Sataro Goto

Systemic adaptation to oxidative challenge induced by regular exercise.

Exercise is associated with increased ATP need and an enhanced aerobic and/or anaerobic metabolism, which results in an increased formation of reactive oxygen species (ROS). Regular exercise seems to decrease the incidence of a wide range of ROS-associated diseases, including heart disease, type II diabetes, rheumatic arthritis, Alzheimer and Parkinson diseases, and certain cancers. The preventive effect of regular exercise, at least in part, is due to oxidative stress-induced adaptation. The oxidative challenge-related adaptive process of exercise is probably not just dependent upon the generated level of ROS but primarily on the increase in antioxidant and housekeeping enzyme activities, which involves the oxidative damage repair enzymes. Therefore, the effects of exercise resemble the characteristics of hormesis. In addition, it seems that the oxidative challenge-related effects of exercise are systemic. Skeletal muscle, liver, and brain have very different metabolic rates and functions during exercise, but the adaptive response is very similar: increased antioxidant/damage repair enzyme activity, lower oxidative damage, and increased resistance to oxidative stress, due to the changes in redox homeostasis. Hence, it is highly possible that the well-known beneficial effects of exercise are due to the capability of exercise to produce increased levels of ROS. Or in other words, it seems that the vulnerability of the body to oxidative stress and diseases is significantly enhanced in a sedentary compared to a physically active lifestyle.

Exercise, oxidative stress and hormesis

Physical inactivity leads to increased incidence of a variety of diseases and it can be regarded as one of the end points of the exercise-associated hormesis curve. On the other hand, regular exercise, with moderate intensity and duration, has a wide range of beneficial effects on the body including the fact that it improves cardio-vascular function, partly by a nitric oxide-mediated adaptation, and may reduce the incidence of Alzheimers disease by enhanced concentration of neurotrophins and by the modulation of redox homeostasis. Mechanical damage-mediated adaptation results in increased muscle mass and increased resistance to stressors. Physical inactivity or strenuous exercise bouts increase the risk of infection, while moderate exercise up-regulates the immune system. Single bouts of exercise increases, and regular exercise decreases the oxidative challenge to the body, whereas excessive exercise and overtraining lead to damaging oxidative stress and thus are an indication of the other end point of the hormetic response. Based upon the genetic setup, regular moderate physical exercise/activity provides systemic beneficial effects, including improved physiological function, decreased incidence of disease and a higher quality of life.

Alzheimer's β‐amyloid peptide specifically interacts with and is degraded by insulin degrading enzyme

Cerebral deposition of β‐amyloid peptide (βA) is a hallmark of Alzheimers disease. Concentration of βA could play a critical role in the rate of amyloid deposition. It is therefore of considerable importance to identify proteases involved in processing of βA. 125I‐labeled synthetic βA specifically cross‐linked to a single protein with M r = 110,000 in cytosol fractions from rat brain and liver. This protein was identified as insulin degrading enzyme (IDE) since the labeling of the 110 kDa protein was completely blocked by an excess of insulin, and anti‐IDE monoclonal antibodies precipitated the labeled protein. Purified rat IDE effectively degraded βA.

Exercise and hormesis: Oxidative stress-related adaptation for successful aging

The hormesis theory purports that biological systems respond with a bell-shaped curve to exposure to chemicals, toxins, and radiation. Here we extend the hormesis theory to include reactive oxygen species (ROS). We further suggest that the beneficial effects of regular exercise are partly based on the ROS generating capability of exercise, which is in the stimulation range of ROS production. Therefore, we suggest that exercise-induced ROS production plays a role in the induction of antioxidants, DNA repair and protein degrading enzymes, resulting in decreases in the incidence of oxidative stress-related diseases and retardation of the aging process.

THE EFFECT OF EXERCISE TRAINING ON OXIDATIVE DAMAGE OF LIPIDS, PROTEINS, AND DNA IN RAT SKELETAL MUSCLE: EVIDENCE FOR BENEFICIAL OUTCOMES

Moderate daily exercise is known to be beneficial to health, reducing risks of a number of age-related disorders. Molecular mechanisms that bring about these effects are not clear. In contrast, it has been claimed that some types of prolonged physical exertion are detrimental to health because active oxygen species are generated excessively by enhanced oxygen consumption. Using two age groups of rats, young (4 week) and middle aged (14 months), we investigated the effects of long-term swimming training on the oxidative status of phospholipids, proteins, and DNA. The concentration of thiobarbituric acid reactive substances and 4-hydroxynonenal protein adducts did not differ in the gastrocnemius muscle between exercised and nonexercised animals in the two age groups. The extent of carbonylation in a protein of molecular weight around 29 KDa and the amount of 8-hydroxydeoxyguanosine in nuclear DNA were smaller (p<.05) in the exercised rats than in the sedentary animals. Activities of DT-diaphorase (C1: 29.3+/-1.9; C2: 36.1+/-2.6; E1: 27.2+/-1.3; C2: 33.4+/-2.9 nmol/mg protein) and proteasome, a major proteolytic enzyme for oxidatively modified proteins were significantly higher in the exercised animals of both age groups (p<.05). The adaptive response against oxidative stress induced by moderate endurance exercise constitutes a beneficial effect of exercise.

