What New Science Reveals About Mitochondria & How We Age | Dr. Siobhan Mitchell

In this episode of New Frontiers in Functional Medicine, Dr. Kara Fitzgerald sits down with neuroscientist and mitochondrial health researcher Dr. Siobhan Mitchell to explore emerging research on mitochondrial dysfunction, aging, and longevity. They discuss how mitochondria change as we age, how mitochondrial dysfunction may contribute to chronic inflammation and age-related disease, and why supporting mitochondrial health could be an important strategy for extending healthspan.

The conversation explores the relationship between mitochondrial dysfunction and biological aging, inflammation, cardiovascular and metabolic health, cognitive decline, and chronic disease. Dr. Mitchell also discusses emerging biomarkers of mitochondrial stress, including GDF-15, and what they may reveal about mitochondrial health and aging trajectories.

Dr. Fitzgerald and Dr. Mitchell also examine practical and emerging approaches to supporting mitochondrial function, including creatine, NAD+ precursors, S-equol, exercise, and targeted mitochondrial support, along with research on vascular function, cellular energy production, and mitochondrial DNA damage.

In this episode of New Frontiers, learn about:

Dr. Kara Fitzgerald: Hi, everybody. Welcome to New Frontiers in Functional Medicine, where we are interviewing the best minds in functional medicine. And of course, today is no exception. I am joined by Dr. Siobhan Mitchell. She’s a longtime friend and colleague. She’s a brilliant neuroscientist and researcher who’s spent more than 15 years studying brain health, aging, nutrition, and cellular health. She brings an interesting perspective to the question I think many of us are asking. And that is: are mitochondria really becoming one of our most important targets for healthy aging and longevity.

Dr. Kara Fitzgerald: Today’s conversation is brought to you by MitoQ, where Siobhan serves as the Chief Science Officer. In our conversation today, we’re going to drill down, and in fact, Siobhan posited the most compelling argument with solid mechanistic discussion on why mitochondria – the deterioration, acquired mitochondropathy, if you will – may be driving the whole phenomenon of aging. And in driving that, drive the d chronic diseases of aging.

Dr. Kara Fitzgerald: And if we target mitochondria with some of the new interventions we now have at our disposal, yes, including MitoQ, we’re also going to talk about S-equol, we’re going to talk about NAD precursors. We’re also going to talk about creatine. But if we target mitochondria specifically, you know, what does that show? What’s the science out there? We’re gonna dig into it. There’s a ton of good science. So let’s get right to it.

Dr. Kara Fitzgerald:  Siobhan, it’s always, always, always great to get to be with you and just pick your amazing scientific brain. We’re gonna be talking about mitochondria, all things mitochondria. And I was reflecting on our podcast you know, just before we hit go. And thinking about sort of the history of our approach to mitochondria in my, you know, 20 years practicing medicine, and and that originally started in a laboratory setting. And, you know, a couple of thoughts came to mind.

Dr. Kara Fitzgerald: One was we mostly only recognized early on, you know, genetic mitochondropathies. And I remember it was a serious revolution for me, revolution, revelation, when a book, a textbook came out called Acquired Mitochondropathy that really put the phenomena on the map that our mitochondria go through hell. This was some years back though, and it was an amazing book. I wanted to buy it, but I was in my post doc. I was a poor student back then basically and I never did end up with it.

Dr. Kara Fitzgerald: But you know, I pulled up some of the papers and just and the idea that mitochondria can become damaged with the wear and tear of life and and mimic what we might, you know, look at as being something that’s genetically associated was revelatory for me. And I really started to think about it a lot in regard to patient care, how we tend to the mitochondria. And you know, one thing back then was that our hands were somewhat tied with regard to our tools.

Dr. Kara Fitzgerald: And, you know, we’re – you and I – are going to talk about mitochondria. We’re gonna talk about interventions with your brain and background. And it’s very satisfying for me these days to feel like we’ve got more and more meaning. A: we’re recognizing that mitochondropathy is a thing. It’s a phenomena that’s occurring in all of us, really, over the course of aging. Like probably maybe we could all be categorized as having, you know, acquired mitochondropathies on this aging journey, but B: that we now also have these tools, these meaningful tools with nice science behind it.

Dr. Kara Fitzgerald: And so I just want to say again, thank you so much for bringing your brilliance to the podcast. And talk to me, you know, if you have any thoughts on that. And, you know, just mitochondria is getting its moment in the sun, as it were, as a longevity organ, something we need to tend to. So talk to me about that as well.

Dr. Siobhan Mitchell: Yeah, yeah. And it’s interesting that you bring up the sort of mitochondria disease is where people thought it’s just those few people that get a mutation when they’re born, and that’s called primary mitochondrial disease. And yeah, it’s very severe and and all the rest, but the rest of us are okay. And what’s now being understood is that there’s actually secondary mitochondrial disease, which is we’ve acquired mutations. And we’re acquiring mutations because mitochondria are so vulnerable.

Dr. Siobhan Mitchell: The DNA for mitochondria is so vulnerable because of all the oxidative stress going on inside the mitochondria. And so just to even give you a sense of like how bad it is, I think over the course of our life, we’ll have maybe, you know, one, two hundred nuclear mutations sort of occurring year after year. But then in mitochondria, we’re having one in 250 mitochondrial mutations. So we’re picking up a lot of mitochondrial mutations. all the time.

Dr. Siobhan Mitchell: And that does, of course, affect us pretty early on. And so affecting obviously the mitochondrial function, but then also how the rest of the cell works. And I think this is really interesting because I think we talk about the mitochondria as the powerhouse of the cell. We talk about oxidative stress, which I’ve done on this podcast before. But another area of the mitochondria is that they control a lot of how the cell functions. They’re kind of like the CEO of the cell.

Dr. Siobhan Mitchell: And they especially are important for how the cell reacts to stress. And this is really fascinating. And I I want to just go into this a tiny bit. Yeah. So if you think about mitochondria and why we have them, basically it’s this organelle that makes power for us, makes energy for us, that used to be its own bacteria way back billions of years ago. And so it’s got its own mitochondrial DNA, as I just discussed, and this DNA is bacterial in nature.

Dr. Siobhan Mitchell: It looks kind of bacterial. And as soon as it leaves the mitochondria, which happens during cell stress, especially mitochondrial stress as well, that DNA looks like a foreign thing and needs to be attacked. So it makes an inflammatory kind of cascade in the cell. And it can also make an inflammation kind of signaling pathway outside the cell. And the way this happens is when mitochondria gets stressed, the DNA actually starts to leak out of the mitochondria.

Dr. Siobhan Mitchell: And then this sets out this whole kind of inflammatory cascade, which I will go into, but basically it’s kind of like almost like a cytokine storm that it’s causing. And then when mitochondria DNA leave the cell and gets kind of emitted outside the cell, this causes even more of a distress signal. And can sometimes even lead to apoptosis of that cell, or actually leads to apoptosis of other cells surrounding it. So, what we’re really understanding now is that mitochondria might be the origin of a lot of the information that we see.

Dr. Siobhan Mitchell: And so some of the data that we have that supports that is, for instance, I’ll mention a really cool epidemiology study called the Dunedin study. Yeah. And I feel like this is maybe something that people have not heard about before, but it’s one of these first kind of longitudinal studies, you know, following people from when they were born and looking at all sorts of biomarkers related to their health, up until now the people that are in this this study are age fifty or fifty-five.

Dr. Siobhan Mitchell: And this was started in this town in New Zealand, which I’m in right now, New Zealand. And they were really trying to understand like how does health change over a lifetime? What are the things, what are the predictors of health over a lifetime? So this kind of cohort is kind of famous, for instance, showing depression genes that can cause depression later on in life or increase risk of depression. And one of the things they’re starting to really focus on right now is how mitochondrial health changes over time.

Dr. Siobhan Mitchell: So what I think is really cool about the Dunedin study is it’s getting to the heart of what’s causing us to age, what’s causing us to accelerate in our aging. So they spent a lot of work looking at these biomarkers that might predict how we’re going to age. And they’ve also developed an epigenetic aging test called the DunedinPACE test, which is basically showing the rate of your aging. And so what they’ve been able to do with this tool, this DunedinPACE, is look at how people are aging f faster, and then also saying, all right, what else is going on with them that can kind of indicate why this is?

Dr. Siobhan Mitchell: And one of the things they keep on seeing time and time again is mitochondrial dysfunction. So that’s really interesting to me. So of course, we have mitochondrial dysfunction being shown in many diseases. And I can go into some of the areas where mitochondrial dysfunction is first seen and things like diabetes and all the rest, but I think it’s really interesting when you get to the actual aging situation of just who’s showing the most kind of inflammation and all those 12 hallmarks of aging. And so that’s what DunedinPACE is really showing.

