RESUMEN
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.
RESUMEN
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, ß-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<5×10-8). 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.