[Angela Foster] (0:15 - 3:25)
If you're doing all the right things, training, eating well, sleeping well, but still feel like your energy and focus aren't where they should be, or you simply want to level up your energy, today's episode is going to help you fix that. One of the biggest shifts for me, especially through perimenopause, has been supporting my cellular energy. Alongside high quality nutrition, sleep, and exercise, one of the key ways I do this is by supporting my mitochondria with NAD precursors.

NAD is like your phone's battery capacity. You can be doing all the right things, charging it, closing apps, optimising everything, but if the battery only holds half the power, you'll still run out of energy faster. And in real life, that looks like you're doing all the right things, eating high quality nutrient dense food, exercising regularly, sleeping well and managing your stress, but still feeling off.

And that's exactly what can happen in midlife. NAD levels naturally decline as we age. And by around 40, most people have roughly half the NAD they had in their 20s.

So even if you are doing all those things, eating well and exercising, your cells have less capacity to produce energy, repair themselves, and stay resilient under stress. That's why supporting NAD has made such a noticeable difference to my energy focus and mental clarity, and exactly why I wanted to invite today's guest on to explain this properly. Dr. Siobhan Mitchell is the chief scientific officer at MitoQ, with a PhD in neuroscience, postdoctoral research in brain ageing, and senior research roles across global companies, where she's led large scale studies on cognition, mood, performance, and metabolic health. And in this episode, we go deep into the science that most people never fully understand, but directly affects how you age and perform. So by the end of this conversation, you'll understand what's really driving low energy and faster biological ageing at a cellular level. You'll also learn how mitochondrial health and declining NAD affect focus, fatigue, and recovery in midlife.

And you'll get clarity on which interventions actually move the needle and which are just noise in the longevity space. We cover quite a bit of science here, so we're always trying to apply this practically, but if you want the studies, summaries, and resources that we reference, you'll find everything over on my website at angelapositiveperformance.com. I've also added links in the show notes, including the NAD supplement I personally use, which is NAD plus by MitoQ, and a discount code using code ANGELA.

This episode is really about working with your biology rather than pushing harder against it. So let's dive in. Siobhan, we hear so much at the moment around mitochondrial health, inflammation, these terms that kind of get banded around.

And I think that my audience listening will be familiar with these mitochondria being the battery packs of ourselves. I think we're all aware that they impact our energy. But I'd love to dive deeper with you because it's such an area that's so important for longevity.

And I know that you're an expert in this field. Can you explain to us really what our mitochondria are and how they are affecting our energy and cellular ageing?

[Siobhan Mitchell] (3:27 - 7:04)
Yeah, for sure. And that's a pretty big question to start off, but let me just get going. It might take a while.

So mitochondria, yes, they are the powerhouse of ourselves. They make up to 95% of the energy of ourselves. And so they're very, very important for all cellular function.

And so what they're doing is they're making ATP through all the foods that we eat, so carbohydrates, protein, fat. And it's great that they make this energy and they do it all the time. I can give you all the sorts of stats about how much ATP you make every day, literally kilos and kilos of it.

But I think what's really important to realise is that there's a trade-off in making all this energy. And so the fact that we have this incredible powerhouse in ourselves is also meaning that we make a lot of oxidative stress to create that ATP. And the way that happens is that we all know that we need to breathe oxygen to live.

And so this oxygen is so important because we're using it to make that ATP. So every time you're making an ATP molecule, you're using some oxygen. And oxygen is highly reactive when you start to use it, when you break it apart.

So when I say oxidative stress, I'm talking about the fact that oxygen causes oxidative stress when you break it apart because then becomes something called a free radical. And this free radical basically is like looking for electrons. It's on this hunt for electrons because it doesn't feel complete.

And when it looks for electrons, it looks for the closest thing. And so that's usually the mitochondria membrane, mitochondria proteins, and also its DNA because mitochondria also have DNA. And so when you have that damage going on where it's grabbing electrons from your membranes, from your DNA, your protein, this can cause dysfunction over time.

And so oxidative stress that's continually happening in the mitochondria can cause a lot of damage that can lead to ageing. And the great thing is, like this sounds really scary, the mitochondria over billions of years have developed a lot of ways to deal with that oxidative stress. So a lot of enzymes that they use that they're making themselves to keep that down.

But the same thing as you age, these enzymes, these antioxidant enzymes, things like CoQ10, you probably heard of that. These all start to get depleted because the mitochondria are just still having so much damage and they're not able to kind of renew themselves very well. So it's this constant battle inside ourselves to make all that energy that we need.

But even when we're making more energy, when we're having high stress, high intensity, anything, we're making more oxidative stress at the same time. And this can be more damaging if you're not doing a good job with your oxidative stress systems and having the right antioxidants. So that's one thing that we should all be aware of with mitochondria.

It's a little bit a deal of the devil. And so when I hear people say that when they're stressed out and they're having that energy depletion, I'm like, yeah, because stress causes your mitochondria to rev up. And at the same time, you're making more oxidative stress and causing more damage.

And so over time, that can be much more of a depletion of how your mitochondria can function. So yeah, that's the whole thing. I could now just go on to another thing that mitochondria do that is also really important in the way that we age, but I want to just take a breather and see if there's anything else you want to follow up on.

[Angela Foster] (7:05 - 8:06)
Yeah, thank you for that. Before we go on to the other things that mitochondria do, I guess if we could clear up some terms, because I think these are also people hearing more and more about. So we have mitochondria, these powerhouses of ourselves.

And then what you were describing now, I believe, is we need to renew our mitochondria, right? And recycle parts of them, just like we have people have heard of autophagy, because people are familiar with fasting. My understanding is that we have mitophagy in terms of our mitochondria.

