Energy is not only fuel. It is the body’s capacity to respond, repair, and adapt. In this conversation from The Energy Blueprint, the useful thread is not novelty for its own sake. It is the way small physiological signals become practical guidance for a more resilient life.
Transcript from The Energy Blueprint. Timestamps open the original YouTube video at the corresponding moment.
Hello and welcome back to the Energy Blueprint Podcast. I'm your host, Ari Whitten, and I am incredibly excited about today's guest, who is an expert in my personal favorite topic, which is mitochondria. So, his name is Dr. Martin Picard. He's an assistant professor of behavioral medicine and psychiatry and neurology at Columbia University. He obtained his PhD in mitochondrial biology of aging in 2012. He then moved to the University of Pennsylvania for a postdoctoral fellowship in the Center for Mitochondrial and Epigenomic Medicine with the famed mitochondrial researcher Doug Wallace. For over a decade, Martin has been studying mitochondria and has worked closely with leading experts in the field of mitochondrial research. In 2015, he joined the faculty at Columbia University, where he established the Mitochondrial Signaling Laboratory. He's currently investigating mechanisms of mind-body interactions, specifically regarding novel principles that underlie mitochondrial responses to stressors, the maintenance of human health, and the influence of mitochondrial health on complex cellular and physiological processes, including aging and resistance to disease and stress, resilience, and many, many other aspects of health, including, of course, energy levels. So, I am incredibly excited to introduce you all to Dr. Martin Picard, and I think you are going to absolutely love this episode. So, that's a a brief, you know, sort of official bio, but
you know, sort of official bio, but let's simplify a lot of this stuff. So, what you do, Dr. Picard, is you you work in a field called mitochondrial psychobiology. So, can you tell everyone exactly what that means? Mhm. Yes, that's a good question. It's basically the intersection of mitochondria and the the biological, you know, processes and things that happens there in the cell inside the organelle. Um and then what happens in the mind, right? So, if we simplify this, it's basically mind-mitochondria science, kind of like, you know, mind-body. But here we we dive a little deeper uh than just the body generally and we specifically focus on mitochondria. Uh in part because mitochondria are the source of energy, right? That's where the reason we breathe, the reason we eat is to fuel the mitochondria, right? The ultimate purpose of breathing and maybe why the breath is is so common across all ancient traditions and and, you know, religions, the breath is connected to bring oxygen into the body and then where does oxygen go in the body? It goes in the mitochondria. So, uh so we study uh because mitochondria are so essential to energy, we study how how the the mind and the mitochondria interact and and hopefully it's going to help us understand better how, you know, we humans experience the world and, you know, manage to stay healthy most of the time and and then why we get sick once in a while. Yeah. Okay, so I I want to back up just a minute. I I want to get back to uh mitochondrial psychobiology in just a minute, but let's let's back up and just
minute, but let's let's back up and just talk about what mitochondria are and kind of the and you can do that very quickly. I know that, you know, that topic in and of itself could be 3 hours long, but just a brief description of what mitochondria are and their you know, their their vision or their their role in human health has for a long time been conceptualized as, you know, sort of just these mindless energy generators in our cells that just pump out energy. They take in glucose and fat and they pump out ATP and that's kind of what mitochondria are good for. And in the last 10 or so years, uh there's been a really I like a a reimagining uh within the scientific community of the role of mitochondria in human health. So, kind of talk to me about your perception of how uh the the scientific community's perception of mitochondria has changed over the last couple decades. Mhm. That's a I'm really good um I think an important transition that is currently happening and uh you know, a long time ago about 1. 5 billion years ago um something happened that there were the only thing that existed on the planet were unicellular organisms, right? They were bacteria. There were different kinds of bacteria. Uh little cells that didn't talk to each other uh very much probably. Some could use oxygen to make energy and some others could not use oxygen and they were fermenting type bacteria like yeasts. And then at some point a bigger kind of cell bacterium engulfed a smaller
cell bacterium engulfed a smaller oxygen-consuming bacterium. And then that smaller oxygen-consuming bacterium uh instead of you know, being digested and used for food by the bigger one, actually managed to stick around. Um and that theory goes became the mitochondria. And so and for some reason in evolutionary history, that event seemed to have been critical to the development of what's called multicellular life, right? Like animals including like you know, from as small as little worms, flies, you know, mice, dogs, and then humans thinking, feeling, conscious um organisms, you know, evolved from from this this uh it's called endosymbiosis. Uh the symbiosis of things living together and then endo because it's inside uh of. So, the endosymbiotic origin of mitochondria apparently was a key evolutionary piece in making complex life possible. And then you know, the complex animals that we are. Um and so from this their bacterial ancestry and and origin the mitochondria were discovered in about in the, you know, late 1800s, early 1900s. First observed under the microscope, and people saw that they could move and they could, you know, um, do things. And they were named, um, you know, after their actual morphology. They change Sometimes they can look like small little beans. That's mostly what you see in the textbook. And and if you
you see in the textbook. And and if you Google mitochondria images, uh, that's what you see, a bunch of beans or, uh, you know, peanut-shaped, uh, things. And then they have like an outer membrane and inner membrane. And and inside of that is the mitochondrial DNA, which is actually circular that like the bacterial DNA. So, those are the kind of things that make us let us know that they used to be bacteria. And then in the, uh,' 40s,' 50s,' 60s, uh, people started to focus heavily on, uh, the energy production capacity or function of mitochondria. And, uh, you know, Peter Mitchell won a Nobel Prize for understanding how mitochondria could uh, store energy and actually transform energy from food and oxygen into membrane potential. And how do mitochondria become charged like little batteries? Uh, and then they figured out that this energy potential and once you once a mitochondria charge, that energy can be used to make ATP. Uh, I think most people on your podcast will know about ATP, adenosine triphosphate, as the energy currency of the cell and and of, you know, most living organisms. Um, and then that was the pervading view of mitochondria. They're energy powerhouse. And I think most people know about the the powerhouse of the cell analogy. We actually think it's it's a bad analogy, uh, because it's very, um, mechanistic. It's very, uh, you know, uh, mechanical, I should say. And mitochondria are so much more than powerhouses. and that's I think in line
powerhouses. and that's I think in line with the the new transition away from this powerhouse analogy, uh which portray mitochondria as little machines, right? The powerhouse had it takes an input, transforms it into an output, and then then that that's, you know, power generation or transformation. Mitochondria actually have this beautiful, complex life where they interact with each other. They can fuse. Uh so, two smaller mitochondria can come together, fuse, become a longer one, so they change shape uh via their interactions with each other. Then they can undergo the opposite process of fission. So, a longer tubular, imagine like a long spaghetti, uh can become fragmented into little beans. So, that's called fission, mitochondrial fission. Um and the fused mitochondria or the fragmented or fissed mitochondria also have different functions. Uh so, their shape is linked to their function, which is what we see a lot in in biology. Um and now our view is you're transitioning from this dynamic view of mitochondria, which you can observe um you know, through movies and videos, some of which are in on our website, and you can see find some of those on the internet now. Uh and then people are starting to realize actually mitochondria are great, you know, they move, they make energy, but they actually produce signals, you know, they're sensitive to stuff, and they generate stuff. Um so, what we're finding is that mitochondria can respond to different hormones or to different metabolic signals. And that's fairly well documented. And then mitochondria release other kind of
