In this episode, I have the pleasure of speaking with Dr. Martin Picard, a mitochondrial researcher who directs the Mitochondrial Psychobiology Group at Columbia University Irving Medical Center and is an Associate Professor of Behavioral Medicine in Psychiatry and Neurology.
We explore the fascinating topic of how stress affects your mitochondria and the link to aging, resilience, disease resistance, and, of course, energy levels!
This conversation was one of my personal favorites, and I can’t wait for you to hear it!
(This podcast was originally released in August 2019)
Table of Contents
In this podcast, Dr. Picard and I discuss:
- What is psychobiology? This is an incredible field you need to know about!
- The evolution and roles of mitochondria in humans…they’re much more than mindless, machine-like energy generators
- Do faulty mitochondria make us sick, or does disease cause faulty mitochondria?
- Dr. Picard’s top 2 recommendations to keep your mitochondria functioning optimally, including a factor you might not expect!
- Where cortisol—our main stress hormone—is actually made…if you think it’s the adrenal glands, you’re only partially right!
- Mitochondria’s amazing, evolutionary-based ability to communicate with the rest of our body through subtle signals…remember, they’re not just the “powerhouses of the cell!”
- Do mitochondria contribute to anxiety and depression? Dr. Picard provides a practical but nuanced answer
- One simple factor that determines 10-15% of mitochondrial energy production…you will definitely want to hear this!
- The role of mitochondria in stress resilience…listen in to learn Dr. Picard’s number one tip for boosting energy and becoming more capable at dealing with even big life stressors!
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Transcript
Ari Whitten: 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. His name is Dr. Martin Picard. He’s an assistant professor of behavioral medicine in Psychiatry and Neurology at Columbia University. He obtained his Ph.D. 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.
Mitochondrial Psychobiology explained
So that is a brief, you know, sort of official bio, but let’s simplify a lot of this stuff. So, what you do, Dr. Picard, is you work in a field called mitochondrial psychobiology. So, can you tell everyone exactly what that means?
Dr. Martin Picard: Yes, that is a good question. It is basically the intersection of mitochondria and the biological processes of things that happen there in the cell, inside the organelle, and then what happens in the mind, right? So, if we simplify this, it is basically mind-mitochondria science. Kind of like, you know, mind-body but here we dive a little deeper than just the body generally and we specifically focus on mitochondria, in part because mitochondria are the source of energy, right? That is where the reason we breathe and the reason we eat is to fuel the mitochondria. Right? The ultimate purpose of breathing and maybe why the breath is so common across all ancient traditions and, you know, religions. The breath is connected to bringing oxygen into the body. And then where does oxygen go in the body? It goes into the mitochondria. So, we study, because mitochondria are so essential to energy, we study how the mind and the mitochondria interact. And hopefully, it is 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 then why we get sick once in a while.
The role of mitochondria in the body
Ari Whitten: Yeah, okay. So, I want to back up just a minute. I want to get back to mitochondrial psychobiology in just a minute, but 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 three hours long. But just a brief description of what mitochondria are. And their vision or their role in human health has for a long time been conceptualized as, you know, sort of just these mindless energy generators in ourselves that just pump out energy. They take in glucose and fat and they pump out ATP. And that is kind of what mitochondria are good for. And in the last 10 or so years, there has been a really, like a re-imagining within the scientific community of the role of mitochondria in human health. So, kind of talk to me about your perception of how the scientific community’s perception of mitochondria has changed over the last couple decades.
Dr. Martin Picard: That is really good, I think an important transition that is currently happening. And, you know, a long time ago, about 1.5 billion years ago something happened that the only thing that existed on the planet were unicellular organisms, right? They were bacteria. There were different kinds of bacteria, little cells that didn’t talk to each other very much, probably. Some could use oxygen to make energy and some others could not use oxygen. And they were fermenting type bacteria like yeast. And then at some point, a bigger kind of cell bacterium engulfed a smaller oxygen-consuming bacterium. And then that smaller oxygen-consuming bacterium, instead of, you know, being digested and used for food by the bigger one actually managed to stick around. And that, the theory goes, became the mitochondria. And so, and for some reason in evolutionary history, that event seems to have been critical to the development of what is called multicellular life, right?
Like animals, including, you know, from as small as little worms, flies, you know, mice, dogs, and then humans. Thinking, feeling, conscious organisms, you know, evolved from this. It is called endosymbiosis. The “symbiosis” of things living together, and then “endo” because it is inside 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. And so, from their bacterial ancestry and origin, mitochondria were discovered about in, you know, the late 1800s, early 1900s first observed under the microscope. And people saw that they could move, and they could, you know, do things and they were named, you know, after their actual morphology, they change. Sometimes they can look like small little beans. That is mostly what you see in the textbook.
