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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    • "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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    • "A new take on reactive oxygen species that has recently emerged is the theory of mitohormesis (mitochondrial hormesis). In Caenorhabditis elegans, CR induces increased stress resistance and promotes health and longevity via an adaptive response to the increased generation of reactive oxygen species (Ristow and Zarse, 2010), and this increase in oxidative stress is actually required for the beneficial effects of CR. It seems unlikely that this concept would translate exactly to mammalian systems in light of the evidence presented above; however, it would explain why treatment with antioxidants has sometimes proven deleterious (Selman et al., 2013). "
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    ABSTRACT: Caloric restriction (CR) is a dietary intervention that robustly extends lifespan in diverse species. In mammals CR extends the period in which the animal is fit and vig-orous, and attenuates age-related disease vulnerability. Benefits of CR include reduced incidence of cancer, improved cardiovascular health, increased insulin sensi-tivity, and resistance to neurodegenerative diseases. The fact that CR extends not only average lifespan but also maximum lifespan has led to the consensus that an opti-mised CR diet slows the aging process itself. Here we outline the effects of CR on physiology and metabolism and where these may fit with current theories of aging. The authors describe factors that are likely to mediate the physiological adaptations to CR, placing an emphasis on nutrient sensitive regulators of metabolism. A major incentive for research into the mechanisms of CR is the promise of novel treatments for age-related diseases and disorders that are relevant to human aging.
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