then mitochondria release other kind of uh biochemical signals. And maybe use other kinds of, you know, vibrational signals or, you know, electromagnetic or something else uh that can be transmitted between the mitochondria, between mitochondria and other parts of the cell, including a nucleus where the nuclear genome um kind of rests and waits for signals and information to know which genes to turn on, which genes to turn off through epigenetics, and maybe we'll talk about that. Um and then ultimately to the rest of the cell, the rest of the body. So, mitochondria can send signals, including their own genome. They can release their DNA uh into the the cell cytoplasm, the internal part of the cell, or even into the bloodstream. And then those mitochondria-derived signals can go everywhere in the body. So, now the the view that we're starting to develop is one of a kind of a communicating uh collective of mitochondria distributed across different organs, different cells that uh talk to each other. Yes. And I want to get into that. I want to get into this kind of mitochondrial DNA leaking into the bloodstream and uh and several of the other things you talked about how mitochondria sense things that are going on in the environment and modulate gene expression. First, I want to ask you to kind of briefly summarize uh what we now know about the role of mitochondria in human health, very broadly. And And you know, just very quick summary, but again, we used to think of mitochondria, as you said, as these just powerhouses of the cell, just kind of taking orders from the DNA, which was the big boss of the cell, and their job is just to burn off
cell, and their job is just to burn off carbs and fats and produce energy. Uh and we now know they're so so much more than that. Um what is the role of these mitochondria? Why are mitochondria so important? And what do we now know in the science as far as the links with different diseases and and aging and so on? Mhm. Yes. So, the the uh medical community and the scientific community um have found associations between mitochondrial dysfunction which is kind of broadly uh it means a lot of things, but mitochondria don't functioning well. And if we know mitochondria make energy, but they also move and they also produce other things. And so, dysfunction can happen at multiple uh different levels. It's similar to human dysfunction. We can be sick in different ways, right? So, the mitochondria can be dysfunctional or sick also in different ways. But, the medical and the scientific community has linked mitochondrial dysfunction to every disease that I know of. So, if you go on PubMed or, you know, you Google whatever disease you you want and mitochondrial dysfunction, there is most likely an article that documents some evidence of mitochondrial dysfunction in in that disease. So, what we don't know there And and even the aging process itself more broadly. Yes. Aging that there's a very large body of scientific evidence linking aging process and mitochondria. And I think quite convincingly showing that mitochondria and dysfunctional
mitochondria and dysfunctional mitochondria actually can precipitate or accelerate aging process. Mhm. And one question you look at the scientific literature and you Google, you know, whatever disease you're interested in like Alzheimer's or cardiovascular or cancer and mitochondrial dysfunction, then you find all these papers. You never know if it's the disease that happened through some process that we don't understand that caused mitochondrial defects or dysfunction or if it's a mitochondrial dysfunction that is a primary cause or driver of the disease, right? Uh most studies don't allow us to to understand this. So, um the state of the field is there's a lot of evidence showing mitochondria are not happy. Mitochondria don't work normally in disease. Now, are they the cause of disease or are they the result of disease? Uh and that's where, you know, there's a smaller body of research that addresses this directionality. And um a big piece in that uh effort to uh came in the 1980s actually where Doug Wallace and Ian Holt in in England, they almost simultaneously discovered that there were defects in the mitochondrial DNA. So, mutations or deletions in the mitochondrial genome Um that were the cause of human disease. So, that was the first time that it was demonstrated that when the mitochondria don't work properly, this can actually cause disease. Yeah. And since then, there has been a hundreds of studies that document these kind of connections. And you know, every week here in in the clinic, we see
here in in the clinic, we see patients who who walk in with defect in their mitochondria and then you you see the consequences. You see the consequences on their ability to exercise, to move, their ability to digest food, their ability to, you know, move about, and their ability to think, and to process things, you know, with cognitive function. So, it's very clear now that when the mitochondria don't work properly, they can cause disease and and they can precipitate a lot of age-related disorders. Right. And one of the other lines of evidence from lots of studies is, you know, interventions that target mitochondrial health, whether it might it could be something natural like, you know, let's say polyphenols or EGCG from green tea or something like that that acts to bolster mitochondrial health in some way. Or, you know, various other types of hormesis, exercise, or many other types of hormesis that we know have effects on mitochondria, we know also confer various protective effects against various kinds of diseases and have the potential to increase lifespan or at the very least healthspan. Yeah, for sure. And you know, like you mentioned, exercise. I think exercise is probably the best, you know, health promoting intervention. If it was a drug, it'd be amazing. You know, people would take it all the time. There there are so many good side effects and we don't actually know why exercise is good for you. You know, there's there's no mechanistic understanding of why exercise is is so good for Yeah,
of why exercise is is so good for Yeah, healthspan and and it's not quite sure it makes uh you know it extends longevity. You know people who exercise a lot don't tend to live you know 200 years old and there's a lot of people who never formally exercise. They don't do you know marathon running and all of this and they do end up you know living healthy and living very long but physical activity, you know, being active. Uh we don't know why that's good and one theory that we tend to favor is that exercise and physical activity is good for you because it stimulates your mitochondria. Mhm. Yeah, that's hard to prove empirically. So this is a nice segue. So we know that exercise, physical exercise and movement is very important for mitochondrial health. Um what what are some of the other factors that you think are really important in mitochondrial health and then I want to transition into what your area of focus is which is the mind and the mitochondria like So can you is are there any other factors before we get to the mind mitochondria are there other any other factors worth mentioning here that are key players in mitochondrial health? Uh Uh something that's been studied a lot you know exercise is um we've known for a long time exercise increases the number of mitochondria in your body. Uh so if you go from being a completely not physically active individual like you know couch potato situation scenario chronically and then you go and you say I'm going to run a
you go and you say I'm going to run a marathon and then you start working out a lot. You can double the amount of mitochondria in your body. Right? So per per amount of muscle per gram of muscle you can double the number of mitochondria in your muscle just just by stimulating the body and we think that this probably happens also in the brain. The brain makes more mitochondria and the muscle has more mitochondria if you're more active. So that we've known a long time. Exercise improves the number of mitochondria and also changes how they function. Uh another thing that's been studied quite a bit is the health benefits of not eating too much. So, some people have called this calorie restriction because that's how it was done in animals originally. You would restrict the number of food pellets that you gave animals and then kind of magically animals started to live longer and and be healthier. You know, there are some issues with these studies because the control group the control animals that, you know, eat as much as they want, they're they're housed always in little cages, right? That's very unnatural to live for a rat or a mouse or, you know, any animal that we're using these studies to live in such a smaller shoe size box. That's how laboratory animals are kept. Shoe size box, no ability to exercise. Now, most studies don't have a running wheel or any anything else. And then there's an abundance of food. As much as you want.