And if you Google mitochondria images, that is what you see, a bunch of beans or, you know, peanut-shaped things. And then they have like an outer membrane and an inner membrane. And inside of that is the mitochondrial DNA which is actually circular like the bacterial DNA. And so those are the kinds of things that make us, let us know that they used to be bacteria. And then in the ’40s, ’50s, ’60s, people started to focus heavily on the energy production capacity or function of mitochondria. And Peter Mitchell won a Nobel prize for understanding how mitochondria could store energy and actually transform energy from food and oxygen into membrane potential. How mitochondria become charged like little batteries. And then you figure it out that this energy potential, once a mitochondrion is charged, that energy can be used to make ATP.
And I think most people on your Podcast will know about ATP, adenosine triphosphate, as the energy currency of the cell and of, you know, most living organisms. And then that was the pervading view of mitochondria as an energy powerhouse. And I think most people know about the powerhouse of the cell, the analogy. We actually think it is a bad analogy because it is very mechanistic. It is very, you know, mechanical I should say. And mitochondria are so much more than powerhouses. And that is, I think, in line with the new transition away from this powerhouse analogy which portrays mitochondria as a little machine, right? A powerhouse. It takes an input, transforms it into an output, and then that, you know, power generation or transformation. Mitochondria actually have this beautiful complex life where they interact with each other, they can fuse.
So, two smaller mitochondria can come together, fuse, become a longer one. So, they change shape. They interact with each other. And then they can undergo the opposite process of fission. So, a longer tubular, imagine like a long spaghetti, it can become fragmented into little beans. So that is called fission, mitochondrial fission. And the fused mitochondria or the fragmented or fission mitochondria also have different functions. So, their shape is linked to their function which is what we see a lot in biology. And now our view is transitioning from this dynamic view of mitochondria which you can observe, you know, through movies and videos, some of which are on our website and you can find some of those on the Internet now. And then people are starting to realize actually mitochondria great, you know, they move, they make energy, but they actually produce signals, you know, they are sensitive to stuff and they generate stuff.
So, what we are finding is that mitochondria can respond to different hormones or to different metabolic signals. That is fairly well documented. And then mitochondria release another kind of biochemical signals and release other kinds of, you know, vibrational signals or you know, electromagnetic or something else, that can be transmitted between the mitochondria, between mitochondria and other parts of the cell, including the nucleus where the nuclear genome 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 will talk about that. 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 into the cell cytoplasm, the internal part of the cell or even into the bloodstream. And then those mitochondrial-derived signals can go everywhere in the body.
So now the view that we are starting to develop is one of a kind of a communicating collective of mitochondria distributed across different organs, different cells that talk to each other.
The importance of mitochondria for health
Ari Whitten: Yes. And I want to get into that. I want to get into this kind of mitochondrial DNA leaking into the bloodstream 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 what we now know about the role of mitochondria in human health very broadly, and just a 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 was just to burn off carbs and fats and produce energy.
And we now know there is so, so much more than that. But 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 aging and so on?
Dr. Martin Picard: Yes. So, the medical community and the scientific community have found associations between mitochondrial dysfunction, which is kind of broadly… It means a lot of things, but mitochondria not 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 different levels. The same way that 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 want and mitochondrial dysfunction, there is most likely an article that documents some evidence of mitochondrial dysfunction and that disease. So, what we don’t know there…
Ari Whitten: And even the aging process itself, more broadly.
Dr. Martin Picard: Yes, yes. Aging. There is a very large body of scientific evidence linking aging process and mitochondria, and I think quite convincingly, showing that mitochondria and dysfunctional mitochondria actually can precipitate or accelerate the aging process. And one question, you look at the scientific literature and you Google, you know, whatever disease you are interested in like Alzheimer’s or cardiovascular or cancer and mitochondrial dysfunction, then you find all these papers. You never know if it is the disease that happened through some process that we don’t understand that caused mitochondrial defects or dysfunction, or if it is mitochondrial dysfunction that is a primary cause or driver of the disease.
