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Mitohormesis: Promoting Health and Lifespan by Increased Levels of Reactive Oxygen Species (ROS)
Mitohormesis: Promoting Health and Lifespan by Increased Levels of Reactive Oxygen Species (ROS)
Increasing evidence indicates that reactive oxygen species (ROS), consisting of superoxide, hydrogen peroxide, and multiple others, do not only cause oxidative stress, but rather may function as signaling molecules that promote health by preventing or delaying a number of chronic diseases, and ultimately extend lifespan. While high levels of ROS are generally accepted to cause cellular damage and to promote aging, low levels of these may rather improve systemic defense mechanisms by inducing an adaptive response. This concept has been named mitochondrial hormesis or mitohormesis. We here evaluate and summarize more than 500 publications from current literature regarding such ROS-mediated low-dose signaling events, including calorie restriction, hypoxia, temperature stress, and physical activity, as well as signaling events downstream of insulin/IGF-1 receptors, AMP-dependent kinase (AMPK), target-of-rapamycin (TOR), and lastly sirtuins to culminate in control of proteostasis, unfolded protein response (UPR), stem cell maintenance and stress resistance. Additionally, consequences of interfering with such ROS signals by pharmacological or natural compounds are being discussed, concluding that particularly antioxidants are useless or even harmful.
Physical inactivity promotes the onset of a variety of diseases like obesity, cardiovascular disease, DM type 2, and cancer. Consistently, regular physical activity unquestionably exerts beneficial or preventive effects on the above mentioned diseases, and additionally delays depressive symptoms, neurodegeneration (including Alzheimer’s disease), and general aging (Warburton et al. 2006, James et al. 1984, Hu et al. 2001, Brown et al. 2012, Lanza et al. 2008, Manini et al. 2006, Powers et al. 2011). Exercise is not only linked to enhanced mitochondrial biogenesis and oxidative metabolism, but also to increased generation of mtROS (Powers and Jackson 2008, Chevion et al. 2003, Davies et al. 1982, Alessio and Goldfarb 1988, Alessio et al. 1988). Thus, and because of its obvious beneficial effects in regards to health and aging, make it a paradigm of adaptive response processes and finally mitohormesis (Radak et al. 2008, Radak et al. 2005, Ji et al. 2006, Watson 2013). However, similar to physical inactivity, overtraining or excessive exercise represents the other end of the hormesis curve as the adaption process is inhibited, leading to incomplete recovery (Chevion et al. 2003) and resulting in maladaptation and possibly increased risk of diseases (Alessio et al. 1988).
To our knowledge, the first direct evidence that increased ROS production following exercise may act as stimulus to activate mitochondria biogenesis and mediates potential health-beneficial effects dates back to 1982 (Davies et al. 1982). An indirect clue was already given in 1971 with an antioxidant, namely vitamin E, causing unfavorable effects on the endurance performance of swimmers (Sharman et al. 1971). Since then, a bulk of studies (in most cases inadvertently) proved the hypothesis that ROS are required for the health-promoting effects of physical activity, causing an increase in antioxidant defense mechanisms and with this, prolong health span and mean lifespan (Crawford and Davies 1994, Davies 1986, Kim et al. 1996, Marzatico et al. 1997, Balakrishnan and Anuradha 1998, Ji et al. 2006, Powers and Lennon 1999, Niess et al. 1999, Hollander et al. 2001, Higuchi et al. 1985, Gomez-Cabrera et al. 2008b, Quintanilha 1984, Vincent et al. 1999, Boveris and Navarro 2008).
One of the main changes due to regular physical activity is the increase in mitochondria energy metabolism. Exercise activates PGC-1α, which is capable of controlling mitochondrial gene expression via NRF1 and the mitochondrial transcription factor A (TFAM). This mediates enhanced replication of mitochondrial DNA, leading to increased mitochondrial biogenesis and efficient muscle contraction (Nikolaidis and Jamurtas 2009, Akimoto et al. 2005, Baar 2004, Arbogast and Reid 2004). Furthermore, PGC-1 promotes the response to oxidative stress through activation of NRF2 and induction of antioxidant enzyme expression (St. Pierre et al. 2006). Another important point is the massive consumption of ATP followed by an increase in AMP, which activates AMPK, leading again to induction of PGC-1 and enhanced mitochondrial biogenesis (Bergeron et al. 2001, Atherton et al. 2005). This increase in mitochon -drial metabolism leads to enhanced oxygen consumption in muscle fibers followed by lower intracellular oxygen tension during exercise, promoting ROS generation (Franco et al. 1999, Puntschart et al. 1996). There are also other so-called contraction-induced changes that stimulate ROS production in muscle, for instance increased CO2 tension, decreased cellular pH, and rise in muscle temperature (Arbogast and Reid 2004). The main source of ROS during exercise is probably skeletal muscle (Davies et al. 1982, Powers and Jackson 2008), but other tissues such as heart, lungs, and blood are also likely to be important contributors (Powers and Jackson 2008, Nikolaidis and Jamurtas 2009). On cellular level, mtROS were considered to be the predominant fraction of ROS produced during physical activity over decades (Koren et al. 1983, Davies et al. 1982), whereas recent research pointed out also important roles for nicotin-amide adenine dinucleotide phosphate (NADPH) oxidase, phospholipase A2, and xanthine oxidase (Powers et al. 2011).