abundance of food. As much as you want. So, in evolutionary history, you know, these little animals, us included, we always had to do some movement or some hunting or, you know, something else to get calories. And then all of this sudden, you know, in evolutionary history that's a very kind of abrupt change where you're you have zero need to do physical activity and then there's as much food as you want. So, you could argue in all the calorie restriction studies, the control group is actually an overfed uh sedentary couch potato situation. And then it's not surprising that if you just bring down the number of calories, you actually maybe normalize things a bit more. Right. That's interesting. I never thought about it that way, but it's it's absolutely true. Especially I assume there were running wheels in the cages. Not. Yeah, they were not. That's not good. Yeah. So, from those studies, you know, they were called calorie restriction and then now there've been a lot of human interest in calorie restriction and there are some studies that are underway, you know, where people try not to eat too much and then they're perpetually hungry for for life. And apparently I I actually I've never done a study on this, but I know some people who have worked with these people and apparently these people are not very nice to work with cuz they're a little grumpy and you know, feeling hungry is chronically you know, it is not a a super pleasant thing to do and that's why a lot of people cannot stick with this for very long. Yeah. There's more recent interest in intermittent fasting and and maybe you know, you and your
and and maybe you know, you and your audience is familiar with this where you you know, you eat normally but then you don't eat for you know, a half day or for a full day or for two days there are different models of this. But I think the idea here is once in a while feeling hungry is a good thing. Mhm. Uh and what we know from the animal studies and some human literature is feeling hungry actually recruits and stimulates in the organism a lot of very good adaptive processes. So the the same way that when you exercise you stress the body and then you stress the muscle then the muscle responds to this becomes bigger and becomes stronger for the next time it's recruited or it's used and it's it's stronger and it's adapted. So the same kind of thing happens if you feel a little hungry the body feels like oh like now I there's no sugar around I need to start using my mitochondria to use the fats and to use the the proteins and then it start the mitochondria needed for this are not needed necessarily to burn up sugar. Mhm. So if you feel hungry typically you know, there's in the the blood and the tissue sugars are a little low and then that forces uh tissues to adapt by using the mitochondria. So, uh it seems like feeling hungry a little bit, uh not overeating, and not perpetually overloading your system with too much of anything, sugar or fat or or proteins, is is a good thing. And for some reason that stimulates uh good um you know, quality control in the cells
you know, quality control in the cells like autophagy, mitophagy, so that the bad stuff gets removed and and uh digested away and then new stuff, new mitochondria that are good well-functioning or synthesized. So, exercise, not eating too much, these are two things that we know are tend to be good for health and probably at least part of their uh part of the mechanism or part of their action is through this, through promoting mitochondria health. Yeah. Uh so, we know one of the third factors now that thanks to your research and the work of some of your colleagues, uh we know that the mind and a person's psychology can have a profound influence on our our mitochondrial health as well. Uh and you've done quite a bit of work, you've you've done some you've you've published some really amazing research papers that I I recommend people read. One's called an energetic view of stress, focus on mitochondria. Another one's called psychological stress and mitochondria, a conceptual framework. Uh and these are really well worth digging into for anybody listening who's uh a health professional or just a science geek who's really interested in this topic. Um so, as you mentioned, mitochondrial psychobiology, this mind-mitochondria link. And this kind of gets at the the whole, you know, Descartes mind-body dualism and the fact that, you know, we now know it's it's pretty widely accepted, of course, that uh it's very widely accepted that we know that the mind has a profound influence on the body. There's lots of
influence on the body. There's lots of lines of evidence that we can speak to about how psychological factors influence biological health more broadly and various kinds of diseases. And we know, for example, childhood trauma can greatly increase risk of of diseases later on in life and many, many other aspects of this. So, we know there's a link there and yet despite that, there is this kind of blurriness of what exactly is that communication? How does our mind communicate with our body? What are these channels of communication? And I think your work has has uncovered uh a really important aspect of that. So, can you speak to that? So, what is this mind mitochondria link all about? Mhm. Yeah, it So, that's that's probably my favorite topic. So, I appreciate you know, talking with you about this. The the I would say exactly, you know, the mind-body connection and you know, just dissociating these, as we know, is a little artificial, right? We, you know, as humans are really good to break things down into pieces and that's maybe that's the whole point of analysis, right? To break down it to pieces. And all of our research methods are ways to break things down into into little digestible pieces that we can understand and you know, test mechanisms and all of that. But really, the whole system is an integrated system and uh as you say, you know, it's there's well-documented effects, for example, of
