Biomarkers of antioxidant capacity in the hydrophilic and lipophilic compartments of human plasma

Antioxidants located in both the hydrophilic and lipophilic compartments of plasma are actively involved as a defense system against reactive oxygen species (ROS), which are continuously generated in the body due to both normal metabolism and disease. However, when the production of ROS is not controlled, it leads to cellular lipid, protein, and DNA damage in biological systems. Several assays to measure 'total' antioxidant capacity of plasma have been developed to study the involvement of oxidative stress in pathological conditions and to evaluate the functional bioavailability of dietary antioxidants. Conventional assays to determine antioxidant capacity primarily measure the antioxidant capacity in the aqueous compartment of plasma. Consequently, water-soluble antioxidants such as ascorbic acid, uric acid and protein thiols mainly influence these assays, whereas fat-soluble antioxidants such as tocopherols and carotenoids play only a minor role. However, there are active interactions among antioxidants located in the hydrophilic and lipophilic compartments of plasma. Therefore, new approaches to define the 'true' total antioxidant capacity of plasma should reflect the antioxidant network between water- and fat-soluble antioxidants in plasma. Revelation of the mechanism of action of antioxidants and their true antioxidant potential will help us to optimize the antioxidant defenses in the body.     

Theoretical study of the pH-dependent antioxidant properties of vitamin C

Molecules acting as antioxidants capable of scavenging reactive oxygen species (ROS) are of utmost importance in the living cell. Vitamin C is known to be one of these molecules. In this study we have analyzed the reactivity of vitamin C toward the $ \cdot OH $ and $ \cdot OOH $ ROS species, in all acidic, neutral and basic media. In order to do so, density functional theory (DFT) have been used. More concretely, the meta-GGA functional MPW1B95 have been used. Two reaction types have been studied in each case: addition to the ring atoms, and hydrogen/proton abstraction. Our results show that $ \cdot OH $ is the most reactive species, while $ \cdot OOH $ displays low reactivity. In all three media, vitamin C reactions with two hydroxyl radicals show a wide variety of possible products.     

A review of the interaction among dietary antioxidants and reactive oxygen species

During normal cellular activities, various processes inside of cells produce reactive oxygen species (ROS). Some of the most common ROS are hydrogen peroxide (H(2)O(2)), superoxide ion (O(2)(-)), and hydroxide radical (OH(-)). These compounds, when present in a high enough concentration, can damage cellular proteins and lipids or form DNA adducts that may promote carcinogenic activity. The purpose of antioxidants in a physiological setting is to prevent ROS concentrations from reaching a high-enough level within a cell that damage may occur. Cellular antioxidants may be enzymatic (catalase, glutathione peroxidase, superoxide dismutase) or nonenzymatic (glutathione, thiols, some vitamins and metals, or phytochemicals such as isoflavones, polyphenols, and flavanoids). Reactive oxygen species are a potential double-edged sword in disease prevention and promotion. Whereas generation of ROS once was viewed as detrimental to the overall health of the organism, advances in research have shown that ROS play crucial roles in normal physiological processes including response to growth factors, the immune response, and apoptotic elimination of damaged cells. Notwithstanding these beneficial functions, aberrant production or regulation of ROS activity has been demonstrated to contribute to the development of some prevalent diseases and conditions, including cancer and cardiovascular disease (CVD). The topic of antioxidant usage and ROS is currently receiving much attention because of studies linking the use of some antioxidants with increased mortality in primarily higher-risk populations and the lack of strong efficacy data for protection against cancer and heart disease, at least in populations with adequate baseline dietary consumption. In normal physiological processes, antioxidants effect signal transduction and regulation of proliferation and the immune response. Reactive oxygen species have been linked to cancer and CVD, and antioxidants have been considered promising therapy for prevention and treatment of these diseases, especially given the tantalizing links observed between diets high in fruits and vegetables (and presumably antioxidants) and decreased risks for cancer.     

Diabetes,oxidative stress and therapeutic strategies

Background

Diabetes has emerged as a major threat to health worldwide.

