Plasma GSH levels and Alzheimer's disease. A prospective approach.: Results from the HELIAD study.

BACKGROUND: Potential links between oxidative stress and the pathophysiology of Alzheimer's disease (AD) have been reported in the existing literature. Biological markers of oxidative stress, such as the reduced form of glutathione (GSH), may have a potential role as predictive biomarkers for AD development. The aim of the present study was to explore the longitudinal associations between plasma GSH and the risk of developing AD or cognitive decline, in a sample of community-dwelling, non-demented older adults. METHODS: Participants from the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD) were included in the present prospective study. The sample used in the analyses consisted of 391 non-demented individuals over the age of 64 (mean age = 73.85 years; SD = 5.06), with available baseline GSH measurements and longitudinal follow-up. Plasma GSH was treated both as a continuous variable and as tertiles in our analyses. Cox proportional hazards models were used to evaluate the hazard ratio (HR) for AD incidence as a function of baseline plasma GSH. Generalized estimating equations (GEE) models were deployed to explore the associations between baseline plasma GSH and the rate of change of performance scores on individual cognitive domains over time. Models were adjusted for age, years of education and sex. Supplementary exploratory models were also adjusted for mild cognitive impairment (MCI) at baseline, risk for malnutrition, physical activity and adherence to the Mediterranean dietary pattern. RESULTS: A total of 24 incident AD cases occurred during a mean (SD) of 2.99 (0.92) years of follow-up. Individuals in the highest GSH tertile group (highest baseline plasma GSH values) had a 70.1% lower risk for development of AD, compared to those in the lowest one [HR = 0.299 (0.093-0.959); p = 0.042], and also demonstrated a slower rate of decline of their executive functioning over time (5.2% of a standard deviation less decline in the executive composite score for each additional year of follow-up; p = 0.028). The test for trend was also significant suggesting a potential dose-response relationship. CONCLUSION: In the present study, higher baseline plasma GSH levels were associated with a decreased risk of developing AD and with a better preservation of executive functioning longitudinally.

Nicotinamide riboside supplementation dysregulates redox and energy metabolism in rats: Implications for exercise performance.

NEW FINDINGS: What is the central question of this study? The aim was to investigate the potential metabolic and redox mechanisms that impaired exercise performance after 21 days of supplementation with 300 mg (kg body weight)-1 of nicotinamide riboside in rats. What is the main finding and its importance? Nicotinamide riboside disturbed energy and redox metabolism and impaired exercise performance in heathy rats. Exogenously administered redox agents in heathy populations might lead to adverse effects. ABSTRACT: Nicotinamide riboside is a recently discovered form of vitamin B3 that can increase NAD(P) levels. NAD(P) plays key roles in energy metabolism, and its main function is the transfer of electrons in various cellular reactions. Research in aged or diseased mice reported that nicotinamide riboside increases NAD(H) levels, reduces morbidity and improves health and muscle function. We have recently shown that in healthy young rats, chronic administration of nicotinamide riboside marginally non-significantly decreased exercise performance by 35% (P = 0.071). As a follow-up to this finding, we analysed samples from these animals, in an attempt to reveal the potential mechanisms driving this adverse effect, focusing on redox homeostasis and bioenergetics. Thirty-eight Wistar rats were divided into four groups: control (n = 10), exercise (n = 9), nicotinamide riboside (n = 10) and exercise plus nicotinamide riboside (n = 9). Nicotinamide riboside was administered for 21 days [300 mg (kg body weight)-1 daily]. At the end of administration, the exercise and the exercise plus nicotinamide riboside groups performed an incremental swimming performance test until exhaustion. Nicotinamide riboside supplementation increased the levels of NADPH in the liver (P = 0.050), increased the levels of F2 -isoprostanes in plasma (P = 0.047), decreased the activity of glutathione peroxidase (P = 0.017), glutathione reductase (P < 0.001) and catalase (P = 0.024) in erythrocytes, increased the level of glycogen in the liver (P < 0.001) and decreased the concentration of glucose (P = 0.016) and maximal lactate accumulation in plasma (P = 0.084). These findings support the prevailing idea that exogenously administered redox agents in heathy populations might lead to adverse effects and not necessarily to beneficial or neutral effects.

Adaptations to endurance training depend on exercise-induced oxidative stress: exploiting redox interindividual variability.

AIM: The aim of this study was to reveal the role of reactive oxygen and nitrogen species (RONS) in exercise adaptations under physiological in vivo conditions and without the interference from other exogenous redox agents (e.g. a pro-oxidant or antioxidant). METHODS: We invented a novel methodological set-up that exploited the large redox interindividual variability in exercise responses. More specifically, we used exercise-induced oxidative stress as the 'classifier' measure (i.e. low, moderate and high) and investigated the physiological and redox adaptations after a 6-week endurance training protocol. RESULTS: We demonstrated that the group with the low exercise-induced oxidative stress exhibited the lowest improvements in a battery of classic adaptations to endurance training (VO2 max, time trial and Wingate test) as well as in a set of redox biomarkers (oxidative stress biomarkers and antioxidants), compared to the high and moderate oxidative stress groups. CONCLUSION: The findings of this study substantiate, for the first time in a human in vivo physiological context, and in the absence of any exogenous redox manipulation, the vital role of RONS produced during exercise in adaptations. The stratification approach, based on a redox phenotype, implemented in this study could be a useful experimental strategy to reveal the role of RONS and antioxidants in other biological manifestations as well.

Going retro: Oxidative stress biomarkers in modern redox biology.

The field of redox biology is inherently intertwined with oxidative stress biomarkers. Oxidative stress biomarkers have been utilized for many different objectives. Our analysis indicates that oxidative stress biomarkers have several salient applications: (1) diagnosing oxidative stress, (2) pinpointing likely redox components in a physiological or pathological process and (3) estimating the severity, progression and/or regression of a disease. On the contrary, oxidative stress biomarkers do not report on redox signaling. Alternative approaches to gain more mechanistic insights are: (1) measuring molecules that are integrated in pathways linking redox biochemistry with physiology, (2) using the exomarker approach and (3) exploiting -omics techniques. More sophisticated approaches and large trials are needed to establish oxidative stress biomarkers in the clinical setting.

The effects of a water polo game on the blood redox status of male water polo players.

AIM: The purpose of this study was to examine the effects of a real water polo game on the oxidative stress and antioxidants markers of male water polo players. The importance of this study is that it is the first to examine the oxidative stress and antioxidants markers after a water polo game, considering the specific and high demands of the latter. METHODS: Twelve players (25.8±3.7 years) were assessed from two teams. The oxidative stress and antioxidants markers which were measured were TBARS, Protein Carbonyls, GSH and GSSG, Total Antioxidant Capacity (TAC) and Catalase. RESULTS: An increase was found after the game for TBARS, for catalase, for GSH, and GSSG. Protein Carbonyls, TAC and the GSH/GSSG ratio did not change significantly. CONCLUSION: The water polo game was found to be a strong stimulus for oxidative stress, while alterations seem to appear for the antioxidant capability, as indicated by increase of catalase and GSH. The increase of the latter is controversial to the usual effect post exercise. A possible explanation for this effect could be the activation of GSH synthesis in order to meet the increased needs for antioxidant protection. Also, it should be considered that blood samples were taken 10-20 min. after the game, so it is possible that in well-trained subjects, this time period is enough for the conversion of GSSG back to GSH. Yet, it can be stated that, despite the enhanced antioxidant defense of the players, oxidative stress could not be prevented.