ROS signals caused by a single bout of exercise only already activate antioxidant defense enzymes like mitochondrial SOD and inducible nitric oxide synthase (iNOS) (Hemmrich et al. 2003, Hollander et al. 2001). Regular exercise leads to proper adaptation to oxidative stress due to upregulation of diverse SODs, catalase, HSPs, and glutathione peroxidase (Powers and Lennon 1999, Leeuwenburgh and Heinecke 2001, Franco et al. 1999, Puntschart et al. 1996). The second line of antioxidant response which includes repair systems is important to minimize the damaging effects of ROS and is also activated through regular physical activity (Crawford and Davies 1994, Davies 1986), assigning important roles for proteasomal degradation and DNA repair enzymes (Radak et al. 2000, Radak et al. 1999, Radak et al. 2003).
Correspondingly, there is convincing evidence that supplementation of antioxidants is useless (Gey et al. 1970, Keren and Epstein 1980, Maughan 1999, Theodorou et al. 2011, Yfanti et al. 2010) or even harmful for athletes, potentially abolishing the beneficial effects on endurance performance, immune status, muscle development, and prevention of diseases (Gomez-Cabrera et al. 2008a, Strobel et al. 2011, Ristow et al. 2009, Marshall et al. 2002, Khassaf et al. 2003). For instance, athletes supplementing vitamin C and E did not display an induction of insulin sensitivity and endogenous antioxidant defense regulators due to exercise as seen in the control group (Ristow et al. 2009). It was shown that enhanced mitochondrial biogenesis and with this, increased respiration and ROS generation according to physical activity is prevented by co-treatment with antioxidants, leading to the inhibition of the beneficial mitohormetic response (Gomez-Cabrera et al. 2008a, Strobel et al. 2011, Kang et al. 2009, Fischer et al. 2006, Ristow et al. 2009). Furthermore, studies proved the harmful effect of antioxidants in regards to performance as it has shown to delay the recovery process (Close et al. 2006, Jackson 2008). Hence, supplementation of antioxidants should not be recommended to healthy athletes due to evidence that antioxidants have counter-productive effects on performance, health, and the onset of diseases.
Mitohormesis: Promoting Health and Lifespan by Increased Levels of Reactive Oxygen Species (ROS)
Increasing evidence indicates that reactive oxygen species (ROS), consisting of superoxide, hydrogen peroxide, and multiple others, do not only cause oxidative stress, but rather may function as signaling molecules that promote health by preventing or delaying a number of chronic diseases, and ultimately extend lifespan. While high levels of ROS are generally accepted to cause cellular damage and to promote aging, low levels of these may rather improve systemic defense mechanisms by inducing an adaptive response. This concept has been named mitochondrial hormesis or mitohormesis. We here evaluate and summarize more than 500 publications from current literature regarding such ROS-mediated low-dose signaling events, including calorie restriction, hypoxia, temperature stress, and physical activity, as well as signaling events downstream of insulin/IGF-1 receptors, AMP-dependent kinase (AMPK), target-of-rapamycin (TOR), and lastly sirtuins to culminate in control of proteostasis, unfolded protein response (UPR), stem cell maintenance and stress resistance. Additionally, consequences of interfering with such ROS signals by pharmacological or natural compounds are being discussed, concluding that particularly antioxidants are useless or even harmful.
Physical inactivity promotes the onset of a variety of diseases like obesity, cardiovascular disease, DM type 2, and cancer. Consistently, regular physical activity unquestionably exerts beneficial or preventive effects on the above mentioned diseases, and additionally delays depressive symptoms, neurodegeneration (including Alzheimer’s disease), and general aging (Warburton et al. 2006, James et al. 1984, Hu et al. 2001, Brown et al. 2012, Lanza et al. 2008, Manini et al. 2006, Powers et al. 2011). Exercise is not only linked to enhanced mitochondrial biogenesis and oxidative metabolism, but also to increased generation of mtROS (Powers and Jackson 2008, Chevion et al. 2003, Davies et al. 1982, Alessio and Goldfarb 1988, Alessio et al. 1988). Thus, and because of its obvious beneficial effects in regards to health and aging, make it a paradigm of adaptive response processes and finally mitohormesis (Radak et al. 2008, Radak et al. 2005, Ji et al. 2006, Watson 2013). However, similar to physical inactivity, overtraining or excessive exercise represents the other end of the hormesis curve as the adaption process is inhibited, leading to incomplete recovery (Chevion et al. 2003) and resulting in maladaptation and possibly increased risk of diseases (Alessio et al. 1988).