Right? Most studies don’t allow us to understand this. So, the state of the field is, there is 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? And that is where, you know, there is a smaller body of research that addresses this directionality. And, a big piece in that effort came in the 1980s, actually, where Doug Wallace and [inaudible] in England, they almost simultaneously discovered that there were defects in the mitochondrial DNA, so mutations or deletions in the mitochondrial genome 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. And since then there has been hundreds of studies that document these kinds of connections. And, you know, every week here in the clinic, we see patients who walk in with defects in their mitochondria and then 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, cognitive function. So, it is very clear now that when the mitochondria don’t work properly, they can cause disease and they can precipitate a lot of age-related disorders.
Ari Whitten: 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 life span or at the very least health span.
Dr. Martin Picard: Yeah, for sure. And you know, as you mentioned, exercise. I think exercise is probably the best, you know, health-promoting intervention. If it was a drug it would be amazing, you know, if people would take it all the time. There are so many good side effects and we don’t actually know why exercise is good for you. You know, there is no mechanistic understanding of why exercise is so good for healthspan and not quite sure it makes, it extends longevity. You know, people who exercise a lot don’t tend to live, you know, to 100 years old. And there is a lot of people who never formally exercise, and they don’t do, you know, marathon running and all of this and they end up, you know, living healthy and living very long. But physical activity, you know, being active, we don’t know why that is good. And one theory that we tend to favor is that exercise and physical activity is good for you because it simulates your mitochondria. It is hard to prove empirically.
The most important factors for mitochondrial health
Ari Whitten: Yeah. So, this is a nice segue. So, we know that exercise, physical exercise, and movement is very important for mitochondrial health. 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 link. So, can you, are there any other factors before we get to the mind-mitochondria, are there any other factors worth mentioning here that are key players in mitochondrial health?
Dr. Martin Picard: Something that has been studied a lot, you know, exercise is… We have known for a long time exercise increases the number of mitochondria in your body. So, if you go from being a completely not physically active individual like, you know, couch potato scenario chronically, and then you go and you say, “I am going to run a marathon.” And then you start working out a lot, you can double the number of mitochondria in your body, right? So, per amount of muscle, per gram of muscle, you can double the number of mitochondria in your muscle just by stimulating the body. And we think that this probably happens also in the brain. The brain makes more mitochondria and the muscles make more mitochondria if you are more active. So that we have known for a long time. Exercise improves the number of mitochondria. It also changes how they function.
Another thing that has been studied quite a bit is the health benefits of not eating too much. So, some people have called this calorie restriction because that is 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 be healthier. You know, there are some issues with these studies because of the control group, the control animals that, you know, eat as much as they want, they are housed always in little cages, right? That is very unnatural to live, for a rat or a mouse or, you know, any animal that we are using in these studies, to live in such a small shoe size box. And that is 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 is an abundance of food, as much as you want. Though 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 they are all of a sudden, you know, in evolutionary history that is a very kind of abrupt change where you are, you have zero need to do physical activity and then there is as much food as you want. So, you could argue in all the calorie restriction studies, the control group is actually an overfed, sedentary couch potato situation. And then it is not surprising that if you just bring down the number of calories, you actually maybe normalize things a bit more.
Ari Whitten: That is interesting, I never thought about it that way, but it is absolutely true. Especially, I assumed there were running wheels in the cages.
Dr. Martin Picard: Not. There were not.
Ari Whitten: That is not good.
Dr. Martin Picard: So, from those studies, you know, they were called calorie restriction. And then, now there has 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 are perpetually hungry for life. And apparently, I have 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 because they are a little grumpy. And, you know, feeling hungry chronically, you know, is not a super pleasant thing to do. And that is why a lot of people cannot stick with this for very long. There is more recent interest in intermittent fasting. And maybe, you know, you and your audience are familiar with this, where you know, you eat normally but then you don’t eat for 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. 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 same way that when you exercise you stress the body and then you stress the muscles and the muscle responds to this, becomes bigger and becomes stronger for the next time it is recruited or it is used, and it is stronger, and it is adapted. So, the same kind of thing happens. If you feel a little hungry, the body feels like, “Oh, like now I, there is no sugar around. I need to start using my mitochondria to use the fats and to use the proteins.” And then it starts, the mitochondria needed for this are not needed necessarily to burn off sugar.
So, if you feel hungry, typically, you know, there is, the blood and the tissue sugars are a little low and then that forces different tissues to adapt by using the mitochondria. So, it seems like feeling hungry a little bit, not overeating and not perpetually overloading your system with too much of anything, sugar or fat or proteins is a good thing. And for some reason that stimulates good, you know, quality control in the cells, like autophagy, mitophagy, so that the bad stuff gets removed and digested away and then you use the mitochondria that are good, well-functioning, or synthesized. So, exercise, not eating too much. These are two things that we know tend to be good for health and probably at least part of their… Part of the mechanism or part of the action is through this, through promoting mitochondrial health.