And then we also have mitochondrial biogenesis, which is the creation of new mitochondria. So would it be fair to say that as we age, we get less good at three things, right? Effective use of our mitochondria in the way that we did when we were young, effective recycling of those mitochondria and renewal, and then less creation of new mitochondria.

Would it be fair to say all those three things start to take place with ageing?

[Siobhan Mitchell] (8:08 - 8:55)
Yeah, that's exactly what happens. So perfect, like you're just adding on to the story that it's true that mitochondria, because of the damage that is occurring in them, it's good to recycle them from time to time. And that's part of the process of all your cells all the time.

But as you age, they don't get recycled as much. And so you just have these dysfunctional mitochondria just sitting there. And for instance, you've probably heard of senescent cells, zombie cells.

So these cells that just sit there do nothing and actually cause inflammation. They're being caused by mitochondrial dysfunction. So when mitochondrial dysfunction turnover, so that term mitophagy is not happening.

This leads to more chance of senescence, these cells just sitting there and becoming zombies and doing nothing.

[Angela Foster] (8:56 - 9:43)
And these are in all cells, right? I learned like even in skin cells, and then they deplete collagen and things like that. So we don't want more of those.

You talked there about oxidative stress. And when we are under stress, there is more oxidative stress. So one area, I think you mentioned there was us just being under stress, right?

And we are modern life is very stressful, both in terms of I guess, mental stress, but also toxins and things that we're exposed to. But then also high intensity training, for example. Can we distinguish in any way between those types of stress?

My understanding is that with high intensity training, for example, this can actually help with the creation of new mitochondria. Is stress, different types of stress, are there differences in the way it's impacting our mitochondria?

[Siobhan Mitchell] (9:44 - 11:28)
Yeah, yeah, exactly. This is a really important point is that there's stress, things like, as you say, toxins, mental stress. And there's, I would say, this is a very interesting term, hormetic stress.

And hormetic or hormesis is basically this term that means when you kind of push a system to adapt and make it stress a little bit, and then it's able to deal with bigger stresses in the event of like a bigger stress, right? So that's hormesis. And that's basically what's happening when you exercise.

So you're stressing out your muscle cells, you're telling them, okay, you need a lot of ATP, you need a lot of oxygen, and they get a little bit stressed. But then this causes them to adapt. And in exercise, you adapt by making more mitochondria, that mitochondrial biogenesis, you make more ability to take that oxygen and turn to ATP.

So that's sort of machinery of it. And this is good over time, because the more mitochondria you have, the better able you'll be able to deal with things like mental stress and deal with, you know, other kinds of inflammation and ageing and all the rest. So exercise is great for you in terms of telling your body, okay, we need more ATP, we need more oxygen to deal with this intensive exercise.

But what is not good over time is when you just have a stress that's not controlled, you don't have a recovery time. So exercise, of course, has a nice recovery time where you get everything back to normal and all the rest. A lot of these toxins don't give you that chance to go back to normal.

A lot of the mental stress we have don't give you that chance to go back to normal. And that's when it becomes a real problem.

[Angela Foster] (11:30 - 12:09)
Yeah, yeah, exactly. Especially in how we're living today. When we look at exercise, from the research I've seen, we can kind of almost bucket exercise into two areas where when we go, as you were mentioning earlier, high intensity exercise, that helps us create new mitochondria.

My understanding is that if your body thinks you outran the tiger, then it's going to upgrade itself in case it happens again. And then when you're going at low intensity, kind of classically zone two, you're improving the way those mitochondria behave the way they act and support your energy. I'd love you to like share, you know, if that's right, and more on that, really.

[Siobhan Mitchell] (12:10 - 13:04)
Yeah, that that is really how it works. So what's interesting is when we talk about intensity, we know that people who professionally are athletes have twice as much mitochondria in their muscle cells than other people. And the fact that they have that extra mitochondria helps with their metabolism.

So they're now able to take in glucose much better than normal people. And that helps protect them against diabetes, for instance. So if you're not exercising a lot, and you're not having that ability or for muscles to use that glucose really quickly, through making more glucose transporters, for instance, and having this mitochondria that can use all that glucose, you are much more likely to start showing prediabetes and then have also ageing acceleration.

So there's there's all sorts of benefits of exercise in various ways, these adaptations, I could go on and on. But that's just one example.

[Angela Foster] (13:05 - 13:56)
Hmm. Yeah, great example. And it like, as you say, makes you more resilient.

So hopefully, we can give people permission who feel a bit too busy to add in, you know, more exercise, because actually, as you mentioned, there is making you better able to deal with stress, you actually show up better at work, take more on potentially mentally, right, because you have better mitochondria can have better attention, better focus, better energy. When we look at before, and I know you're going to talk about another role that mitochondria have when we look at oxidative stress. So this is just as you said, it's kind of the deal with the devil, right?

We've got to, we've got to breathe oxygen, otherwise, we're not going to stay alive. But then as soon as we use oxygen, we create oxidative stress. What can we do to support that, in terms of like, reducing oxidative stress in the body?

[Siobhan Mitchell] (13:57 - 15:02)
Yeah, and this is a tricky one, because the oxidative stress that happens in the mitochondria, there's not a lot you can get inside the mitochondria. So it's a very privileged area, because it's so important to the cell. It doesn't allow a lot of things, and it's got lots of special transporters that allow certain things in, but it has this double membrane, and it just only lets a few things in.

So in terms of the antioxidants that no can get into mitochondria, there aren't that many, you can use something like vitamin C or vitamin E, but they tend to go elsewhere in the cell, not really that much in the mitochondria all the time. CoQ10, I know people are very excited about CoQ10, but CoQ10 is very large, and there's no transport system inside the mitochondria. So even though people always hear about, oh, CoQ10 is really good for mitochondria, when it's made inside the mitochondria, naturally, but when you're taking an oral CoQ10 supplement, it's not really going inside the mitochondria.