To our knowledge, the first direct evidence that increased ROS production following exercise may act as stimulus to activate mitochondria biogenesis and mediates potential health-beneficial effects dates back to 1982 (Davies et al. 1982). An indirect clue was already given in 1971 with an antioxidant, namely vitamin E, causing unfavorable effects on the endurance performance of swimmers (Sharman et al. 1971). Since then, a bulk of studies (in most cases inadvertently) proved the hypothesis that ROS are required for the health-promoting effects of physical activity, causing an increase in antioxidant defense mechanisms and with this, prolong health span and mean lifespan (Crawford and Davies 1994, Davies 1986, Kim et al. 1996, Marzatico et al. 1997, Balakrishnan and Anuradha 1998, Ji et al. 2006, Powers and Lennon 1999, Niess et al. 1999, Hollander et al. 2001, Higuchi et al. 1985, Gomez-Cabrera et al. 2008b, Quintanilha 1984, Vincent et al. 1999, Boveris and Navarro 2008).
One of the main changes due to regular physical activity is the increase in mitochondria energy metabolism. Exercise activates PGC-1α, which is capable of controlling mitochondrial gene expression via NRF1 and the mitochondrial transcription factor A (TFAM). This mediates enhanced replication of mitochondrial DNA, leading to increased mitochondrial biogenesis and efficient muscle contraction (Nikolaidis and Jamurtas 2009, Akimoto et al. 2005, Baar 2004, Arbogast and Reid 2004). Furthermore, PGC-1 promotes the response to oxidative stress through activation of NRF2 and induction of antioxidant enzyme expression (St. Pierre et al. 2006). Another important point is the massive consumption of ATP followed by an increase in AMP, which activates AMPK, leading again to induction of PGC-1 and enhanced mitochondrial biogenesis (Bergeron et al. 2001, Atherton et al. 2005). This increase in mitochon -drial metabolism leads to enhanced oxygen consumption in muscle fibers followed by lower intracellular oxygen tension during exercise, promoting ROS generation (Franco et al. 1999, Puntschart et al. 1996). There are also other so-called contraction-induced changes that stimulate ROS production in muscle, for instance increased CO2 tension, decreased cellular pH, and rise in muscle temperature (Arbogast and Reid 2004). The main source of ROS during exercise is probably skeletal muscle (Davies et al. 1982, Powers and Jackson 2008), but other tissues such as heart, lungs, and blood are also likely to be important contributors (Powers and Jackson 2008, Nikolaidis and Jamurtas 2009). On cellular level, mtROS were considered to be the predominant fraction of ROS produced during physical activity over decades (Koren et al. 1983, Davies et al. 1982), whereas recent research pointed out also important roles for nicotin-amide adenine dinucleotide phosphate (NADPH) oxidase, phospholipase A2, and xanthine oxidase (Powers et al. 2011).
ROS signals caused by a single bout of exercise only already activate antioxidant defense enzymes like mitochondrial SOD and inducible nitric oxide synthase (iNOS) (Hemmrich et al. 2003, Hollander et al. 2001). Regular exercise leads to proper adaptation to oxidative stress due to upregulation of diverse SODs, catalase, HSPs, and glutathione peroxidase (Powers and Lennon 1999, Leeuwenburgh and Heinecke 2001, Franco et al. 1999, Puntschart et al. 1996). The second line of antioxidant response which includes repair systems is important to minimize the damaging effects of ROS and is also activated through regular physical activity (Crawford and Davies 1994, Davies 1986), assigning important roles for proteasomal degradation and DNA repair enzymes (Radak et al. 2000, Radak et al. 1999, Radak et al. 2003).
Correspondingly, there is convincing evidence that supplementation of antioxidants is useless (Gey et al. 1970, Keren and Epstein 1980, Maughan 1999, Theodorou et al. 2011, Yfanti et al. 2010) or even harmful for athletes, potentially abolishing the beneficial effects on endurance performance, immune status, muscle development, and prevention of diseases (Gomez-Cabrera et al. 2008a, Strobel et al. 2011, Ristow et al. 2009, Marshall et al. 2002, Khassaf et al. 2003). For instance, athletes supplementing vitamin C and E did not display an induction of insulin sensitivity and endogenous antioxidant defense regulators due to exercise as seen in the control group (Ristow et al. 2009). It was shown that enhanced mitochondrial biogenesis and with this, increased respiration and ROS generation according to physical activity is prevented by co-treatment with antioxidants, leading to the inhibition of the beneficial mitohormetic response (Gomez-Cabrera et al. 2008a, Strobel et al. 2011, Kang et al. 2009, Fischer et al. 2006, Ristow et al. 2009). Furthermore, studies proved the harmful effect of antioxidants in regards to performance as it has shown to delay the recovery process (Close et al. 2006, Jackson 2008). Hence, supplementation of antioxidants should not be recommended to healthy athletes due to evidence that antioxidants have counter-productive effects on performance, health, and the onset of diseases.