1. **NEW Mini Body Light** MBL1 - Orange & Red Light Therapy Mini Body Light
    CLICK HERE!
    Dismiss Notice
  2. Cholesterol Powder
    CLICK HERE!
    Dismiss Notice
  3. Pau D'arco Bark
    CLICK HERE!
    Dismiss Notice
  4. Metabasoap - Handcrafted Soap
    CLICK HERE!
    Dismiss Notice
  5. Cocoa Butter - Organic & Fair Trade Certified
    CLICK HERE!
    Dismiss Notice
  6. Charcoal Soap - For Deep Cleansing
    CLICK HERE!
    Dismiss Notice
  7. Orange & Red Light Therapy Device - LGS1
    CLICK HERE!
    Dismiss Notice
  8. Cascara Sagrada Powder From Farmalabor In Italy
    CLICK HERE!
    Dismiss Notice

A Case For High ROS, Antioxidants Are Useless And Potentially Harmful!

Discussion in 'Health' started by Obi-wan, Mar 5, 2019.

  1. Obi-wan

    Obi-wan Member

    Joined:
    Mar 16, 2017
    Messages:
    986
    Gender:
    Male
    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.
     
  2. OP
    Obi-wan

    Obi-wan Member

    Joined:
    Mar 16, 2017
    Messages:
    986
    Gender:
    Male

    I have a spelling mistake in the title. How do I fix?
     
  3. Blossom

    Blossom Moderator

    Joined:
    Nov 23, 2013
    Messages:
    7,090
    Gender:
    Female
    It should be fixed. If not let me know.
     
  4. Captain_Coconut

    Captain_Coconut Member

    Joined:
    Feb 26, 2018
    Messages:
    837
    Gender:
    Male
    I think it is a matter of state of health. If one is already deficient in the various antioxidants or not. If you have enough antioxidant reserves then low grade pro-oxidant events will be beneficial because of this mitohormesis. If you are already low in antioxidants then the small stress will beget more stress. I think this was demonstrated through various studies where bodybuilders under a certain age had worse muscle gains when given anti-inflammatories / antioxidants, while older bodybuilders had improved gains.

    When I take a break from all anti oxidants my health is usually fine for the first week or two, and then problems come back.
     
  5. OP
    Obi-wan

    Obi-wan Member

    Joined:
    Mar 16, 2017
    Messages:
    986
    Gender:
    Male
    Thank you Blossom
     
  6. methylenwhite

    methylenwhite Member

    Joined:
    Aug 21, 2018
    Messages:
    169
    Gender:
    Male
    I've heard from another member that you avoid antioxidants. Could you share your experience? How do you feel?
     
  7. OP
    Obi-wan

    Obi-wan Member

    Joined:
    Mar 16, 2017
    Messages:
    986
    Gender:
    Male
    I have been slowly avoiding antioxidants as I learn the value of high ROS as a cancer patient (I am my first round of Chemo). Just started taking Idea labs Pyrucet which is a GSH (Glutathione inhibitor). Afterward I felt like I just had another round of chemo with fatique but high ROS will kill the cancer cells so I must have patience. Cancer cells produce high GSH to protect themselves from ROS death. I will have to adjust dosage and timing of Pyrucet around my Chemo seasons as it will make Chemo stronger. I think it is very obvious why I avoid all antioxidants at this time. See the chart below.
    [​IMG]

    This chart shows the redox is in homeostasis in a normal cell. Plus this:

    [​IMG]