So that's a real issue. So one thing I would recommend is...

[Angela Foster] (15:02 - 15:06)
If you have the form ubiquinol, does that make a difference in terms of the mitochondria?

[Siobhan Mitchell] (15:06 - 18:21)
No, it does not. So ubiquinol is really about its oxidation status. So it's still kind of the same molecule, this very bulky molecule that's very hydrophobic, so it doesn't like being in water.

So it's just not even getting absorbed in your gut very well, and it's not really getting through cells or sort of mitochondria that well. It needs its transport system. So the other thing that I like to tell people is that there are antioxidants out there that have been designed for getting into the mitochondria, and that's mitoquinol mesylate, also known as MitoQ.

So that can get inside your mitochondria and address a lot of the oxidative stress. There's a lot of other things that, you know, on top of something like MitoQ that just makes sure that you're not going to have that much oxidative stress in the first place. So good diet, lots of exercise, you know, keeping that stress level down, that sort of thing, like very basic stuff.

But the other area that is really good for keeping down oxidative stress is keeping your NAD levels up as well. So I think people have heard a lot about NAD, but I can just go into a little bit about how NAD, because it's got such an important role in the mitochondria. And I can kind of go into all its sort of functions in the mitochondria, but one of its functions is to help with your redox state of your mitochondria.

And when I say redox, it sounds like a terrible word, but it just really means how much oxygen is in your mitochondria and how much oxidative stress is in your mitochondria. So it helps regulate that so we have less oxidative stress in your mitochondria. And one way that does that is through activation of sirtuins.

Sirtuins are these big family of molecules that basically do that kind of adaptation to stress that I told you about, that hormesis. So sirtuins are basically turning on a lot of cascade of genes that help our cells deal with oxidative stress and all sorts of, I would say, very complex pathways. But the end result is they turn on a lot of longevity pathways as well.

So a lot of the pathways that sirtuins turn on are then able to keep our cells going for longer, have more of that mitochondrial biogenesis and mitophagy. And this is where I think it's really fascinating because people have heard about sirtuins a lot. But what is really interesting about sirtuins is that they're one of the first longevity pathways that we have ever learned about.

So the way we learned that you can actually extend your lifespan is through calorie restriction. So through mice, they saw that if you restrict your calories up to 40%, you can have a mouse live like 25% longer, 30% longer. And they're like, this is great, but no one's going to do calorie restriction.

We know that. What's the pathway that's getting turned on in calorie restriction? And they found out that the pathway getting turned on was through sirtuins.

Sirtuins were basically telling cells to be better at clearing away oxidative stress, have the cells being ready for more stress coming through, and also use energy very efficiently. And so they're really a master switch of longevity.

[Angela Foster] (18:24 - 20:32)
You can't out-train low energy. It starts deeper than that. I'm often asked how I juggle running my business, raising three kids and still training the way I do.

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If you want to feel stronger rather than just trying harder this year, this is a smart place to begin. And that's why I've partnered with Timeline long-term. Get 35% off a one month subscription of mito-pure gummies at timeline.com forward slash Angela35. That's timeline.com forward slash Angela35 while the offer lasts. I mean, when you talk about that, the thing that springs to mind is that's a better route, right? Um, then caloric restriction, because when you start to have caloric restriction, it becomes, well, your energy is going to go down.

So you're probably less likely to exercise anyway. Um, but it can have profound implications, right? For muscle health, um, for bone health.

Um, so then we start affecting other areas that are really fundamental for longevity, um, through like really extreme caloric restriction. Um, before we come back, I do want to talk about sirtuins and NAD. I think everyone wants to really dive into that.

You mentioned there was another role that you wanted to touch on of the mitochondria. Did we, did we go over?

[Siobhan Mitchell] (20:32 - 25:09)
Yeah. Yeah. Let's, let's go into that because I think this is maybe not what people heard in their high school biology class, but super interesting.

In fact, it's the big, interesting field of mitochondria right now. So this is big and it's the fundamental role of mitochondria in your immune system and also being the master switch of your cells and how you deal with inflammation and immune responses. So this is very exciting right now, because I think we're all very worried about immunity and inflammation.

Everyone's aware that inflammation is a huge cause of ageing. And so what is new is in the last few years, understanding that mitochondria might be the reason why we have a lot of this kind of uncontrolled inflammation over time. And just to make sure everyone understands what inflammation is, inflammation is basically when you turn on a whole bunch of immune cells that are supposed to clear away infections like viruses, bacteria, that kind of thing.

But if they're getting turned on a lot of time, they, they end up causing more damage to cells because they're causing a lot of chaos in their cells through these things called cytokines, which I can go into. But the main thing is that we're now seeing that mitochondria might be the reason why you have inflammation just getting turned on all the time and staying on all the time. So for instance, with COVID, they showed that with COVID, an infection, basically when the virus enters the cell, it makes the mitochondria release a lot of its DNA.

So I mentioned that mitochondria has its own DNA. And the reason why mitochondria has its own DNA is it used to be a separate organism billions of years ago that got swallowed up by a larger cell. And this larger cell was like, oh, this thing makes a tonne of energy.

How useful, you know, we're going to keep this. And so then it got incorporated into this larger cell, and then was just used as a powerhouse. But it still has this DNA that's kind of considered foreign.

And so whenever you have foreign DNA coming into a cell, that's kind of a sign that something's infecting you, right? Because that's what viruses do. They come into your cell and they try to insert their own DNA or their RNA into your system, you have to attack that.

So what's happening is mitochondria are being kind of used as a canary in the coal mine, kind of a master switch of like something is wrong, something is wrong with the cell. And so when it releases that DNA, or even when mitochondria release a lot of oxidative stress, so they usually try to keep all the oxidative stress within itself, but the low oxidative stress gets out into the cell, it basically causes this immune response. And this immune response, I could give you all the names of it, of how it works and everything.

