The complex role of physical exercise and reactive oxygen species on brain

AbstractReactive oxygen species (ROS) are continuously generated during aerobic metabolism and at moderate level. They play a role in redox signaling, but in significant concentration they cause oxidative damage and neurodegeneration. Because of the enhanced sensitivity of brain to ROS, it is especially important to maintain the normal redox state in different types of neuron cells. In last decade it became clear that regular exercise beneficially affects brain function, and can play an important preventive and therapeutic role in stroke, Alzheimer, and Parkinson diseases. The effects of exercise appear to be very complex and could include neurogenesis via neurotrophic factors, increased capillariszation, decreased oxidative damage, and increased proteolytic degradation by proteasome and neprilysin. Data from our and other laboratories indicate that exercise-induced modulation of ROS levels plays a role in the protein content and expression of brain-derived neurotrophic factor, tyrosine-related kinase B (TrkB), and cAMP response element binding protein, resulting in better function and increased neurogenesis. Therefore, it appears that exercise-induced modulation of the redox state is an important means, by which exercise benefits brain function, increases the resistance against oxidative stress, facilitates recovery from oxidative stress, and attenuates age-associated decline in cognition

Redox-regulating sirtuins in aging, caloric restriction, and exercise.

The consequence of decreased nicotinamide adenine dinucleotide (NAD(+)) levels as a result of oxidative challenge is altered activity of sirtuins, which, in turn, brings about a wide range of modifications in mammalian cellular metabolism. Sirtuins, especially SIRT1, deacetylate important transcription factors such as p53, forkhead homeobox type O proteins, nuclear factor κB, or peroxisome proliferator-activated receptor γ coactivator 1α (which controls the transcription of pro- and antioxidant enzymes, by which the cellular redox state is affected). The role of SIRT1 in DNA repair is enigmatic, because it activates Ku70 to cope with double-strand breaks, but deacetylation of apurinic/apyrimidinic endonuclease 1 and probably of 8-oxoguanine-DNA glycosylase 1 decreases the activity of these DNA repair enzymes. The protein-stabilizing effects of the NAD+-dependent lysine deacetylases are readily related to housekeeping and redox regulation. The role of sirtuins in caloric restriction (CR)-related longevity in yeast is currently under debate. However, in mammals, it seems certain that sirtuins are involved in many cellular processes that mediate longevity and disease prevention via the effects of CR through the vascular, neuronal, and muscular systems. Regular physical exercise-mediated health promotion also involves sirtuin-regulated pathways including the antioxidant-, macromolecular damage repair-, energy-, mitochondrial function-, and neuronal plasticity-associated pathways. This review critically evaluates these findings and points out the age-associated role of sirtuins

Voluntary Exercise Can Ameliorate Insulin Resistance by Reducing iNOS-Mediated S-Nitrosylation of Akt in the Liver in Obese Rats

Voluntary exercise can ameliorate insulin resistance. The underlying mechanism, however, remains to be elucidated. We previously demonstrated that inducible nitric oxide synthase (iNOS) in the liver plays an important role in hepatic insulin resistance in the setting of obesity. In this study, we tried to verify our hypothesis that voluntary exercise improves insulin resistance by reducing the expression of iNOS and subsequent S-nitrosylation of key molecules of glucose metabolism in the liver. Twenty-one Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of type 2 diabetes mellitus, and 18 non-diabetic control Long-Evans Tokushima Otsuka (LETO) rats were randomly assigned to a sedentary group or exercise group subjected to voluntary wheel running for 20 weeks. The voluntary exercise significantly reduced the fasting blood glucose and HOMA-IR in the OLETF rats. In addition, the exercise decreased the amount of iNOS mRNA in the liver in the OLETF rats. Moreover, exercise reduced the levels of S-nitrosylated Akt in the liver, which were increased in the OLETF rats, to those observed in the LETO rats. These findings support our hypothesis that voluntary exercise improves insulin resistance, at least partly, by suppressing the iNOS expression and subsequent S-nitrosylation of Akt, a key molecule of the signal transduction pathways in glucose metabolism in the liver

