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Martin Picard | Mitochondria, Aging, Cellular Energy, Metabolism, Gray Hair Reversal & Brain-Body

Full episode transcript below. Beware of typos!

Nick Jikomes

Dr. Martin Picard, thank you for joining me.

Martin Picard 4:37

Thank you. Pleasure.

Nick Jikomes 4:38

Can you start off by just telling everyone what you do in your lab and what you research?

Martin Picard 4:43

Sure. So what we do everything that we think about or you know, doing the library relates in some way or another to mitochondrial psychobiology. So we're mitochondrial psychobiology Lab, which basically means we're using mitochondria and some of the The tools and insights and knowledge we have around mitochondrial biology to understand how brain and body talk to each other, right? Or this synergy of, of mind and mind body. So we think a lot about mind mitochondria.

Nick Jikomes 5:14

I see so so when you say psychobiology, you mean this, this communication between the brain and the body?

Martin Picard 5:20

Yes, I think the we can reduce the psyche, this the psyche, part of psycho biology to the brain? I think there's probably more than that. But, yes, mostly that that's what we're talking about how do how do subjective experiences are related to you know, the human experiences, you know, more generally, the psychological states that we experience, the things we think about the emotions we we live in, you know, more elaborate construct psychological construct, like, you know, feeling like your life has purpose and as meaning like, there's good evidence, this actually relates to how well people age, or your risk of developing certain diseases. You know, over time, we don't really know how these things the subjective human experiences are related to the biology, right? How are they transduced into biological molecular changes that manifest in some way or another in health, right, the ability to resist decay over time and to remain healthy for decades, or your risk of disease. So that's that interface is, I think, where there's a lot of unknown and a lot of gaps in knowledge.

Nick Jikomes 6:27

Yeah, I think, you know, a lot of people, when they think about the mind and how the brain relates to that, they think naturally, both scientists and non scientists, you know, about circuits and networks and very complicated patterns of activity that are happening at, you know, what you call the the higher level of function, they don't often think about what's going on at the single cell level, or even inside of cells, whether that could be like, in a moment to moment way actually important for what our mental experience is like, and what our psychological experiences are like. So we're gonna dive down to that level, which is super interesting. But to set the stage for people that don't have much background in cell biology, and you don't, you know, you don't want to think about like psychology or neuroscience or consciousness, you don't necessarily a lot of people don't think about cell biology first. It's sort of like a separate field. You many people think, so what sort What are mitochondria? And why? What led you to sort of come out these questions from cell biology?

Martin Picard 7:26

Yes. And another way think about this is what justifies our Mitel centric perspective and our Mito centric approach. Yeah. I fundamentally, I think what drew me to mitochondria originally, and what drives the focus of our lab on mitochondria, is this fundamental role that energy plays in life. And, you know, if we think about where we come from, ultimately, every life form on the planet comes from energy that travels as a light beam, you know, from this nuclear reactor in outer space. So you get this beautiful energy that travels almost without loss, right, and then boom, it's absorbed by plants, and then that energy gets stored in some way in the carbon oxygen bond of the plant. And then at some point, an animal comes along, and then you know, eat that, and then either we eat this, or we eat the animal that ate that. And then what the major difference between a cadaver, like a dead body or a thinking feeling, you know, conscious person that experiences stuff, right, is really to flow energy, like the cadaver and the thinking conscious person that enjoys life, the main difference is not the number of cells right mostly is the same, if you die, you're the cells, number of cells stay the same, the number of genes stay the same, the organization of the cells stay the same in the brain, right? All the neurons, then the glial cells, all the networks are still there, but without the flow of energy, then you're more you know, like, your brain is a fatty blob. And the body is a bag of cells, but with the flow of energy, then this whole thing comes to life. And then you know, experiences kind of emerges from this Energizer animated system. So recognizing that energy is fundamental to everything that lives and the reason we breathe, right and you could go so far as saying, The reason we evolved the lungs and a heart and a cardiovascular system, like our anatomy, was all optimized to deliver oxygen to you know, to fuel the process of life to fuel the kind of the inner regulated fire that you know, burns inside your cells. And then if you think well, where does where does that happen? Right? Where is that energy being converted because we eat you know, chemical substance we eat chemistry, those carbon oxygen bonds, right that store the energy of the of the sun, and then we breathe in oxygen that the plants released in doing this, this reaction powered by the sun. And then at some point, this carbon oxygen, the energy that's stored between the carbon and oxygen is freed, boom, right? You, you pop those away from one another, you know, with the help of oxygen, and that releases energy. And what life and your biology has learned to do is to harness that energy in a beautiful, you know, way that just opens up I think degrees of complexity for for biological systems, this very special life giving reaction or process happens inside this little cellular structure. That's called mitochondria.