well-documented effects, for example, of psychological stress on the immune system. And they were seminal studies done, you know, by uh uh the Kiecolt-Glaser uh who showed medical students during uh exam periods, like at the end of the semester, who were super stressed out um cuz they think their their life's going to be done if if they don't pass this exam, then they're more susceptible to infections. So, they actually, if you uh expose them to um to serve some stress. Sheldon Cohen did studies like this where they would sequester people, stress them or not stress them, and then expose them to like a flu, um, virus in the nose, and then showed that and when people are stressed, their their immune system is down, and they're more vulnerable to getting the cold, and, uh, and to, um, uh, to infections. And then the Kiecolt-Glaser showed that wound healing, you know, something as fundamental as if there's a a wound on your skin, or, you know, on your gum, uh, how quickly that wound heals, uh, which is also an integrated process. You need cells to, you know, kick in for in their proliferation. You need the immune system to come in, produce some cytokines, and, you know, the blood flow needs to change, and it's a whole organized, uh, process. And they showed people when you're stressed, and if you experimentally stress someone, that slows down the wound healing, and it makes the person more vulnerable to infections. The immune system is modulated. Uh, so these are some of the, you know, old seminal work, um, that's, uh, I I I'm not sure if it's taught so much in medical school, but it's not part of
in medical school, but it's not part of of kind of the framework, the general biomedical framework. And what we think one of the reasons is is because we don't have a really good understanding of the basic, um, molecular or biological mechanisms by which this happens, right? So there's the mind here, you experience something, there's a subjective experience, which is very real, right? Whatever is in your head. Whatever we experience subjectively, it's very real to the person who's experiencing it. And then there is these biological changes that happen in the immune system, in the wound, right? Or in the brain. These are very real biological changes. What's connecting these things? Right? How do subjective experience, uh, get translated in a language that the biology actually follows, um, uh, and then responds to him. And our guiding hypothesis is that mitochondria and the flow of energy is that connection or that interface. Now, uh, a quick question here. There there's a lot of people out there who have conceptualized stress, psychological stress, and how it affects the body through different conceptual models. So, for example, you know, one of the most basic ones and that's been around in the natural medicine community has been the adrenal fatigue model. And it's like stress is bad for you because it taxes the adrenals, which produce this stress hormone called cortisol. And if you do that too much, then it wears the adrenals out, then you get low cortisol,
adrenals out, then you get low cortisol, and that's what mediates all these negative effects. Okay, then it was, you know, as people realized that that model was really way overly simplistic, a lot of people moved towards this HPA axis dysfunction model, which started to realize, "Hey, there's a couple players upstream of the adrenals, the hypothalamus and the pituitary, and those are really the key players." And so, those are the most upstream things as far as what's sensing stress and mediating different effects in the body. And you know, there's other people out there, like there's a a guy out there who specializes in chronic fatigue syndrome, who I've interviewed on this podcast named Ashwag Gupta, who really says, "No, the the hypothalamus and pituitary are not the most upstream thing. It's actually the limbic system and the amygdala that are the most upstream thing." And and then we have, you know, for example, there was an article, I believe it was in the Scientific American, about some of your research with Douglas Wallace, where you guys, and I want to talk about some of the details of the study, but uh, you basically subjected people to stress and then you measured mitochondrial DNA in their blood. Uh, and I believe Douglas Wallace, I'm not going to get the quote exactly right, but he said something to the effect of, "Mitochondria are probably the most sensitive thing in the body. And so, you could maybe make the case in this model that it's actually the mitochondria that are the most upstream thing before any, you know, sort of processing takes place in some of these brain centers. So, what what's your thoughts on how that should be conceptualized as far as what's the
be conceptualized as far as what's the most upstream, most sensitive thing that is detecting the first immediate signals of what's going on in the environment? Mhm. Yes, uh So, the work that you referred to was the work that was done in collaboration with uh Anna Marsland and Brett Kaufman in Pittsburgh, which shows that psychological stress, if you expose someone to a psychological stress, you ask them to do, you know, to speak in front of a camera, and then they feel stressed and they feel a bit angry and uncomfortable, we found that 30 minutes later, if you take blood, and then you look in serum, there's more mitochondrial DNA that's released. And uh So, that demonstrates that mitochondria somehow respond to to that subjective experience, and then respond by releasing the mitochondrial genome. And, you know, Doug uh is is fantastic, and he commented on this study. Um and that's his view, right? That the mitochondria are the most sensitive thing in the body. I tend to agree, and I imagine that it's because, you know, everything in the organism, you know, from just being alive requires the flow of energy. And anything that is stressful, and by definition, you know, stress something that's stressful is something that perturbs us. Right? Something that is uh not stressful and then doesn't elicit anything in the organism, and it's it's very hard to not be stressed or influenced by anything. I think you If you're dead, you know, if if there's no flow of energy in the body, and the the body is not animated by energy anymore, then the body cannot respond to, you know, to a stressor.