Mitochondrial Psychobiology – how stress affects mitochondrial health
Ari Whitten: Yeah. So, we know one of the third factors now that, thanks to your research and the work of some of your colleagues, we know that the mind and a person’s psychology can have a profound influence on our mitochondrial health as well. And you have done quite a bit of work, you have done some, you have published some really amazing research papers that I recommend people read. One is called, “An Energetic View of Stress Focused on Mitochondria.” Another one is called, “Psychological Stress and Mitochondria: A Conceptual Framework.” And these are really well worth digging into for anybody listening who is a health professional or just a science geek who is really interested in this topic. So, as you mentioned mitochondrial psychobiology, this mind-mitochondria link. And this kind of gets at the whole, you know, Descartes mind-body dualism and the fact that…we now know it is pretty widely accepted of course, that it is very widely accepted, that we know that the mind has a profound influence on the body.
There are 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 the risk of diseases later on in life, and many, many other aspects of this. So, we know there is 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 uncovered a really important aspect of that. So, can you speak to that? So, what is this mind-mitochondria link all about?
Dr. Martin Picard: Yeah, so that is probably my favorite topic. So, I appreciate, you know, talking with you about this. I would say exactly, you know, the mind-body connection and, you know, just disassociating 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 is, maybe, is a whole point of analysis, right? To break down into pieces. And all of our research methods are ways to break things down 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, as you say, you know, there are well-documented effects, for example, of psychological stress on the immune system. And there were seminal studies done by Kiecolt-Glaser who showed medical students during exam periods like at the end of the semester who were super stressed out because they think their life is going to be done if they don’t pass this exam, then they are more susceptible to infections. So, they actually, if you expose them to some stressors… 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 virus in the nose and then showed that. And when people are stressed their immune system is down and they are more vulnerable to getting the cold and to infections. And then Kiecolt-Glaser showed that wound healing, you know, something as fundamental as if there is a wound on your skin or, you know, on your gum, how quickly that wound heals, which is also an integrated process. You need cells to, you know, to kick in for their proliferation. You need the immune system to come in, produce some cytokines. And, you know, the blood flow needs to change, and that is a whole organized process. And they showed people when you are stressed and if you experimentally stress someone, that slows down wound healing and it makes the person more vulnerable to infections, the immune system is modulated. So, these are some of the, you know, old seminal work that, I’m not sure if it is taught so much in medical school, but it is not part 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 molecular or biological mechanisms by which this happens, right? So, there is the mind here, you experience something, there is a subjective experience which is very real, right? Whatever is in your head, whatever we experience subjectively, it is very real to the person who is experiencing it. And then there are these biological changes that happen in the immune system, in the wounds, right? Or in the brain. These are very real biological changes. What is connecting these things, right? How do subjective experiences get translated into a language that the biology actually follows and then responds to? And our guiding hypothesis is that mitochondria and flow of energy is that connection or that interface.
Ari Whitten: Now, a quick question here. There is 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 that have been around in the natural medicine community has been the adrenal fatigue model. And it is 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, and that is 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 is a couple of 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 is sensing stress and mediating different effects in the body. You know, there are other people out there, like there is a guy out there who specializes in chronic fatigue syndrome who I have interviewed on this Podcast named Ashok Gupta who really says, “No, the hypothalamus and pituitary are not the most upstream thing. It is actually the limbic system and the amygdala that are the most upstream thing.” And then we have, you know, for example, there was an article, I believe it was in “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 you basically subjected people to stress and then you measured mitochondrial DNA in their blood. 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 is 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’re your thoughts on how that should be conceptualized as far as what is the most upstream, most sensitive thing that is detecting the first immediate signals of what is going on in the environment?
Dr. Martin Picard: So the work that you referred to was the work that was done in collaboration with the Anna Marsland and Brett Kaufman in Pittsburgh, which showed 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 stress 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 is more mitochondrial DNA that is released. And so that demonstrates the mitochondria somehow respond to that subjective experience and then respond by releasing the mitochondrial genome. And, you know, Doug is fantastic, and he commented on this study and that is his view, that the mitochondria are the most sensitive thing in the body.