Scope of Review

The exact mechanisms underlying the disease are unknown; however, there is growing evidence that excess generation of reactive oxygen species (ROS), largely due to hyperglycemia, causes oxidative stress in a variety of tissues. Oxidative stress results from either an increase in free radical production, or a decrease in endogenous antioxidant defenses, or both. ROS and reactive nitrogen species (RNS) are products of cellular metabolism and are well recognized for their dual role as both deleterious and beneficial species. In type 2 diabetic patients, oxidative stress is closely associated with chronic inflammation. Multiple signaling pathways contribute to the adverse effects of glucotoxicity on cellular functions. There are many endogenous factors (antioxidants, vitamins, antioxidant enzymes, metal ion chelators) that can serve as endogenous modulators of the production and action of ROS. Clinical trials that investigated the effect of antioxidant vitamins on the progression of diabetic complications gave negative or inconclusive results. This lack of efficacy might also result from the fact that they were administered at a time when irreversible alterations in the redox status are already under way. Another strategy to modulate oxidative stress is to exploit the pleiotropic properties of drugs directed primarily at other targets and thus acting as indirect antioxidants.

Major Conclusions

It appears important to develop new compounds that target key vascular ROS producing enzymes and mimic endogenous antioxidants.

General significance

This strategy might prove clinically relevant in preventing the development and/or retarding the progression of diabetes associated with vascular diseases.     

活性氧诱发人类11号染色体基因突变

对体外产生的和内源性刺激产生的活性氧 (ROS)诱发人类 11号染色体 (Hchr 11)基因突变规律及其突变谱进行研究 .体外羟自由基 (·OH)用过氧化氢 (H2 O2 )与Fe2 + 反应产生 ,并用化学发光(CL)进行相对定量分析 ;内源性ROS用佛波醇酯 (PMA)刺激人外周血白细胞产生 ,并用CL和特异性抗氧化物检测和鉴定 ;用包含单条Hchr 11的人 中国仓鼠卵巢细胞 (AL)为靶 ,经CD59表面抗原抗体筛选突变细胞克隆 ,研究ROS诱发的Hchr 11基因突变 ;突变克隆细胞DNA用Hchr 11上 5种标志基因引物进行多重PCR分析 ,结合琼脂糖凝胶电泳绘制基因突变谱 .结果表明 ,体外ROS可诱发Hchr 11基因突变 ,且·OH诱发基因突变的能力明显强于H2 O2 ,两者的突变谱也存在明显差异 ;PMA可刺激人外周血白细胞产生大量的多种ROS ,并诱发Hchr 11基因突变 ,突变谱综合了H2 O2 和·OH的所有特征 ;一些抗氧化物对内源性产生的ROS诱发Hchr 11基因突变有明显抑制作用 .提示体外和内源性ROS可诱发Hchr 11基因突变 ,不同的活性氧分子诱发的基因突变可能具有特异性     

Interactions of lipoic acid radical cations with vitamins C and E analogue and hydroxycinnamic acid derivatives

As a powerful natural antioxidant, lipoic acid exerts significant antioxidant activities in vivo and in vitro by deactivation of reactive oxygen and nitrogen species. In this study we present a novel synergistic interaction of lipoic acid with other endogenous or exogenous antioxidants. Antioxidants vitamins C and E analogue (Trolox C) and hydroxycinnamic acid derivatives were found to recycle lipoic acid by donating electrons to lipoic acid radical cations, thereby increasing the antioxidant capacity of lipoic acid in vivo and in vitro. The rate constant of the electron transfer is in the order 10(9)dm(3)mol(-1)s(-1), close to the diffusion-controlled limit, and transfer quantum yield is above 95%.     

Chemical and molecular mechanisms of antioxidants: experimental approaches and model systems

Free radicals derived from oxygen, nitrogen and sulphur molecules in the biological system are highly active to react with other molecules due to their unpaired electrons. These radicals are important part of groups of molecules called reactive oxygen/nitrogen species (ROS/RNS), which are produced during cellular metabolism and functional activities and have important roles in cell signalling, apoptosis, gene expression and ion transportation. However, excessive ROS attack bases in nucleic acids, amino acid side chains in proteins and double bonds in unsaturated fatty acids, and cause oxidative stress, which can damage DNA, RNA, proteins and lipids resulting in an increased risk for cardiovascular disease, cancer, autism and other diseases. Intracellular antioxidant enzymes and intake of dietary antioxidants may help to maintain an adequate antioxidant status in the body. In the past decades, new molecular techniques, cell cultures and animal models have been established to study the effects and mechanisms of antioxidants on ROS. The chemical and molecular approaches have been used to study the mechanism and kinetics of antioxidants and to identify new potent antioxidants. Antioxidants can decrease the oxidative damage directly via reacting with free radicals or indirectly by inhibiting the activity or expression of free radical generating enzymes or enhancing the activity or expression of intracellular antioxidant enzymes. The new chemical and cell-free biological system has been applied in dissecting the molecular action of antioxidants. This review focuses on the research approaches that have been used to study oxidative stress and antioxidants in lipid peroxidation, DNA damage, protein modification as well as enzyme activity, with emphasis on the chemical and cell-free biological system.     