respond to, you know, to a stressor. But, we respond to just a little word, right? Someone says one word, and that can trigger a whole kind of cascade. The heart starts to beat faster, hormones are released, blood pressure increases, you know, we get warmer, the body actually gets warmer when when we're stressed. So, there are all of these changes. Every little bit of the stress response from increasing heart rate or blood pressure to producing a a new hormone or releasing a hormone, every little bit requires energy. So, there's there's nothing in the body that moves or that changes that doesn't require energy. So, because energy is so central to every little part of the stress response, all the you know, from the single gene to the whole person, we think energy is you know, most likely one of the first thing to change when there's stress. And then because energy flows mainly in the mitochondria in in human beings and in you know, complex animals, then mitochondria must be one of the first places to actually perceive to have the ability to perceive that change in energy flux. And and then respond to that. So, and there is mitochondria everywhere, you know, the the three models that you mentioned, the adrenal fatigue, the HPA axis and the limbic amygdala, you know, models. I think these overlap in different ways and you know, there's mitochondria everywhere in in the amygdala, in the hypothalamus and thalamus and the pituitary gland and the adrenal glands. And what's remarkable
adrenal glands. And what's remarkable is that you know, the stress hormones, most people will know about cortisol, which is made in the adrenal glands. Well, where in the adrenal glands is cortisol being made? Right? It's actually in the mitochondria. Yep. So, the every stress hormone and every also sex hormones, all of these hormones that are derived from cholesterol, they're called steroid hormones, they're all made in the mitochondria. Um so, the for some evolutionary reason, the body thought it was a good idea to, you know, put the synthesis of one of the most important family of hormones, the sex hormones that define, you know, female from male and the the stress hormones that allow us to survive different events, you know, throughout life. Those are actually synthesized in in the organelle that sustains energy. So, there's not really a good, um, you know, we can speculate as to why that is, but from our view I think it's it's a good illustration of how tightly knit those things are, the stress response and the the energetic, um, capacity of of the organism. Yeah. I'm curious, are you familiar with Dr. Robert Naviaux's work on the cell danger response? Yes. I feel like this ties in to your model perfectly. I think you you're doing these two lines of research that you guys have been doing completely separately, and yet you're basically arriving to a large extent conclusion,
arriving to a large extent conclusion, which is mitochondria are essentially the most sensitive thing they in the body as far as detecting environmental signals, and then they are determining and from the model of Dr. Robert Naviaux, they're determining whether they're going to stay in peacetime metabolism as he calls it, which is energy mode where they're actively taking in fuel and producing ATP and powering the organism, or if they're detecting threats, whether they be pathogens, infections, or you know, chemical exposures, or sleep deprivation, or psychological stress, or physical stress and over exercise, or any other number of stressors, uh, and then they if they're detecting lots of that input, then they switch out of peacetime metabolism, out of producing energy towards defense mode, or cell danger mode, which directs energy and resources of the organism towards defending the organism against the threat. And obviously the work that I do with people with fatigue and increasing their energy from this model, the most basic way we define fatigue is from the mitochondrial perspective too much of your mitochondria have been shifted out of energy mode into cell danger mode. Now, he talks about uh purines, purinergic signaling and the leakage of like ATP and ADP outside of the cell and this being a critical signaling molecule that signals
critical signaling molecule that signals other cells in the system about the the threat present. Now, in some of your research, you guys have found that mitochondrial DNA actually gets leaked into the bloodstream and that this in in your words, uh this is a quote from you and commenting on some of this research, you said this circulating mitochondrial DNA acts like a hormone and so it's somewhat mimicking the adrenal gland's response to cortisol and it's uh and it's having all these effects on the rest of the cells where it's communicating, "Hey, there's a threat present. There's danger. We're under stress. We need to shift more into defense mode." So, uh there's a lot of similarities like I said between your two lines of research and yet you're to some extent talking about different molecules being the key signaling molecules. So, can you kind of make sense of all that for me? Yeah, I I think uh both models converge and I I love Bob's uh you know, we actually met about a year ago at a conference and it was fantastic to get to chat with him. So, I think there's a lot of overlap and I think we we resonate on on many different levels. Uh I think the same way that if you think about mitochondria not again as a powerhouse but as you know, communicating organelles and organisms uh you know, other kind of you know, living organisms that uh coexist in the same space, right? That share information, that actually communicate and physically interact. Uh that, you know, synchronize their
that, you know, synchronize their function. These are all properties of mitochondria. They're also properties of every other social animals. Social organisms. So, we're starting to see mitochondria as social organisms. And organisms that communicate with each other don't communicate through only one mechanism. Right? So, there's not one type of thing that that you do to talk to another person. There's, you know, there're words, they're also nonverbal, right? We all know that whatever expression you have on your face, whatever you do with your hands, with your gestures, that can communicate a lot. Right? And nowadays classic the classic wife statement, it's not what you said, it's how you said it. The tone, yes, exactly. And nowadays we have like phones, right? And like emails, and you can text, and you can FaceTime, and you can do like all sorts of things. So, we have multiple redundant modes of communication. And the same way, you don't know if you look at neurons in the brain, neurons talk to each other through a variety of mechanisms. There are electrical gap junction, you know, related processes where electrical signals can communicate uh can be uh um transmitted, you know, very quickly. And then there's chemical in neuro chemical signals you know, at the synapses. And with serotonin and dopamine and some other things. So, even, you know, very specific biological systems have multiple redundant ways of of communication. Uh and if you take an analogy,
and if you take an analogy, the you know, the mitochondria trying to communicate states of threat or, you know, states of well-being to the rest of the organism, uh if they only had one switch, it's either on or off, that might not work really well. You know, it's like if we only had one word to talk to each other. Either it's good or it's bad, right? That that would not be great. We have a vocabulary with thousands of words that we can combine with, you know, in different sequences and and so on. And and it's the same thing, you know, for for computers and, you know, digital information. That's the flexibility you have when you have multiple signals you can combine in different ways. You know, the the texture you can get out of this and an image and, you know, a picture or in a biological system is is remarkable. So, the same way we we take all sorts of words and and can communicate some very sophisticated ideas, biological systems have also learned to do this. And that's why there's not only one neurotransmitter in the brain, you know, there's several. And that's why there's, I think, multiple different kinds of communication uh molecules that come from mitochondria. And I think it's to communicate the complexity of of what's happening at the subcellular level that needs to be communicated throughout the organism. Yeah. Now, what sort of big picture what is this signaling all about? So, we know that psychological stress, what's going on in the mind, affects mitochondria, can cause mitochondrial dysfunction, can cause the contents of