Nick Jikomes 10:39

So So what exactly are these things? And how are they different from some of the other basic structures in ourselves? But like, what, what are they?

Martin Picard 10:47

Yes, so the, if you look at a cell, you know, people tend to think of the cell membrane, right, so there's kind of the skin of the cell. And then inside, there's a nucleus, most people have heard about the nuclear genome and the 23 pairs of chromosomes, half from mom, half from dad. And then the, in the soup, the inner soup of the cell, the cytoplasm, there, all of these organelles, these organ of the cell, right, so these kinds of specialized sub cellular structures, and different organelles specialize in different things. So you have the endoplasmic reticulum that specializes and you're making specific proteins and little like working units for the cell, you have the Golgi that specializes in taking those proteins, processing them kind of doing quality control and packaging and shipping out if that's the purpose of that cell. And then one of those origins of the internal cellular Origins is mitochondria, which there's a long history we can talk about if you're interested of how these came to be. And there's really good evidence that when mitochondria came into the picture, as endosymbionts, they enabled complex multicellular life. So there's hundreds or 1000s of them that are kind of running around inside the cell, and they're beautiful. They're probably the most dynamic and complex organelles inside the cell. They're also the only organelle to have their own genome, which is, which makes them a little special. All the other organelles don't have DNA, it's all in the nucleus, and then the mitochondria have their own genome, it's a very small circular piece of DNA. That's, you know, not very big, only has 37 genes on it, and only 13 of those 37 codes for proteins. And there, but those are essential for energy transformation, this process of, you know, taking extracting energy from these carbon oxygen bonds, turning this into electrical energy or voltage potential, just like, you know, the energy in a battery. And then once you charge your battery, you can do all sorts of things. So mitochondria, as a result, do all sorts of things. They make ATP, right, but they also do dozens of other critical functions that either allow the cells to live or cells to die. And so they have a very big say, in what how cells behave. So we see them a lot more, you know, closer to the driver's seat, than the nucleus, which is more like a passive repository of information, you have this nucleus is more like a library, right? With 25 ish, 1000 books. Each book has a recipe, you know, which can be pretty complex, spread out over a really long, you know, regions of genome. But those books, right, unless someone goes into the library, turns on the lights energy, and then grabs a book and has an intention to do something with this gene with this book, you know, it never gets read. So and what actually goes in there picks up a book turns it on and then decides to do something with it is first moved by energy. If there's no energy in the cell, you know, books stay closed. And once it's entered, the system is energized. Now there's a potential right to get some of those books out and actually create something using the information that's encoded in the books. So mitochondria play a really big role, right as bringing genes to life and, and others. And we have shown how mitochondria also produce signals that decide which books you know, get open, and when so there's a big fraction of the nuclear genome that's under mitochondrial regulation or under the control of energetic signals, and evolution. Evolutionary speaking, this probably makes a lot of sense. You would want to tailor which genes are turned on what the cell decides to do, based on how much energy is available and based on other signals that mitochondria can perceive and, and integrate.