I tend to agree, and I imagine that it is because, you know, everything in the organism, you know, or from just being alive requires a flow of energy. And anything that is stressful and by definition, you know, something that is stressful is something that perturbs us, right? Something that is not stressful then doesn’t elicit anything in the organism. And it is very hard to not be stressed or influenced by anything. I think if you were dead, you know, if there is no flow of energy in the body and the body is not animated by energy anymore, then the body cannot respond to, you know, to a stressor. But we respond to just a little word. 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 we are stressed. So, there are all of these changes. Every little bit of the stress response, from increased heart rate or blood pressure to producing a new hormone or releasing a hormone, every little bit requires energy. So, there is nothing in the body that moves or that changes that don’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 things to change when there is stress. And then because energy flows mainly in the mitochondria in human beings and in 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 then respond to that.
So, there are mitochondria everywhere. You know, 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 are mitochondria everywhere, in the amygdala, in the hypothalamus and thalamus and the pituitary gland and the adrenal glands. And what is remarkable is that 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 is actually in the mitochondria. So, every stress hormone and every, also sex hormones, all of these hormones that are derived from cholesterol, they are called steroid hormones, they are all made in the mitochondria.
So for some evolutionary reason the body thought it was a good idea to put the synthesis of one of the most important families of hormones, the sex hormones that defined, you know, female from male and the stress hormones that allow us to survive different events, you know, throughout life, those are actually synthesized in the organelle that sustains energy. So, there is not really good… You know, we can speculate as to why that is. But from our view, I think it is a good illustration of how tightly knit those things are, the stress response and the energetic capacity of the organism.
The cell danger response and mitochondrial health
Ari Whitten: Yeah. I am curious, are you familiar with Dr. Robert Naviaux’s work on the cell danger response?
Dr. Martin Picard: Yes.
Ari Whitten: I feel like this ties into your model perfectly. I think you are doing these two lines of research that you guys have been doing completely separately and yet you are basically arriving to a large extent at the same conclusion, which is mitochondria are essentially the most sensitive thing in the body as far as detecting environmental signals. And then they are determining, from the model of Dr. Robert Naviaux’s, they are determining whether they are going to stay in peacetime metabolism as he calls it, which is energy mode, where they are actively taking in fuel and producing ATP and powering the organism. Or if they are 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. And then if they are 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 purines, purinergic signaling, and the leakage of like ATP and ADP outside of the cell and this being a critical signaling molecule that signals other cells in the system about the threat present.
In some of your research, you guys have found that mitochondrial DNA actually gets leaked into the bloodstream. And this, in your words, this is a quote from you in commenting on some of this research. You said, “This circulating mitochondrial DNA acts like a hormone.” And so, it is somewhat mimicking the adrenal glands’ response to cortisol and it is having all of these effects on the rest of the cells where it is communicating, “Hey there is a threat present, there is danger, we are under stress. We need to shift more into defense mode.” So, there is a lot of similarities, like I said, between your two lines of research and yet you are, to some extent, talking about different molecules being the key signaling molecules. So, can you kind of make sense of all that for me?
Dr. Martin Picard: Yeah. I think both models converge, and I love Bob’s… 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 is a lot of overlap and I think we resonate on many different levels. I think the same way that… If you think about mitochondria not, again, as a powerhouse, but as, you know, communicating organelles and organisms. You know, another kind of, you know, living organisms that co-exist in the same space, right, that share information that actually communicate and physically interact, that, you know, synchronize their function. These are all properties of mitochondria. They are also properties of every other social animals, social organisms. So, we are starting to see mitochondria as social organisms. Organisms that communicate with each other do not communicate through only one mechanism. Right?
So, there is not one type of thing that you do to talk to another person. There is, you know, there are words. There are 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 now…
Ari Whitten: [Crosstalk] the classic wife statement, “It is not what you said, it is how you said it.”
Dr. Martin Picard: 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 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 can be transmitted, you know, very quickly.
And then there are chemical or chemical signals, you know, at the synapses with serotonin and dopamine and some other things. So even, you know, very specific biological systems have multiple redundant ways of communication. And if you take an analogy, you know, the mitochondria trying to communicate states of threat or, you know, states of wellbeing to the rest of the organism. If they only had one switch, it is either on or off. That might not work really well. You know, it is like if we only had one word to talk to each other, either it is good or it is bad, right? That would not be great. We have a vocabulary with thousands of words that we can combine with, you know, in different sequences and then so on. And the same thing, you know, for computers and you know, digital information.
The flexibility you have when you have multiple signals, you can combine in different ways. You know, the texturing you can get out of this and the image and, you know, a picture or in a biological system is remarkable. So, the same way we think all sorts of words and can communicate some very sophisticated ideas, biological systems have also learned to do this. And that is why there is not only one neurotransmitter in the brain, you know, there is several. That is why there is, I think, multiple different kinds of communication molecules that come from mitochondria. And I think it is to communicate the complexity of what is happening at the subcellular level that needs to be communicated throughout the organism.