Dr. Siobhan Mitchell: And they actually now are being able to show that, for instance, inflammation, which you know we’re all kind of suffering all the time, can be predicted in terms of, you know, when you’re going to die. And this is also something that the DunedinPACE clock can also predict as well. And it seems to be driven mostly by CD4 T cells and B cells and also really underlies a metabolic dysregulation as well.

Dr. Siobhan Mitchell: And so what I think is really interesting about the DunedinPACE and some of these other kind of cohorts that are looking at mitochondrial dysfunction is that it’s been really challenging to look at how mitochondria are working. We haven’t had the best ways of looking at it. So GDF-15, this mitochondrial stress kind of molecule is is becoming more and more important in terms of showing, for instance, that it’s going up when you start to have neurological diseases like Alzheimer’s disease.

Dr. Siobhan Mitchell: It goes up when you have diabetes, it goes up when you have even depression. And they can even show in various kinds of cohorts that people who have the most fatigue seem to have the most GDF-15. So this kind of signal, this mitochondrial stress signal seems to really correlate with a lot of things that go wrong with you during aging. So I think it’s really cool that that we’re starting to develop those kinds of clues. But even more so they’re they’re looking at now just even mitochondrial function and in terms of mitochondrial copy number, like how much mitochondria we have in our blood cells and our white blood cells that sort of indicate what a trajectory of disease is going to be like.

Dr. Siobhan Mitchell: So for instance, mitochondrial copy number has also been correlated to many of the things I just discussed. So Alzheimer’s disease, cardiovascular disease, various autoimmune diseases. So these are all just indicators that mitochondria are very, very important for our overall health, just in terms of our aging trajectory, but also signaling when we’re at the early stages of these diseases.

Dr. Kara Fitzgerald: Which are the chronic diseases of aging. So it’s just I mean, I think you’ve just made a really incredibly interesting point that, you know, in the phenomena of aging, mitochondria appear to become under greater and greater stress. And they bust open, they release that DNA. This is a sticky point for me, big time, Siobhan, that looks like bacteria. And so our immune system is like whoop whoop whoop, you know, free DNA. What is this? Let me attack this weird-looking bacteria.

Dr. Kara Fitzgerald: And that kicks in this inflammatory response, which might be the underlying inflammaging that we’re all talking about and trying to arrest. It may be sourced to just the natural aging journey where things begin to break down. And maybe, and you know, maybe it really kicks in with these changes to the mitochondria and they signal this greater breakdown and they’re just intimately linked to the diseases of aging. Wow. That’s a compelling reason to like love on our mitochondria.

Dr. Siobhan Mitchell: I know, I know. And this comes to the question of like how can you take care of your mitochondria through life? Like what do you have to do? So yeah, maybe that’s the other thing that we should talk about rather than just the the doom and gloom of like your mitochondria dysfunctioning and this is making everything worse. What can you do to stop that? Yeah.

Dr. Kara Fitzgerald: Well before you jump into that, I would just hang on, folks, because we are gonna get there. And I do think there’s some good news around this. I just wanted to say that you’re in Dunedin, by the way. That’s where you live. You live at the heart of where this research study has been going on. I just think that that study that you cited that really put mitochondrial– the mitochondrial damage phenomena at the front of the aging journey is an incredible worthy study to point out because they’ve been very intimately tracking these humans since birth, like measuring every biomarker under the sun and all sorts of functional biomarkers and everything.

Dr. Kara Fitzgerald: And I know interestingly that cohort is still together 50+ years into the journey and they go back to New Zealand and they get their workups at least annually. And it’s an incredible, incredible cohort that’s yielded so much information. And so I podcasted with one of the guys who developed the the tool, the pace of aging tool from it, Dan Belsky. But I just have such an appreciation for it. And so I thank you for bringing it forward and really pointing out the mitochondrial link in their investigations.

Dr. Kara Fitzgerald: And I hope that we can access GDF-15 at some point in clinic. You know, ’cause that maybe isn’t–

Dr. Siobhan Mitchell: Well- actually you can, so you can start to look at it. So yeah, for sure you should start to look at it.

Dr. Kara Fitzgerald: Thank you for that pearl. Okay. That’s awesome, Siobhan. Thank you. You’re just super useful. We’ve been talking about testing you and I for a while. So this is– we’ll do it. We’ll immediately do it. okay. Let’s talk. Yeah, solutions. How do we tend to our mitochondria?

Dr. Siobhan Mitchell: Yeah, so obviously there’s exercise, but I don’t think I need to tell any of your listeners about exercise. I think that’s been really well discussed. That exercise resistance training, high intensity, whatever, kind of endurance, all of that is helpful for your mitochondria in myriad ways. So that is for sure. And then obviously having a good diet, maintaining a good weight, and all the rest, all the usual kind of lifestyle factors that you can think of.

Dr. Siobhan Mitchell: So maybe what I would probably want to go into is what kinds of extra things can you do for your mitochondria? Because that’s a really interesting area. And this is where I believe a lot of the research is being done. Because for a long time, especially when I was a postdoc, it felt like you just couldn’t tweak your mitochondria. They’re very protected. It’s hard to get anything into the mitochondria. And so when I was a postdoc, it was just kind of like there’s nothing that gets in there.

Dr. Siobhan Mitchell: It’s just a really tough place. And if you tweak it too much, you make the mitochondria stressed out and then it dies. So it felt like you can’t modulate it that much. But–

Dr. Kara Fitzgerald: We had massive hope around CoQ10 and as high as we went, like it just never seemed to live up to what we were wanting it to.

Dr. Siobhan Mitchell: Yeah, yeah. And this is where I think the concept is good that CoQ10 is very important as an antioxidant that the mitochondria needs. But just once again, CoQ10 just doesn’t get inside the mitochondria that well. But some of the other things that seem to get inside the mitochondria, like I will first point to creatine, and creatine is a really interesting one because it’s gotten a lot of attention right now. And I think it’s just all kind of like it’s great for your muscles and it’s gonna help with resistance training.

Dr. Siobhan Mitchell: But I also just want to point out that creatine can be very good for your mitochondria, and that’s a really important thing. So just to kind of quickly say what creatine’s doing, it’s basically having a kind of recycling effect on the ATP you’re producing already through oxidative phosphorylation. So the way this happens is that creatine basically gets this active form, so phosphocreatine. That can then donate a phosphate group to a kind of spent ATP molecule that’s now an ADP, but you can turn it back into an ATP.

Dr. Siobhan Mitchell: And so you kind of recharge your energy basically in a kind of quick, quick way. And so this quick energy from creatine is super important for mitochondria, especially when they’re stressed out. So I’ll just give you an example. So in the brain, so I’m a neuroscientist, so I always want to talk about the brain. The brain is often having these kind of moments of extreme energy needs. And this is where oxidative phosphorylation, you know, the usual kind of mitochondria energy production doesn’t always suffice.

Dr. Siobhan Mitchell: And this is especially happening when, for instance, you have a slight amount of hypoxia or a kind of slight amount of loss of blood flow to the brain, which I don’t know if people realize this. Like, so you hear about strokes, and strokes are really bad, but what’s also happening as we age is we’re having lots of micro strokes. So we have these little areas in our brain, capillaries that are no longer getting the blood that needs at the right time.

Dr. Siobhan Mitchell: And the blood flow can come back a little bit, but there’s just this moment of like not having the right blood flow. So it seems to me that there’s more and more data coming out showing that creatine can be protective against those kind of losses of energy, that kind of loss of nutrients that can be just for a few seconds. And so there’s studies, for instance, showing that creatine can be useful for traumatic brain injury, it can be useful for things like stroke, and it can also be even useful for just maintaining cognitive function.

Dr. Siobhan Mitchell: And so this is a whole area that I think is now being paid attention to of just how creatine can be helpful for Alzheimer’s disease, and also just even things like when you have a poor night’s sleep, you can take some creatine. And the fact that, yeah, you’re you’re kind of lacking in energy because of that poor night’s sleep, your mitochondria are a little bit more enfeebled. This is kind of bringing them back. So that’s that’s what I’m really excited about with creatine.

Dr. Siobhan Mitchell: But I will say the one thing that I’m frustrated with is that we don’t have a good way of getting creatine into the brain when we take it orally. So it’s the same kind of problem as a lot of things that we try to get into the brain, the blood-brain barrier won’t let a lot of things in. And so creatine will go into your muscle just fine. It won’t go into your brain as well.

Dr. Siobhan Mitchell: So one thing I want to kind of point out to people is that there are ways to help increase the amount of creatine, especially the active form of phosphocreatine in your brain. And that, for instance, is citicoline. So citicoline is basically a form of choline that yeah, is helpful for your neural membranes. It’s helpful for donating choline to increase acetylcholine, but it’s also really helpful for increasing the overall kind of phosphocreatine reserves in your brain. This has been shown in a clinical study.

Dr. Kara Fitzgerald: Orally?

