Dietary intake and blood concentrations of vitamins E and C, lycopene, and carotenoids have been associated with a lower risk of incident (ischemic) stroke. However, causality cannot be inferred from these associations. Here, we investigated causality by analyzing the associations between genetically influenced antioxidant levels in blood and ischemic stroke using Mendelian randomization. Methods and Results For each circulating antioxidant (vitamins E and C, lycopene, beta-carotene, and retinol), which were assessed as either absolute blood levels and/or high-throughput metabolite levels, independent genetic instrumental variables were selected from earlier genome-wide association studies (P<5x10(-8)). We used summary statistics for single-nucleotide polymorphisms-stroke associations from 3 European-ancestry cohorts (cases/controls): MEGASTROKE (60 341/454 450), UK Biobank (2404/368 771), and the FinnGen study (8046/164 286). Mendelian randomization analyses were performed on each exposure per outcome cohort using inverse variance-weighted analyses and subsequently meta-analyzed. In a combined sample of 1 058 298 individuals (70 791 cases), none of the genetically influenced absolute antioxidants or antioxidant metabolite concentrations were causally associated with a lower risk of ischemic stroke. For absolute antioxidants levels, the odds ratios (ORs) ranged between 0.94 (95% CI, 0.85-1.05) for vitamin C and 1.04 (95% CI, 0.99-1.08) for lycopene. For metabolites, ORs ranged between 1.01 (95% CI, 0.98-1.03) for retinol and 1.12 (95% CI, 0.88-1.42) for vitamin E. Conclusions This study did not provide evidence for a causal association between dietary-derived antioxidant levels and ischemic stroke. Therefore, antioxidant supplements to increase circulating levels are unlikely to be of clinical benefit to prevent ischemic stroke.Diabetes mellitus: pathophysiological changes and therap

Stress evokes stronger medial posterior cingulate deactivations during emotional distraction in slower paced aging

Pathophysiology, epidemiology and therapy of agein

Associations between Lifestyle Factors and Vitamin E Metabolites in the General Population

The antioxidant vitamin E (α-tocopherol, α-TOH) protects lipids from oxidation by reactive oxygen species. We hypothesized that lifestyle factors associate with vitamin E metabolism marked by urinary α-tocopheronolactone hydroquinone (α-TLHQ) and α-carboxymethyl-hydroxychroman (α-CEHC levels), as potential reflection of lipid oxidation. We conducted a cross-sectional study in the Netherlands Epidemiology of Obesity Study. Serum α-TOH, and urinary α-TLHQ and α-CEHC were quantified by liquid chromatography coupled with tandem mass spectrometry. Information on the lifestyle factors (sleep, physical activity (PA), smoking and alcohol) were collected through questionnaires. Multivariable linear regression analyses were performed to assess the associations between the lifestyle factors and α-TOH measures. A total of 530 participants (46% men) were included with mean (SD) age of 56 (6) years. Of the examined lifestyle factors, only poor sleep was associated with a higher serum α-TOH (mean difference: 4% (95% CI: 1, 7%)). Current smoking was associated with higher urinary α-CEHC (32%: (14%, 53%)), with evidence of a dose-response relationship with smoking intensity (low pack years, 24% (2, 52%); high pack years, 55% (25, 93%)). Moderate physical activity was associated with a lower α-TLHQ relative to α-CEHC (-17%: (-26, -6%), compared with low PA). Only specific lifestyle factors associate with vitamin E metabolism. Examining serum α-TOH does not provide complete insight in vitamin E antioxidant capacity