Nick Jikomes 14:40

Yeah, you want. You want a library and you want some mechanism to direct where you're looking and what you're, what you're reading and how to read it. It can't all just sit there on its own. So you mentioned some interesting things about mitochondria. There's a lot of them in each cell. It sounded like hundreds or 1000s in every single one of our cells. They've got their own A genome. And they're like, literally, as I think you're going to explain to us, they're like cells within cells. So before we get to what they were or where they came from, maybe we should start with the most famous function associated with mitochondria, which is ATP and essentially energy production. So can you give everyone a basic overview of what, what is ATP? And what did mitochondria do to create

Martin Picard 15:25

it? Yes. So they're hundreds to 1000s. So if you look at a cell, there's typically like a few hundreds, maybe up to like 1000, or 2000, in the cells that have the most mitochondria. So that's kind of the the spectrum, let's say 100 to 5000 mitochondria per cell, and then these change shape, so like counting them is actually a little difficult. But yes, what's ATP. And I'd say the mitochondria don't produce energy, right, they transform energy I see. So they take the energy that you eat in the form of glucose, let's say break and then it's broken down into two pieces pyruvate by the glycolysis. pathway, and then mitochondria can take in pyruvate, and then break those down into you know, smaller pieces, strip off the hydrogen and the electrons from the from those little three carbon backbones and then transform that energy into a membrane potential, which is Chemi asthmatic theory. And then we use that membrane potential, that voltage and pH differential across the inner mitochondrial membrane, so exactly like a battery, right? Then once that battery is charged, there's dozens of things and you said it, well, you know, which ATP synthesis as one of the functions, right with an S of mitochondria. So ATP synthesis happens when mitochondria decide to use this membrane potential, right? So the mitochondria is my mitochondrion is charged because it did all of this electron ripping off the the carbon backbones, flowing the electrons, oxygen accepts it, which creates a driving force to pump protons across the plasma membrane, now that this charge is there, the mitochondria and can decide what to do with it. And it decides not kind of on its own, but based on what the cell needs. And right, so there's a lot of inputs that are integrated. And if there's a need for energy, right, so if in the cytoplasm somewhere, there are processes that are consuming ATP, so they're breaking ATP into ADP and phosphate. Now, this is a signal that mitochondria can be are sensitive to, and their pores in the mitochondria where ADP can come in. And then if ADP comes in, this kind of drives the whole thermodynamic flux, of, of wanting to make ATP, right, and that happens in a very special protein. That's a rotor like multiprotein. Big molecule, it's a bit complex. It's called complex five, or the eight f0, f1, ATP synthase, and the mitochondrial intermembrane. And what this basically does is a couple's the flux of something through a turbine looking like structure, it's called the C ring inside the inner mitochondrial membrane. And this is just like an electric turbine, like in a dam, right? If you think about hydro electricity, you have a big dam. On one side, there's, you know, emptiness, the bed of the river that used to be there. And then on the upside, there's all of the water accumulated. So that's your, that's your potential potential energy. Yes, exactly. So that's this potential energy that's stored right here in the height of the water in the mitochondrion. It's stored as this separation of charge, right? Protons on one side. And then if you open the gate, and you have the water flow through the dam in through a turbine, right, it's going to use the force the potential energy of the water, turn the turbine, and then you can decide to do something with this right. So theoretically, you could couple the turbine to do a mill right to grind out. So like windmill, or if you have a little stream, you can like that's that used to be done a lot, right. So in a hydroelectric dam, you couple this to an electric motor, and then you can actually generate electricity and then send this off and people can power their home, charge your phone and power the computers with. So that's that's the fundamental process of ATP synthesis happens through extracting the, this membrane potential having the little turbine and the mitochondria turn in and coupling this here, not to electricity production, but to ATP synthesis. So it's by turning the this complex five this ATP synthase. You can bring ADP and phosphate very close to one another and then boom, you push them together, and then that stores energy and this bond.

Nick Jikomes 19:49

Yeah, so these these really are like little molecular machines that behave like like little like battery like little smart batteries that can move around and they somehow suck in energy in the form of stuff from our food. And they do these transformations to power to power these little machines, as you were describing. And I think I, you know, we'll talk about what else they do. But it's so cool to hear about this, if you've never heard about it before. And it also starts to make sense of like, why an organelle is there and behaves like this in the first place to understand the evolutionary history. So where did these mitochondria come from? And and how does that start to relate to why they're so unique? Why they have their own genome and why they can sort of behave almost like a little autonomous, autonomous cell within a cell?