The effects of training and detraining on memory, neurotrophins and oxidative stress markers in rat brain

In the current investigation we tested how swimming training (T) (8 week, 5 times/week, 2 h/day), and detraining (DT) affects brain functions and oxidative stress markers in rat brain. The free radical concentration, measured by electron paramagnetic resonance, decreased in brain of T and DT rats compared to controls (C). The level of brain-derived neurotrophic factor (BDNF) increased as a result of training, but decreased below the control level after 6 weeks of detraining. In addition, the concentration of nerve growth factor (NGF) also declined with DT. The passive avoidance test was used to assess the memory of rats, and training-induced improvement was observed but the enhancement disappeared with detraining. When the content of mitochondrial electron transport complexes, as a potent free radical generator, was evaluated by the blue native gel method, no significant alterations were observed. The repair of nuclear and mitochondrial 8-oxodeoxyguanosine, as measured by the activity of OGG1, showed no significant difference. Therefore, the results suggest that regular exercise training improves memory, decreases the level of reactive oxygen species, and increase the production of BDNF and NGF. On the other hand, it appears that the beneficial effects of training are reversible in the brain, since detraining down-regulates the neurotrophin level, and memory. It is suggested that exercise training is more likely to beneficially effect the production of reactive oxygen species and the related oxidative damage.

Exercise alters SIRT1, SIRT6, NAD and NAMPT levels in skeletal muscle of aged rats

Silent information regulators are potent NAD(+)-dependent protein deacetylases, which have been shown to regulate gene silencing, muscle differentiation and DNA damage repair. Here, changes in the level and activity of sirtuin 1 (SIRT1) in response to exercise in groups of young and old rats were studied. There was an age-related increase in SIRT1 level, while exercise training significantly increased the relative activity of SIRT1. A strong inverse correlation was found between the nuclear activity of SIRT1 and the level of acetylated proteins. Exercise training induced SIRT1 activity due to the positive effect of exercise on the activity of nicotinamide phosphoribosyltransferase (NAMPT) and thereby the production of sirtuin-fueling NAD(+). Exercise training normalized the age-associated shift in redox balance, since exercised animals had significantly lower levels of carbonylated proteins, expression of hypoxia-inducible factor-1 alpha and vascular endothelial growth factor. The age-associated increase in the level of SIRT6 was attenuated by exercise training. On the other hand, aging did not significantly increase the level of DNA damage, which was in line with the activity of 8-oxoguanine DNA glycosylase, while exercise training increased the level of this enzyme. Regular exercise decelerates the deleterious effects of the aging process via SIRT1-dependent pathways through the stimulation of NAD(+) biosynthesis by NAMPT.

Age-associated increases in oxidative stress and nuclear transcription factor κB activation are attenuated in rat liver by regular exercise

The combined effects of aging and regular physical exercise was investigated on the production of reactive oxygen species (ROS), lipid peroxidation, glutathione status, and the activity of nuclear factor‐κB (NF‐κB) in rat liver. A group of 24 male F344 rats was divided into the following categories: adult control (18 months), adult exercised (18 months), and aged control (28 months) and aged exercised (28 months). The ROS formation increased as a function of age and exercise training decreased the rate of ROS formation in the two age groups. Significant positive correlation was found between ROS production and lipid peroxidation (LIPOX). The reduced glutathione (GSH) level was higher and the oxidized glutathione (GSSG) level lower in exercised groups compared with the sedentary controls (P<0.05). An age‐associated increase in NF‐κB activity was attenuated by the regular exercise. The content of p50 and p65 subunits of NF‐κB increased with age and decreased with exercise training. The content of inhibitory factor‐κB was inversely related to NF‐κB activation. Regular exercise‐induced adaptive responses, including attenuation of an increase in ROS production, LIPOX level, NF‐κB activation, and reduced GSH/GSSG ratio, appear to be capable, even in old age, of reducing increases in inflammatory and other detrimental consequences that are often associated with advancing age.

Age-associated neurodegeneration and oxidative damage to lipids, proteins and DNA

Lipids, proteins and DNA in the central nervous system have a high sensitivity to oxidative stress. Reactive oxygen species (ROS)-induced damage increases with aging, especially in the last quarter of the life span. The so called base level of oxidative modification of lipids could be important to cell signaling, and membrane remodeling, but the ROS-mediated post translation modifications of proteins could be important to the homeostasis of protein turnover. Low levels of 8-oxo-7,8-dihydroguanine (8-oxoG) might be necessary for transcription. A high level of accumulation of lipid peroxidation, oxidative protein damage or 8-oxoG, on the other hand, accelerates the progress of aging and neurodegenerative diseases. Therefore, agents that induce the activity of repair enzymes, such as Ca(2(+))-independent phospholipase A(2) (iPLA(2)beta), methionine sulfoxide reductase, and 8-oxoguanine DNA glycosylase, or the activity of enzymes that could prevent the accumulation of oxidized, toxic proteins, such as proteasome, Lon protease, neprilysin or insulin degrading enzyme, may act as potential therapeutic tools to slow the aging process and the progress of neurodegenerative diseases.

The effects of moderate-, strenuous- and over-training on oxidative stress markers, DNA repair, and memory, in rat brain

We have tested the hypothesis that training with moderate- (MT), strenuous- (ST), or over- (OT) load can cause alterations in memory, lipid peroxidation, protein oxidation, DNA damage, activity of 8-oxoG-DNA glycosylase (OGG1) and brain-derived neurotrophic factor (BDNF), in rat brain. Rat memory was assessed by a passive avoidance test and the ST and OT group demonstrated improved memory. The content of BDNF was increased only in the OT group. The oxidative damage of lipids and DNA, as measured by thiobarbituric acid reactive substances (TBARS), and 8-hydroxydeoxyguanosine (8-OHdG), did not change significantly with exercise. Similarly, the activity of DNA repair enzyme, 8-oxoguanine DNA glycosylase (OGG1), was not altered with exercise training. On the other hand, the content of reactive carbonyl derivatives (RCDs) decreased in all groups and the decrease reached significance levels in the ST and OT groups. The activity of the proteasome complex increased in the brain of OT. The findings of this study imply that over-training does not induce oxidative stress in the brain and does not cause loss of memory. The improved memory was associated with enhanced BDNF content.