    Lifespan-promoting ROS signaling can occur transiently and hence requires time-resolved quantification. A) Disruption of the insulin/IGF-1 receptor, named DAF-2, in C. elegans extends lifespan. The constitutive daf-2 mutant exhibits reduced ROS levels. This has led to the conclusion that impairing DAF-2 primarily causes reduced ROS levels. However, as recently published (Zarse et al. 2012), the opposite is the case: When studying the acute effects of an RNAi-mediated daf-2 knockdown, a transient increase in ROS production was observed (“acute response”). As shown in the publication (Zarse et al. 2012), this ROS signal induces various endogenous ROS defense mechanisms that ultimately reduce ROS levels. This leads to a persistent reduction of ROS levels in daf-2 RNAi-treated worms in the steady state. This also exemplifies that quantifying ROS at an inappropriate time point may lead to opposing results: ROS determined during the acute response against RNAi would indicate increased levels, while ROS determined three days later during the steady-state would indicate reduced levels. B) Exogenously added antioxidants prevent the acute induction of a ROS signal (Zarse et al. 2012). The lack of this ROS signal leads to a complete lack of the original adaptive response shown in panel A. This causes higher steady-state ROS levels than in the absence of exogenous antioxidants which only can be explained in the framework of mitohormesis, while the linear dose-response would consider this phenomenon as paradoxica'

    My understanding of this is by taking continuous supplemental antioxidants you diminish the original adaptive stress response (acute response) and also keep ROS higher for a longer period of time in a normal cell. Therefor not getting high ROS when needed (initial stress) and unnecessary higher ROS when not needed (chronic stress)
     
  8. Mito

    Mito Member

    Joined:
    Dec 10, 2016
    Messages:
    1,251
    Abstract
    Historically, mitochondrial reactive oxygen species (mROS) were thought to exclusively cause cellular damage and lack a physiological function. Accumulation of ROS and oxidative damage have been linked to multiple pathologies, including neurodegenerative diseases, diabetes, cancer, and premature aging. Thus, mROS were originally envisioned as a necessary evil of oxidative metabolism, a product of an imperfect system. Yet few biological systems possess such flagrant imperfections, thanks to the persistent optimization of evolution, and it appears that oxidative metabolism is no different. More and more evidence suggests that mROS are critical for healthy cell function. In this review, we discuss this evidence following some background on the generation and regulation of mROS.
    Physiological roles of mitochondrial reactive oxygen species

    Abstract
    Reactive oxygen species (ROS), now appreciated for their cellular signaling capabilities, have a dual role in cancer. On the one hand, ROS can promote protumorigenic signaling, facilitating cancer cell proliferation, survival, and adaptation to hypoxia. On the other hand, ROS can promote antitumorigenic signaling and trigger oxidative stress–induced cancer cell death. To hyperactivate the cell signaling pathways necessary for cellular transformation and tumorigenesis, cancer cells increase their rate of ROS production compared with normal cells. Concomitantly, in order to maintain ROS homeostasis and evade cell death, cancer cells increase their antioxidant capacity. Compared with normal cells, this altered redox environment of cancer cells may increase their susceptibility to ROS-manipulation therapies. In this review, we discuss the two faces of ROS in cancer, the potential mechanisms underlying ROS signaling, and the opposing cancer therapeutic approaches to targeting ROS.
    https://www.annualreviews.org/doi/abs/10.1146/annurev-cancerbio-041916-065808
     
  9. Captain_Coconut

    Captain_Coconut Member

    Joined:
    Feb 26, 2018
    Messages:
    837
    Gender:
    Male
    In the simple terms which I prefer to think about this subject; it is like exercising a muscle. Overtrain and you can do serious damage, train at the right volume and you adapt to the stress and get stronger, undertrain and you progressively get weaker. In the context of the immune system: overoxidize and you can do serious damage, oxidize at the right volume and your cells adapt and respond intelligently and efficiently, impede oxidation too extremely and the cells become lazy.

    This is why I like ozone therapy, it is gentle enough to strengthen the immune system / adaptation to oxidative stress.

    I also think this is why our cells store pufa, because the oxidation they provide is beneficial so long as stress is not chronic.

    It is also what is intriguing about many anti oxidant substances, that can also serve as pro oxidant. Things like blueberries if IIRC, are actually pro oxidant, but because of the gentle nature of oxidation actually stimulate our ability to handle oxidants efficiently, so they end up resolving much like an anti oxidant.
     