The protective effects of nutritional antioxidant therapy on Ehrlich solid tumor-bearing mice depend on the type of antioxidant therapy chosen: histology, genotoxicity and hematology evaluations

Strong evidence indicates that reactive oxygen species (ROS) play an important role in the initiation as well as the promotion phase of carcinogenesis. Studies support the role of ROS in cancer, in part, by showing that dietary antioxidants act as cancer-preventive agents. Although results are promising, the research on this topic is still controversial. Thus, the aim of this study was to investigate whether vitamins C, E and pequi oil can, individually, provide prevention and/or be used afterward as an adjuvant in cancer therapy. Ehrlich solid tumor-bearing mice received antioxidant as follows: before tumor inoculation, before and after tumor inoculation (continuous administration), and after tumor inoculation; morphometric analyses of tumor, genotoxicity and hematology were then carried out. Antioxidant administrations before tumor inoculation effectively inhibited its growth in the three experimental protocols, but administrations after the tumor's appearance accelerated tumor growth and favored metastases. Continuous administration of pequi oil inhibited the tumor's growth, while the same protocol with vitamins E and C accelerated it, favoring metastasis and increasing oxidative stress on erythrocytes. Except for continuous administration with vitamin E, the development of ascites tumor metastases was linked with increased inflammation. Results suggest that the efficiency and applicability of antioxidants in the medical clinic can depend not only on the nature of the antioxidant, the type and stage of cancer being treated and the prevailing oxygen partial pressure in the tissues, but also on the type of antioxidant therapy chosen.     

Effects of reactive oxygen species and interplay of antioxidants during physical exercise in skeletal muscles

A large number of researches have led to a substantial growth of knowledge about exercise and oxidative stress. Initial investigations reported that physical exercise generates free radical-mediated damages to cells; however, in recent years, studies have shown that regular exercise can upregulate endogenous antioxidants and reduce oxidative damage. Yet, strenuous exercise perturbs the antioxidant system by increasing the reactive oxygen species (ROS) content. These alterations in the cellular environment seem to occur in an exercise type-dependent manner. The source of ROS generation during exercise is debatable, but now it is well established that both contracting and relaxing skeletal muscles generate reactive oxygen species and reactive nitrogen species. In particular, exercises of higher intensity and longer duration can cause oxidative damage to lipids, proteins, and nucleotides in myocytes. In this review, we summarize the ROS effects and interplay of antioxidants in skeletal muscle during physical exercise. Additionally, we discuss how ROS-mediated signaling influences physical exercise in antioxidant system.     

NNK诱发BEP2D细胞产生活性氧及其对DNA的损伤

通过测定细胞内和细胞上清中活性氧（ｒｅａｃｔｉｖｅ ｏｘｙｇｅｎ ｓｐｅｃｉｅｓ,ＲＯＳ）水平,以及ＤＮＡ 加合物——８－羟基脱氧鸟嘌呤核苷（８－ｈｙｄｒｏｘｙｄｅｏｘｙｇｕａｎｏｓｉｎｅ,ＯＨ８ｄＧ）含量,对烟草特异亚硝胺类化合物４－甲基亚硝胺－１（３－吡啶基）－１－丁酮（４－（ｍ ｅｔｈｙｌｎｉｔｒｏｓａｍ ｉｎｏ）－１－（３－ｐｙｒｉｄｙｌ）－１－ｂｕｔａｎｏｎｅ,ＮＮＫ）诱发人乳头状病毒永生化的人支气管上皮细胞（ｈｕｍ ａｎ ｐａｐｉｌｌｏｍ ａｖｉｒｕｓ－ｉｍ ｍ ｏｒｔａｌｉｚｅｄ ｈｕｍ ａｎｂｒｏｎｃｈｉａｌｅｐｉｔｈｅｌｉａｌｃｅｌｌｌｉｎｅ,ＢＥＰ２Ｄ）产生的ＲＯＳ及其对ＤＮＡ 的氧化损伤进行研究,并观察纳米硒的保护作用．结果表明,ＢＥＰ２Ｄ 细胞经不同浓度的ＮＮＫ 作用后,细胞内和细胞上清中ＲＯＳ以及ＯＨ８ｄＧ含量均显著增加,并有较好的剂量效应关系．１ μｍ ｏｌ·Ｌ－ １纳米硒（ｎａｎｏｓｅｌｅｎｕｉｍ ,ＮＳ）能明显抑制ＮＮＫ 诱发ＢＥＰ２Ｄ细胞产生的ＲＯＳ及ＯＨ８ｄＧ 水平．揭示ＮＮＫ 能造成细胞的氧化损伤,而ＮＳ对ＮＮＫ 所致细胞的氧化损伤有保护作用．     