But what is interesting is it then can lead to something called a cytokine storm. I don't know if you've ever heard that term before. It's used a lot around COVID.

Yeah. So basically that's mitochondria orientated a lot of the time. And this cytokine storm is basically causing the cell to often die or become damaged.

And then that cytokine storm gets released into the bloodstream and causes more damage elsewhere. So I think it's really interesting for people to be aware of that, you know, we want more energy and we should take our mitochondria for more energy, but we also want to keep your mitochondria just really happy, really in a good balance, because this can help prevent that constant inflammation, that immune response that we don't want, that doesn't have anything to do with an infection. It's just kind of there and it's causing a lot of damage to our cells.

And this is especially bad in the brain. So the brain has a lot of this kind of inflammation that's just occurring, like a lot of immune cells in the brain are just getting turned on. And there's more and more sort of demonstration that this immune activation in the brain might be leading to Alzheimer's, for instance, and a lot of other neurological diseases.

So if you target your mitochondria, if you take care of your mitochondria, this is the big secret to helping keep your brain healthy as well too. And in fact, there's a lot of evidence right now that if you can target your mitochondria to something like MitoQ or CoQ10 or other kinds of NAD activating mechanisms, so increasing NAD in the brain, you can get rid of a lot of Alzheimer's pathology. So it's a really exciting field.

[Angela Foster] (25:09 - 26:14)
Do you know, it's really, really interesting because sort of observationally what I've noticed is, so when we look at kind of from a fitness perspective, one of the sort of fitness tests that I do with my clients is to look at how many watts of power they can produce at a low intensity. So when they're doing their, you know, it's fully aerobic exercise. So they're at 75% of max heart rate.

And we would look to see, can they produce at least two watts of energy per kilogramme of body weight? And in people who are having a lot of like inflammation or they have immune problems, they're struggling with their energy. They just can't get there, right?

Their heart rate has to go up in order for them to produce that power. And so one of the things we work on alongside all the other things is actually how can we get them better at lower intensities, right? Of producing this power and work on the mitochondria and then also mitochondria renewal.

And so it's very interesting what you were saying because observationally, that's what I've noticed is people who seem to be under pressure from an immune perspective also have problems with producing this power.

[Siobhan Mitchell] (26:15 - 27:13)
Yeah. And this is why a lot of people with autoimmune disorders have so much fatigue. So that's literally just their mitochondria just having a super amount of dysfunction.

And it's just, yeah, you're not making as much energy, but you're also creating this vicious cycle of more and immune activation, which then leads to more mitochondrial dysfunction, which leads to more immune sort of dysfunction. So it's, yeah, it's really a little bit scary when you think about it. So it's, I always tell people, you really have to clamp down on inflammation as soon as you can through your mitochondria, but then also through a lot of other things that you can do to at least address the cytokine levels.

And that's a lot of polyphenols. So I always tell people like you have to do a lot of polyphenols. So all those berries and green tea and spices.

And I know everyone right now is like really into carnivore diet and I gotta get more protein. And I'm like, no, no, you need more polyphenols. Like, don't forget those.

[Angela Foster] (27:14 - 27:26)
They're so important. So important. And what you were saying there around the mitochondria now, your mitochondria may be affecting brain health.

So making it more likely that you suffer with Alzheimer's. What was the mechanism there?

[Siobhan Mitchell] (27:27 - 30:21)
Oh yeah. So the mechanism is basically that the brain is the most energy intensive place in the body, right? So it's continually needing all its neurones to have this endless supply of ATP to do all the functions that we do, even at resting state, even when you're sleeping.

And so I have a PhD in neuroscience. I've studied this all my life. Like my life has been dedicated to trying to understand how do we prevent brain ageing and things like dementia.

And I used to think it was, oh, it's amyloid. This is like what everyone talks about, like amyloid plaques, tau pathology. But over the last few decades, it seems clear that there's more probably an inflammation and mitochondrial origin that leads to problems with the way that, yeah, obviously the brain makes energy.

And so if the brain's not making energy, this can lead to that inflammation. It can lead to more amyloid, for instance. So people think of amyloid is like, oh, that's the main problem, but what's causing the amyloid to get overproduced?

The amyloid is getting overproduced as immune response. So that immune response can be triggered by mitochondria and it also can be dampened down if you get your mitochondria back to a more functional state. So, and this is something where I can really get into in terms of women, because what I really want women to know about, especially with menopause transition is that when you're going through the menopause transition, oestrogen is really important for the brain and really important for your mitochondria.

It's protective for your mitochondria. And when we lose oestrogen in the brain, your brain mitochondria start to have a lot more issues making the right ATP, having more inflammation, that kind of thing. And, you know, even things like these menopause symptoms, like night sweats can be an indication that your brain is having dysfunction, that your brain through these night sweats is now needing more energy than it did before suddenly, and it doesn't know where to get that energy.

So it starts to use the white matter of your brain. And the white matter of your brain are basically these kind of like fatty little sheaths around all our neurones that make our neurones work faster. So it kind of helps the signal.

It's like a telephone pole kind of thing. It's sort of helping the signal go faster than normally does. When you take away those fatty sheaths, the white matter, your brain becomes slower.

Your neurones are not as fast as they used to be. So then it can beat to things like brain fog. And then over time, it can lead to actual cognitive decline.

So it's especially important for women to take care of their mitochondria. And also, you know, find ways to do something, especially around the menopause time. So that's my big message.

And to think about oestrogen, right?

[Angela Foster] (30:21 - 30:22)
It's also important.

[Siobhan Mitchell] (30:23 - 30:36)
Yeah, definitely. And I love talking about phytoestrogens too, but maybe for another time. Phytoestrogens can also be really good for mitochondrial function as well.