Dr. Siobhan Mitchell: Orally, yeah. So about 500 milligrams was able to do this. And so that’s one thing you can do. So that kind of gives you another kind of area of, you know, kind of energy reserve. And then the other thing to focus on is the precursors to creatine. So things like arginine and glycine, but I would really actually focus on glycine because glycine is actually the rate limiting step in creatine formation. So you’ll probably have enough arginine in your brain. But you might not have enough glycine.

Dr. Siobhan Mitchell: So it’s it’s also worth it to kind of take an extra bit of glycine to kind of get your creatine reserves up in your brain. And then lastly, because the step in creatine where you need to kind of, you know, make it ready to take the phosphocreatine, you need a lot of methyl donation. And so methyl donation is basically things like B vitamins, so B12, S-adenosylmethionine, so SAMe, that kind of stuff to help with methylation as well.

Dr. Siobhan Mitchell: Cause a lot of people don’t realize this. That methylation also gets more and more, I would say, challenging for the brain to do as you get older as you’re not getting as much B vitamins into your brain as well. So keeping that kind of at high levels is also important.

Dr. Kara Fitzgerald: We do a lot of we prescribe a lot of, and I actually take myself, magnesium glycinate at bedtime. So that’s a a nice little double use for that. You know, we sometimes refer to – because creatine uses so much of the methyl group as SAMe – it’s a real methylation kind of a hog to produce it. We would sometimes think about prescribing creatine as like backdoor methylation. You’re sort of supporting methylation by giving the body some creatine because then it doesn’t have to make it and use all that SAMe.

Dr. Kara Fitzgerald: Do you think if you’re peripherally supporting adequate creatine that that might extend to preserving brain reserves? Or can we really not think of it that way?

Dr. Siobhan Mitchell: I mean, it does seem that eventually some creatine can get into the brain, but just most of the time the brain’s making its own creatine. So that’s not the same thing for the muscle. Muscle can’t make its own creatine. So it really just needs whatever creatine it can get from the bloodstream. So whatever you’re eating, the creatine you’re taking can get in there pretty quickly. But just with the brain, it’s it’s just more selective. So for sure, taking oral creatine will help the brain, but I like to think about what else you can do to help that creatine synthesis in the brain, especially the phosphocreatine, which I don’t think people are aware that’s really what you need is the phosphocreatine to have that kind of energy recharging.

Dr. Kara Fitzgerald: It’s a serious pearl, the citicoline, you know, we should be using this as like the backdoor methylation for the brain, backdoor creatine support. I just want to circle back to a question you said because it was compelling to me. So it seems like you’ve put forward a really good, juicy argument for, you know, mitochondrial deterioration as just an aging phenomena, associated with disease or just more broadly with the phenomenon of aging itself. And you talked about the sort of early initiating steps for that breakdown being, you know, the stress. Can you– what prompts the stress, what prompts mitochondria to get stressed out?

Dr. Siobhan Mitchell: Yeah, so many things, right? So it can be, for instance, obviously the fact that the mitochondria are going to have a lot more oxidative stress as you rev up energy use. So that’s something that I always want people to understand. Like people kind of think like, I want the mitochondria to have as much energy production as possible. Well, actually you want your mitochondria to just have enough, like exactly what it needs at the right time.

Dr. Siobhan Mitchell: And so that’s really the way that body would work best is that if you have too much energy, and this happens with obesity, the mitochondria are actually revved up too much, and you get this kind of lipotoxicity state where it’s trying to make too much ATP, it’s trying to make too many proteins from the ATP that it’s making, and you get like piles up of protein, you get kind of this sort of, I would say, also incredible amounts of oxidative stress that then can lead to things like diabetes and you know cardiovascular disease.

Dr. Siobhan Mitchell: So this is where I think oxidative stress is one thing. But then the other thing that’s also happening is that a lot of the environmental kind of factors like pollution, like obviously this summer we’re having a lot of air pollution with all the wildfires, things like microplastics, all these other kinds of chemicals that are kind of encountering in our bloodstream. are definitely making the mitochondria send out a stress signal and just say like this is not good, this is something foreign.

Dr. Siobhan Mitchell: And yeah, can also lead the mitochondria to start doing that kind of like taking out DNA and emitting it into this sort of cellular kind of matrix, but then also outside of the cells, that kind of thing as well. So there’s, I would say, a lot of things about the mitochondria that I really want to make sure this is very clear. That is just intrinsically difficult to kind of uphold for a long time. So there’s obviously outside forces making mitochondria kind of go wrong, but I really want to point out that it’s also just intrinsically the way the mitochondria is structured that is causing the mitochondria to age faster.

Dr. Siobhan Mitchell: And of course, we have these turnover mechanisms. We have like mitophagy and all the rest that kind of clear away the dysfunctioning mitochondria. But what we can see is that over time we’re not as good at clearing out that mitochondria and all that quality control, because we are now actually having that kind of problem of we are making so much oxidative stress, and even mitophagy is not going well. You know, it’s not having the sort of effect that we want.

Dr. Siobhan Mitchell: And I think it’s kind of interesting right now because people are aware of mitophagy, so the turnover of mitochondria, and of course it’s a good thing, but actually, what happens a lot when you get older, when you kind of hit sixties, seventies, is you have too much mitophagy. Your body’s kind of saying, like, all our energy is is not working as well. We’re trying to get rid of this mitochondria, trying to get some renewed mitochondria. But you don’t want to keep renewing mitochondria all the time.

Dr. Siobhan Mitchell: You want to also just have mitochondria functioning the way they should.

Dr. Kara Fitzgerald: Right. If you have excess renewal going on, would you see the GDF-15 rise? I mean, would that be a worthy tracking

Dr. Siobhan Mitchell: Yeah. So this is where almost everything makes GDF-15 go up. And just to be really clear, GDF-15 can sometimes just be a signal to to fix things. So when mitochondria are stressed, they usually send out GDF-15 is like, okay, can also work as a myokine. So it can actually help with, you know, muscles and things like that. But if it’s kind of on all the time, that’s when it becomes problematic.

Dr. Kara Fitzgerald: Right.

Dr. Siobhan Mitchell: So it is actually part of this TNF-alpha family so it can kind of act a little bit like a cytokine in that way as well. So causing more inflammation.

Dr. Kara Fitzgerald: So you may not want to measure GDF-15 right after you’ve done a HIIT training, right? Right after right? ‘Cause you might be dumping a lot just because of the energy output. Okay. What were you gonna say?

Dr. Siobhan Mitchell: No, just yeah, like it’s something where they see it going up from even just like mental stress, but then it should go down again. But then the problem is is when it’s not actually going down. So it’s a little bit like a cortisol type thing, actually. Right.

Dr. Kara Fitzgerald: Well, it’s fascinating. I will bring that to our rounds at clinic and we’ll be dialoguing.

Dr. Siobhan Mitchell: So much literature on it right now, it’s crazy. It’s amazing how much there is. Yeah.

Dr. Kara Fitzgerald: Thank you for that. what else? So what else do we want to be thinking about with regard to just loving on our mitochondria and supporting them to have a mitochondrial healthspan?

Dr. Siobhan Mitchell: Yeah. Another one that I am particularly interested in, as a woman, is phytoestrogens. And this is because estrogen is actually a very important activator of mitochondrial functions. So estrogen, because of the fact that there’s estrogen receptors on mitochondria, can help with mitobiogenesis. So make more mitochondria. It can help increase the expression of oxidative phosphorylation proteins, so we have you know better ATP production. And estrogen can also make more antioxidants, sort of endogenous antioxidants, in our mitochondria.

Dr. Siobhan Mitchell: So we’re more protected. And what I’m also just aware of is like sometimes you don’t want to go straight for estrogen. That’s not always the solution. So when you’re younger, maybe that’s you know not something that you’re gonna try to like elevate more. And then obviously, when you get to perimenopause, it’s like everyone’s decision of whether they want to take a hormonal replacement therapy. But what I think is really interesting is that phytoestrogens, so stuff from soy, for instance, so genistein, daidzein, they’re actually working on more of the estrogen beta receptor. And the estrogen beta receptor is kind of the estrogen that is good for your metabolism. Good for your mitochondria, kind of you know, keeping your mitochondria healthy, and not so much this estrogen alpha receptor, which is more the proliferative receptor, which is kind of the stuff that people get more worried about, you know. So estrogen alpha is usually more expressed in your reproductive tissues, so your breasts, your uterus, your ovary, while this beta is more kind of in your brain and places like that, and obviously in your mitochondria.

Dr. Siobhan Mitchell: So the main phytoestrogen I’m most excited by right now, though, is S-equol. And I don’t know if you’ve ever had anyone talk about S-equol, but it’s a phytoestrogen that is derived from soy. But the way it works is that when you take in soy and you get daidzein from soy, so that’s an isoflavone that’s a phytoestrogen, it then gets metabolized into S-equol if you have the right microbiome. And so what–

Dr. Kara Fitzgerald: Which most of us don’t, right?