Reactive Oxygen Species and Antioxidants in Plants: An Overview

Plants exposed to biotic and abiotic stresses generate more reactive oxygen species (ROS) than their capacity to scavenge them. Biological molecules are susceptible to attack by ROS, including several proteins, polyunsaturated fatty acids and nucleic acids. The cellular arsenal for scavenging ROS and toxic organic radicals include ascorbate, glutathione, tocopherol, carotenoids, polyphenols, alkaloids and other compounds. Enzymatic antioxidants including superoxide dismutase, peroxidase, catalase and glutathione reductase detoxify either by quenching toxic compounds or regenerating antioxidants involving reducing power. Various aspects relating to sensors for ROS and signaling role of ROS in plants, improvement of antioxidant systems in transgenic plants and functional genomics approaches used to unravel the reactive oxygen gene network has been discussed.     

Restorative and synergistic efficacy of Kalpaamruthaa, a modified Siddha preparation, on an altered antioxidant status in adjuvant induced arthritic rat model

BACKGROUND: Rheumatoid arthritis (RA) is a prevalent and debilitating disease that affects the joints. Infiltration of blood-derived cells in the affected joints upon activation generate reactive oxygen/nitrogen species, resulting in an oxidative stress. One approach to counteract this oxidative stress is the use of antioxidants as therapeutic agents. OBJECTIVES: Kalpaamruthaa (KA), a modified indigenous Siddha preparation constituting Semecarpus anacardium nut milk extract (SA), Emblica officinalis (EO) and honey was evaluated for its synergistic antioxidant potential in adjuvant induced arthritic rats than sole SA treatment. MATERIALS AND METHODS: Levels/activities of reactive oxygen species (ROS)/reactive nitrogen species (RNS), myeloperoxidase, lipid peroxide and enzymic and non-enzymic antioxidants were determined in control, arthritis induced, SA and KA treated (150 mg/kg b.wt.) animals. RESULTS AND CONCLUSION: The levels/activities of ROS/RNS, myeloperoxidase and lipid peroxide were increased significantly (p<0.05) and the activities of enzymic and non-enzymic antioxidants were in turn decreased in arthritic rats, whereas these changes were reverted to near normal levels upon SA and KA treatment. KA showed an enhanced antioxidant potential than sole treatment of SA in adjuvant induced arthritic rats. KA via enhancing the antioxidant status in adjuvant induced arthritic rats than sole SA treatment proves to be an important therapeutic modality in the management of RA and thereby instituting the role of oxidative stress in the clinical manifestation of the disease RA. The profound antioxidant efficacy of KA than SA alone might be due to the synergistic action of the polyphenols such as flavonoids, tannins and other compounds such as vitamin C and hydroxycinnamates present in KA.     

抗氧化系统研究新进展

氧化还原系统主要由活性氧、自由基、活性氧生成系统和抗氧化系统组成。大量的研究表明,氧化还原系统在机体多种生物学功能中发挥关键的调节作用。抗氧化系统主要包括酶类抗氧化剂和非酶类抗氧化剂。抗氧化系统一方面可以通过调节活性氧的水平影响各种生物学功能,另一方面各种酶类抗氧化剂和非酶类抗氧化剂本身也可以参与多种生化反应,调节机体功能。近年来的研究表明,机体内除了典型的抗氧化酶,如超氧化物歧化酶和过氧化氢酶等,还存在多种抗氧化新型抗氧化酶,如硫氧还蛋白、谷氧还蛋白和金属基质蛋白酶等。在本文中,我们将回顾近年来的一些文献,综述抗氧化系统的研究新进展,旨在为抗氧化系统的深入研究提供理论基础。     

Molecular mechanisms of transformation of SkQ mitotropic quinones and the search for new approaches to creation of selective free radical traps