So along with polyphenols. Yeah.

[Angela Foster] (30:36 - 30:40)
Right. Interesting. And creatine, also really good, right?

[Siobhan Mitchell] (30:40 - 30:51)
Yeah, creatine is literally that way of helping your brain maintain its energy. So getting that ATP recycled in a super quick way. Yeah.

[Angela Foster] (30:52 - 31:48)
Yeah, really important. When you're talking then, so when we talk about hormetic stress, just briefly, you're talking about a stress that we place on the body that basically makes us more resilient. So this would be things like exercise stress, sauna, cold exposure.

I think wild plants, right? Things like that. Or hormetic stress.

The sirtuins, just so we can come back to that, because I think this is also really important. So the sirtuins are kind of our longevity genes, would you say? How do these operate?

Some of them I know, for example, I can't remember which one it is, whether it's SIRT1 or SIRT3, but one of them affects our metabolic rate, right? And how lean we say, I think as well, has an impact to a degree on that. Yeah, they have many roles.

Sorry? They have many roles, but yeah, go on. They have many roles, yeah.

So when we're thinking about sirtuins, can you just explain how these are affecting our longevity and the best way to support them?

[Siobhan Mitchell] (31:49 - 32:39)
Yeah, so they're supporting our longevity through these pathways that I think some people have heard of before. So for instance, I don't know if people have heard of Nrf2. Nrf2 is this longevity pathway that basically prepares your cells for more stuff, more damage to happen in the future by, as I said, helping use energy more efficiently and also turning on genes that can kind of clear up stuff, like have that autophagy, mitophagy, and also these other pathways that help rebuild the cell.

And then there's other things that sirtuins do that are even more around what you just talked about, helping people lose weight or use energy more efficiently, and that's through AMPK. So I don't know if you've heard AMPK?

[Angela Foster] (32:39 - 32:39)
Yeah.

[Siobhan Mitchell] (32:40 - 33:50)
Yeah. So these are all different things that it can do, but they can get really complex. So sirtuin 3, for instance, sirt3 is one that's in the mitochondria.

And this one is really important for the mitochondria to have resilience, especially in the mitochondria. Other ones, sirt1, for instance, is more about helping with DNA repair, so turning on genes that help with DNA repair. So they do all sorts of different stuff.

And it's, I would say, really interesting to look at all the different kinds of molecules and, I have to say, also supplements that can turn on these genes. So probably the one that everyone knows about is resveratrol. Resveratrol is very good at turning on some of these sirtuins, like sirt1.

But then there's also a lot of other things that can turn these things on as well, too, like PQQ, like MitoQ, which I also mentioned. So yeah, I think just finding these different kind of pathways, all sort of working together is really important. So I try to tell people, use a lot of different kind of sirtuin-activating situations, and that includes NAD as well, so NAD precursors.

[Angela Foster] (33:51 - 34:24)
Yeah, so NAD is something that is becoming more and more popular that people have heard of, right? And it's definitely becoming a bit of a buzz around it, I think, because when we think of NAD, now we think of energy. And from my understanding is this halves about every 20 years, right?

So I think we're not as good at supporting our NAD levels. So now we've also got another mechanism, right, that can be lowering our energy, causing some of that brain fog and things like that. Can you explain what NAD is?

[Siobhan Mitchell] (34:25 - 38:26)
Yeah, yeah. So I will try to use maybe some analogies, because I think that always helps with this kind of thing. So NAD is kind of like the, I would say, fuel oil, or kind of like precursors that help you make the ATP.

So they're something that the mitochondria make as they break down things like carbohydrates and fats. And so it's basically really important for the mitochondria to make a lot of these NAD, because these NAD have a very important role of carrying what's called protons. And protons are basically what's used to make the ATP.

So you want to have a good collection of these protons being carried by these NAD molecules that at some point kind of get collected at this one part of mitochondria machinery, the ATP synthase. And basically what's happening is all these protons are getting kind of released from the mitochondria, and this causes ATP to be made. It's sort of like this electrical force that NAD is basically delivering to the mitochondria.

So it's basically kind of delivering sort of a battery to the mitochondria. And so then if you don't have NAD, if you don't have a good supply of NAD, you can't make this ATP, or you're not going to make as much ATP. So that's a real problem.

But that's just one role of NAD. NAD is also used for a lot of other things that the body needs to kind of turn on for things like dealing with cell stress. And so I mentioned sirtuins.

NAD is really important for turning on sirtuins and all those longevity pathways. It's also used as an immune response. So kind of fascinatingly enough, there's another pathway that's called the CD38 pathway.

And CD38 is basically this receptor that tells cells that you need to turn on a whole bunch of immune response machinery. And it needs NAD. It basically breaks NAD in half to do that.

The problem with CD38 is this is another thing that tends to go up when you age. And so it's located especially on fat. So for instance, people who are overweight tend to have more of this CD38 in their fat cells, and just more of it just in general, because they have more fat cells adipose tissue.

And this CD38 then basically requires more and more NAD. So if you're overweight, or you have a lot of inflammation, or mental stress, things like that, then you're using a lot of this CD38. And then you're using up a lot of your NAD.

So one of the hypotheses of why does NAD go down as you age is that you're having more CD38 expression. And this causes more NAD to get used up. So yeah, that's a sort of interesting hypothesis right now that people are exploring.

But then it becomes also really interesting to understand like, how do we prevent that? You know, how do we turn off the CD38 gene? And they show now through a lot of MAPs knockouts, where they don't have CD38, that these mice are healthier, they have a longer lifespan, they don't get as many diseases.

And also, if you apply a CD38 inhibitor, that you can overall kind of improve function in these mice. They're probably now, I would say, getting more data in humans, but that's sort of initial promising data. But what's interesting is just to kind of round that out, is that you can actually have a CD38 inhibition through also some other kinds of molecules.

