How Oxidative Stress Impacts Performance and Healthspan [transcript]

Written by Christopher Kelly

May 22, 2018

[0:00:00]

Christopher:    Megan, thank you so much for joining me this morning.

Megan:    You're welcome. It's my pleasure.

Christopher:    The last few months coming up on a year has been a remarkable journey. I feel so privileged to have you not only as a scientist and researcher keeping our program at the pointy end of things but also as an amazing coach. You must be a rare bird indeed, someone that's able to be a scientist and a practitioner at the same time. How have you been enjoying working with NBT and all of our athletes over the past year?

Megan:    I absolutely love it. It's been a journey for me as well. I came into this with not a lot of coaching background and now I've learned a ton just working with clients and having a lot of fun doing both the researching and the writing and also the coaching side and working with people and seeing their improvements over time. It's just amazing.

Christopher:    If I have to force you to pick a favorite child, research or coaching, which would it be?

Megan:    It almost depends on what I'm doing more of at a time. If I pour myself into research I almost miss the coaching and vice versa. Being able to have a balance of the two, not at one time, but over a period of months is really great.

Christopher:    I feel like the two go really well together. The main reason I want to read research is because I'm trying to solve a very specific problem probably for a client. If I wasn't working with clients I wouldn't have any problems to solve, right? I think the two go really nicely together but maybe you have other motivations.

Megan:    I completely agree. When I get a question from my client, I often go into PubMed, do some researching myself, ask you and Tommy, and then I'll come back with a good evidence-based explanation for them. So, while I'm doing the coaching I'm also getting to learn and read the literature at the same time. That's super great as well.

Christopher:    That's my absolute favorite thing. When I'm on a coaching call on Zoom and then someone asks me a question that I don't know the answer to, and that happens all the time, I pose the question in Slack and I know that you and Tommy and others are hanging out there. Sometimes I can get the answer, if it's something that you and Tommy have researched before and you already know the answer and you can give me the answer in Slack and then I can tell the client whilst they're still on Zoom. It's the most amazing thing like, yeah, I've got a doctor and a researcher on my Slack.

Megan:    I agree. It's a fun team to work with for sure.

Christopher:    I feel like we've done a really amazing job building an interdisciplinary team to build the blood chemistry calculator too, like having this combination of me as a computer programmer and you and Tommy and Bryan as doctors and researchers, is working great. I've never been in a team like this before in my professional career and felt such synergy between a group of people working on a very specific problem.

Megan:    Absolutely. If we had two of us together, we couldn't even do it. I think the four of us, we're looking at it from different angles and we're able to discuss it from different places. I think it's been amazing to work with you guys on the calculator for sure.

Christopher:    People who have already run a blood chemistry calculator report may have noticed these scores popping up on the report over the past few weeks. One of those scores is a score that indicates the level of oxidative stress. At first glance, you think, what's that? How does that apply to me? How is this useful? How does this change my clinical decision making? The goal of this podcast is to talk a little bit about oxidative stress and why you care about that dashboard. How does that sound? Did you have anything to add to that, Megan?

Megan:    No. I think that's perfect. We can jump right in if you're ready to.

Christopher:    I think it's a really important topic. At first glance, you might dismiss it as just noise but actually if you are a high performance human being, and I don't care whether your sport is running or cycling or strength training or maybe just your sport is life, maybe you just want to be a better parent and increase your health span, I think that understanding the why behind the oxidative stress score in the blood chemistry calculator is really important. Hopefully, you're interested to know some of the details that we're going to talk about today. My first question for you then, Megan, is: What is oxidative stress?

Megan:    Very good question. Oxidative stress is this term that we throw out in the functional medicine or medical field or health space and nobody really has a good grasp of what it means. The most basic definition I can give you is it's the imbalance between the production of free radicals, and I'll explain what a free radical is in a minute, so the imbalance of the production of free radicals and the body's antioxidant defense systems. If you think of it as like this teeter-totter, if the production of free radicals is higher than the body's antioxidant defenses then that's going to cause an elevation in oxidative stress.

Christopher:    So, what do you mean by free radical?

Megan:    Right. A free radical can be a reactive oxygen species or reactive nitrogen species. If you see the term ROS, that stands for reactive oxygen species.

[0:05:01]

    A free radical is any chemical species that has an unpaired electron which ultimately will increase the reactivity of the molecule. These free radicals will accept or donate electrons to create their own stability, ultimately creating more free radicals in the process. The equation would look like a radical plus some kind of non-radical molecule which would be a lipid, a protein DNA carbohydrates in the cells in the body. Those two combine and react to form this free radical chain reaction and more free radicals are then formed as byproducts. Those free radicals in excess create the oxidative stress.

Christopher:    And so is the oxidative stress always a bad thing?

Megan:    No, it's absolutely not. We want oxidative stress in the right amounts to make sure that our cells are signaling in the right ways, and I'll talk about that in a little bit, but then too much can cause improper cell signaling and also cell damage. There's definitely two sides of that coin and we want to make sure that it's in balance.

Christopher:    Can you give us some examples of reactive oxygen species?

Megan:    A couple of them people may or may not have heard before. There's the super oxide radical, there's the hydroxyl radical, there's the peroxy radical nitric oxide, and then also peroxy nitrate as well. These free radicals are made by largely unavoidable biochemical processes, things like energy metabolism, immune cells such as activated neutrophils can create free radicals and so in the case of an immune cell, that's telling the cells to destroy pathogens and also participate in cellular cleanup and housekeeping.

    And then free radicals are also made through radiation. So, ionizing radiation, radiation from the sun, electromagnetic radiation, environmental pollutants and chemical toxins can create free radicals. Smoking, excessive exercise, poor diet and also certain pharmaceutical medications can increase the overall free radical load in the body.

    Like you were saying before, free radicals have this physiological role and also a pathological role in the body. The good is cell signaling. We need some reactive oxygen and nitrogen species for proper cell signaling in our body. The bad would be, one, pathological signaling and, two, excessive oxidative damage to DNA, lipids and other proteins.