How our bodies are designed to react to stress and why
Ari Whitten: Yeah. Now, what, sort of big picture, what is this signaling all about? So we know that psychological stress, what is going on in the mind affects mitochondria, can cause mitochondrial dysfunction, can cause the contents of mitochondria, whether it is the DNA, whether it is purines like ATP and ADP to leak out of the cell into the bloodstream where it is 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?
Dr. Martin Picard: One way to think about it is not as, you know, a purely kind of dysfunctional system. Like stress is bad. It causes these molecules and then that causes disease. But, 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 if you have zero stress, you know, some people need quite a bit of stress to actually get something done and, you know, with stress can come motivation and some other things. There is, you know, Bruce McEwen likes to call it “toxic stress,” when it is not good anymore. But, you know, all of this stuff before toxic stress can actually stimulate, you know, healing and stimulate adaptation and you know, the strength of different functions.
Ari Whitten: And actually, bolster the organism’s health and resistance to increase longevity.
Dr. Martin Picard: Yeah. Then you mentioned hormesis earlier, right? That is that idea. There are little stressors will stimulate processes in the body that if those, if that stress persists, that can become damaging. But if it is 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 then, you know, your body will become a little stronger as a result. So that is hormesis, the body adapting to challenge or to stress and then becoming stronger as a result.
So, I think the different processes you were mentioning we see as communication. Why, you know, why would mitochondria release all of these things? We think it is the same reason as, you know, why do people talk to each other? Right? Because that is how things need to work. You know, why do different organs in the body talk to each other? Why do the different organs that are connected with our cardiovascular system through blood? Information needs to be exchanged. I think it is a basic property of life. And that is how complex systems, you know, function and operate. That is how things, living organisms fight entropy, you know, to remain healthy is to go against the, you know, the forces of physics. You know, if we were subjected to the forces of physics and we didn’t have energy flow to resist that, then we would just decay. Right?
We manage to go against that and to go against the dissipation of matter for, you know, 80, 100 years because of the flow of energy and because, you know, there is communication. So, it is a bit similar if we were to look at the brain from a primitive, you know, view. Like, I don’t know how long ago, a century ago we would say when you stress a 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 is all of these chemicals being released in the back part of the brain, the occipital region where the visual information is processed. There is like GABA and serotonin and like dopamine and these things will be released. Then you would say, “Oh, this must be dysfunctional.”
But then, you know, in hindsight it is like, “No this is, neurons need to talk to each other to make sense of the information that is coming in.” And that stress, that perturbation that is 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 remain alive and to remain healthy and to adapt to it, there needs to be communication, right? That is how complex networks and complex systems work and process information and adapt to it. I think that is how we see those signals that mitochondria release. If you look at it simplistically you say, “Mitochondrial DNA release, bad. Triggers inflammation, bad.” You say, “Mitochondria releases these molecules. It has multiple effects.” We have 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 overly simplistic explanation or interpretation comes from our lack of sufficient knowledge and maybe the simplicity of our minds.
The link between mitochondrial dysfunction and depression and anxiety
Ari Whitten: Yeah, absolutely. So, we know that there is 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. We also know that there is an emerging link, through a number of studies, with mitochondrial dysfunction and psychological factors like, or brain-related conditions, like depression and anxiety and even neurodegenerative diseases going more into brain conditions. But we know that there is this link there. Do you think that this, you know, kind of a simple model of this, and I am sure that this is oversimplifying it and leaving out a lot of complexity, but do you think it is reasonable to say that stress on the system can cause mitochondrial dysfunction that can contribute very directly to things like anxiety and depression?
Dr. Martin Picard: I think that is very likely. And at this point, we don’t have all of the pieces of the puzzle to say for sure that this is how it happens and that depression and anxiety and bipolar disorder and schizophrenia and so on, are mitochondrial disorders. We do see these psychiatric disorders more frequently in people who come in with a genetic defect in the mitochondria as I mentioned earlier. So that is fairly strong evidence that if something is wrong with the mitochondria, this can cause defects of, you know, perception of reality or perception of the world and regulation of mood and affect and so on. So, there is some evidence, but we don’t know for sure that the stress causes cycle pathology through the mitochondria, but I think it is likely.