Dr. Siobhan Mitchell: Yeah. Which most of us don’t. So what’s been seen in in studies is that a lot of Asian women have the right microbiome to get S-equol. So maybe about 50% of Asian women, or at least women living in China, Japan, have that ability. But women in the West, like America, Europe, maybe about 20% of women have the ability to make S-equol from soy. So yeah, this is kind of interesting because what’s known is in a lot of studies from Asia, like in Japan, for instance, is that your ability to make S-equol seems to also give you better overall health.

Dr. Siobhan Mitchell: So S-equol production has been associated with better body composition, better vascular health, better blood glucose, better cognition. And just to be clear, this is not just for women, this is also for men. So S-equol also helps men as well, too. That’s like a whole other thing about estrogen signaling being actually, a good thing for for guys, you know, it’s a little bit kind of like, no, I don’t want that, but no, actually you do.

Dr. Siobhan Mitchell: And then the interesting thing about S-equol is that it’s very good for your mitochondria. So it’s a very potent activator of that estrogen beta receptor. And not only that, it’s very bioavailable. So a lot of phytoestrogens are not bioavailable, but S-equol is extremely bioavailable. So it can get into the brain, it can get everywhere, and it can protect your mitochondria in your brain, for instance, by protecting it against glucose and fat kind of toxicity.

Dr. Siobhan Mitchell: So we talked about lipotoxicity as being a problem for mitochondria and you know generating too much oxidative stress. Well, guess what? S-equol could actually protect your mitochondria by helping with your antioxidant defenses. And then also mitochondria are basically, I would say, the sort of mediators of a lot of other vascular metabolic benefits that. When you start to go into perimenopause and you don’t have those as much anymore, you can take something like S-equol.

Dr. Siobhan Mitchell: And this has been seen in a lot of clinical studies, and kind of get that vascular function back. You know, things like artery stiffness goes down when you take S-equol and you’re a postmenopausal woman. So things like that are very intriguing to me. And then, you know, I would say also just even seeing some clinical studies where when they looked at people who could make S-equol, they actually have. better mitochondrial function. So better mitochondria and more mitochondria in their immune cells, for instance.

Dr. Siobhan Mitchell: So all these things make me realize like this is one of those nutrients that people in Asia, you know, get more access to, but we don’t have as much access to.

Dr. Kara Fitzgerald: Right. That’s right. There is a lab that that offers S-equol measurement. It’s a metabolomics assay. So it’s it’s big. It’s big, but gosh, it does make me really kind of eager to look at it again. That is just extremely interesting across the board. So it influences the beta receptors, but doesn’t exert sort of the classic estrogen effect, it would appear.

Dr. Siobhan Mitchell: Yeah. So you’re getting that selective estrogen effect that is more helping your metabolism and not so much, you know, the kind of like estrogen alpha kind of proliferation of, you know, breast tissue that you get, for instance, you know, during your cycle and things like that. So this is where it’s it’s much more just kind of helping tweak your metabolism to be better.

Dr. Kara Fitzgerald: Would there be any – I know clinicians are thinking this, I’m just gonna ask it – any contraindication in using HRT plus S-equol together?

Dr. Siobhan Mitchell: No, not at all. So that’s actually something that I looked into as well, too. And there are some clinical studies where they had women enrolled that could use birth control or were using birth control. And they also gave S-equol. And just to be clear, there’s a lot of people out there that are just making a ton of S-equol anyway. But yeah, they’re also taking birth control. Though I will say, interestingly enough, if you’re an S-equol producer, you usually also have less PMS.

Dr. Siobhan Mitchell: So, you know, the reasons why you might want to take birth control that it’s not just about contraception, it seems like if you have S-equol production, you’re more likely not to have those issues. So it’s kind of fascinating right now, just looking at all the data coming out. Yeah.

Dr. Kara Fitzgerald: Yeah, that’s super interesting to me. Have they looked at it in perimenopause and menopause, like S-equol producers and what that journey is like?

Dr. Siobhan Mitchell: Yeah, so it’s definitely effective for the vasomotor problems like the hot flashes and the night sweats, but it’s also very effective for things like joint health. So helping take away joint pain that’s related to perimenopause and also helping preserve bone, which is another thing that I think doesn’t get as much attention during perimenopause. So yeah, so it’s really cool data. I’ve always been asked like, how do you make it so that you become an S-equol producer?

Dr. Siobhan Mitchell: And this is where I have to tell you, nobody knows. It’s still mysterious. So it seems like, yeah, if you’re a Western woman, it’s a little bit like the Urolithin A story. You’re probably just best off finding an S-equol supplement and using that.

Dr. Kara Fitzgerald: Yeah, right, right. I did a little digging into to to see whether there were any bacteria that I  was familiar with that support S-equol production and they were all names that I had not come across. There were some distant links to bifido, you know, and maybe some lacto species touching pretty indirectly, but the you know, what we’re familiar with here and in functional medicine doesn’t seem to be particularly involved.

Dr. Kara Fitzgerald: You know, a lot of women listening or a lot of clinicians listening are– there’s a revolution happening in HRT and we’re using it more and more. Women have access to it more and more and are more educated to know that once estrogen really tanks, there’s an accelerated aging phenomena that can happen, both as measured by biological aging– I’d be curious to see if the DunedinPACE, if they see any leaps during… wouldn’t it be interesting to see when estrogen drops?

Dr. Siobhan Mitchell: Yeah, yeah.

Dr. Kara Fitzgerald: Just the drop in estrogen has this significant, far-reaching, profound effect in women, especially the earlier we hit menopause. And so we’re using it. It’s appropriate for some of us, it’s not appropriate for everyone, but you know, concurrently with S-equol, or S-equol as your standalone. I’m just really excited that you bring it forward. It is a compound, it’s a postbiotic compound, that I’ve been kind of in love with for a long time and it actually I wrote about it in Younger You. And the reason that I did– and wrote about the soy precursors to S-equol– because there’s in vitro data. Now granted it’s not… I think there’s some suggestion in the human literature, and you can corroborate or challenge this, that there’s maybe a decreased association with certain cancer types with higher S-equol producers. Have you looked?

Dr. Siobhan Mitchell: This is true. So yeah. Even though people get worried that anything with a phytoestrogen is gonna increase cancer risk, it seems that, yeah, once again, S-equol production, like being able to make it yourself, seems to be correlated to less incidence of reproductive cancers.

Dr. Kara Fitzgerald: And for me in the book, the thing that I was in love with is that it acts like– in vitro they’ve shown that it turns on previously hypermethylated tumor suppressor genes and specifically BRCA. So the BRCA gene, you don’t have to have a mutation to have a BRCA associated cancer. It can be hypermethylated and inhibited and drive hormone sensitive cancers forward in this hypermethylation phenomenon. There’s a  million tumor suppressor genes that can become hypermethylated.

Dr. Kara Fitzgerald: And these polyphenols or related compounds seem to really sweet talk the epigenome and help turn these genes back on. And S-equol seems to be, the soy-associated isoflavones and the derivative compound, the S-equol, the business end of it. Just quite frankly seems badass in that arena. And I hope that there’s a leap into looking at that in humans and moving out of the preclinical work. But that really made me kind of fall in love with it, you know, back in when we were doing our early research in 2021 and earlier. So thank you for bringing that up.

Dr. Siobhan Mitchell: It’s funny because I also fell in love with it like fifteen years ago when I was understanding how it can be so important for your health if you can produce it. And then just going like, but how do you make it? And for years and years there was no way you could supplement it or anything. So I’m excited that you could now supplement it.

Dr. Kara Fitzgerald: And well  it’s available. We can get it–

Dr. Siobhan Mitchell: Yeah, yeah. Exactly. You don’t have to just be like one of the “unlucky-s”.

Dr. Kara Fitzgerald: Are you taking it? Has it become a part of your supplement regimen?

Dr. Siobhan Mitchell: Yeah, yeah. And it’s funny because I started taking it as soon as it became available. And what I really noticed was it helped with my sleep because I had a lot of sleep issues. And then S-equol, even though it doesn’t have any clinical data showing it can help with sleep, it really fixed my sleep.

Dr. Kara Fitzgerald: That’s weird. But the vasomotor issues–

Dr. Siobhan Mitchell: I think it was because it was also helping with the vasomotor symptoms since those went away, everything else just kind of clicked. So yeah. So it’s definitely one of those things that you when you know when it works, you’re just like, this works. Yeah.

Dr. Kara Fitzgerald: Gosh, that’s awesome. That’s a great story, Siobhan. I wanna add it to my regimen. I do. I mean I’ve been a huge fan of it for a long time. And I also am curious to see whether I make it or not. So I might check that lab. But I think even if I did, you know, thinking about the Urolithin A stories that we probably– well A: I don’t eat enough soy. It’s not a standard food in my diet, it’s just not my habit. But and B: it’s probably not quite a therapeutic amount. Although if I were in Asia, it seems like they’re hitting therapeutic amounts because they could they can make it.