Christopher:    Can you talk about some of the cell signaling effects?

Megan:    Yes. Ultimately, there's these elements called antioxidant response elements in the cell. Those are needed to upregulate antioxidant defense and to reactive oxygen species in the form of a hormetic stressor can actually go and work on pathways such as the Nrf2 pathway which ultimately increases our antioxidant defense signaling which is important to combat any excessive oxidative damage that we find in our day to day lives.

Christopher:    Right. And so we discussed this topic before on the podcast. You're talking about hormetic stressor, right? This is the idea that a little bit of what doesn't kill us makes us stronger.

Megan:    Exactly, yeah.

Christopher:    Talk about the benefits, because I think that's something that everybody listening to will be interested in. I know that when I first learned about oxidative stress in exercise physiology, my understanding was that it was all bad and I should probably take an antioxidant supplement to try and stomp out the effects of oxidative stress after I worked out. Now, I realize that's probably misguided. Perhaps you can start by talking about some of the benefits of reactive oxygen species around workouts.

Megan:    Yeah, absolutely. One thing I want to start with is Tommy did a podcast with Dr. Andy Galpan and they were talking about this idea of if you're optimizing you're not adapting and vice versa. There's this notion of are we supporting adaptation for exercise or are we supporting recovery? You can't optimize one at the same time as the other.

    This is important for the reactive oxygen species and free radical story because you need a certain amount of stress, and this includes oxidative stress, on the body to promote a physiological adaptation. Antioxidants can help ultimately speed the recovery process from a hard race or a hard training bout but they ultimately can also block the adaptations of recovery. Exercise induced free radicals are critical signaling molecules for the adaptation but high dose antioxidants can ultimately blunt their action making the adaptation not as powerful.

    We also have to remember that it could depend on the type of antioxidant that we're talking about. So, vitamin C, vitamin E, n-acetylcysteine, these are all being shown in high doses to blunt training responses. However, there is a little bit of literature suggesting that things like polyphenols, green tea, polyphenols from berries and things like that, those might not be as detrimental as the high dose synthetic Vitamin C, E and NAC. The timing, the type and the dose matters for both the exercise and the antioxidant that we're talking about.

[0:10:20]

Christopher:    Okay. And so it's all about context then. There may be a time when you do want to stomp out the hormetic stressor. Maybe you were doing a stage event where you were racing every day for a week or something like that then in that case you don't care so much about the training response but rather you care more about recovery. Maybe supplemental antioxidants might be justified in that instance.

Megan:    I would definitely agree.

Christopher:    And are we always talking about supplements or is it possible to blunt some of the effect of training from some of the food choices that we make?

Megan:    To my knowledge, I did do some PubMed-ing around this, there haven't been any studies to show, okay, you eat a cup of blueberries after a training run and you blunt the response to the exercise. I'm guessing that it's more the synthetic high dose antioxidants. I would be hard pressed to believe that a handful of blueberries post run is really going to do much in the form of blunting any kind of adaptation. However, that's to be determined for sure.

Christopher:    When do reactive oxygen species become a problem with training? Is it possible to do too much? That's kind of a stupid and a leading question but I'll ask it anyway.

Megan:    Yeah, absolutely. We see especially in overtraining or underperformance syndromes. Those are usually accompanied by an increase in oxidative stress and a decrease in antioxidant capacities.

Christopher:    Okay. And this leads to problems?

Megan:    Yeah.

Christopher:    So, can you talk about some of the problems that can be caused by an imbalance of reactive oxygen species and the body's natural antioxidant defenses?

Megan:    Yeah. There are a handful of modern diseases that are associated with an increase in oxidative stress. Those include cancer, cardiovascular disease, diabetes, different neurodegenerative diseases such as Alzheimer's disease, Parkinson's and MS. Also, some autoimmune conditions are associated with increases in oxidative stress or the decrease in antioxidant defenses. Also fatty liver and some kidney diseases as well.

    There's a whole host and that's not a comprehensive list, but there's a whole host of modern diseases that are associated with an increase in oxidative stress. There's this question of, okay, is it the chicken or the egg? Did the diseases cause the increase in oxidative stress or is oxidative stress causing the diseases? We don't necessarily know. In the context of something like diabetes, we know that oxidative stress can impair things like insulin signaling.

    But then on the flipside, diabetes itself is a state that increases oxidative stress. So, asking chicken or the egg may not be the most insightful thing, I guess, to ask with some of these conditions but they're all definitely associated with an increase in oxidative stress.

Christopher:    Can you talk about some of the mechanisms there? Exactly what is going on at the cellular level that leads to some of these problems?

Megan:    So, a lot of times like in the context of cardiovascular disease or even type II diabetes, oxidative stress, these free radicals can ultimately cause lipid peroxidation in the cell membranes and so that can lead to excessive inflammation, this cascade of excessive oxidative stress which can ultimately contribute to the disease and the progression of the disease. That's just one kind of example with the lipid peroxidation. There's a whole lot of other examples that can be given as well though.

Christopher:    That's interesting to think about, isn't it? So, the phospholipid membrane that surrounds a cell, that phospholipid is capable of giving up some of its electrons to some reactive oxygen species and then if enough of that happens then the cell membrane is no longer a cell membrane and something could happen to either that cell. But then I was also reviewing Dr. Bryan Walsh's Metabolic Fitness Pro of which I'm sure you're also a fan, Megan. You've done that course too.

Megan:    Yes.

Christopher:    I was reviewing Module 13 this morning and Bryan mentioned something that I have forgotten about, that not just the cell is surrounded by a membrane but also the organelles. The mitochondria, for example, are also surrounded by a membrane. If something were to happen to that membrane then maybe you would damage your mitochondria and that might lead to the demise of the cell too.