Features of the mechanism of action of positively charged benzoquinone derivatives (SkQ), which are the analogs of coenzyme Q (I), plastoquinone (II), and tocopherol (III), are discussed. It is usually considered that the main target of these compounds is mitochondria, where they accumulate due to the positive charge of the molecule. In the present work, it is shown with model systems that the reduced forms of compounds (I–III) under certain conditions can transform into electrically neutral cyclic zwitterions, which theoretically can escape from the matrix of energized mitochondria against the concentration gradient. A weak uncoupling effect of molecules I–III has been found on mitochondria. Its existence is in agreement with the abovementioned transformation of positively charged hydroquinones of type Ia–IIIa into electrically neutral molecules. The data obtained with model systems suggest that the target of SkQ hydroquinones as free radical traps may be not only mitochondria but also biochemical systems of the cytoplasm. Due to the presence of a large number of reactive oxygen species (ROS)-dependent signal systems in a cell, the functioning of cytoplasmic systems might be disturbed under the action of antioxidants. The problem of selective effect of antioxidants is discussed in detail in the present work, and a functional diagram of selective decrease of the “background level” of ROS based on differences in the intensity of background and “signal” ROS fluxes is considered.     

Magnificant role of intracellular reactive oxygen species production and its scavenging encompasses downstream processes

Environmental stresses are often associated with production of certain deleterious chemical entities called reactive oxygen species (ROS), which include hydrogen peroxide (H₂O₂), superoxide radical (O₂^?), hydroxyl radical (OH^?). In plants, ROS are formed by the inevitable leakage of electrons onto O₂ from the electron transport activities of chloroplasts, mitochondria, peroxisomes, vacuole and plasma membranes or as a byproduct of various metabolic pathways. Plants have their own antioxidant defense mechanisms to encounter ROS that is of enzymic and non-enzymic nature. Coordinated activities of these antioxidants regulate ROS detoxification and reduces oxidative load in plants. Though ROS are always regarded to impart negative impact on plants, some reports consider them to be important in regulating key cellular functions; however, such reports in plant are limited. On the other hand, specific ROS function as signaling molecules and activate signal transduction processes in response to various stresses is a matter of investigation.     

Exercise,depletion of antioxidants and antioxidant manipulation

Strenuous physical activity is known to increase the production of reactive oxygen species (ROS), associated with depletion of antioxidant defence. In the present work we evaluated the level of lipid peroxidation and antioxidant components in blood of sportsmen under resting conditions and compared the data obtained with those in age- and sex-matched sedentary controls. A significant increase was noted in the levels of thiobarbituric acid reactive substances (TBARS) and conjugated dienes while a decrease was observed in ascorbic acid and glutathione levels in sportsmen. α-Tocopherol was unaltered in plasma of sportsmen as compared to controls. The activity of superoxide dismutase was increased (52 per cent) and glutathione peroxidase was decreased (43 per cent) in the erythrocytes of sportsmen compared to controls. Basal glutathione levels were negatively correlated with conjugated dienes and maximal oxygen uptake (VO_2max) of the subjects. Dietary supplementation with antioxidant vitamins has been shown to be beneficial in combating oxidative stress without enhancing performance while exogenous glutathione was found to influence the endurance capacity of athletes. Such studies demonstrate the critical role played by glutathione and suggest that intervention trials should include a mixture of antioxidants rather than a single antioxidant. Copyright © 1998 John Wiley & Sons, Ltd.     

Basal superoxide as a sex-specific immune constraint

There is increasing evidence that reactive oxygen species (ROS), a group of unstable and highly reactive chemical molecules, play a key role in regulating and maintaining life-history trade-offs. Upregulation of ROS in association with immune activation is costly because it may result in an imbalance between pro- and antioxidants and, hence, oxidative damage. Previous research aimed at quantifying this cost has mostly focused on changes in the pro-/antioxidant balance subsequent to an immune response. Here, we test the hypothesis that systemic ROS may constrain immune activation. We show that systemic, pre-challenge superoxide (SO) levels are negatively related to the strength of the subsequent immune response towards the mitogen phytohaemagglutinin in male, but not female painted dragon lizards (Ctenophorus pictus). We therefore suggest that systemic SO constrains immune activation in painted dragon males. We speculate that this may be due to sex-specific selection pressures on immune investment.     