  10. Mito

    Mito Member

    Joined:
    Dec 10, 2016
    Messages:
    1,251
  11. OP
    Obi-wan

    Obi-wan Member

    Joined:
    Mar 16, 2017
    Messages:
    986
    Gender:
    Male
    As mentioned earlier, mROS are implicated in a variety of diseases including diabetes, cancer, inflammatory disorders, and neurodegeneration. These diseases exhibit alterations in the physiological cellular redox system. For example, neurodegeneration is associated with overproduction of mROS that induces cellular damage and subsequent neuronal deficits (Schon and Przedborski, 2011). In contrast, cancer cells utilize mROS to constitutively activate proliferation pathways to promote tumor growth (Cairns et al., 2011). Yet a large number of clinical trials have failed to demonstrate beneficial effects of antioxidants on these pathologies, and a handful of trials suggested antioxidants increased mortality (Bjelakovic et al., 2007).

    We hypothesize that the dual function of mROS to both promote cell damage and promote cell adaptation makes it a potentially difficult therapeutic target. In other words, inhibition of mROS by antioxidants does not have a predictable outcome on cell function since the role of mROS changes under differing environmental conditions. Going forward, it will be important to identify specific molecular targets of mROS under different environmental conditions with the goal of modulating pathways downstream of mROS that increase adaptation to stress.
     
  12. OP
    Obi-wan

    Obi-wan Member

    Joined:
    Mar 16, 2017
    Messages:
    986
    Gender:
    Male
    Nice, as David Masterjohn clearly shows is that energy demands through exercise create mitochondrial biogenesis (more mitochondria) via increased respiration and ROS generation but according to studies is prevented by co-treatment with antioxidants. Furthermore, studies proved the harmful effect of antioxidants in regards to performance as it has shown to delay the recovery process. Cells have their own antioxidant defense system. Cells know when to create high ROS and when to dampen ROS with their own antioxidants. Consuming antioxidants only serves to dampen the initial high ROS response which is needed for excess energy demands.
     
  13. Amazoniac

    Amazoniac Member

    Joined:
    Sep 10, 2014
    Messages:
    5,575
    Gender:
    Male
    Location:
    Uganda
    Obi, I was expecting such reply. I doubt that their depletion is the answer, and perhaps without them PSA level rises just as much but compromising the rest of the body.

    From your article:
    "[..]glucose (besides a few amino acids) is the only macronutrient that can be metabolized and generate ATP without producing ROS."
     
  14. OP
    Obi-wan

    Obi-wan Member

    Joined:
    Mar 16, 2017
    Messages:
    986
    Gender:
    Male
    Even without external antioxidants the cell produces its own antioxidant defense system via glutathione (GSH) but then we have Idea labs Pyrucet and I am on Chemo. (high ROS)...plus hypoxia (holding your breath) produces ROS plus exercise (working on that) produces high ROS... I asked @haidut if glucose oxidation produces ROS. I am sure he will say no but the Pyruvate in Pyrucet does and the Acetoacetate limits GSH. So hopefully a game changer...Redox shifts to oxidation. Plus I think the cancer cell produces its own ROS but limits it for signaling via GSH. Haidut was actually amazed on how fast Acetoacetate will bring down GSH to a zero level in a matter of days! Interesting...
     
  15. bzmazu

    bzmazu Member

    Joined:
    Oct 29, 2015
    Messages:
    1,043
    Gender:
    Male
    Location:
    Corozal, Belize
    Artemisinin is an oxidant...a very effective one, it seems.
     
  16. Rah

    Rah Member

    Joined:
    Jan 13, 2017
    Messages:
    18
    Gender:
    Male
    Following
     
  17. AnonE

    AnonE Member

    Joined:
    Jan 21, 2018
    Messages:
    99
    Gender:
    Male
    How can I consume more ROS? :)
     
  18. Mito

    Mito Member

    Joined:
    Dec 10, 2016
    Messages:
    1,251
    Interactions between mitochondrial reactive oxygen species and cellular glucose metabolism