    I mean, it seems like at a microscopic level it's hard to get your head around but when you think about it, really all disease can be boiled down to a dysfunction at the cellular level. And if you have enough dysfunctional cells then you have a dysfunctional tissue, then if you have enough dysfunctional tissues, and so it goes on, at least to some of the diseases that you talked about. Is it possible then that too much exercise could be causal in this scenario that we just talked about?

[0:15:04]

Megan:    Theoretically I could see that happening with the increases in oxidative stress and there have been some studies linking excessive exercise. things like ultra marathon running and such, to an increase in cardiovascular disease whether or not that's really a true causal thing or whether that's just an association for another reason. That hasn't been parsed out in the literature. But certainly over production of reactive oxygen and nitrogen species from exercise could ultimately theoretically contribute to some of these diseases down the road.

Christopher:    Right. Just to be clear, what other things can increase oxidative stress other than exercise?

Megan:    I mentioned some of them before, but energy metabolism. We're always creating a reactive oxygen species whenever we eat, whenever we digest food. It's not something that we can get away from. We just want to manage ultimately the free radicals in our body. Also some electromagnetic radiation, environmental pollutants and toxic chemicals as well, poor diet, some pharmaceutical medications. Those are all things that can ultimately increase the oxidative stress and load on the body.

Christopher:    So, the question then becomes how do we assess whether the imbalance is present or not? How do we assess whether there is balance?

Megan:    Right. And so there are some markers, some simple blood markers of oxidative stress which I can talk about, and then we can also get into a little bit of the fancier markers where you can look at the antioxidant status and then ultimately using the blood chemistry calculator which is a combination of the blood markers and then the predictions of the antioxidant deficiencies. It's how we're looking at oxidative stress currently.

    I'll start with just the basic blood markers of oxidative stress and those include GDT, bilirubin, uric acid, albumin, and then also you can look at other markers such as HDL cholesterol and ferritin as well. I'll briefly go over those just to give people an idea of what each marker means.

    So, GGT was historically looked at as elevated in people with alcohol related liver disease but high GGT is also linked with other metabolic diseases associated with oxidative stress, things like cardiovascular disease, diabetes, even all cause mortality. Elevated levels of GGT contribute to its pro-oxidant activity especially when free metal such as iron or copper aren't excess.

    GGT can be an early predictor when it's elevated of both metabolic and infectious diseases and also some cancers and it can also potentially be a marker of glutathione which is another endogenous antioxidant, glutathione depletion in the liver. The last thing to say about GGT here is honestly we could have a podcast--

Christopher:    Just on GGT, right?

Megan:    Yeah. But there's been shown in the literature to be in inverse relationship of GGT with serum antioxidants as well.

Christopher:    And if I'm listening to this right now and I know that I've already measured GGT on a recent blood test, am I going to be able to look at that blood test and know whether I have a problem or not using the standard reference range? So, the standard reference range I have in front of me here is five to 65. 65 is pretty high, isn't it?

Megan:    Yeah. I certainly would not want my GGT at 65. Using the standard reference range, you may not be looking at the whole picture but fortunately with the blood chemistry calculator we've gone through and looked at all cause mortality data, we're looking at data from different diseases associated with elevated GGT and so we can say, okay, you really don't want your GGT above -- Do you have the references?

Christopher:    I do.

Megan:    At your fingertips? Okay, I don't know if it's on my head what the higher end of the range thus far?

Christopher:    Yes. Ten to 22 U per liter here, I've got.

Megan:    Right. That's quite significantly different from the standard range.

Christopher:    I think this is one of the main value propositions of the blood chemistry calculator. All the talk of machine learning has cast a shadow over some very important work that you and Tommy and Bryan have done and that is looking at some of these markers with respect to health outcomes, not two standard deviations either side of the mean but what does this mean for me in my health outcomes?

Megan:    Yeah, exactly. Exactly.

Christopher:    Let's go on and talk about another marker.

Megan:    The next one, I guess, would be bilirubin. Bilirubin is an antioxidant that's usually low when oxidative stress is high. They have an inverse relationship. One of its major roles is to inhibit lipid peroxidation. We can assume that low bilirubin might be associated with diseases that are also associated with oxidative stress and lipid peroxidation such as cardiovascular disease and diabetes. This is true. We see these associations from the literature. Higher levels of bilirubin have been shown to be potentially protective against these diseases because bilirubin is acting as an antioxidant.

[0:20:00]

    And then uric acid is the next one. If uric acid is the final product in the metabolic breakdown of purines and it was originally considered as just to be an antioxidant, so it scavenges selective free radicals, however, there's this paradox now where sometimes it's a pro-oxidant and sometimes it's an antioxidant. And so uric acid, there's a lot more behind the story of how it works.

    I'll give an overview as best as I can and people will just have to know that there's definitely more to the story than we're just talking about here. But elevated uric acid can be one of the body's ways to deal with oxidative stress but low uric acid can also indicate poor antioxidant capacity in the body. Like I said, this paradox, is it a pro-oxidant? Is it an antioxidant? It really depends.

    Uric acid can become a pro-oxidant by forming radicals in reactions with other oxidants. These new radicals that are formed usually target lipids, LDL, the cell membranes as well. And it also depends on where. Where are we looking at in the cell? At the uric acid. So, uric acid is a good antioxidant in a hydrophilic or water loving environments. This would be like the plasma. But lipids create this hydrophobic environment or water fearing environment, and if uric acid is in a hydrophobic environment its antioxidant capacity is decreased.

    Something like an adipocyte, a fat cell, is going to create a hydrophobic environment in which case uric acid will become more of a pro-oxidant versus an antioxidant. This may have implications for obesity. Another implication for obesity would be the fact that an already oxidized lipid can turn uric acid into an oxidant. There's this kind of vicious cycle.

    Uric acid is complicated but one thing that we can generally say is that low uric acid is typically associated with neurodegenerative diseases, so MS, Parkinson's, Alzheimer's. Also low uric acid may be associated with cancer and some autoimmune conditions. And then animal models suggest that increase in uric acid could be beneficial for the treatment of some of the neurological conditions that I talked about.