Martin Picard 20:36

Yeah. And probably the simplest answer is, because he used to be autonomous. They used to be, you know, cells of their own. And the story goes that about 1.21 point 5 billion years ago, right, the only thing on the planet that existed were single cells that couldn't use, you know, some of those cells couldn't use oxygen for energy. So all they could do was fermentation, right? So they could take, let's say, a carbohydrate, and then ferment it to generate some ATP. And then let's say to make ethanol, and then there were these other Alpha Proteobacteria, that could use oxygen, they were aerobic, right? Aerobic, meaning they could use oxygen, to derive energy from, from food substrates. So the aerobic bacterium, this alpha Proteobacteria, at some point, either it was eaten up, right, by the bigger, an aerobic cell, the bigger fermenting cell, or maybe it invaded it, you know, I think the jury's still out as to how this initial date, you know, went,

Nick Jikomes 21:42

but somehow a little cell got in a bigger cell, correct? Yeah, yes.

Martin Picard 21:45

And that little cell, which was to be to become the mitochondria was able to use oxygen, right. And then there's a few theories as to why why this small cell, aerobic, with its own genome, right, remained why it was in digested and you know, eaten up phagocytosed. And, you know, their theories about oxygen, and like this smaller cell now was eating off the oxygen, so the oxygen was not so toxic to the bigger cell. There's some theories about energy. Right now, the smaller cell was somehow producing energy that the bigger cell was able to use, which is kind of the situation that we have now, where the mitochondria can produce ATP. And then ATP is used to power stuff, you know, throughout the whole cell. And then there may be other things that, you know, haven't been fully developed that enabled complexity, and enabled kind of turned this unicellular, fermenting an aerobic cell into a cell that now was able to engage into multicellular kind of social cooperative behavior. And there's very good evidence that whatever the reason is, that mitochondria kind of became set as an organelle of the cell, that transition, or that that event of Endosymbiosis was critical in the development of multicellular life, and then one cell was able to, you know, grow and then divide, and instead of two cells going their own way, now they started to derive some benefit. And so maybe mitochondria played a role in allowing cells to exchange information with one another. And somehow that sets the stage for, you know, cells talking to each other. And then if you have a cell sharing something with another cell, now, you know, they become kind of two pieces of a shared a shared collective.

Nick Jikomes 23:41

Yeah, that's interesting. Yeah, cuz all the cells of our body need to communicate with each other, like, in some sense, right? They're all separate cells, but like, what compels them to cooperate? That's an interesting question. But then at the lower level, right, you've got cooperation between each individual mitochondrion itself, and the cell that it's inside of. So what like there must be some kind of community communication in there that keeps everything in sync and the sense of like, you know, if the big cell ate the little cell and kept it around, what prevents the little cell from just dividing and dividing, dividing until the big cell blows up? How are they literally communicating with each other inside of that bigger cell?

Martin Picard 24:17

Yeah, that's a great question. I mean, there are labs around the world that focus on this understanding biogenesis mitochondrial biogenesis and their regulation of how does the cell know how many mitochondria are there? Right, and how many how does cell know how many to make at any given point in time, and controlling number of mitochondrial genomes, right so there's, there's a lot of good work that's being done on this and there's some known you know, parts to this and was clear as a necessary event right for to two units, let's say two people, two cells, or two organelles to coexist right then be You mutually beneficial is that there needs to be communication. And communication is just this fundamental process that needs to happen at every level of, of biological organization from, you know, single proteins to, to living animals and societies and you know, swarms and so on. So, communication happens between the mitochondria and the nucleus. So imagine the situation, way back the, the to be mitochondria alphaproteobacteria enters, and somehow now they were able to, there was some form of communication that developed between the ancestral mitochondria, and then the nucleus, the genome, and maybe the most kind of dramatic one way, or permanent, I should say permanent form of communication was mitochondria, shipping pieces of their genomes, right, so shipping genes into the nucleus. And so, as a result, now we have this small mitochondrial genome, like I mentioned, only has 37 genes, they used to have 1000s. Ah, right. So, like there are 1000s of genes and that you and the ancient mitochondrial genome that were shipped to the nucleus, and now, mitochondria have about 1300 proteins that are the best estimates. So it takes 1300 proteins to make all the different kinds of mitochondria in a human body, right? different cell types have different kinds of mitochondria, different Mitel types. And all of those genes are at 99% of those 1300 genes are in a nucleus. So their nucleus contains like 25,000 ish genes of those 25,000. There are about 1300, that code proteins that need to travel and then there are actually mitochondrial proteins encoded in the nucleus. I