Dr. Siobhan Mitchell: And they have a lot of soy in their diet though, or at least they used to. I mean, I think that’s changing over the past few decades. But yeah. So this is where I think even if you are a soy producer, an extra bit of S-equol can make a difference because there was another study showing that even if you had that S-equol production, you could benefit from things like, you know, having better belly fat. So just things like that.

Dr. Siobhan Mitchell: Which, you know, obviously there’s the aesthetic appeal of that, but also to the fact that belly fat, visceral, adipose tissue is also correlated to a lot of metabolic issues and higher risk of various diseases. So yeah, you wanna take care of that.

Dr. Kara Fitzgerald: So kind of an unexpected mitochondrial nutrient for us to be thinking about in practice. And you can get it.

Dr. Siobhan Mitchell: Right, yeah, and you can get it. I’m gonna bring up NAD precursors, even though I know that you’ve probably talked about them a lot. I wanna bring them up because there was a study, I think, very recently, a few months ago, that was published showing that NAD, when you track it in people from, you know, various decades in life didn’t seem to go down during aging. And so I think this was like a big study. People are like, you know what? We’re told NAD was this big problem, we need to supplement it to like keep our mitochondria going and and all the rest.

Dr. Siobhan Mitchell: And this study seemed to say, like, uh-uh, you know, it’s not necessary. And I would just want to counter that by, for example, another study that actually just got published last month that shows that if you look at things like NAD in your muscle, that does seem to be going down during aging. And in fact, this study looked at looking at giving nicotinamide riboside (NR) or giving people an exercise regime, kind of like a high-intensity interval exercise.

Dr. Siobhan Mitchell: And when they looked at epigenetic aging, so once again, like this kind of biological aging clock, they saw that the nicotinamide riboside was actually better at improving epigenetic aging, especially in your muscle. So your muscle aging kind of improved with NR. But it didn’t improve as much with just exercise, which I thought was kind of fascinating. So yeah.

Dr. Kara Fitzgerald: NR plus exercise or NR in the alone NR alone rivaled exercise?

Dr. Siobhan Mitchell: By itself. So it helped improve your epigenetic aging of your muscles. But the high intensity– so there was a little bit of discussion like why wasn’t the exercise helping with muscle aging? And I can tell you, obviously, there is a lot of things going on when you do something very high intensity intensity to your muscles. And so, for example, there’s a study showing that just doing a lot of high intensity training can cause DNA damage in both your cells and also in your mitochondrial DNA.

Dr. Siobhan Mitchell: So this is where, yeah, like you need to recover from that. And maybe what they’re doing in that particular kind of regime was not enough to recover from.

Dr. Kara Fitzgerald: Maybe they were taking the measurements, getting the specimen too soon before they really allowed the body to fully recover after that high intensity event or something. It’d be worth exploring. I mean, I think it’s compelling though. It’s still interesting nonetheless. And it opens the window into considering the NAD precursors for sure. And as an intervention in our toolkit for mitochondrial support. But yeah, definitely people shouldn’t hear that as a call to stop exercising.

Dr. Siobhan Mitchell: No, no, no. They shouldn’t think of it that way. But I think of it as just kind of like, all right, there’s things that get a lot of attention when the media takes some sort of like paradigm and goes like, NAD wasn’t so important after all. And it’s like, no, no– you have to look at the nuance. And I think we get a lot of that kind of data. Like there was a recent study on DHA, like not helping with, you know, cognition and brain aging.

Dr. Siobhan Mitchell: And people are like, look at that, DHA doesn’t work. I’m like, Well, no, it does work. There’s lots of studies showing it works. But maybe just for instance, in that particular study, people were using a lot of oxidized DHA kind of supplements. And so maybe that was the issue. So I think you have to look at the whole of the data rather than getting too fixated on different kinds of studies. Yeah.

Dr. Kara Fitzgerald: A study came out a long time ago associating DHA with prostate cancer and you know, buried what didn’t make the news, because I don’t know, it was less sexy, was that in that same paper, trans fats were shown to be protective. So if you have these two really obviously kind of findings that are a little bit questionable, you know, maybe you need to dig into looking a little more carefully at whether that study is useful or really gonna inform clinical decision. Okay, more trans fats, I’ll protect my prostate.

Dr. Siobhan Mitchell: I know. Something’s wrong here.

Dr. Kara Fitzgerald: Yeah, something’s wrong with that paper. All right. So what about let me just ask you this, Siobhan, and then we’re gonna continue on talking about our interventions. You and I talked about this before, and we’ll, by the way, people, we’ll link to my previous conversations with Siobhan, and then we’ll also, some of these papers you’re referencing, we’ll pop them onto our show notes as well because I know people are gonna want to see them.

Dr. Kara Fitzgerald: You and I have talked about antioxidants, kind of like if you give antioxidants post-exercise that you can actually have kind of a blunting effect on the benefits– on the kind of the mitochondrial cleanup that happens. You can sort of blunt the oxidative stress that happens that’s helpful that signals, you know–

Dr. Siobhan Mitchell: Yeah, to kind of make more muscle. Yeah, yeah. And make more mitochondria. Mm-hmm.

Dr. Kara Fitzgerald: Yeah. So if you take antioxidants too close to exercise, it can actually have a negative effect. The reason that I thought of that is because, I just wanted to bring it up here and you can talk about it, but would we think about NAD precursors as such in that bucket and maybe want to separate them from exercise? But just talk about your thoughts on that. Answer the NAD and then let’s move into talking about MitoQ.

Dr. Siobhan Mitchell: Yeah. So I mean NAD precursors are not really truly antioxidants. So they are obviously components that help with the production of ATP. So NAD is part of this whole complex kind of, you know, generation of this respiratory chain of electron transport. And that’s of course gonna be something that will be beneficial to exercise before, after, whatever. You know, you just need NAD supplies to be what they should be. And I think that that study really showed that really well.

Dr. Siobhan Mitchell: And then obviously NAD precursors can then help with things like DNA repair through sirtuins. And so that’s like a whole other area that probably would be very beneficial for exercise. And I can’t really see any downsides of taking an NAD precursor with exercise. So all those things they just talked about, like that’s gonna be something synergistic with exercise rather than blocking any effect. So I think there’s no problem there.

Dr. Siobhan Mitchell: Those other antioxidants like vitamin C and vitamin E, I tend to agree. I would not take those, especially before exercise. I mean, vitamin C is great. I am very aware that for instance, you don’t get as much of it in your brain after a certain age. So once again, the transport of vitamin C is not great. So I think we should all be very careful about getting enough vitamin C, but maybe just don’t take that supplement right before exercise. Take it a few hours later, something like that.

Dr. Kara Fitzgerald: Right, right, right. Or get food based antioxidants because I don’t think they have any downside.

Dr. Siobhan Mitchell: Yeah. Yeah. That is also an option.

Dr. Kara Fitzgerald: Yeah. Yeah, you could eat your antioxidants.

Dr. Siobhan Mitchell: But just Yeah. When I think a lot about these different things I mentioned, like the creatine. I mean, creatine, like I know so many women that don’t eat a lot of red meat, all the things that you normally need to get a sufficient supply of creatine, that you know, I feel like it makes sense to supplement, especially as–

Dr. Kara Fitzgerald: There’s no issue. Totally. Yeah. Yeah. The only reason I bring that up in this context is that some people will be thinking like, all right, when am I going to take my antioxidants? And yes, you could parse them out or just not worry about it and eat, you know, have yourself a nice big salad with, you know, whatever, rather than staggering them. Staggering my supplements is really difficult. I’m just not good at it. All right. Anyway, let’s keep going.

Dr. Siobhan Mitchell: Yeah, so then I think what I really want to also spend a little bit more time on actually is my favorite mitochondria kind of protector and that is MitoQ. And so I especially just want to highlight MitoQ because there’s some new data that’s come out recently that’s really putting MitoQ as a preventative kind of mitochondria therapeutic that can really keep your health intact. And that’s I think what is really important. Like that is the main message I want to give for people with longevity is that it’s never too soon to think about this.

Dr. Siobhan Mitchell: And it’s something where I think most people are just like, you know, I’ll start worrying about, for instance, cholesterol or hypertension or diabetes when my numbers start to look bad. But my answer to that is always like, you know what, those numbers, like there’s something happening behind them that is perhaps happening like a decade before you see, for instance, your A1C going up or your hypertension kind of manifesting into like stage two.

Dr. Siobhan Mitchell: So that’s my big message. And what MitoQ was actually really helpful in, was a study with people who are relatively young, so average age 36, they were starting to show signs of aging in terms of having somewhat elevated liver enzymes like ALT and AST, and then also some hypertension. And so, yeah, obviously hypertension is one of these things that everyone is kind of aware of is like an older person’s disease. But what I really want to point out is like one in four people in America have hypertension and a lot of it is not getting treated.