    High uric acid, on the other hand, is typically associated with metabolic diseases, so cardiovascular disease, type II diabetes, fatty liver, hypertension. There's kind of two different ideas to explain this paradox of the pro versus antioxidant capacity of uric acid. The first would be an increase in uric acid is used as a protective response to the oxidative stress caused by these metabolic conditions. The second hypothesis is more, okay, where is uric acid located? We already talked about that.

    So, it can be a pro-oxidant or an antioxidant depending on which compartment it resides in the body. In the plasma, it's an antioxidant. Inside the cell, it's a pro-oxidant. That's a whirlwind little explanation of uric acid and how it can be both a pro or antioxidant depending on the context.

Christopher:    Okay. I'm looking at my blood chemistry calculator report and there's a little dial there. The needle is pointing in the green. My uric acid is 5.4. That is towards the top end of the green compartment. And so I should probably be happy with that although there may be some caveats. Looking at the oxidative stress score overall would help me know whether I should be more or less happy with my needle being in the green compartment, right?

Megan:    Exactly. That needle, it's a little bit complicated but that needle might change whether or not somebody has a neurodegenerative disease or metabolic disease. So, the next marker here, we have albumin. This is a protein made by the liver. Its ligand binding capacity accounts for a lot of its antioxidant properties.

    So, it binds. Albumin binds to fatty acids, drugs, hormones, metal ions and functions as antioxidant. Typically, we see albumin decease when oxidative stress increases. Free radicals can also impair albumin's antioxidant capacity. Albumin is another potential blood marker we could be looking at. The other two, HDL cholesterol and ferritin are as direct markers of oxidative stress but they correlate nicely.

    HDL, both low and high HDL are associated with oxidative stress. Often low HDL is associated with lipoprotein subspecies with a lower antioxidant capacity. But then high HDL can result in something called dysfunctional HDL and so in states of inflammation HDL can actually become oxidized and lose its antioxidant and anti-inflammatory properties.

    Higher isn't always better with HDL. I know you and Tommy did a podcast about cholesterol reference ranges and I believe you guys talked about it in that podcast as well.

[0:25:00]

    An example of this would be in the presence of something like lipopolysaccharide, LPS, HDL can lose its anti-inflammatory properties and ultimately contribute to oxidative stress. That's why  when we see high HDL for typically we say over, I think, around 80 for men and maybe 100 for women, we want to say, okay, is there some kind of infection going on and get to the root cause of that high HDL if there is one.

Christopher:    And so just to summarize what you just said, the LPS, lipopolysaccharides, and this is something that appears in the cell wall, a gram-negative bacteria, they're always present in the gut but for certain people at certain times these endotoxins can be translocated across the gut wall into the blood and then they cause problems or HDL helps mitigate the problems or how does that work from there?

Megan:    The LPS can bind the HDL and cause it to become dysfunctional.

Christopher:    Okay.

Megan:    So, it's causing the HDL to lose its anti-inflammatory and antioxidant properties and to become pro-oxidant.

Christopher:    Okay. Yes, so, I'm looking at my HDL here. Mine's 83, which is into the red zone and so not necessarily a good thing. I think that may correspond to the current and historical state of my gut and my continuing insistence on doing endurance exercise which may be contributing to the situation.

Megan:    Right. And there are other reasons for excessively elevated HDL such as exercise can do it, excessive omega three intake can do it, those other reasons other than just LPS. But it's important to know that high HDL and low HDL can both correlate with and contribute to oxidative stress.

Christopher:    Again, it's probably important to look at the individual marker in the overall setting of the blood chemistry using some of these scores maybe rather than just looking at individual markers and coming to some conclusion just there.

Megan:    Exactly.

Christopher:    Well, talk about ferritin. That's an interesting marker that I had some fun with recently too.

Megan:    So, ferritin is our best marker of our total body iron stores. We know that iron is critical for a lot of biological processes but too much free metal iron could actually promote oxidative damage through something called the Fenton reaction. This reaction is free metal iron binding with hydrogen peroxide to ultimately create superoxide free radical.

    Cells need a mechanism to keep this free iron check so that there's not a ton of oxidative stress going on. Ferritin is one of the ways they do this and ferritin sequesters or binds to the iron in the cell. We know that ferritin is also an acute-phase reactant. Meaning, that it can increase during times of inflammation but it can also increase the expression of pro inflammatory molecules which ultimately down the road increase oxidative stress.

    Again, we could ask this chicken or the egg question and debate about whether ferritin is acting as an antioxidant by sequestering the iron or pro-oxidant by increasing the expression of pro-inflammatory molecules. But regardless, we know that elevated ferritin is positively correlated with markers of oxidative stress and associated diseases. For instance, 8-OHdG, which I know is one of your favorite molecules to say--

Christopher:    Yes. I'll say it right now, 8-hydroxy-2-deoxyguanosine. There you go.

Megan:    I don't think anyone else can say it as precisely and as quickly as you can. You've had a lot of practice. That's when it correlates with ferritin and also elevated iron and ferritin are associated with redox imbalances in many different diseases.

Christopher:    Let's talk a little bit about how ferritin is involved in the acute-phase response. I just find this stuff absolutely fascinating. I'd been reading a little bit around the idea of nutritional immunity. What fantastic term that is. If you type that into PubMed, you'll find all kinds of interesting stuff about nutritional immunity. The idea is that your body is capable of sequestering nutrients including metals away from microbes. This is part of our immune response. Without the metals that microbe cannot proliferate and so this is part of our defense mechanism. Isn't that fascinating that your body can do that? Like steal nutrients away from microbe? I think that's absolutely amazing.

Megan:    It is pretty cool. It's one of those things where, again, there’s a Goldilocks zone for everything. We need iron but too much iron can feed those microbes that you were talking about and so that's when ferritin comes in, as an acute-phase reactant, then sequesters the metals so that we can stop feeding the bad bugs.