dysfunction, can cause the contents of mitochondria, whether it's the DNA, whether it's purines like ATP and ADP to leak out of the cell into the bloodstream where it's doing some sort of signaling. What is this all about? What is this signaling actually trying to accomplish? Like from an evolutionary perspective, why are our bodies designed this way? What good is it actually doing? Mhm. One way to think about it is not as um you know, a purely kind of dysfunctional system like stress is bad, it causes these molecules and then that causes disease, but uh you know, not all stress causes disease, right? And you know, I think many people will relate to stress being actually a pretty stimulating thing, right? And And if you have zero stress, you know, some people need quite a bit of stress to actually get something done. Uh and you know, with stress can come motivation and and some other things. There's uh you know, Bruce uh McEwen likes to call it toxic stress when it's it's not good anymore, but you know, all of this stuff before toxic stress can actually stimulate uh you know, healing and stimulate adaptation and and you know, uh strength of of different functions. Um And actually bolster the organism's health and resistance. Yes. longevity. Mhm. Yeah, and you mentioned hormesis uh earlier, right? That's the that idea. There's little stressors will stimulate processes in the body that if those if
processes in the body that if those if that stress persists, that can become damaging, but if it's acute, like you go to the gym for an hour or, you know, you walk up the stairs instead of taking the elevator, that will stimulate things in your legs and in your heart and in your brain and and then, you know, your body will become a little stronger uh you know, as a result. Um so, that's hormesis uh the the body adapting to challenge or to stress and then becoming stronger as a result. Um So, I think the the different processes you were mentioning um we see as as communication. Why? You know, why would mitochondria release all of these things? Uh we think it's the same reason as, you know, why do people talk to each other? Right? Cuz cuz that's how things need to work. You know, why do different organs in the body talk to each other? Why do the different organs are connected with our a cardiovascular system through blood? Yeah. Information needs to be exchanged. I think it's a basic property of of life. Um and and that's how complex systems, you know, function and and operate. That's how um things uh living organisms fight entropy. You know, to remain healthy is to go against the um you know, the the forces of physics. You know, if we were subjected to forces of physics and we didn't have energy flow to to resist that, then we would just decay, right? We manage to uh to go against that and to go against just dissipation of of
to go against just dissipation of of matter for, you know, 80 100 years uh because of the flow of energy and because, you know, there's communication. So, the um it's a bit similar if we were to look at the brain from a a primitive, you know, view like I don't know how long ago, like a century ago, it was like, "Oh, you know what? When you stress the brain through the eye, so that would be like stimulating something from the eye of an animal, let's say, and then, you know, there's all of these chemicals being released uh in the back part of the brain, the occipital region where the visual information is processed. And there's like GABA and serotonin and like dopamine and these things, you know, would be released." Then you would say, "Oh, you like this must be dysfunctional." But then, you know, in hindsight, it's like, "No, this is Neurons need to talk to each other to make sense of the information that's coming in." And that stress that perturbation that's coming in is actually meaningful information if you can decode it. So, in order for the system to decode it, make sense of it, and then mount an intelligent response that will allow the organism and the system to to remain alive and to remain healthy and to adapt to it, there needs to be communication. Right? That's how complex networks and complex uh systems work and and uh process information and adapt to it. I think that's how we see those signals that mitochondria release. If you look at it simplistically, you say mitochondrial DNA release bad,
say mitochondrial DNA release bad, triggers inflammation bad. You say mitochondria release these molecules, it has multiple effects. We've looked at one thing, inflammation. Yes, inflammation can be bad, but inflammation is also important for the adaptation of the adaptive processes and so on. So, I think the the overly simplistic explanation or interpretation comes from our lack of sufficient knowledge and uh maybe the the simplicity or simplicity of our minds. Yeah. absolutely. So, we know that there's this link between stress, the brain's perception of stress or the mind's perception of stress, and causing these various potentially negative effects in mitochondria. And certainly if the stress is very chronic, almost certainly very negative effects on mitochondrial health. Um we also know that there is uh an emerging link through a number of studies with mitochondrial dysfunction and psychological factors like or or brain-related conditions like depression and anxiety, uh and even neurodegenerative diseases going more into to brain conditions. But we we know that there's this this link there. Do you think that uh this you know, kind of a simple model of this and and I'm sure that this is oversimplifying and leaving out of a lot of complexity, but do you think it's reasonable to say that uh stress on the system can cause mitochondrial dysfunction that can contribute very directly to things like anxiety and
directly to things like anxiety and depression? Mhm. I think that's very likely. And at this point, we don't have all of the pieces of the puzzle to say uh for sure that this is how it happens, right? And that depression and anxiety and bipolar disorder and schizophrenia and so on Or mitochondrial disorders. Um we do see these these psychiatric disorders more frequently in people who come in with a genetic defect in the mitochondria, like I mentioned earlier. So, that's fairly strong evidence that if something is wrong with the mitochondria, this can cause defects of you know, perception of reality, or you know, perception of the world, and regulation of mood and affect, and and so on. So, there's there's some evidence, but we don't know for sure that the stress causes psychopathology through the mitochondria, but I think it's likely. Uh and something that we um identified recently, we wanted to know, does how you feel influence your mitochondria? And how you feel meaning both negative stuff, like stress, and um and sadness, and depression, but also positive stuff, like feeling inspired, you know, feeling love, closeness, and trust, and you know, feeling motivated, and uplifted, and you know, these kind of good things that we we feel once in a while. So, we wanted to know, are these things predictive of how well someone's mitochondria work? Uh or is it that the might of how the mitochondria work
mitochondria work predict how you feel in the future? And we worked with Elissa Epel uh at uh in San Francisco, who had this beautiful study where they they had uh women uh fill out questionnaires or diary. So, in the morning, it takes about 10 minutes, and you you say how much stress you feel right now, how stressful do you think the day is going to be, uh and then how much love, closeness, and trust you experience, uh and then how much, you know, sadness, and rejection, and um and anger do you feel? And then they would do this also in the evening. So, then for a whole week, people did this at home. It was like a little take-home homework. Uh and then so, we had measures of how positive and also how negative people felt in the morning and in the evening for 7 days in a row. And then the beautiful thing that Alyssa did is that she had people come in on the fourth day, they came into the the research lab and then they gave blood. And from the blood we isolated white blood cells, which are cells of the immune system that have mitochondria. Then we measured the mitochondrial health. So uh we developed a little method to to get at how much energy uh the mitochondria can can generate for the white blood cells. And then we looked at whether how people felt on the first day, day one, day two, day three, does that predict how well the mitochondria work on day four? So is it the mood that's influencing the mitochondria, the mind and the mitochondria, or is it the mitochondria that's influencing how the mind factors