I think one of the best ones that people have talked about before is apigenin. Have you heard of apigenin?

[Angela Foster] (38:27 - 38:28)
Yes, yeah.

[Siobhan Mitchell] (38:28 - 38:30)
Yeah, that's things in parsley.

[Angela Foster] (38:30 - 38:35)
It also helps with sleep, apigenin, right? Sorry? Apigenin, I understand, can also help with sleep.

[Siobhan Mitchell] (38:36 - 39:20)
Yeah, it can actually. It's, I would say it's like a multifunctional kind of molecule. That's a sort of different pathway, or I mean, it could be a little bit related, I would have to go check.

But definitely, it's a CD38 inhibitor. So it's really fascinating for people to look at how apigenin can help. There are other ones that are also coming out that are really fascinating.

So PQQ is another one that seems to be helpful for decreasing CD38. So a lot of these different kinds of molecules are now being looked at, especially from supplement levels, because it'll probably take 10 years for a CD38 inhibitor to come on the market. But a lot of these supplements do seem to be very helpful.

[Angela Foster] (39:23 - 41:30)
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And with CD38, you're saying it gets more activated in the cases of obesity or inflammation, inflammation tied to obesity. So actually staying lean and healthy is really important, lowering inflammation, but then in order to stay lean and healthy, you need to look after your mitochondria, which is obviously a lot is contained in your muscle as well. Right.

So it kind of is a sort of circular thing, right? We come back to it with NAD. We have precursors that we can take, and then we also have the recycling, right?

So we can create new, more, and there's a new NAD that when we can also recycle some of it. So there's two things going on, I think, for NAD. Yeah.

And I think that's an important thing to look for. I'm going to come into the other areas that you've spoken about that are also important when we're looking at supplements. But my understanding is that when we're looking at a supplement to support NAD within the body, we need to look at precursors to help us create more, and then also other compounds that are actually going to help us recycle what we have.

[Siobhan Mitchell] (41:31 - 45:05)
Yeah. Yeah. And so one of the main ways that we recycle NAD is through a salvage pathway that takes niacin.

So I think everyone's heard of niacin. It's a B vitamin, B3 that should be something that we take more of in our diet, but I know a lot of the time we don't. And this is converted into NAD through this enzyme called NAPT.

And NAPT is basically, yeah, kind of restarting up our NAD supplies in a very quick way. Because if you make NAD from scratch all the way from tryptophan, it can take a long time for our cells to kind of build up supplies. So this is really, I think, the most fundamentally useful way that we can, yeah, build up our NAD supplies really quickly.

So what's really important to think about with when you take an NAD precursor is that a lot of these NAD precursors, whether it's NR, whether it's NMM, they will end up getting converted to nicotinamide. This is like really clear. I think for a while people were like, oh, we're not sure.

But NR, NMM, they basically are converted to nicotinamide, which is a derivative of niacin in your gut and then also in your liver. And then through that pathway, once they're nicotinamide, they get converted into NAD through NAMPT. And so what you need to do is you need to make sure that there's a lot of NAPT that can then convert it into that useful form, which is NAD.

So yeah, you want to have things that activate NAMPT. Things like PQQ has been shown to help with NAMPT expression. And just so people are aware, NAMPT is also something that gets a lot more expressed when you exercise.

So that's another cheap way of getting NAMPT to come alive in your system. So yeah, this is where I definitely think people understand, though, what they take that precursor if they're not having the delivery systems to make that NAD, then it's probably not going to go where you think it's going to go. If you don't have enough NAMPT expression, then all that NR you're taking, all that NMM, just gets converted into nicotinamide and then just gets flushed out of your system.

It becomes kind of useless. So that's a really fundamental thing. The other fundamental thing to know about when you're taking NAD precursor is that it's very helpful to mitochondria, as we just discussed, but you also need to make sure your mitochondria are functioning in other ways.

So mitochondria that are healthy, like they don't have as much oxidative stress and have all their machinery intact. And so then that's where it becomes important to have these kind of other activators of mitochondrial health, other ways you can activate sirtuins like the resgaratrol that I mentioned. And PQQ itself is a really great antioxidant, so that's really important for helping with oxidative stress in the mitochondria.

Yeah, I should mention PQQ is a mitochondrial antioxidant that has good entry into the mitochondria, so it can be very helpful for decreasing oxidative stress and also increasing that AMPT expression that then allows more use of your NAD. So it's really about like a whole system of how to make sure your NAD is working best for your mitochondria, so you get more energy, you get more of those benefits that people are looking for.

[Angela Foster] (45:06 - 45:36)
So just so I can make sure that I'm clear, and there's quite a lot of science here, so I'm just going to try and like summarise it in my sort of layman terms. So we can make NAD, but we also can do it more quickly through NAMPT, which we need to activate. We can activate that ourselves physically through exercise.

Is that all types of exercise or is it particularly aerobic exercise or resistance training or any exercise?

[Siobhan Mitchell] (45:36 - 46:22)
It's I think exercise where it's pretty intense, like it's not going to go crazy if you just take a walk. And I think you've heard of that too, like mitochondria are not going to get that much benefit for a walk. You have to make it so that you're actually breathing hard, you're feeling that lack of oxygen, which then tell the mitochondria like something bad is happening, we need to get ready, we need to turn on those gene expression systems like the NAPT, like the hormetic system.

So you want to get that out of breath feeling, and that's the signal to the mitochondria. You need to do something to make you ready, be more resilient. And yeah, that's why workouts then become easier and easier is that your mitochondria now become more resilient and they can handle more use of energy.

[Angela Foster] (46:23 - 47:00)
Yep. Got you. Okay.