Nick Jikomes 26:48

see. So you're pre empting, a question that was popping up for me, which is, you know, how on earth do we know that you know, a billion years ago or whatever, this little cell inside of a cell shipped some of its genes into the nucleus of the bigger cell? And I guess one piece of evidence there is the proteins that get made from the nuclear DNA that go into the mitochondria, presumably, are good candidates for something that used to be in the mitochondria. What else like confirms that? I'm trying to think of how you would even how do we know that?

Martin Picard 27:18

So I'm not an evolutionary biology expert. So other people would be much better positioned to answer that question. But superficially, you can say circular genome. Yeah, what else in the world that has circular genome? Bacteria, they have plasmids, circular genome with no ends, no, like chromosomes, the telomeres right? So the circular DNA is kind of one very big hint that they used to be bacteria, every other bacteria on the planet that I know of it has a circular genome. And they have this like funny double membrane structure, and some bacteria have this funny double membrane. And then there's a few kind of more minor features that are, you know, shared across other life forms that mitochondria share,

Nick Jikomes 28:02

and I suppose to there is we do know, independently, I believe that at least in certain cases, there are bacteria that can chop off certain pieces of their genome and kind of ship them laterally.

Martin Picard 28:12

Yes, yeah. lateral gene transfer. Exactly. So this Mito to nuclear gene transfer is probably a form of horizontal gene transfer, right, or lateral gene transfer, horizontal lateral are used interchangeably. And you know, this still happens. There's there's a few papers, you know, floating out there in the literature that show that on a regular basis, there might be some mitochondrial genes that make their way inside the nucleus. And these are called New mites and UMTS for nuclear mitochondrial DNA insertions. And so just simply viral, viral DNA can get right incorporated into into the cell that day. In fact, the same thing seems to happen. And we have some recent evidence, that paper that we're working on that actually talks about that. It seems like this still happens. It's not just this evolutionary thing, mitochondria shipped genes. And so they shipped a number of you know, the majority of their genome and there's a lot of people that are thinking about the why is there still DNA in the mitochondria? Yeah, why didn't they ship the whole thing? Right? Yeah. So there must be some some evolutionary advantage to having some genes that stay in this small genome, and of which you have hundreds of copies or 1000s of copies. And so

Nick Jikomes 29:30

yeah, I don't want to get too far into the weeds on this piece. But do they have their own replication machinery? Do they actually replicate that DNA in the mitochondrial genome?

Martin Picard 29:40

Yep, yeah. So they have the whole machinery to replicate the genome, mitochondrial DNA replication, mitochondrial DNA transcription, of course, right? So they can make RNA out of their DNA, and then the whole mitochondrial DNA translation machinery so there's the ribosomes that make proteins inside the mitochondria are different in ribosomes that make protein and the cytoplasm so it And you know, there are drugs and side effects for certain drugs, antibiotics, right that are meant to destroy and prevent bacteria from making proteins actually have side effects. Because they the, the target the bacterial, like, I see mitochondrial translation or transcription machinery

Nick Jikomes 30:16

I see so and like antibiotics can be, I mean, obviously, they can be beneficial, and they have been hugely beneficial to help fight certain types of disease. But we often talk about a side effect of antibiotics being like, you know, killing your micro biome or facilitating the evolution of drug resistant bacteria, but you're saying independent of all of that, they would still actually have some side effects on our own mitochondria.

Martin Picard 30:41

So mitochondria are still bacteria like enough? Yeah, that the, they can be hit in similar ways, as the bacteria in your gut, for example. So just, you know, are, there are differences. And you know, there's a lot of evolutionary kind of divergences that have happened between the mitochondrial transcription and translation replication machinery, and like, still kind of x, I would like to sell bacteria, you know, prokaryotes. But there are there's enough similarities that some of the stuff we've designed and you know, fungi and the life has designed to kind of eliminate or target bacteria can target mitochondria.