Christopher:    And so this means that a chronic infection then could lead to an anemia, an iron deficient anemia because all of the nutrients are locked up in a storage protein to keep them away from the bad guys, right?

Megan:    Yeah. The story, the more you think about it, gets complicated but there are lots of reasons ferritin can be high or low and that's why we're looking at ferritin but we're also looking at total iron binding capacity, we're looking at serum iron, we're looking at transferrin saturation.

[0:30:00]

    There's a whole slew of markers that you need to be able to interpret and look at to determine whether or not somebody has excessive iron overload or if they have a deficiency of some nutrient. It's not as simple as high ferritin, bad, low ferritin, good. Same with the HDL.

Christopher:    I wish it was but it wasn't. It's complicated. That has been our recent experience. We've seen lots of people with iron overload and we've been hypothesizing that the diet that we recommend is really good at causing iron overload. You've asked people to eat a ton of the nutrients that are rich in iron like red meat and we're eating tons of fresh fruits and vegetables, so Vitamin C, and saturated fat are also going to increase the absorption of iron.

    We removed all the things that block the absorption of iron, all the phytates and so now we have the perfect storm to create an iron overload situation. That was certainly the situation for me and I'd been able to manage that quite successfully by donating blood which is probably a very nice thing to do even if you don't have iron overload.

    But know that it's complicated. You can't just look at your ferritin and say, "Oh, yeah, I definitely got iron overload." Maybe you should go and donate blood either way but it's just a little bit more complicated than that.

Megan:    Exactly.

Christopher:    Let's talk about antioxidants then. Can you define what we're talking about when we say antioxidant?

Megan:    Antioxidants are -- We should call it the poor misunderstood antioxidant because we think of them as one thing but they do a whole lot of things in our bodies. There's different types of antioxidants. The broad definition is any substance that when present at a relatively low concentration compared to its oxidizable substrate in the body or in the cell can delay or inhibit the oxidation of substrate.

    And so ultimately the antioxidants keep reactive oxygen and nitrogen species in check and make sure that the free radicals are being used for good and not evil. So, they're being used for proper cell signaling and they're not going and wrecking havoc in the cell through pathological signaling or via excessive oxidative damage.

    And then the other thing here is there are different kinds of antioxidants. There's endogenous antioxidants. People might have heard of glutathione peroxidase, superoxide dismutase, these are all endogenous protein antioxidants. And then we also have non-protein antioxidants such as glutathione itself, CoQ, ALA and also melatonin. There are a whole lot of other examples to give but those were just a couple.

    Glutathione, in particular, as well as superoxide dismutase, these are important for converting hydrogen peroxide into water. Glutathione is also critical for detoxifying environmental toxins and drugs as well.

Christopher:    So, glutathione, ALA, which is alpha lipoic acid, am I right in thinking that? And CoQ which is Coenzyme Q10, all of those things you can buy as a supplement, right?

Megan:    Yeah. And ultimately, our bodies should be able to produce and recycle glutathione. We have endogenous Q10 and ALA and melatonin but an overload of something like environmental chemical or some other overload of oxidative stress can ultimately deplete these endogenous antioxidants and so sometimes it's important to go in and supplement. But the supplementation certainly should not be a long term because we should be ultimately supporting the body systems to produce and recycle these antioxidants.

Christopher:    Talk about dietary resources of antioxidants.

Megan:    Sure. The more exogenous sources of antioxidants in our bodies would be coming from diet. We have beta carotene which you can think of as like the red, orange and yellow vegetables and fruits and then vitamin E which we find in olive oil, raw nuts and seeds, avocados, things like that. Vitamin A, which pre-formed vitamin A, the real vitamin A that your body can use in its active form is typically really only found in liver and egg yolks. Selenium is typically found in nuts and seeds and also beef and fish in a relatively good amount and then vitamin C typically from fresh fruits and vegetables.

Christopher:    Okay. And so this is why when we're working with athletes we try and optimize for micronutrients as well as macronutrients is because these things play important roles in our body.

Megan:    Exactly. Yeah. And the antioxidants, like I said, they're largely misunderstood because paradoxically they're really pro-oxidants that are functioning as a hormetic stressor. These antioxidants have oxidative signaling properties that result in things like mitochondrial biogenesis, so the building of vigorous stronger mitochondria, and also increase antioxidant defense ultimately telling the cells, okay, we're going to give you a little bit of exercise so you can get stronger in the long term.

[0:35:05]

    And then I'll also just briefly mention the fact that antioxidant supplementation especially synthetic supplementation can be contraindicated in certain disease states. It's really best to get our antioxidants from wide variety of colorful fruits and vegetables and nutrient dense foods. An example of this would be beta carotene in smokers can actually increase mortality. It's the question, okay, is it disease or the supplement that's causing this or is it both? Hard to know but ultimately we should be careful with exogenous antioxidant supplements in certain disease states.

Christopher:    Let's talk about measuring oxidative stress.

Megan:    I'll just very briefly go over some of the fancier markers here. I should start by saying the reactions that produce free radicals are merely instantaneous in the body and so direct measurement of the free radicals themselves is problematic. Typically, what we do is we measure the consequences of the free radical damage in a laboratory setting. We're measuring the reaction products of oxidative damage versus the reactive species themselves. So, examples of this would be the 8-OHdG which we already talked about. We can see that on the DUTCH test. That's a nice marker.

Christopher:    And also on the organic acids. Both the Great Plains and the Genova Diagnostics organic acids test measures 8-hydroxy-2-deoxyguanosine. Poor guanosine. Why is it guanosine that gets it always?

Megan:    I don't know. I'm not sure.

Christopher:    That happens to be like that one thing that has the electrons to donate and so it ends up as an oxidized byproduct in the urine.

Megan:    Yeah. And so the 8-OHdG is a marker of DNA and RNA damage in oxidation. And it is a good marker of cumulative body oxidative stress but not necessarily telling us where the oxidative stress is coming from. That's why additional test like that test and such are important to say, okay, where is this stress coming from?