Dr. Siobhan Mitchell: And it’s especially a problem for the younger generations that just don’t think this is a problem for them, that they don’t even know this is an issue. And that’s what happened in this study. So these these subjects didn’t realize that they actually had, I would say, a pre-hypertension stage. And when they took MitoQ for three months, they saw that all this kind of hypertension went away. So they had improvements in diastolic and systolic blood pressure.

Dr. Siobhan Mitchell: And then they also had improvements in these liver enzymes, ALT and AST, which you know are kind of big indicators of liver stress and you know the emergence of things like fatty liver. So this is yeah, where I feel like, okay, this is something where MitoQ has shown a lot of great effects in older populations. And here’s an example of it being really important in your 30s. So that’s kind of cool. And then I would also just want to highlight some studies that are really important for the exercise kind of factor of keeping your mitochondria healthy, because that’s the other area where MitoQ has just been kind of phenomenal.

Dr. Siobhan Mitchell: So we also talked about how when you do a high intensity exercise, you get DNA damage. Well, MitoQ can actually prevent that DNA damage from even happening. So in another study, looking at fairly young people, people in their 20s, they were doing high intensity exercise when they took MitoQ and not even for very long, just a couple of weeks, they saw that the MitoQ could improve DNA damage in both their mitochondria DNA and also their cells, like the regular nuclear DNA.

Dr. Siobhan Mitchell: So yeah, and that helps with recovery over time as well. So allowing your muscles to recover better and being able to work out harder and keep those mitochondria healthy.

Dr. Kara Fitzgerald: If that’s the phenomena that’s really informing the aging, if that’s like one of the first mechanisms that then kicks the other hallmarks or drives the whole aging phenomena forward, lowering the bar to all of the chronic diseases of aging, if it’s that interesting point that you made earlier about, you know, the DNA, the mitochondrial DNA leaking into the cytosol and then into circulation with greater triggering of inflammation. I mean, if that’s it and we can turn it off in young people. I mean, that’s potentially really profound.

Dr. Siobhan Mitchell: Yeah, and I feel like this is where there’s a lot of stuff we talked about with, you know, ways of getting in the mitochondria. But if there’s anything that gets into the mitochondria like best, it’s really MitoQ. And so I just want to highlight that. So for instance, we talked about CoQ10 and how you can take CoQ10 orally, but it doesn’t really have a good active transport system into the mitochondria. So it can’t do that kind of protection that we need, especially when we are having these life stresses. But MitoQ has been engineered basically to have a special triphenylphosphonium (TPP) tag that allows it to get into the mitochondria because it’s very positively charged, the mitochondria negatively charged. So it’s sort of a key chemiosmotic effect. And so MitoQ can get to the mitochondria up like 90% of it, whereas, you know, something like CoQ10, maybe like five percent can get in. So that’s the real game changer there.

Dr. Kara Fitzgerald: Huge. You have to take it– I want to just tell everybody because it’s part of my stack. I take it in the morning. And I just said earlier, I can’t stagger supplements. I’ve made an exception. Like I want to get this one right. Because the data on it are so, so compelling. Maybe give me just like a couple sentences, its full structural name and just a little bit about what it does for anybody else who’s new to this podcast.

Dr. Kara Fitzgerald: And then, you folks– there’s so much good science on this molecule which always makes me excited to talk to Siobhan because she’ll bring up new papers. The website – the clearinghouse – people can go to who want to do their own dive into it. If anybody out there, clinicians, if you’re still imprinted on the idea that this is CoQ10, I would just like to move away. Drop that, take a minute to do your own investigation. Consider the papers on our show notes, but we’ll give you a website as well and just like dispel that unfortunate myth.

Dr. Siobhan Mitchell: Yeah, so this is very different from CoQ10. And the way this molecule looks, basically, it does have one part of the molecule that looks somewhat like CoQ10. So it’s got a sort of ubiquinone on one part. And this does give it this antioxidant capability, especially inside the mitochondria. In fact, it’s very good at going into the mitochondrial inner membrane and preventing lipid peroxidation, which is one of the main ways that mitochondria start to get stressed and then you know, go into kind of all that stress modes that I was telling you about.

Dr. Siobhan Mitchell: But then the thing is that once it’s there, the MitoQ can get recycled in terms of its antioxidant capability through the mitochondria electron transport chain. So it’s just gonna just keep on being able to be an antioxidant kind of forever as long as it’s in your mitochondria. Eventually it’ll go out of your mitochondria when your mitochondria get recycled, but it’s really effective in terms of just keeping your mitochondria protected against all the oxidative stress, especially as you age, that we know are really at the heart of how mitochondria start to dysfunction.

Dr. Siobhan Mitchell: So that’s the beauty of it. And we do have this website. It’s called– well there’s actually two websites you can go to. You can either go to mcrp.dev, so that’s Mitochondrial Collaborative Research Program. And this kind of gives you an overview of what mitoquinol, that’s the chemical name of MitoQ, can do and lists all these clinical studies. There’s 30 different clinical studies on MitoQ. And then also is a way that if you want to do research with MitoQ, you can sign up to do research.

Dr. Siobhan Mitchell: So we love working with professors or physicians or you know any kind of HCP to do more research on MitoQ because we’re always continually surprised by how MitoQ can be used. You know, it’s been effective for things like chronic fatigue syndrome and for COVID and sort all sorts of stuff that we never really would have expected. But obviously mitochondria is so important for so many functions in our body that maybe we shouldn’t have been so surprised.

Dr. Siobhan Mitchell: So the other website you can go to is also very similar. It’s called mitoquinol.org. And yeah, that’s kind of giving you the same sort of information. And yeah, you can see all the papers, we’ve worked with universities like Duke and Harvard and Yale and Cambridge University, so all these top universities to do all sorts of research. So would love if people went and took a look and just kind of thought about their mitochondria some more. This is really the point.

Dr. Kara Fitzgerald: Yeah. The breadth and depth of the science is very compelling. Recommendation– I’m curious about the two studies you mentioned on the podcast, the two younger, the specifically the 36-year-olds with hypertension. Was that maybe their average age or something, but the thirty something. What kind of dosing? You know, generally we do twenty, but talk about that.

Dr. Siobhan Mitchell: Yeah, so that was a 20 milligram dose. And that’s generally what we’re using in a lot of these clinical trials, what we suggest to professors and researchers to use, because that seems to be enough to get, you know, the correct kind of like improvement in actual health issue. So what we sort of suggest to people is that if you’re just looking for mitochondrial maintenance, kind of just overall protection, 10 milligrams is probably enough because I say, as I said, as soon as you start taking MitoQ, it can start to accumulate in your mitochondria, accumulate more and more, and protect it more and more.

Dr. Siobhan Mitchell: It just might take a little longer, but 20 milligrams, you know, it’ll happen a little faster and you can kind of see these effects more. Yeah, and that actually leads me to another study I just wanted to really quickly talk about, because I thought this was a really cool study where with older people, the main thing that is seen in terms of mitochondrial dysfunction is the fact that in their immune cells, so their white blood cells, they start to see their mitochondria membrane potential decrease.

Dr. Siobhan Mitchell: And so what does that mean? No one knows usually people don’t know what that means. Mitochondrial membrane potential is basically the charge in your mitochondria that allows it to make ATP very quickly. So your mitochondria is kind of kept in a very negatively charged state, as I just talked about, very negatively charged, because it’s basically keeping a very strong membrane potential between its inner membrane and its outer membrane. But as you get older, this mitochondrial membrane potential gets kind of decreased.

Dr. Siobhan Mitchell: And so this means you can’t make ATP as well. So ATP is like now going to be a slower rate and you’re not going to make as much of it. And not only that, mitochondrial membrane potential is very important for preventing apoptosis because when your mitochondria start to have a lower membrane potential, this is a sign that your mitochondria and perhaps your whole cell is starting to dysfunction. So it triggers apoptotic signaling, for instance.

Dr. Siobhan Mitchell: And so that could obviously be very detrimental, especially for immune system, so your white blood cells. But you know, we also think this is probably happening elsewhere in your body. So, what this trial did was that they gave MitoQ at 20 milligrams for six weeks to older people. And they saw that not only did their vascular function improve, so they had better blood flow, so they had better flow-mediated dilation, they also had better microvascular dilation.

Dr. Siobhan Mitchell: So when I say microvascular, it’s not just like your main arteries, but it’s actually looking at the vascular blood flow in your skin. Which I think is really interesting because we all know as you get older and you’re having less blood flow to your skin, this is going to cause things like skin aging. And not only that, you know, microvasculature is very important for things like your brain. Like I was talking about your capillaries, these tiny little blood vessels that that need to be kept healthy to keep your brain intact.