And something that we identified recently, we wanted to know does how you feel influence your mitochondria? And, “How you feel” meaning both negative stuff like stress 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 kinds of good things that we feel once in a while. So, we wanted to know, are these things predictive of how well someone’s mitochondria work? Or is it how the mitochondria work predict how you feel in the future? And we worked with Elissa Epel in San Francisco who had this beautiful study where they had women fill out questionnaires, you know, diaries. So, in the morning, it takes about 10 minutes and you say how much stress you feel right now? How stressful do you think the day is going to be? And then how much love, closeness, and trust you experience? And then how much, you know, sadness and rejection 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. That was like a little take-home homework. And then so we had measures of how positive and also how negative people felt in the morning, in the evening for seven days in a row. And then the beautiful thing that Elissa did is that she had people come in, on the fourth day they came into 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, we developed a little method to get at how much energy the mitochondria can generate in 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 is influencing the mitochondria, or the mind and the mitochondria? Or is it the mitochondria that are 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 was where 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. And to us, that was, you know, mind-blowing. The effects were pretty strong. And so it, that would suggest that, the data from that study (and now we need to do more studies and replicate this and look at this and, you know, more people and in men and women) is that 10 to 15% of mitochondrial energy production capacity in the immune system is explained by how you feel the night before. That is a lot.
Ari Whitten: Wow. Yeah. Now, in the other direction, was there a correlation at all as far as the health of mitochondria predicting how a person felt?
Dr. Martin Picard: There was zero association for the things that we looked at.
Ari Whitten: Oh, wow. That is interesting.
Dr. Martin Picard: Yeah. So, I was a bit surprised by that. And, so the strength of the association is definitely stronger to mitochondria 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 in 91 women and, there is definitely a lot more work to be done. And I think it is, there is nothing in biology that is linear, and it is very unlikely that it is a purely unidirectional process.
Ari Whitten: Yeah. Now, speaking to that other direction, do you think it is reasonable to think that there is a relationship between mitochondrial health and specifically the person’s perception of stress or a person’s resilience to stress? So, for example, taken from some research, and it is funny, I have an image that I have used and modified that I took from this random animal study. I am actually wondering if this is one of your studies. I found this study years ago and I kind of repurposed this image from this study and modified it in 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. And it is a concept that I have termed the resilience threshold. And it is basically talking about how, to the degree that we have bigger, stronger, healthier mitochondria, more of them, our cells literally at the cellular level, we know 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 the modern world and to not experience what is 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 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?
Dr. Martin Picard: Yes. I think you portrayed the situation very clearly and very well. I definitely agree with that. And yes, that is, we are 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 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? One of them has a mitochondrial dysfunction, the other doesn’t. But when you stress them, you see all of these, you know, beautiful multi-systemic, you know, response signatures that emerge and that is regulated by the mitochondria.
So, in animals, and there is a lot of research, you know, it starts this way, right? It has 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 have moved away from the animal work and now we are 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 called them the “mitotypes.” And then we quantify each person’s mitotype. Each person’s mitochondria are pretty different. And there is a big spectrum of how much energy a person’s mitochondria can generate. And then what kind of, what style of mitochondria they have. Right? The same way that for personality, there is not like a higher or lower personality. There is different types or qualities of personalities, right? The big five personality characteristics are things like that. So, we are trying to develop at the moment tools to do this same kind of thing, you know, personality profiling of mitochondria.
The importance of exercise (hormesis) for optimal mitochondria
Ari Whitten: Fascinating. So, I want to tie a few things into this. You said something at the beginning of this Podcast talking about exercise, that we know that exercise can basically double the amount of mitochondria 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 is a number of studies that have looked at mitochondrial capacity over the course of people’s lifespan. And you are probably familiar with some or all of this research where they basically take muscle biopsies, they look at the amount of mitochondria in the cells and they measure mitochondrial capacity in various ways. And they have 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 is probably, there is 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 are losing something like 70, 75% of their mitochondrial capacity in most people. So, and I will also say that there is evidence looking at specifically people who are highly active, like people who are athletes but who are 70, and they have shown that those people don’t lose half their mitochondrial capacity.
Dr. Martin Picard: I agree, I agree.
Ari Whitten: That hormesis, the presence of hormesis seems to be the defining factor, not 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. Manmade toxins play a critical role.
We know there is 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 are lacking hormesis, not eating a good diet, not minding their circadian rhythm and sleep habits, not exercising, have psychological stress, have exposure to lots of toxins. They are basically, it is a perfect storm of factors that are, they are losing mitochondria rapidly and the mitochondria they do have are becoming more and more damaged and dysfunctional, ultimately leading to a lower, a progressive lowering of a person’s resilience threshold and capacity to adapt to stressors where they are 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 is my two minute like overarching model of human health. I am just curious if you would agree with my general framework there.