that's influencing how the mind factors or the mood on days five, six, and seven, right? And what we found was that it was particularly how positive people felt on the day just before the blood draw that where the the association was the strongest. So how people felt the day before they came, how positive especially in the evening, was associated with how much energy the mitochondria could generate the next morning. Uh and to us that was, you know, mind-blowing. The effects were pretty strong. And so it does suggest that that the data from that study, and now we need to do more studies and replicate this and look at this in, you know, more people and in men and women, uh is that 10 to 15% of mitochondrial energy production capacity in in the immune system is uh explained by how you feel the night before. Mhm. Wow. That's a lot. Yeah. Now, you know, in the other direction, was there a correlation at all uh as far as the the health of mitochondria pre - predicting how a person felt? There was zero association for the the things that we looked at. Oh, wow. That's interesting. Yeah. So, I was a bit surprised by that and uh so, the the strength of the association is is definitely stronger. The mitochondria uh um don't predict how people feel as much as how they feel predict, you know, how the mitochondria work. But again, this is one study uh in 91 women and uh there
one study uh in 91 women and uh there there's definitely a lot more work to be done and I think it's a there's nothing in biology that's linear and it's very unlikely that it's a purely um unidirectional process. Yeah. Now, speaking to that other direction, do you think it's it's reasonable to think that there is a relationship uh between mitochondrial health and specifically the person's perception of stress or a person's resilience to stress? So, for for example, um I've taken from some research and it's funny, I have a an image that I've used and modified that I took from this random animal study. I'm actually wondering if this is one of your studies. I found the study years ago and I kind of repurposed this image from the study and modified in a a bunch of ways and I literally right before this interview found this exact image, I mean, the original one that I took on your website for your lab. Uh and it it's a concept that I've termed the resilience threshold. Um and it's basically talking about how uh in to the degree that we have bigger, stronger, healthier mitochondria, more of them, our our cells literally at the cellular level, we know at at least at that level, you know, whether this correlates with the mind's perception of stress is another thing, but at least on the cellular level, we know that bigger, stronger, healthier mitochondria and more of them means a much bigger capacity to tolerate the stressors of
capacity to tolerate the stressors of the modern world and to not experience what what's called allostatic overload, and where you get symptoms and pathology and disease where the mitochondria are overwhelmed by the stress, start shutting down energy production, shifting out of that peacetime metabolism into defense mode, throwing off purines, throwing off mitochondrial DNA, causing oxidative stress and oxidative damage, and symptoms like fatigue. So, the more that mitochondria you have, the higher your resilience threshold, and the less likely you are to experience that issue, at least on the cellular level. Now, first of all, so two questions. One, would you agree with the way I explained that? And then two, do you think that this could also potentially translate into the mind's perception of stress and how resilient a person is? Mhm. So, yes, I I think you portrayed the situation very clearly and very well. I definitely agree with that. Um and yes, that's we're testing that idea at the moment. So, what we found a few years ago was that in mice, if you perturb the mitochondria, so you decrease the ability of mitochondria to make energy, or you cause mitochondrial dysfunction, when you expose a mouse with abnormal mitochondria, compared to a genetically identical mouse with normal mitochondria, the mouse with the abnormal mitochondria will perceive the same psychological stressor very
same psychological stressor very differently. And the physiological, the biological response in the body of the mouse in response to that psychological stressor is very different. And even though, you know, under normal conditions, you look at these mice, you can't tell them apart, right? They one of them has a mitochondrial dysfunction, the other doesn't, but when you stress them, you see all of these uh you know, beautiful multi-systemic uh you know, response signatures that emerges and that's regulated by the mitochondria. So, in animals and you know, there's a lot of research of you know, starts this way, right? As a proof of concept, you perturb the mitochondria, you can do this mechanistically and then you can show if I change one thing in the mitochondria, I change stress perception. So, now we've moved away from the animal work and now we're testing this in humans. So, we have people come into the lab and then we profile their mitochondria. So, we measure their mitochondrial phenotypes or we call them the mitotypes. Uh and then we quantify each person's mitotypes. Each person's mitochondria are pretty different and there is a big spectrum of how much energy uh a person's mitochondria can generate and then what kind of of uh what style of mitochondria they have, right? The same way that for personality, there's not like a higher or lower personality. There's different types or qualities of personalities, right? The big five personality characteristics or things like that. So, we're trying to develop at the moment tools to do the same kind of things, you
tools to do the same kind of things, you know, personality profiling of mitochondria. Fascinating. So, I want to tie a few things into this. Um you said something in the beginning of this podcast talking about exercise that we know that exercise can basically double uh the amount of mitochondria in a person's in in a person's muscle tissues and probably other tissues in the body as well. I'll speak to that from a different angle. There's a number of of studies that have looked at mitochondrial capacity over the course of people's lifespan. Uh and you're probably familiar with with some or all of this research where they basically take muscle biopsies, they look at um the amount of mitochondria in the cells and they measure mitochondrial capacity in various ways uh and they've shown in most of these studies, the results are very consistent that between the ages of about 40 to 70, people most people lose about half of their mitochondrial capacity. And there's probably there's evidence suggesting that probably from 20 to 40, people lose about half of their mitochondrial capacity. So, over the course of 20 to 70, most likely they're losing something like 70 75% of their mitochondrial capacity in most people. So, um and I I will also say that there's evidence looking at specifically people who are highly active, like people who are athletes, but who are 70, and they've shown that those people don't lose half their mitochondrial capacity. But that hormesis, the presence of hormesis, seems to be the defining factor, not aging, but the degree of hormesis seems
aging, but the degree of hormesis seems to be the defining factor in how much mitochondrial capacity a person loses. But we know also that, you know, circadian rhythm disruption and sleep deprivation can damage mitochondria in various ways. Melatonin plays a critical role in mitochondrial health. Man-made toxins play a critical role. We know there's a gut mitochondria link. We know nutrition plays a big role. Psychological stress plays a big role. So, we know all of these different factors tie into this. So, the way I would conceptualize this is over the course of a person's lifespan, to the degree that they're lacking hormesis, not eating a good diet, not minding their circadian rhythm and sleep habits, um not exercising, uh have psychological stress, have exposure to lots of toxins, they are basically it's a perfect storm of factors that are they're losing mitochondria rapidly, and the mitochondria they do have are get becoming more and more damaged and dysfunctional, ultimately leading to a a lower a progressive lowering of a person's resilience threshold and capacity to adapt to stressors, where they're much more likely to perceive stress be overwhelmed by stress, have a low have a very low threshold for tolerating stress, and so on, and much more likely to have those mitochondria actually be overwhelmed such that they get pathology and disease. That's my 2-minute like overarching model of human health. I'm just curious if if you would agree with my general framework there. Yeah. Isn't it amazing, you know, with within the context of everything you