Dr. Siobhan Mitchell: So it was really exciting seeing that MitoQ could have an effect on that microvasculature, the capillaries. But then the most important thing was we also saw that mitochondrial membrane potential was improved. And just to give you a sense of what that means, so mitochondrial membrane potential declines about 20 to 35% in the ages between 30 and 80. So everyone’s getting their mitochondrial membrane potential going down, down, down, down, down, up to like 35%. With just six weeks of MitoQ, we saw that the mitochondrial membrane potential was improved 15%. So it’s kind of taking like decades of disturbed mitochondrial function.

Dr. Kara Fitzgerald: Wow.

Dr. Siobhan Mitchell: Back to like, you know, that sort of earlier, earlier kind of ability to make not only ATP, but also protect yourself against sort of apoptosis and all these other things. And the big news too is that it’s really hard to show mitochondrial function improving in humans. So, you know, the actual sort of ability to make things like ATP. So it was really exciting for us to see that. There’s very few supplements that have been able to show that kind of effect.

Dr. Kara Fitzgerald: True improvement. Wow, that’s so interesting. It makes me think about, I was talking to Darshan Shah, who’s a friend of mine and the the founder of the Next Health Clinic Systems, and I asked him about next the things on the horizon, and he talked about mitochondrial transplants being a thing in the future. But what if we actually were using, you know, MitoQ early? You know, what if it really became a meaningful consideration, like vitamin D is?

Dr. Siobhan Mitchell: Yeah, exactly. Yeah. That that’s what I felt like when I saw these results of mitochondrial membrane potential being improved, is that it’s such a fundamental mechanism that will have so many important things for your kind of downstream health. And just to give you a sense of that, like so mitochondrial membrane potential goes down as you age, but it’s also especially decreased in things like Alzheimer’s disease, in diabetes, in various autoimmune diseases.

Dr. Siobhan Mitchell: So it really is like one of those other harbingers of like something is wrong with your mitochondria. You’re not making as much ATP anymore. You’re having issues with you know keeping your mitochondria sort of quality control. So I think that’s a really important thing. And I agree that mitochondrial transplantation might be like the ultimate solution. But while you’re kind of maybe waiting for that moment, like keep your mitochondria healthy with something like MitoQ.

Dr. Siobhan Mitchell: Actually we’ve thought about how– yeah go on.

Dr. Kara Fitzgerald: Well, just thinking about the fifteen percent, that’s you know, and whether we could measure, you know, the biological age of mitochondria. I think that is being investigated. I don’t know whether there’s a tool to do that in prime time. But you are right, you know, that if we’re losing, you know, thirty plus percent between youth and older age, fifteen percent is a massive drop. I mean, it just makes me think of VO2 max and how we’re always gunning to keep it a little bit lower and it tracks, you know, we consistently lose our VO2, how robust it is as we age predictably and could this be another measure and anyway–

Dr. Siobhan Mitchell: Yeah. I think that was cool because it does give an indication of like why MitoQ has such good effects for things like you know improving exercise performance, you know, so improving bicycling times and sort of muscle power output and all that kind of stuff. So it’s really kind of indicating that’s sort of maybe a fundamental thing that it’s able to do. And there’s actually a study also in young people, so once again in their 30s, that shows when they’re given MitoQ that 20 milligram dose that they have improved expression of these oxidative phosphorylation proteins, the things that make the ATP in their muscles. So that was I think a really cool one as well too. So just showing that the mechanism, the main benefit of MitoQ really is happening, that you are actually having improved mitochondrial function.

Dr. Kara Fitzgerald: Well, I’m cycling again a lot, you know, and getting into competition again after many years of hiatus and I’ve been using MitoQ and it’s kind of become one of the darling supplements in my community because people can actually know, when you’re paying attention really carefully and you’ve got all these sensors on bikes now where you’ve got Garmin and Strava and so forth.

Dr. Kara Fitzgerald: I mean you get a lot of data. And so to be able to see, to notice your watt output or  improvements in time and then just the subjective experience of recovery and when you can get back on and go hard again, all of these things. There seems to be an association in those of us who are paying attention and it’s pretty exciting to see.

Dr. Siobhan Mitchell: Yeah, this is the main thing that we hear that workouts have gotten easier, that there’s less time that they need to recover from a really hard workout and just overall energy is better. So yeah, that’s really what seems to be the thing that mitochondria should be actually be able to do for you is that if your mitochondria are healthy enough, they should be able to give you that extra energy when you need it. Not too much, you know, but just the the the right amount at the right time.

Dr. Kara Fitzgerald: Well, unless of that– the lactic acid burn, which I think that’s been disputed mechanistically, but that phenomena of soreness, which I think at least in part is from mitochondrial damage post exertion, right?

Dr. Siobhan Mitchell: I mean, it’s obviously a buildup mechanism that signals to your mitochondria to work harder, but I don’t know if I would think it’s like a damaging thing at all. And in fact it’s interesting. So there’s a study now that’s come out showing that the same thing is actually happening in your brain. Like when you’re doing really cognitively challenging tasks, you’re having lactate [correction: glutamate] buildup in your brain as well, too. And it’s actually making it so that it’s harder to do that cognitive task.

Dr. Siobhan Mitchell: And so they’ve seen actually with some people that, you know, if they’re having more and more lactate buildup, they actually get worse and worse at the task than someone else who’s got like a better sort of lactate kind of ability to kind of use that lactate as fuel like a like an athlete. So I thought that was really interesting as well.

Dr. Kara Fitzgerald: Well, I can tell you I experience much less of that classic lactic acid burn. I wonder it would be interesting to see if that’s happening because of MitoQ and what would be going on in the brain, you know, to turn the volume down. If that were measurable, that’d be a really cool study.

Dr. Siobhan Mitchell: That’s the one area where we have so many studies in the brain that they just haven’t gotten finished yet. So we have a study that’s looking at MitoQ for what’s called cognitive frailty. So it’s people with mild cognitive impairment and also mobility problems, so frailty and that’s going on, so there’ll be results next year. We have a MitoQ study for schizophrenia. We have a MitoQ study for post-stroke rehabilitation, so improving vascular function after stroke, and another study looking at MitoQ for ALS.

Dr. Siobhan Mitchell: But one particular study for the brain that I’m really excited about is one that’s looking at how MitoQ can improve vascular function in people who’ve had early childhood adversity. And I think this is a really fascinating one because this is where there’s a lot of understanding now that the stress that you have as a child can not only cause problems with mitochondrial function, and they’ve shown this in clinical studies when they look at people with child adversity, they actually have dysfunctional mitochondria that it’s also affecting your vasculature.

Dr. Siobhan Mitchell: So you’re no longer having the proper vasodilation that you should have. And this is, you know, many reasons why that’s happening. Maybe they’re just having a lot of cortisol as well, but also probably mitochondrial dysfunction. And so this study is really looking at MitoQ to improve that vascular function in those people with that kind of traumatic childhood adversity issue. And I think that’s really fascinating because I know a lot of people that have that feeling of like, you know, where’s my anxiety coming from?

Dr. Siobhan Mitchell: I don’t know. It could be just the way that my childhood was. And I’m like, well, you actually could be having problems with your vascular function, you should look into how you can improve that, especially your mitochondria. So that one I’m really excited for. That’s gonna be probably sometime in the next six months that we’ll get results for that one.

Dr. Kara Fitzgerald: Cool. All right, so just bringing us home. MitoQ and S-equol, creatine, NAD precursors. All of them sort of– Yeah, I started with MitoQ. All of them having unique contributing uses to support mitochondrial health. And I just want to again confirm, in general, the research is looking at 20 milligrams. Is there any time you would consider going to 40 or higher?

Dr. Siobhan Mitchell: Yeah, there are some studies that have looked at, for instance, 40 milligrams. So there was a study showing that with people with Type 2 diabetes, 40 milligrams of MitoQ could improve their heart function. So actually improve the energy production of their heart, kind of prevent, I would say, chronic heart failure that can actually accompany diabetes a lot. So that was a really exciting one and that took 40 milligrams to do.

Dr. Siobhan Mitchell: The schizophrenia trial that I was telling you about, that’s also 40 milligrams. So I think when it’s, you know, a pretty severe disease, 40 milligrams might be effective. And there’s one really interesting study that just came out where they looked at postmenopausal women that had obviously not as good vascular function because of menopause, obviously, and not as much estrogen. And they gave 40 milligrams of MitoQ for four weeks. And they saw they improved vascular function up to 50%.

Dr. Siobhan Mitchell: So, like really improved their blood flow, yeah, to the point where they they looked very similar to kind of pre-menopausal. So that’s where 40 milligrams can actually make a huge difference. But I would say, my guess, this is you know me just hypothesizing, you could probably that get that effect from 20 milligrams or even 10 milligrams. It will just take longer. So this took just four weeks, but probably another trial, and we’re actually really excited about a study looking at cerebrovascular function in postmenopausal women using 20 milligrams of MitoQ. That’s gonna be for a longer intervention. But the idea is that you should see better blood flow in the brain because of MitoQ. So that’s just started. That’ll take a while to get some results. So maybe another two years.