So that comes back to the hormetic stress. So then we need to create this NAMPT, otherwise we can't use. So if we're just taking NMN or NR, actually, as you were saying, a lot of it is going to get flushed out.

So exercise can help, but then so can PQQ, you mentioned, and then we also have the sirtuins, which are supporting their longevity mechanisms within the body to support healthy cellular health and healthy mitochondria. How are they coming in just so we can, if you could summarise the whole picture, that would be really helpful.

[Siobhan Mitchell] (47:00 - 47:31)
Yeah. And I know it gets really complicated, but yeah, like, so as I said, there are special sirtuins, especially for the mitochondria where they need to get turned on. So things like sirtuin three to have a lot of that mitochondrial turnover, that able ability to have this stress response that helps the mitochondria, you know, have that hormesis for exercise, things like that.

So like a really fundamental pathway to make sure your mitochondria is still healthy is through the sirtuin threes.

[Angela Foster] (47:33 - 47:39)
And PQQ, we know as well, actually gets into the mitochondria, whereas CoQ10 does not seem to.

[Siobhan Mitchell] (47:40 - 47:45)
Yeah. Not that, not that much. Yeah.

Maybe like 5% to get into the mitochondria.

[Angela Foster] (47:45 - 47:45)
Yeah.

[Siobhan Mitchell] (47:46 - 47:47)
Okay.

[Angela Foster] (47:50 - 48:30)
Amazing. And then we have apigenin, which is a CD38 inhibitor. So that's going to help calm this inflammation, but then also taking care of our health and having good mitochondria and not having too much inflammation and not obesity is also going to in turn help deactivate that pathway as much as possible.

MitoQ, right, has these special ingredients. So it's supporting mitochondria on multiple levels. I've certainly noticed big differences in my energy since starting it.

And I know that it's not just me, right? There's really good science behind how this works. Can you explain what's in that and how it's supporting our energy?

[Siobhan Mitchell] (48:32 - 48:36)
Yeah. So I think you're referring to one of our products called NAD Booster.

[Angela Foster] (48:36 - 48:37)
NAD Booster. Yeah.

[Siobhan Mitchell] (48:37 - 50:34)
Yeah. Yeah. And this is one of our newest products.

So I am very passionate about mitochondrial health. As I said, I have dedicated decades of my life to figuring out how do we can, we can make our mitochondria work better for longer. And so MitoQ had a lot of products focussing on this mitochondrial musculate, this special targeted antioxidant.

But what I also felt was really important is that we target NAD and we find ways to replenish NAD. So we basically worked on this supplement that could have the NAD precursors, but we know that's not the whole job that, you know, having those NAD precursors, the NR, the nicotinamide, they might just get flushed away. They might not get used unless you have that ability to convert it into the NAD, the proper form for the mitochondrial function.

And that is through, yeah, making more NAPT, which is that salvage pathway sense or that enzyme. And so we also added PQQ to have more of expression because we know even though you should exercise a lot and get your NAPT to go up that way, not everyone has time to do it all the time. So we want to make sure that that was an activation that was in the product.

And then we also included resveratrol, which is a very well-known sirtuin activator, and sirtuins are very important for overall mitochondrial function, as I just explained. And then we also want to make sure that there's less inflammation overall in the body. So helping tamp down that CD38.

So yeah, the resveratrol, the PQQ with its antioxidant capability could also just tamp down the inflammation and oxidative stress as well too. So your overall NAD levels can stay as high as possible through multiple different mechanisms.

[Angela Foster] (50:35 - 50:37)
Got you. And so then it's actually getting into the cell.

[Siobhan Mitchell] (50:38 - 51:31)
Yeah. Yeah. So this is, yeah, that's the other thing is getting into the cell.

I think people aren't really aware, like this is what I find really frustrating when people say like, oh, I did an NAD IV and it was amazing. I felt amazing. I'm like, that NAD is not really getting into your cell.

It's just in your blood. Yeah. It's not going to get into your cell unless it's in that precursor form.

So the precursors can be very effective, but you just need to make sure you take that precursor that you have a way of converting it into NAD once it gets inside the cell. So super important to think of that. I honestly feel like a lot of those IV NAD infusions, they're just causing a super strong immune response that make people feel like something's happening.

It's almost like a placebo effect, but it's not really doing anything because most of that NAD that is infused is then just getting flushed away.

[Angela Foster] (51:32 - 51:38)
Well, and it has to be delivered very slowly, right? Because it causes rapid palpitations. I mean, I remember having a mini one.

[Siobhan Mitchell] (51:38 - 51:43)
Yeah, yeah. People have bad reactions to it because they're literally having a bad immune response to it. Yeah.

[Angela Foster] (51:43 - 52:11)
Yeah. And as you say, it's going into the blood, which is not really where it's needed. It's in the cell, which are the precursors that's needed.

But then if you're just taking something like NMN, you might end up just flushing it away because you haven't got the other ingredients that you need to help with the NAPT, which is why you formulated it in a very specific way to do that. When thinking about taking it, is it energising on the day? Is it, or is it more of a buildup?

So like, should you take this in the morning?

[Siobhan Mitchell] (52:12 - 53:49)
Yeah, I would say it's energising over time and I would take it in the morning. So in fact, that's when our body's making the most NAD is in the morning. So that's when all these salvage pathways, things like that are turned on the most.

So if you want to get that best kind of conversion to NAD, like definitely take it in the morning. I had some people say that they feel better, you know, in a few days of taking something like an NAD booster. I happen to notice more of an effect, actually, I think after like a month or so, like my workouts get easier.

Yeah. So NAD is especially useful for recovery from workouts, from high intensity workouts. People don't realise that when you do a high intensity workout, you're actually causing DNA damage and a lot of inflammation.