within the context of everything you mentioned, most people remain healthy for most of their life? It's so funny. I was just saying that to my wife the other day. I was like, how it's amazing to me given how many things we're doing wrong, most people are doing wrong, it's amazing that we make it past 40. Yeah, there is you know, it's a superb resilience and you know, a bit ability to adapt. Um you know, you find people who go through the harshest and you know, most horrible things and and they adapt to this and actually, you know, experience growth in some cases. Um And the the organism is just a such a a masterpiece of, you know, of adaptation. We have the ability, you know, physically, physiologically, and but also psychologically and mentally. You know, people adapt to um to amazing things. Uh Again, adaptation requires energy. And you know, to some extent, that's one way when, you know, you see people in the clinic were very sick or people who, you know, end up you know, with disability that you know, last a long time, that's failure to adapt, right? Uh so, we can see disease not necessarily as kind of an anomaly that, you know, arises spontaneously but as a chronic failure to adapt. Um and people who have defective mitochondria seem to show that and and they're unable to bounce back from little things that other people would, um
would, um including circadian rhythms and including maybe you know normal daily stressors and uh and other things. So, yeah, I think it's it's phenomenal to to see how how resilient and and how you know well the organism can adapt to things and um you know ultimately I hope that our research is going to help to build a uh you know a bioenergetic view of of health and we know so little about health. We know a lot about disease. Um We don't know very much about what keeps us healthy and what's the um And I What are the things? That's such a good way of phrasing it. I would agree we need to be spending I would say probably directing like 60 or 70% of funds towards studying health rather than studying how to fix disease. I think we'd get a lot further Oh yeah. in fixing the health care model and and actually helping people be healthy if we did. Yeah, it's kind of a We study disease and then that leads to wanting to fix disease and then that leads to developing you know very targeted specialized um molecules, drugs. Um and then that leads to you know the way that we practice medicine. Uh which is palliative and once disease is there cuz we don't know what to do when there's no disease. So, we need to wait for disease to happen and then we come up with with chemicals that you know suppress some of these symptoms and it's never addressing and
symptoms and it's never addressing and never helping people to be healthy. It's remarkable. And to your point, you know, some of the the key overarching themes that you've been talking about as as far as your work the all of these different systems of the body are intertwined. So, to a large extent I would argue that the whole fundamental paradigm of seeking out some specific you you molecule that's or biochemical process that's gone awry and then developing a drug intervention to target this specific biochemical process and correct it is is just myopic and and so reductionistic and missing the big picture of how all these systems are intertwined. Mhm. Yeah. The thing is we don't know we don't see the bigger picture yet. And if we did, I think we could and if we did and if we had a less kind of mechanical view of how the system works, then we might be able to come up with uh a lot more um you know, intelligent or holistic or personalized ways to to help people, you know, develop and and harness their own resilience and ability to to heal and and recover. Yeah. And then that I think that's the real way forward for for health care. Yeah, right on. I agree with you. I know you have to run, so I have one final question to you, which is given everything you know about mitochondria, given everything you know about mitochondrial psychobiology and the research that you've done, what is one
research that you've done, what is one thing, one tip from the research, you know, that you've done on a practical level, the one thing that you want to leave people with as something they can take from this field of mitochondrial psychobiology to apply in their lives to improve their health, improve their energy levels, improve their mitochondrial health? I I What I I tend to think and I think there's still more work to be done to to be sure that's the case, but you know, the things that you feel that make you that the things that you do that make you feel energetic, uh the the people that you hang out with that make you feel uplifted and inspired and um so that subjective feeling of being energetic is probably so not so divorced from actually you know the the actual energetic function of your mitochondria. Mhm. And so you know engaging in behaviors and in actions that actually stimulate that in you you know whatever that is and I think that's different for for different people. Um is I think likely to have good health effects and and good effects you know on on people's lives. Yeah. Beautiful. Well, Dr. Picard this has been so much fun. This has been amazing. I this is honestly one of my most favorite interviews I've ever done. I I've really really enjoyed talking to
I I've really really enjoyed talking to you. I thank you so much for your the work that you've done. The researches that you've done has had a profound influence on me and my my thinking and the work that I do and I would love to have you on again after you get the results back of the the next study or two that you're doing. This has been just fascinating and and I hope to have you on again maybe a couple more times over the next That sounds great. Yes and I'd be delighted. I had a a lot of fun. Thank you for that. Yeah. Awesome. Well, have a wonderful night. I know you got to get get home to dinner with your wife and your family. So thank you again for staying a little extra with me and have a wonderful evening. Thank you. Also one more thing before you go. I just want to mention for those of you who were fascinated with this topic and this podcast. If you want to follow Dr. Picard's work further, you can check out his website at picardlab. org and you can follow him at Twitter at mitosiglab. Hey there. This is Ari again. One more quick thing before you go. Just make sure to subscribe to our YouTube channel The Energy Blueprint and also make sure to subscribe to this podcast on your favorite podcast platform, whether that's iTunes or Stitcher or anything else. I hope you guys enjoyed this interview, and I will see you again next week.
Transcript auto-generated by YouTube. Verbatim — duplicates intentionally preserved.
The modern wellness world often turns mechanisms into promises. A calmer approach asks better questions. What is the body being asked to adapt to? What dose can it recover from? What practice still feels intelligent tomorrow?
"Mitochondria do more than produce energy; they help cells interpret stress and coordinate adaptation."
Healthspan begins below the surface. Mitochondria, muscle, hormones, glucose control, inflammation for health, and repair systems shape how much capacity the body has available for work, recovery, and presence.
The strongest longevity practices are rarely dramatic. Training, protein, sleep, light, stress regulation, heat, cold, and metabolic steadiness compound because they are repeated. The advanced work rests on the ordinary work done well.
Use the idea as a ritual, not a performance. Start with the least dose that changes your state. Notice breath, sleep, appetite, training quality, and mood. Those signals tell you whether the protocol is building capacity or simply adding load.
Mitochondria do more than produce energy; they help cells interpret stress and coordinate adaptation.
Chronic stress changes the energy economy of the body, which can shape mood, fatigue, and resilience.
Mitochondrial health is built through rhythm: movement, sleep, nutrition, recovery, and psychological safety.
Choose one practice you can repeat consistently for the next two weeks.
Track the felt outcome: sleep, focus, calm, recovery, or energy.
Increase intensity only when the current dose leaves you steadier.