Cardiorespiratory fitness, body mass index, and cancer mortality: a cohort study of Japanese men

Background: The aim of this study is to investigate the independent and joint effects of cardiorespiratory fitness (CRF) and body mass index (BMI) on cancer mortality in a low body mass index population. Methods: We evaluated CRF and BMI in relation to cancer mortality in 8760 Japanese men. The median BMI was 22.6 kg/m2 (IQR: 21.0-24.3). The mean follow-up period was more than 20 years. Hazard ratios and 95% CI were obtained using a Cox proportional hazards model while adjusting for several confounding factors. Results: Using the 2nd tertile of BMI (21.6-23.6 kg/m2) as reference, hazard ratios and 95% CI for the lowest tertile of BMI (18.5-21.5) were 1.26 (0.87–1.81), and 0.92 (0.64–1.34) for the highest tertile (23.7-37.4). Using the lowest tertile of CRF as reference, hazard ratios and 95% CIs for 2nd and highest tertiles of CRF were 0.78 (0.55–1.10) and 0.59 (0.40–0.88). We further calculated hazard ratios according to groups of men cross-tabulated by tertiles of CRF and BMI. Among men in the second tertile of BMI, those belonging to the lowest CRF tertile had a 53% lower risk of cancer mortality compared to those in the lowest CRF tertile (hazard ratio: 0.47, 95% CI: 0.23-0.97). Among those in the highest BMI tertile, the corresponding hazard ratio was 0.54 (0.25-1.17). Conclusion: These results suggest that high CRF is associated with lower cancer mortality in a Japanese population of men with low average BMI

DNA methylation clock DNAmFitAge shows regular exercise is associated with slower aging and systemic adaptation

DNAmPhenoAge, DNAmGrimAge, and the newly developed DNAmFitAge are DNA methylation (DNAm)-based biomarkers that reflect the individual aging process. Here, we examine the relationship between physical fitness and DNAm-based biomarkers in adults aged 33–88 with a wide range of physical fitness (including athletes with long-term training history). Higher levels of VO 2 max ( ρ = 0.2, p = 6.4E − 4, r = 0.19, p = 1.2E − 3), Jumpmax ( p = 0.11, p = 5.5E − 2, r = 0.13, p = 2.8E − 2), Gripmax ( ρ = 0.17, p = 3.5E − 3, r = 0.16, p = 5.6E − 3), and HDL levels ( ρ = 0.18, p = 1.95E − 3, r = 0.19, p = 1.1E − 3) are associated with better verbal short-term memory. In addition, verbal short-term memory is associated with decelerated aging assessed with the new DNAm biomarker FitAgeAcceleration ( ρ : − 0.18, p = 0.0017). DNAmFitAge can distinguish high-fitness individuals from low/medium-fitness individuals better than existing DNAm biomarkers and estimates a younger biological age in the high-fit males and females (1.5 and 2.0 years younger, respectively). Our research shows that regular physical exercise contributes to observable physiological and methylation differences which are beneficial to the aging process. DNAmFitAge has now emerged as a new biological marker of quality of life

Hormetic Effects of Reactive Oxygen Species by Exercise: A View from Animal Studies for Successful Aging in Human

Numerous anti-aging measures have been proposed to cope with age-associated decline of physiological functions and/or onset of diseases, mostly based on free radical (or oxidative stress) theory of aging, though no robust scientific data have been reported to extend human healthspan. This is due to dual (harmful as well as essential) roles of reactive oxygen species (ROS) to a body. Regular moderate exercise provides benefits upregulating defense against oxidative stress in good balance between the opposing dual roles. Sources of ROS in exercise appear to be not only mitochondria as often claimed but also enzymatic reactions catalyzed by NADPH oxidase and other oxidases. It may, therefore, be possible to mimic this aspect of exercise to promote the defense for healthspan extension by other means such as modest alcohol consumption that could upregulate activity of enzymes against oxidative stress

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