Dr. Kara Fitzgerald: Wow. Very cool. Very exciting. Well thank you so much again for that. That was a tour de force. It’s very interesting.

Dr. Siobhan Mitchell: Yeah, thank you. There’s one other thing I want to say about vascular function because I think this is so fascinating. I just read about this recently. So we all know that for men, you know, things like erectile dysfunction is kind of like that sign that there must be something wrong with your vascular function that you might be at risk of cardiovascular disease. Well, this recent review from a co-collaborator of mine actually is talking about how woman and reduced kind of female arousal is also maybe a sign that you’re at risk of cardiovascular disease.

Dr. Siobhan Mitchell: So I thought that was really fascinating as well too. So just not getting the right blood flow to your female parts might not just be “oh, I’m just, you know, not psychologically into it or whatever.” It could be something where your vasculature is not functioning. I don’t want to say that’s everyone, but it definitely they’ve now shown that clinically.

Dr. Kara Fitzgerald: I mean, it seems to me that, you know, just given the mitochondrial density in sperm, you know, given the vascular nature of the penis, and given the mitochondrial density in ovaries, in fact they’re the most mitochondrial dense organ. We talked a lot about the heart, but just thinking about reproductive organs in men and women, you have to have some really good science across the board there.

Dr. Siobhan Mitchell: Yeah, so I’ll start off by saying that MitoQ is very popular with fertility specialists, especially kind of preconception, kind of getting the ovaries ready. And this is because there’s a lot of preclinical data showing that MitoQ can prevent things like ovarian fibroids and also improve egg quality. So like that’s really the number one thing that it seems to be doing. And this is best demonstrated in a preclinical study where they looked at that mice basically and how much kind of damage the overall eggs were having because of things like obesity or advanced age.

Dr. Siobhan Mitchell: And they were able to show that MitoQ could actually prevent all that DNA damage. And for instance, in obese mice they actually have shortened telomeres in terms of their eggs. And this of course can then lead to health issues in offspring, but MitoQ was able to prevent that. And so what I would say is probably the most interesting clinical data is that for women who are older, so older than 37, MitoQ actually is much better at preserving egg quality and also preserving the ability to have the right energy production and less oxidative stress in those oocytes of these older women, which you know this has not been shown yet, but would then technically be something that can help with you know better pregnancy rates.

Dr. Siobhan Mitchell: And we’ve had a lot of fertility specialists say that they are seeing improved pregnancy rates with older women using MitoQ. So that’s really cool, I think, in terms of having that kind of ability. But I think what’s even cooler is just this feeling that if you can keep your ovaries healthy, this will be something that can help your overall health for much longer. And so that’s what I’m really excited by next is seeing how something like MitoQ can just preserve ovarian function so that it might even delay menopause.

Dr. Siobhan Mitchell: So that’ll be the next step. Yeah.

Dr. Kara Fitzgerald: That’s awesome. Any studies looking at erectile dysfunction and MitoQ?

Dr. Siobhan Mitchell: No, people have mentioned this. They’re like, I think I’ve gotten an improvement in there. And I’m like, that’s a nice anecdote. But when we are approached to that kind of study, like that’s not the first study we want to do, obviously. I think we’re just more interested in general vascular function.

Dr. Kara Fitzgerald: It’s fascinating. It’s really interesting. Okay. All right. Well, to be continued and go to the show notes, everybody. We’ll link to all the clearinghouse websites for the papers and then we’ll also link to some specific papers that Siobhan mentioned today. Thank you again for joining me on New Frontiers.

Dr. Siobhan Mitchell: Cute.

Dr. Kara Fitzgerald: Was that a tour de force of a conversation with Siobhan Mitchell or what? I would love your feedback. If you haven’t used MitoQ, are you gonna start MitoQ creatine, S-equol? Really some cool science there. And of course NAD precursors. It was just a tour de force of really brilliant science. And I think her argument, for the inflammaging phenomena of this acquired mitochondropathy, as I was calling it, driving, you know, really driving inflammation, hence aging, is compelling, very compelling.

Dr. Kara Fitzgerald: I’m usually very strongly in the epigenetics camp, and I think there’s room for both, but extremely interesting argument on Siobhan’s part and just backing it with a lot, lot, lot, lot of great science. I just want to thank you for listening to this episode. Please let me know what you think, if it sparked ideas, if it’s sparked, if it’s going to spark changes for you in your work with patients. I would love to hear from you. This community is such an important part of what keeps this work evolving.

Dr. Kara Fitzgerald: And it’s important to me, you know, as a clinician, as a podcast host, as a thinker, to hear what you’re thinking about as well. Scoot over to the show notes where you can find the transcript. you’ll find some of the citations. You can find links to the websites where there’s a clearinghouse of all the science going on in Siobhan’s world, the world of MitoQ. And again, thanks for joining me today on New Frontiers.

Holding a PhD in neuroscience from SUNY Albany, Siobhan Mitchell has also completed a post-doctoral fellowship on brain aging at the University of Washington. She has over 15 years of clinical research experience, seven patents on mood and cognitive food products, and has authored over 50 papers on aging, brain health, nutrition, metabolic health and more.

With a personal passion for brain aging research, Siobhan has worked on metabolic and skin health, appetite, sports physiology and of cellular health – which she now focuses on as the Chief Scientific Officer for research-backed cellular health company, MitoQ – creators of the world’s first mitochondria-targeted antioxidant.

Research Papers

MitoQ Research and Clinical Trials

MitoQ’s Mitochondrial Collaborative Research Program

Aging & longevity

The Dunedin Study

Mitochondrial dysfunction as the “mother” of all hallmarks of aging

Biomarkers of Oxidative and Mitochondrial Stress Are Associated With Accelerated Pace of Aging at Midlife in a Birth Cohort

NAD+ / NR

Human whole-blood NAD+ levels do not vary with age or lifestyle interventions

The Divergent Effects of Nicotinamide Riboside and High-Intensity Exercise Training on Skeletal Muscle Epigenetic Aging

Creatine

The metabolic burden of creatine synthesis

Effects of creatine supplementation with and without exercise and diet intervention on body composition, cognitive function, and markers of health in middle-aged and older adults

S-equol

A pilot study on the effects of S-equol compared to soy isoflavones on menopausal hot flash frequency

Protective effect of equol on mitochondrial damage induced by high glucose and fat in osteoblasts

Urinary equol concentration, body composition, and lifestyle factors were associated with bone mass in young women

S-Equol as a Gut-Derived Phytoestrogen Targeting Estrogen Receptor β: A Promising Bioactive Nutrient for Bone Health in Aging Women and Men: A Narrative Review

MitoQ, muscle & exercise

The mitochondria-targeted antioxidant MitoQ, attenuates exercise-induced mitochondrial DNA damage

MitoQ supplementation augments acute exercise-induced increases in muscle PGC1α mRNA

Age and basal respiratory capacity influence skeletal muscle OXPHOS responses to MitoQ

Reducing the mitochondrial oxidative burden alleviates lipid-induced muscle insulin resistance in humans

MitoQ, cardiovascular function & metabolic health

Effect of a Mitochondrial Antioxidant (MitoQ) Supplementation on Liver Enzymes and Metabolic Health: Results From a 12Week Randomized Controlled Trial

No association between changes in peripheral blood mononuclear cells (PBMC) mitochondrial bioenergetics and cutaneous microvascular function after supplementation with a mitochondrial antioxidant

Over-the-counter supplement could prevent heart disease in Type 2 diabetes patients

MitoQ & immune health

An investigation of the effects of MitoQ on human peripheral mononuclear cells

MitoQ & reproductive health

Female reproductive life span is extended by targeted removal of fibrotic collagen from the mouse ovary (MitoQ and oocyte health)

Other

Sex-specific effects of antioxidant treatment in chronic stress induced behavioral and mitochondrial dysfunction in mice

CNS target engagement of high-dose DHA supplementation in older adults at risk for dementia: a randomised, double-blind, placebo-controlled trial

A neuro-metabolic account of why daylong cognitive work alters the control of economic decisions

Books, Podcasts and other resources

Textbook: Acquired Mitochondropathy

Podcast: Dr. Dan Belsky podcast with Dr. Kara Fitzgerald

Podcast: Hidden Mitochondria Problems Are Accelerating Your Age & Draining Your Health with Siobhan Mitchell PhD and Dr. Kara Fitzgerald

Blog: Is Mitochondria-Targeting the Best New Strategy for Longevity?

Bio Age Self Assessment Quiz

Younger You book

Better Broths and Healing Tonics book