Dr. Martin Picard: Yeah. Isn’t it amazing, you know, within the context of everything you mentioned, most people remain healthy for most of their life.
Ari Whitten: It is so funny. I was just saying that to my wife the other day. I was like, “It is amazing to me given how many things we are doing wrong, most people are doing wrong, it is amazing that we make it past 40.”
Dr. Martin Picard: Yeah. There is, you know, it is a superb resilience and you know, and ability to adapt. You know, you find people who go through the harshest and most horrible things and they adapt to this and actually, you know, experience growth in some cases. And the organism is just such a masterpiece of, you know, of adaptation. We have the ability, you know, physically, physiologically, but also psychologically and mentally. You know, people adapt to amazing things. Again, adaptation requires energy. And, you know, to some extent that is one way when, you know, you see people in a clinic who are very sick or people who, you know, end up, you know, with a disability that lasts a long time, that is the failure to adapt, right? So we can see disease not necessarily as kind of an anomaly that, you know, arises spontaneously, but as a chronic failure to adapt.
And people who have defective mitochondria seem to show that and they are unable to bounce back from little things that other people would, including circadian rhythm, including maybe, you know, normal daily stressors and other things. So, yeah, I think it is phenomenal to see how resilient and how well the organism can adapt to things. And, you know, ultimately, I hope that our research is going to help to build the, you know, bioenergetic view of health. And we know so little about health, we know a lot about the disease. We don’t know very much about what keeps us healthy, and what are the things?
Ari Whitten: Yeah. That is 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 the disease. I think we would get a lot further in fixing the healthcare model and actually helping people be healthy if we did.
Dr. Martin Picard: Yeah. It is 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, molecules, drugs. And then that leads to, you know, the way that we practice medicine, which is palliative and once the disease is there. Because we don’t know what to do when there is no disease. So, we need to wait for disease to happen. And then we come up with chemicals that, you know, suppress some of these symptoms and it is never addressing, it is never helping people to be healthy. It is remarkable.
Ari Whitten: And to your point, you know, some of the key overarching themes that you have been talking about as far as your work, 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 know, molecule that is, or biochemical process that has gone awry and then developing a drug intervention to target the specific biochemical process and correct it is just myopic and so reductionistic and missing the big picture of how all these systems are intertwined.
Dr. Martin Picard: Yup. The thing is we don’t know, we don’t see the bigger picture yet. And if we did, I think we could probably… And if we did and we had a less kind of mechanical view of how the system works, then we might be able to come up with a lot more, you know, intelligent or holistic or personalized ways to help people, you know, develop and harness their own resilience and ability to heal and recover. And I think that is your real way forward for healthcare.
Ari Whitten: 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 have done, what is one thing, one tip from the research you know, that you have 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?
Dr. Martin Picard: That is a deep question. What I tend to think, and I think there is still more work to be done to be sure that it is the case, but you know, the things that you feel that make you, the things that you do that makes you feel energetic, the people that you hang out with that make you feel uplifted, inspired, so that subjective feeling of being energetic is probably so, not so divorced from actually, you know, the actual energetic function of your mitochondria. 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 is different for different people, is I think likely to have good health effects and good effects on people’s lives.
Ari Whitten: Yeah, beautiful. Well, Dr. Picard, this has been so much fun. This has been amazing. This is honestly one of my most favorite interviews I have ever done. I have really, really enjoyed talking to you. I thank you so much for the work that you have done. The research that you have done has had a profound influence on me and 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 next study or two that you are doing. This has been just fascinating, and I hope to have you on again maybe a couple more times over the next …
Dr. Martin Picard: That sounds great. Yeah, so, and I, would be delighted. I had a lot of fun, thank you for that.
Ari Whitten: Yeah. Awesome. Well, have a wonderful night. I know you have got to 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.
Dr. Martin Picard: Thank you.
Show Notes
00:00 – Intro
00:50 – Guest Intro
02:19 – Mitochondrial Psychobiology explained
03:38 – The role of mitochondria in the body
10:47 – The importance of mitochondria for health
16:31 – The most important factors for mitochondrial health
22:12 – Mitochondrial Psychobiology – how stress affects mitochondrial health
33:40 – The cell danger response and mitochondrial health
39:47 – How our bodies are designed to react to stress and why
44:56 – The link between mitochondrial dysfunction and depression and anxiety
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