And so you want to be able to deal with that as quickly as possible. And so DNA damage can be stopped or it can be kind of repaired through PARP, which is another NAD kind of activating system. So you need a lot of good NAD levels when you're exercising to make sure that your PARP system is activated and you get that DNA repair after a workout.

So then you get the recovery to go and do more exercise. So that's another thing, because I feel so frustrated and I hear people say like, oh, I did a good workout, but not exhausted. I don't really want to do anything for the rest of the week, or I feel like my next workout felt terrible and then they get demotivated.

So I want every workout to feel great. So I really recommend taking something like an NAD booster to make sure that every workout feels great. And that's what I've noticed as well.

[Angela Foster] (53:50 - 54:18)
Yeah, I've noticed that. And also just your, as you say, your recovery time between workouts, but also your recovery time between intense efforts. So between sprints, for example, is improved.

Sounds great. Is what I've seen. Yeah.

So it's great for exercise. It's great for strength. It's great for power.

Is there then a best time of day to take these NAD precursors? Should they be taken in a fed state? Should they be taken pre-exercise?

What's the best time?

[Siobhan Mitchell] (54:19 - 54:41)
Yeah, I would say still in the morning is the best time, because I'd even heard that people who take it in the evening feel a little bit like they're, they're not able to sleep as well. So I would say, yeah, in the morning, when you have all your kind of NAD expression for synthesis and all the rest, kind of it's most active.

[Angela Foster] (54:42 - 54:48)
Is there any irritation on the stomach if you take it fasted? Is it best taken with food?

[Siobhan Mitchell] (54:49 - 55:12)
I think it doesn't really make a difference. I tend to say to people, if you are noticing any kind of like gut issues, like then take it with food and then they'll go away. In terms of bioavailability, it doesn't really matter if you have food.

I do always tell people to take water, like a decent amount of water with it, just to kind of help its absorption and make sure that it's getting to everywhere it should go.

[Angela Foster] (55:13 - 55:46)
Yeah. Okay. Amazing.

Super interesting. And as you say, this is really important for women in particular, right? Going through perimenopause, just there's multiple mechanisms here because so often I think the most common thing we recently did a survey of over a thousand women.

And the most common thing coming out of it was my energy just feels really low. I feel off. I'm putting in the effort, but I'm not getting the same results and I'm not recovering from exercise.

And I've definitely found these NAD boosters to make a massive, massive difference.

[Siobhan Mitchell] (55:47 - 56:03)
Yeah. It makes a tonne of sense. Like literally oestrogen is helping regulate your sirtuins as well.

And so yeah, once you lose the oestrogen, your sirtuins are kind of a little bit dampened down and yeah, you just need that NAD to help activate that all and get your ATP up.

[Angela Foster] (56:04 - 56:19)
Yeah. Thank you, Siobhan. This has been so interesting.

Where can people go to find out more? Is it over? I think we have a special discount code as well for them to try the NAD+.

It's over at mitoq.com is it? And I think.

[Siobhan Mitchell] (56:20 - 56:57)
Yep, just mitoq.com. Yep, mitoq.com. You can see all the prints of the mitochondrial supplements and mitochondrial kinds of activity advice that we think people should be aware of because we feel really strongly that people need to get educated a lot more on their mitochondria.

So I'm always happy to spread the word, but yeah, mitoq.com has got all of our research. We actually help sponsor and fund a lot of research as well too on mitochondrial health and NAD boosters and things like magnesium and fish oil, like all the good stuff for your mitochondria are all there.

[Angela Foster] (56:58 - 57:30)
I think that's what's been so useful for me because it's like, you can literally go and explore the science and everything that we've been talking about in a bit more detail there over at mitoq.com. And then we'll link with them if you want to try it with a special discount code with my name, with Angela in the, in the show notes below this episode. It's been super interesting speaking to you.

I think I'd love to have you back and we can talk about phytoestrogens and the brain and things like that run out of time Is there anything around mitochondria that I didn't ask you that you want to share?

[Siobhan Mitchell] (57:34 - 58:05)
Yeah, I think we covered a lot about mitochondria. I, I just want people to be aware that like, even though I think mitochondria seems like a really crazy subject, it's not that hard. It's mitochondrial health through, you know, a lot of exercise, a lot of just paying attention to, to your overall energy levels and finding the things that work for you to, to kind of, you know, keep your mitochondria feeling good.

And yeah, then the rest is simple, like healthy ageing should not be hard. That is why I think.

[Angela Foster] (58:06 - 59:36)
I love that. Yeah, it shouldn't be hard. Amazing.

Thank you so much, Siobhan. Really, really appreciate your time and sharing all this research. I hope today's episode inspired you on your journey to vibrant health and high performance.

Make sure you check out the show notes for a summary of all the important links to everything we talked about. And if you enjoyed this episode, hit the follow button and share it with a friend on social media or leave a review over on Apple podcasts. Remember, achieving high performance health is about getting 1% better each day.

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Today I’m joined by neuroscientist and mitochondrial health expert Siobhan Mitchell to cut through the noise around mitochondria, inflammation, NAD, and what actually matters for energy, recovery, and brain health in midlife

We unpack why mitochondria are not just “battery packs”, they are a master regulator of oxidative stress, immune signalling, and cellular aging. Siobhan explains the difference between hormetic stress that upgrades your system (like training) versus chronic stress that drains it

WHAT YOU’LL LEARN:

• What mitochondria actually do, beyond “energy production”

• Mitophagy and mitochondrial biogenesis, and why both decline with age

• The difference between hormetic stress (exercise) and chronic stress (modern life)

• Why mitochondrial dysfunction can drive inflammation and immune overactivation

• How brain energy demand and oestrogen loss intersect in menopause symptoms

• CD38, inflammation, and why staying lean matters for NAD preservation

• Why NAD precursors can be wasted, and what supports conversion inside the cell

• The practical take on timing, training, and recovery support