The Concept of Mitochondrial Hormesis (Mitohormesis)
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Experimental Gerontology 45 (2010) 410–418 Contents lists available at ScienceDirect Experimental Gerontology journal homepage: www.elsevier.com/locate/expgero Review How increased oxidative stress promotes longevity and metabolic health: The concept of mitochondrial hormesis (mitohormesis) Michael Ristow a,b,*, Kim Zarse a a Dept. of Human Nutrition, Institute of Nutrition, University of Jena, 29 Dornburger Str., Jena D-07743, Germany b Dept. of Clinical Nutrition, German Institute of Human Nutrition, 114 Arthur-Scheunert-Allee, Nuthetal D-14558, Germany article info abstract Article history: Recent evidence suggests that calorie restriction and specifically reduced glucose metabolism induces Received 1 July 2009 mitochondrial metabolism to extend life span in various model organisms, including Saccharomyces cere- Received in revised form 9 March 2010 visiae, Drosophila melanogaster, Caenorhabditis elegans and possibly mice. In conflict with Harman’s free Accepted 19 March 2010 radical theory of aging (FRTA), these effects may be due to increased formation of reactive oxygen species Available online 27 March 2010 (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 ret- Keywords: rograde response has been named mitochondrial hormesis or mitohormesis, and may in addition be Aging applicable to the health-promoting effects of physical exercise in humans and, hypothetically, impaired Metabolism Reactive oxygen species insulin/IGF-1-signaling in model organisms. Consistently, abrogation of this mitochondrial ROS signal by Oxidative stress antioxidants impairs the lifespan-extending and health-promoting capabilities of glucose restriction and Glucose physical exercise, respectively. In summary, the findings discussed in this review indicate that ROS are Glycolysis essential signaling molecules which are required to promote health and longevity. Hence, the concept Calorie restriction of mitohormesis provides a common mechanistic denominator for the physiological effects of physical exercise, reduced calorie uptake, glucose restriction, and possibly beyond. Ó 2010 Elsevier Inc. All rights reserved. 1. Calorie restriction cantly decreased in M. mulatta. It should be noted, though, that age-related mortality (as defined in this study) accounted for only A limited reduction of nutritional calorie uptake, so-called calo- 54% of deaths during the study period. In contrast and quite strik- rie restriction (CR), has been shown to extend life span in multiple ingly, age-related gluco-regulatory impairment was completely species and model organisms, as initially observed by McCay et al. abolished in calorically restricted monkeys. Hence and due to addi- (1935). It is beyond the scope of this review to summarize the mul- tional findings (Fontana et al., 2004; Heilbronn et al., 2006; Ingram tiple findings on CR, since excellent reviews on this topic have been et al., 2006a; Weindruch, 2006; Fontana and Klein, 2007) it appears published in the past (Weindruch and Walford, 1988; Masoro, possible that CR extends life span in primates and/or humans. 2000; Speakman et al., 2002; Heilbronn and Ravussin, 2003; In- The initial conceptual background for restricting dietary calo- gram et al., 2004; Anson et al., 2005; Gredilla and Barja, 2005; Sin- ries is based on the assumption that reducing nutritive calorie clair, 2005; Wolff and Dillin, 2006; Bishop and Guarente, 2007; availability would reduce the metabolic rate of an organism. Piper and Bartke, 2008). It should be emphasized, however, that Accordingly, it was proposed more than a century ago that maxi- unequivocal evidence for the effectiveness of CR in primates and mum life span is inversely proportional to the amount of nutritive especially humans is missing. A recent publication on an ongoing energy metabolized (Rubner, 1908). Subsequently, the rate-of-liv- study in Macaca mulatta shows that CR has no statistically signifi- ing hypothesis evolved, suggesting that an increased metabolic cant effect on overall mortality (Colman et al., 2009). However, rate would decrease life span in eukaryotes (Pearl, 1928). Several since about half of the study group was still alive at the time of decades later it was proposed that increased metabolic rate would manuscript preparation, future findings from this ongoing study promote increased formation of reactive oxygen species (ROS) to may show whether CR in rhesus monkeys significantly affects mor- cause cumulative damage to the cell, and hence the organism (Har- tality. Nevertheless, so-called ‘‘age-related mortality” was signifi- man, 1956). Notably, respiratory enzymes using oxygen to gener- ate readily available energy were explicitly proposed to be the most relevant culprit in this regard (Harman, 1956). This concept * Corresponding author at: Dept. of Human Nutrition, Institute of Nutrition, was named free radical theory of aging (FRTA). University of Jena, 29 Dornburger Str., Jena D-07743, Germany. Tel.: +49 3641 949630; fax: +49 3641 949632. Based on these assumptions, considerable experimental effort E-mail address: [email protected] (M. Ristow). has been made to elucidate the underlying mechanistic principles. 