    Abstract

    Mitochondrial reactive oxygen species (ROS) production and detoxification are tightly balanced. Shifting this balance enables ROS to activate intracellular signaling and/or induce cellular damage and cell death. Increased mitochondrial ROS production is observed in a number of pathological conditions characterized by mitochondrial dysfunction. One important hallmark of these diseases is enhanced glycolytic activity and low or impaired oxidative phosphorylation. This suggests that ROS is involved in glycolysis (dys)regulation and vice versa. Here we focus on the bidirectional link between ROS and the regulation of glucose metabolism. To this end, we provide a basic introduction into mitochondrial energy metabolism, ROS generation and redox homeostasis. Next, we discuss the interactions between cellular glucose metabolism and ROS. ROS-stimulated cellular glucose uptake can stimulate both ROS production and scavenging. When glucose-stimulated ROS production, leading to further glucose uptake, is not adequately counterbalanced by (glucose-stimulated) ROS scavenging systems, a toxic cycle is triggered, ultimately leading to cell death. Here we inventoried the various cellular regulatory mechanisms and negative feedback loops that prevent this cycle from occurring. It is concluded that more insight in these processes is required to understand why they are (un)able to prevent excessive ROS production during various pathological conditions in humans.

    Summary and conclusion
    ROS are produced as a consequence of normal mitochondrial energy metabolism. When transiently and/or moderately increased, ROS can activate signaling pathways involved in cellular adaptation to various types of (metabolic) stress. One of these pathways is the stimulation of glucose uptake. When ROS levels are too high and/or remain increased during a prolonged period of time, a vicious circle of ROS-stimulated glucose uptake and glucose-stimulated ROS production can be triggered. This pathological cycle can be broken by restoring mitochondrial ROS production to normal levels. We presented three major mechanisms that, in principle, can lower mitochondrial ROS production: (1) reducing glucose uptake, (2) increasing lactate secretion and (3) depolarization of Δψ. Unfortunately, these mechanisms have also been associated with increases in ROS and/or appear to be not effective in all experimental models. Undesirable side effects include reduced NADPH production during reduced glucose uptake, a high rate of lactate secretion potentially inducing lactic acidosis and induction of mitochondrial dysfunction and apoptosis by (high-magnitude) and/or prolonged Δψ depolarization. We conclude that cellular glucose metabolism and mitochondrial ROS production are coupled by various signaling mechanisms, which need to be controlled by the cell to avoid oxidative stress. A more detailed understanding of how these pathways interact with mitochondrial ROS production, endogenous antioxidant systems and mitochondrial/cellular function is required to explain why oxidative stress induction still appears to contribute to pathology induction in humans (e.g., diabetes, cancer, mitochondrial dysfunction).

    Interactions between mitochondrial reactive oxygen species and cellular glucose metabolism
     
  19. Amazoniac

    Amazoniac Member

    Joined:
    Sep 10, 2014
    Messages:
    5,575
    Gender:
    Male
    Location:
    Uganda
    If there are oxygen species, it means that oxygen is present but it's not being used properly. Cancer cells produce more of those than a normal cell, and one of the reasons for the antioxidant upregulation is in response to such stress. So even though the glutathiod ratio reflects the tendecy towards reduction, it's a high-everything situation.

    But the main focus should be on nourishing the body, not on stressing the tumor. I guess we can't deal with advanced cancer using flower petals, but what you're trying to accomplish by limiting those nutrients can in fact contribute to a more reducing environment of the cell because there can't be adequate function without them, oxygen likely being diverted.

    They can indeed weaken the effect of chemotherapy, but most of the material available on reduced glutathione and resistance to such therapies seem so fixated on destroying the tumor that they appear to neglect that there might a taxed body harboring it.

    Acetoacetate should be helpful, I assume because it oxidizes NADH and relieves such state of cells, and it will reflect on the ratio of reduced to oxidized glutathiod.

    The podophile (not to be confused with pedophile, I already commented that I'm not into that anymore) here is confused by the usefulness of pyruvate because of the following:
    - Considering the role of pyruvate in tumor cells during hypoxia
    What am I missing?
     
  20. SB4

    SB4 Member

    Joined:
    Sep 25, 2016
    Messages:
    155
    Gender:
    Male
    Hey amazoniac, how would you recomend getting acetoacetate, I assume you are not referring to ketosis, ethyl/methyl acetoacetate? Or something else?
     
Loading...