How increased oxidative stress promotes longevity and metabolic health: The concept of mitochondrial hormesis (mitohormesis)

Dept. of Human Nutrition, Institute of Nutrition, University of Jena, Germany. <>
Experimental gerontology (Impact Factor: 3.49). 03/2010; 45(6):410-8. DOI: 10.1016/j.exger.2010.03.014
Source: PubMed


Recent evidence suggests that calorie restriction and specifically reduced glucose metabolism induces mitochondrial metabolism to extend life span in various model organisms, including Saccharomyces cerevisiae, Drosophila melanogaster, Caenorhabditis elegans and possibly mice. In conflict with Harman's free radical theory of aging (FRTA), these effects may be due to increased formation of reactive oxygen species (ROS) within the mitochondria causing an adaptive response that culminates in subsequently increased stress resistance assumed to ultimately cause a long-term reduction of oxidative stress. This type of retrograde response has been named mitochondrial hormesis or mitohormesis, and may in addition be applicable to the health-promoting effects of physical exercise in humans and, hypothetically, impaired insulin/IGF-1-signaling in model organisms. Consistently, abrogation of this mitochondrial ROS signal by antioxidants impairs the lifespan-extending and health-promoting capabilities of glucose restriction and physical exercise, respectively. In summary, the findings discussed in this review indicate that ROS are essential signaling molecules which are required to promote health and longevity. Hence, the concept of mitohormesis provides a common mechanistic denominator for the physiological effects of physical exercise, reduced calorie uptake, glucose restriction, and possibly beyond.

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    • "The term mitohormesis describes health effects of exercise through affecting mitochondrial performance by inducing mild oxidative stress and cellular adaptation [22]. Indeed, mitohormesis protects the cells against more severe and potent cellular stressors. "
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    ABSTRACT: While beneficial properties of physical activity and exercise on human health have been extensively reported in literature, the exact mechanism(s) underpinning impacts of exercise are not well understood. Focusing on metabolic disorders, as the main causes of social and economic burden in current century, exercise exhibited promising effects in prevention, alleviation and retardation of these disorders including, type 2 diabetes (T2D), Alzheimer's disease (AD), major depressive disorder (MDD) and obesity. Recent evidence has unmasked the role of mitochondrial dysfunction and chronic inflammation in pathophysiology of these disorders. Despite of the wealth of research on the etiology of metabolic disorders, intimate connections between these diseases, complex pathophysiology and their comorbidity still remains a challenging dilemma. In addition, although physical activity has improving effects on human health, it is not clear that how exercise is able to exert its modulatory effects on outcomes of metabolic disorders. Among several mechanisms, we assumed the hypothesis that exercise mitigates the production of mitochondrial-induced reactive oxygen species (ROS) and danger associated molecular patterns (DAMPs) as the main triggering factors for inflammasome formation. Since inflammasomes are of highly deleterious molecules relevant to pathogenesis of metabolic disorders, we hypothesized that beneficial effects of exercise may be associated with its ability to enhance the mitochondrial biogenesis and glucose transportation through generation of brain derived neurotrophic factor (BDNF). Also, we proposed that boosting impact of exercise on autophagy process accelerates the elimination of damaged mitochondria and thus, results in considerable decrease in production of ROS and DAMPs and consequently sterile inflammation.
    Medical Hypotheses 10/2015; 85(6). DOI:10.1016/j.mehy.2015.10.026 · 1.07 Impact Factor
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    • "CR was originally thought to slow aging by reducing mitochondrial ROS generation. However, recent studies have revealed that mitochondrial respiration and ROS are not necessarily decreased but are actually increased by CR (Ristow et al. 2010). In Fig. 7 Cox6b1 overexpression induces Nrf2 nuclear translocation and upregulates antioxidant enzymes. "
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    ABSTRACT: Calorie restriction (CR), a non-genetic intervention that promotes longevity in animals, may exert anti-aging effects by modulating mitochondrial function. Based on our prior mitochondrial proteome analysis, we focused on the potential roles of cytochrome c oxidase (Cox or Complex IV) subunit 6b1 on formation of mitochondrial supercomplexes comprised of Complex I, III, and IV. Blue native polyacrylamide gel electrophoresis followed by immunoblotting showed that the amount of Cox6b1 and the proportion of high molecular weight supercomplexes (SCs) comprised of Complexes I, III, and IV were increased in the liver of mice subjected to 30 % CR, compared with the liver of mice fed ad libitum. In in vitro experiments, in Cox6b1-overexpressing NIH3T3 (Cox6b1-3T3) cells, Cox6b1 was increased in the SC, III2IV1, and III2IV2 complexes and Cox was concomitantly recruited abundantly into the SC, compared with control (Con)-3T3 cells. The proportions of III2IV1, and III2IV2, relative to IV monomer were also increased in Cox6b1-3T3 cells. Cox6b1-3T3 cells showed increased oxygen consumption rates, Cox activity, and intracellular ATP concentrations, indicating enhanced mitochondrial respiration, compared with Con-3T3 cells. Despite the increased basal level of mitochondrial reactive oxygen species (ROS), cell viability after inducing oxidative stress was greater in Cox6b1-3T3 cells than in Con-3T3 cells, probably because of prompt activation of protective mechanisms, such as nuclear translocation of nuclear factor E2-related factor-2. These in vivo and in vitro studies show that Cox6b1 is involved in regulation of mitochondrial function by promoting the formation of SC, suggesting that Cox6b1 contributes to the anti-aging effects of CR.
    Age 06/2015; 37(3):9787. DOI:10.1007/s11357-015-9787-8 · 3.45 Impact Factor
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    • "Thus increased ROS production has now come to be viewed as an adaptive response of mitochondria [16], often called mitohormesis, to mitigate dangerous changes rather than representing an inevitable byproduct of mitochondrial respiration. Mitohormesis also increases stress resistance, maintains mtDNA levels, preserves mtDNA fidelity, enables cells to tolerate high levels of mtDNA mutations [33], and generally prolongs lifespan [34] [35] [36]. This represents a novel-upsetting paradigm, which explains the failure of antioxidants to delay aging in clinical trials [37] [38]. "
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    ABSTRACT: Decline in human muscle mass and strength (sarcopenia) is one of the principal hallmarks of the aging process. Regular physical exercise and training programs are certain powerful stimuli to attenuate the physiological skeletal muscle alterations occurring during aging and contribute to promote health and well-being. Although the series of events that led to these muscle adaptations are poorly understood, the mechanisms that regulate these processes involve the “quality” of skeletal muscle mitochondria. Aerobic/endurance exercise helps to maintain and improve cardiovascular fitness and respiratory function, whereas strength/resistance-exercise programs increase muscle strength, power development, and function. Due to the different effect of both exercises in improving mitochondrial content and quality, in terms of biogenesis, dynamics, turnover, and genotype, combined physical activity programs should be individually prescribed to maximize the antiaging effects of exercise.
    Oxidative medicine and cellular longevity 05/2015; 2015:1-15. DOI:10.1155/2015/917085 · 3.36 Impact Factor
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