0531-5565/$ - see front matter Ó 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.exger.2010.03.014 M. Ristow, K. Zarse / Experimental Gerontology 45 (2010) 410–418 411 On the one hand, it has repeatedly been shown that CR is capable conversion of fatty acids and/or (most) amino acids into ATP de- of delaying a number of age-related diseases, including obesity, pends on oxidative phosphorylation (OxPhos) and hence oxygen. type 2 diabetes, hypercholesterolemia, atherosclerosis, different cancers, as well as neurodegeneration and cardiomyopathy. This has been attributed to specific and diverse effects of CR on the 3. Glucose restriction respective molecular processes assumed to cause these disorders. According to some of these approaches, delayed aging would sim- A specific restriction of nutritive glucose is, with the exception ply reflect a cumulative reduction of age-associated and mortality- of yeast and D. melanogaster, difficult to achieve in eukaryotic mod- promoting medical conditions as a consequence of CR. On the other el organisms. In Saccharomyces cerevisiae, it was shown that re- hand, it was shown that CR per se promotes increased stress de- duced glucose availability significantly extends chronological life fense, and specifically induces endogenous defense mechanisms span, and this extension depends on induction of respiration (Lin against ROS (Koizumi et al., 1987; Semsei et al., 1989; Rao et al., et al., 2002) as well as sirtuins (Lin et al., 2000). While the depen- 1990; Pieri et al., 1992; Youngman et al., 1992; Xia et al., 1995; dence on sirtuins is a matter of debate (Kaeberlein et al., 2004; Masoro, 1998a; Barros et al., 2004). In most cases, this was inter- Agarwal et al., 2005; Guarente, 2006; Smith et al., 2007), alterna- preted as a consequence of reduced metabolic rate, and hence re- tive mechanisms independent of sirtuins have been proposed (Bar- duced ROS production. More recently, a different perspective has ros et al., 2004; Roux et al., 2009). emerged, suggesting that CR causes an adaptive response to spe- In C. elegans and mammals, a specific restriction of intracellular cific metabolic alterations in states of reduced food uptake. glucose availability is commonly achieved by application of a com- petitive inhibitor of glycolysis, 2-deoxy-glucose (DOG) (Wick et al., 1957). In C. elegans, it was shown that application of DOG induces 2. Reduction of specific macronutrients respiration and extends life span (Schulz et al., 2007), in this regard reflecting previous findings in yeast (Lin et al., 2002). However and Nutritional, i.e. metabolizable calories are derived from carbohy- in conflict with these aforementioned findings in yeast, this pro- drates, triacylglycerols (fat) and proteins. These contain a few differ- cess was independent of sirtuins, but rather required activation ent monosaccharides (including glucose), and significant numbers of AMP-activated kinase (AMPK) (Schulz et al., 2007). This kinase of fatty acids and amino acids, respectively. Limited evidence exists was previously established as a sensor of cellular energy depletion whether the generally accepted effects of calorie restriction can be in both mammals (Hardie et al., 2006) and specifically C. elegans attributed to specific macronutrients, i.e. whether restriction of a (Apfeld et al., 2004; Greer et al., 2007), and has been found to in- single macronutrient may exert the same effects than overall CR duce a health-promoting metabolic state particularly by inducing does. This topic has been reviewed in detail elsewhere (Piper and mitochondrial metabolism (Hardie et al., 2006). Accordingly, appli- Bartke, 2008), hence the following paragraphs will focus on specific cation of DOG to rodents efficiently mimics features of the meta- aspects of macronutrient choice only. bolic state of CR (Lane, 1998) as well as carbohydrate restriction In invertebrate model organisms, restriction of proteins as well (Garriga-Canut et al., 2006), suggesting that DOG acts as a CR mi- as carbohydrates, mostly glucose, has been studied with different metic (Duan and Mattson, 1999; Sinclair, 2005; Zhu et al., 2005; In- and sometimes opposing outcomes, whereas studies on triacylgly- gram et al., 2006b). cerols are lacking for invertebrates.