    And then we also have advanced glycation end products, so AGEs. And these occur when there's a reaction of sugars with amino acids of lipids, protein in DNA. These occur during normal metabolism but excessive AGEs form under conditions such as oxidative stress, hyperglycemia and also hyperlipidemia.

    We also have oxidized LDL, lipid peroxides from polyunsaturated fatty acids and also something called TBARS which are formed as a byproduct of lipid peroxidation. Those are the fancier measures which really aren't used as much outside of the lab setting but now we can--

Christopher:    I was going to say I have never seen those apart from 8-OHdG, is the only one of those. Oh, no, oxidized LDL I see.

Megan:    Yeah. Whether that's because they're expensive or it's hard markers to run, it's hard to know but that's why we're using the blood chemistry calculator oxidative stress score to determine and track oxidative stress.

Christopher:    Yeah. I mean, and that was the central thesis of the interview that I did with Bryan. I'll link to that and everything that Megan mentions in the show notes. But are we missing the low hanging fruit here? So, 8-OHdG was my introduction to the idea of oxidative stress because somebody measured it on an organic acids profile and then only later on do I find out that some of the markers on the basic blood chemistry can tell you much the same thing. And so this idea of are we missing the low hanging fruit, I think the answer is probably yes. So, talk about the oxidative stress score.

Megan:    The oxidative stress score was created similar to the other scores but was created based on a blood markers that we discussed above, so GGT, uric acid, albumin, bilirubin, all those. So, created based on those markers that had been shown to protect against and also correlate with oxidative stress and the diseases associated with oxidative stress.

    And then also built into the score are the predictive presence and absence and the strength of each prediction for each of the antioxidant micronutrient deficiencies that had been shown to also be associated with the oxidative stress. So, we have the blood markers, we have the predicted absence or presence of the antioxidant micronutrient deficiencies and we put them together to create the score. And just like the inflammation score and the toxicity score actually, the lower the score is better or the more blue your score is on the color scheme the better.

Christopher:    I've tried to be consistent with the color scheme in the blood chemistry calculator report. So, when you see one of these dials the more blue it is the better it is. You don't want it to be red. Some of the scores, like the five year wellness score, for example, is the other way around. Higher is better. Still blue is better. Hopefully, it's consistent in that way and not confusing was my goal.

Megan:    I think it's intuitive. You want your oxidative stress score to be low whereas you want your wellness score to be high. That makes sense to me.

Christopher:    Or at least you want your oxidative stress score when you're in a fasted state first thing in the morning to be relatively low, right? Maybe sometimes you want your oxidative stress high but certainly not on an ongoing and uncontrolled basis.

Megan:    Yeah. I would certainly say so.

Christopher:    Okay. So, what do I do if I have an elevated oxidative stress score?

[0:40:00]

Megan:    This is one of my favorite things to talk about. It's ultimately what I talk to people about every day. When I'm going through the blood chemistry calculator with a client, we're looking at the scores sometimes, we're looking at the individual markers, we're looking at the predictions, we say, okay, what are the big take home points from the blood chemistry calculator?

    For the oxidative stress, ultimately what we want to do is get to the root cause. Is there a gut infection? Is it poor diet? Is it poor blood glucose regulation? Is it exposure to environmental toxins for which we could use the toxicity score? Is it something like overtraining, that they do a really hard training bout the day before or did they run a marathon the day before?

    Ultimately, we want to get to the root cause. We also can look at lifestyle factors. So, there was a great study that we can link to in the show notes that found simple lifestyle modifications such as going on a walk in the morning, getting sleep, doing some kind of breathing practice, healthy diet, increasing water intake, simple things that everybody can be doing, ultimately positively changed oxidative stress markers. And this was in older people.

    So, definitely some lifestyle factors we can focus on there, things like increasing the color in your plate. So, more polyphenols, more fruits and vegetables, eating a wide variety of nutrient dense foods. Glutathione, you can actually get from fresh and unadulterated fruits and vegetables. Also eating, like I mentioned, nutrient dense foods. So, nutrients such as selenium, copper, zinc, these are all cofactors for both superoxide and glutathione peroxidase.

Christopher:    Right. So, if you don't have the micronutrients you can't run the enzyme and then you end up with that imbalance of reactive oxygen species and the body's antioxidant defenses.

Megan:    Yes. And the other thing we want to do is, on the note of food, is support digestion and absorption. Because ultimately you're only using what you can digest and absorb. It's not just what you eat. So, if there's an underlying gut infection that's causing malabsorption, that you want to get to the root cause of them.

    The other thing that's important to do to decrease your oxidative stress load is to avoid processed and damaged fats. So, polyunsaturated fats in particular are very vulnerable to oxidation. These are omega sixes and omega threes. And we do need some but we all get way too many omega sixes. And even omega threes, some people don't know are very vulnerable to oxidation due to their double bonds compared to something like a monounsaturated or a saturated fatty acid.

Christopher:    Where do I find more monounsaturated and saturated fatty acids?

Megan:    Monounsaturated are going to be the olive oils, the avocados, even some animal fats if they're pasture raised grass fed grass-finished, you'll get more saturated and monounsaturated versus the polyunsaturated. And saturated is going to be butter, coconut oil and other animal fats. Those are just more stable because they don't have those double bonds that the PUFAs have.

Christopher:    Right, right.

Megan:    It's the carbon in particular between the two double bonds or between the double bonds that's particularly vulnerable to oxidation and so there's this cascade of events that happens where there's the initiation and the propagation and ultimately potentially if vitamin E is around termination of this chain reaction of lipid peroxidation that happens.

    And Vitamin E, like I said, was particularly important to terminate the propagation of the chain reaction of the polyunsaturated fats. Interestingly, just a random thing here, but when vitamin E breaks that chain reaction, it creates its own Tocopherol radical which is then converted back into alpha-Tocopherol by Vitamin C. So, you not only need vitamin E but you also need the other antioxidant vitamin C.