Oxidant,antioxidant and physical exercise

Generation of reactive oxygen species (ROS) is a normal process in the life of aerobic organisms. Under physiological conditions, these deleterious species are mostly removed by the cellular antioxidant systems, which include antioxidant vitamins, protein and non-protein thiols, and antioxidant enzymes. Since the antioxidant reserve capacity in most tissues is rather marginal, strenuous physical exercise characterized by a remarkable increase in oxygen consumption with concomitant production of ROS presents a challenge to the antioxidant systems.An acute bout of exercise at sufficient intensity has been shown to stimulate activities of antioxidant enzymes. This could be considered as a defensive mechanism of the cell under oxidative stress. However, prolonged heavy exercise may cause a transient reduction of tissue vitamin E content and a change of glutathione redox status in various body tissues. Deficiency of antioxidant nutrients appears to hamper antioxidant systems and augment exercise-induced oxidative stress and tissue damage. Chronic exercise training seems to induce activities of antioxidant enzymes and perhaps stimulate GSH levels in body fluids. Recent research suggest that supplementation of certain antioxidant nutrients are necessary for physically active individuals.     

Antioxidants, Oxidative Damage and Oxygen Deprivation Stress: a Review

Oxidative stress is induced by a wide range of environmentalfactors including UV stress, pathogen invasion (hypersensitivereaction), herbicide action and oxygen shortage. Oxygen deprivationstress in plant cells is distinguished by three physiologicallydifferent states: transient hypoxia, anoxia and reoxygenation.Generation of reactive oxygen species (ROS) is characteristicfor hypoxia and especially for reoxygenation. Of the ROS, hydrogenperoxide (H₂O₂) and superoxide (O₂^·–) are bothproduced in a number of cellular reactions, including the iron-catalysedFenton reaction, and by various enzymes such as lipoxygenases,peroxidases, NADPH oxidase and xanthine oxidase. The main cellularcomponents susceptible to damage by free radicals are lipids(peroxidation of unsaturated fatty acids in membranes), proteins(denaturation), carbohydrates and nucleic acids. Consequencesof hypoxia-induced oxidative stress depend on tissue and/orspecies (i.e. their tolerance to anoxia), on membrane properties,on endogenous antioxidant content and on the ability to inducethe response in the antioxidant system. Effective utilizationof energy resources (starch, sugars) and the switch to anaerobicmetabolism and the preservation of the redox status of the cellare vital for survival. The formation of ROS is prevented byan antioxidant system: low molecular mass antioxidants (ascorbicacid, glutathione, tocopherols), enzymes regenerating the reducedforms of antioxidants, and ROS-interacting enzymes such as SOD,peroxidases and catalases. In plant tissues many phenolic compounds(in addition to tocopherols) are potential antioxidants: flavonoids,tannins and lignin precursors may work as ROS-scavenging compounds.Antioxidants act as a cooperative network, employing a seriesof redox reactions. Interactions between ascorbic acid and glutathione,and ascorbic acid and phenolic compounds are well known. Underoxygen deprivation stress some contradictory results on theantioxidant status have been obtained. Experiments on overexpressionof antioxidant production do not always result in the enhancementof the antioxidative defence, and hence increased antioxidativecapacity does not always correlate positively with the degreeof protection. Here we present a consideration of factors whichpossibly affect the effectiveness of antioxidant protectionunder oxygen deprivation as well as under other environmentalstresses. Such aspects as compartmentalization of ROS formationand antioxidant localization, synthesis and transport of antioxidants,the ability to induce the antioxidant defense and cooperation(and/or compensation) between different antioxidant systemsare the determinants of the competence of the antioxidant system.     

Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress

Increasing cellular glucose uptake is a fundamental concept in treatment of type 2 diabetes, whereas nutritive calorie restriction increases life expectancy. We show here that increased glucose availability decreases Caenorhabditis elegans life span, while impaired glucose metabolism extends life expectancy by inducing mitochondrial respiration. The histone deacetylase Sir2.1 is found here to be dispensable for this phenotype, whereas disruption of aak-2, a homolog of AMP-dependent kinase (AMPK), abolishes extension of life span due to impaired glycolysis. Reduced glucose availability promotes formation of reactive oxygen species (ROS), induces catalase activity, and increases oxidative stress resistance and survival rates, altogether providing direct evidence for a hitherto hypothetical concept named mitochondrial hormesis or "mitohormesis." Accordingly, treatment of nematodes with different antioxidants and vitamins prevents extension of life span. In summary, these data indicate that glucose restriction promotes mitochondrial metabolism, causing increased ROS formation and cumulating in hormetic extension of life span, questioning current treatments of type 2 diabetes as well as the widespread use of antioxidant supplements.