Christopher:    To recycle the vitamin E. That's fascinating, isn't it?

Megan:    Yeah. It's funny when you think of, okay, high PUFA foods such as nuts and seeds, they're usually packaged in nature with high vitamin E content. And so eating things like raw nuts and seeds may not be a big deal whereas eating something like a processed vegetable oil with very low vitamin E but high PUFA content which may be oxidized already PUFAs, that's where you're going to run into trouble.

Christopher:    So, that's where the recommendation, the minimally processed diet is something that we talk about a lot and that's what we're talking about, eat the whole nut or the whole seed, not some oil that's been pressed out and industrially processed.

Megan:    Exactly.

Christopher:    I could say it's so hard to avoid this stuff. I've just got back from the UK and so I found myself hunting for food in the local service station, those terrifying situations. Canola oil or grapeseed oil, as it's called in the UK, is now everywhere. I guess, it got trendy. I don't know what happened, whether some of the celebrity chefs in the UK have been talking about it or something.

    But now I'm not sure if everyone realizes a lot of British people know that canola oil is bad but they don't realize that at home it's called grapeseed oil. It's literally in every single product. If it's got any kind of added fat, it's definitely going to be grapeseed oil. It's all very well for us to talk about avoiding these things but how do you that at a practical level? What do you say to clients when you're asking them to avoid this stuff?

[0:45:09]

Megan:    Yes. I say when you're in control, when you're eating at home, do the best you can. Cook with the more traditional fats. And then when you go out, honestly, if you're not eating out every day and it's an occasional thing, then I personally think that stressing about it is probably going to cause more oxidative stress on top of the vegetable oils. Just try to do the best you can and don't fret if your steak was fried or cooked in a little bit of canola oil or whatever. Your body should be able to take care of it and the extra stress is just going to be counterproductive, in my opinion.

Christopher:    So, the enzymes that break down the catecholamines and cortisol cause oxidative stress and that may be worked. So, my neurotransmitter is going while I'm sniffing around Marks and Spencer in a service station in the UK. It's probably be going to be causing me more problems than just eating the grapeseed oil, right?

Megan:    I think so. Yeah.

Christopher:    That's fascinating and interesting idea. I could tell you in the end what I did was I just ate what I brought with me. So, Julie packed me up with a ton of food. There's so much great stuff that you can get online that will last for ages. My favorite thing and I know your favorite thing as well, Megan, is Wild Planet sardines. That's so easy to take anywhere.

Megan:    I have a funny story about sardines. When I travel sometimes my suitcase is too heavy because I have so many cans of sardines in my suitcase. I have to put them on my carryon bag. But anyway, I digress.

Christopher:    Do you ever eat them on the airplane? That's my other favorite thing to do, just crack open a can of sardines on an airplane.

Megan:    Do you do that? I won't do it. I'm too scared.

Christopher:    Yeah. Certainly because I'm married and I've got kids. I don't know. I'm not sure I would have done that as a young single guy. I care less about what other people think about me now.

Megan:    Yeah. That's true.

Christopher:    So, let's move on.

Megan:    We were talking about what to do if your oxidative stress score is high. I've a couple more things. In appropriate amount of hormetic stress and this can then be another whole podcast in itself, but we're talking temperature so extremes of hot and cold, short bouts of sauna or ice is great but you don't want too much. Exercise as well, again, those Goldilocks Zone.

    There's also Hormetea. We've talked about Hormetea before on the podcast. We could link to our product page. Ultimately, Hormetea is created by Dr. Tommy Wood and it has certain compounds that up regulate our antioxidant defense systems through things like Nrf2 activations. So, the sulforaphane which are from the broccoli seeds is great at activating Nrf2. Then we also have the EGCG from the matcha green tea, the polyphenols from the blueberry and then curcumin from the turmeric.     Though Hormetea is a great kind of antioxidant punch that you can add into your diet, also hormetic stresses will ultimately help increase glutathione in the body as well.

Christopher:    So, it's not acting as an antioxidant but rather as a hormetic stressor that leads to greater antioxidant capabilities. And interestingly though, we did a podcast a long time ago. I'll link to it in the show notes. I think that was a good one. I still drink Hormetea not because I can remember all the biochemistry of antioxidant defenses but just because it's good.

    I like it with Phat Fibre in it, a little bit of the C8 MCT oil. It's quite bitter and astringent but when you put a little bit of fat on it, it takes the edge of that astringent taste. I don't know what it is. I guess, people are drawn towards things like that, that spicy or just a little bit -- They got a little bit of bite. So, I continue to manufacture and sell _ just because I like drinking it.

Megan:    My favorite way, I think Julie brought this up originally but is to put it in bone broth. And then I've been adding to it a little bit of the Four Sigmatic 10 Mushroom Blend. It's really good that way. I recommend people try it.

Christopher:    That's right, yes. Julie tasted it and she said, "Oh, I want to put that in bone broth because it kind of tastes like split pea soup." And I was like, what are you talking about? Like I can't taste that at all. But I wouldn't be surprised if her palate is much more refined than me.

Megan:    I think it tastes good that way so I'm glad that she recommended that. Okay. So, we talked about hormetic stress. Two other things here. So, sleep, melatonin, I briefly mentioned, I believe, is an antioxidant. Sleep disorder such as obstructive sleep apnea and also insufficient sleep are related and associated with an increase in oxidative stress.

    Get enough sleep and also look at your sleep environments. So, sleep in a cool dark room, avoid blue light at night, get outdoor light in the morning, all of the good kind of sleep environment tactics that we talk about. And then the last thing which you briefly mentioned on the ferritin discussion will be to donate blood. So, we know that iron overload can promote oxidative damage and impair insulin signaling, many other things. So, donating blood, if you have the iron overload can certainly help decrease overall oxidative stress on your body.

[0:50:04]

    The other thing here and we briefly talked about this with the whole idea of exercise but just to wrap up this conversation, we need to remember that not all oxidative stress is bad. I like to think about oxidative stress just like any other stressor in life. The idea is not to eliminate it completely because that would be a completely futile endeavor. We can't do it. Our metabolic processes are creating reactive species all the time. But we rather need to keep the oxidative stress in check and direct it to the right place. We use it for the physiological cell signaling and we direct it away from things like oxidative damage and improper cell signaling.

    We talked about some of the benefits of free radicals in the context of exercise. We can also use antioxidant functioning as pro-oxidants. They can be used as therapeutic agents for things like cancer and also metabolic diseases. There is one study that I found yesterday actually. We can link too. But it was showing -- It was called Dietary Phytochemicals: Natural Swords Combating Inflammation and Oxidation-Mediated Degenerative Diseases.

    And they have these two great tables. The first table was mechanism of action and the side effects of specific drugs and medications used in the treatment of things like cardiovascular disease, diabetes and rheumatoid arthritis. And then the table below it had the evidence of clinical trials with natural products attenuating oxidative stress and inflammation in people with these conditions, so cardiovascular disease, rheumatoid arthritis and diabetes.

    Guess what? There were no side effects on table two whereas on table one there was a whole list of side effects. And so we can definitely, we can leverage antioxidants and the benefits of free radicals for some of these specific diseases of the modern time. Really what we need to pay attention to is the fact that context ultimately matters.

Christopher:    Makes sense. In summary, the blood chemistry calculator, looking at your oxidative stress score is going to give you a beginning point for an investigation. I'm not sure how you're working at the moment, Megan, but that's how I use the scores that I've built in to the blood chemistry calculator. I start at the top and then I work my way down. How is this person doing overall? How is the five-year wellness score? And then I drill down from there.

    And so is the case with the oxidative stress score. Like what's your score overall? And then I scroll down and I look at the individual components and I see where that person has picked up the points and then I drill down from there and consider what might be going on for that person before making recommendations.

    You could argue that -- You said how do you improve your score? Well, you need to do other things. You need to be sleeping. You need to be eating a nutrient dense diet. You need to be exercising some but not too much. You need to be getting hot. You need to be getting cold. You need to be not stressed out. You need to be part of a social group and all of the rest of the things.

    You could argue that you should be doing all of those things without doing a blood test and I would wholeheartedly agree. But the people who are interested in performing better or at a higher level I think it's really helpful to take a look inside to see what's going on in order to know where you need to improve.

    Let me ask you this though, Megan. Is that the way that you work? Do you start by looking at the blood markers directly? Because we do have that view. If you just want to look at your blood markers directly and then see our optimal reference ranges you can absolutely do that. But do you start with the scores and then work your way down or do you work some other way, Megan?

Megan:    Oftentimes I do just start with the scores. I also like the tab on the forecast that shows the top four for each category just because if you're looking at either the input markers and then the individual reference ranges for each or you're looking at the forecast tab with all of the forecast, it can get really, really complicated. I mean, overwhelming for people.

    And so that's why looking at the scores it gives you kind of a general overall overview of how is this person doing relating to the categories and then we can dive in and say, okay, if your toxicity score is elevated then have you gone through all of your personal care products to make sure that you're not using nasty stuff on your skin? Or if your oxidative stress is high, okay, we go down the list of things that we talk about today and say, okay, where might you be missing something here?

    And if your oxidative stress is high and you're also having some indications that there might be an infection going on then we can look at a stool test or something like that. So, yes, I think that starting with the scores when we're viewing this with clients is good overall picture of how they're ultimately doing.

Christopher:    Yeah. And I love looking at the score before and after an intervention and because this is a blood test that's both easy to do and relatively inexpensive. You can do it every two weeks. We do that all the time now which is fantastic.

[0:55:03]

    I'm thinking about creating a single page that looks a little bit like the dashboard on a car that has all of these scores that we developed. So, we have a wellness score. We have an inflammation score. We have a metabolic health score, a nutrition score. I can actually predict some of the deficiencies that we talked about as being important in this podcast. I think it would be nice to see all those on one page like a dashboard, right?

Megan:    I think that would be really great. In that way people can get a good idea instead of flipping through the tabs of saying, okay, this is, my toxicity score is rock bottom but oxidative stress or inflammation is super high. So, what's going on there?

Christopher:    Yeah. Where should I go next?

Megan:    Yeah.

Christopher:    And, obviously, the other scores are equally as complicated and we'll drill down into those in some future podcasts but if you're interested in ordering your own blood chemistry calculator report, you've got a couple of options actually. You can come to bloodcalculator.com and if you've already run a blood test recently chances are you have most of the required markers.

    Because we're not doing a whole bunch of fancy stuff here. We're just getting more out of the basic blood chemistry. If you haven't run a blood test recently then I can solve that problem for you too. If you are in the United States or if you're in the UK or if you're in Australia then you can get the blood work done in any of those countries.

    And then when the results come back, we'll run them through the calculator and then send you a link to your report. So, all you need to do is place an order and then take a PDF requisition form to the lab or you can order a mobile phlebotomist. That's my favorite thing to do now. They're difficult in there's no one place to go to get one.

    They're like taxis. In fact, there is an app like Uber for mobile phlebotomist. You can just Google that term mobile phlebotomist. And then you order one and they show up your house first thing in the morning before you've had breakfast because you need to be in a fasted state when you do the blood test. They'll just do the blood drawing. It's over in less than a minute. That's all you need to do.

    They deal with the rest. They take away the vials. And then the results come back to you electronically. So you get both the raw data from Quest, if you're in the US, or other laboratories if you're outside of the US and then also you'll get our report that includes the oxidative stress score that we'd been talking about in this podcast.

    I think that's about it. Thanks so much for your time, Megan. I think you're doing amazing work and we're very lucky to have you. Thank you for your time putting this podcast together for us.

Megan:    Thank you and you're very welcome.

Christopher:    Excellent. Thank you.

[0:57:39]    End of Audio

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