Nick Jikomes 31:29

Interesting. There's lots of interesting stuff that we're going to talk about that we're sort of building up. But I want to spend a little bit more time just talking about the core functions that are associated with mitochondria. So we've discussed one another, I would like you to just describe like, what else do they do that they're less famous for that you don't you know, like in high school biology, I learned about the ATP synthesis side of mitochondria, but we didn't really learn about anything else. So what are some of these other core functions? And how does that start to tie in to the, the active rather than passive nature of mitochondria?

Martin Picard 32:06

That's a yes. So there's, I think one thing that comes to mind that I can't, you know, ignore now is, you know, some people probably know of the old analogy of mitochondria. Right? That's the popular you know, mitochondria is the powerhouse of the cell, the powerhouse of the cell. I think this is, so this was first written about, like, this term comes from a Scientific American paper from the 1970s. And that, you know, came after the work of Britain chance and other that have, you know, established the processes and the regulatory control, you know, mechanisms for ATP production, and how ADP drives, right respiration, all of this. And then, also from the work of Peter Mitchell, who won a Nobel Prize for figuring out the Kimbie osmotic, you know, theory of for oxidative phosphorylation and ATP synthesis, through consuming oxygen. So, at that time, you know, pretty much the only thing that people knew mitochondria did was to make ATP. So the powerhouse of the house, the power cell, the powerhouse of the cell analogy, seemed well justified and appropriate. Now, I think this analogy has been damaging in the past couple of decades, because we know so much more about mitochondria and analogies are really powerful, right? Because that's the reason we use them because they tap into this knowledge bases, right, that most humans share. So if you can use an analogy, or a metaphor to convey a complex, you know, concept, and right away the person gets it right. And, but not only does you know, someone get it, but then the analogy kind of limits the spectrum, right, the degrees of freedom that your mind can go into. So if you say to power house, well, what does a power house do? Right, it makes power, or transforms, you know, energy from one form to the other. And that's it, right? And what mitochondria do is amazing, you look at them under a microscope, and you see them move around, and they actually, you know, sense each other and they can fuse with each other. So you have two mitochondria, they come and then boom, the fuse and they become, you know, one longer bigger mitochondria. And so to became one, they have a life cycle. Right? So if you think about how am i How do mitochondria reproduce? And so they actually age and then at some point, you know, the longer spaghetti like mitochondria, they're not all beans and, and peanuts, unlike, you know what the textbook shows you so they're they have this beautiful, more morphological complexity, and then they can undergo what's called fission. Right so they can fuse with each other. So two can become one and then you can have a really long tubules on mitochondria. That's a arises from diffusion, multiple small ones, but then the small these long ones can also fragment or undergo fission, and then the little fist mitochondria. Either will survive and refuel with another one or that can be the end of its life. Right? So if it's not energized enough, if it cannot sustain the membrane potential, right, so do all of the carbon oxygen ripping off electrons pumping protons, maintaining membrane potential, if it's not able to do this anymore, then it will not reintegrate the dynamic network, you know, of mitochondria that is in the cytoplasm, and then it will be degraded. Cells have processes called autophagy. Right autophagy. So, the self eating, and then that when that's applied to mitochondria, it's called My toffee G. So the cell will eat its own mitochondria that are, you know, no longer useful. So that's mitochondria of this lifecycle, right? The fuse they they face, the new ones are born out of, you know, existing ones that grow or grow, and then boom, they separate and now you have a new one. And they interact with each other. They produce signals, like reactive oxygen species, right? We everyone knows about oxidative stress, oxidative stress comes from the production of reactive oxygen species, so oxygen that acquires an extra electron, and then it wants to give it to something, then it becomes a reactive oxygen species. So it's kind of on the lookout for a recipient for this extra electron. Mitochondria can produce a lot of those, because, you know, oxygen is right there. And they're flowing electrons kind of freely in the electron transport chain. So there's a lot of potential for electron to fly out, react with an oxygen,

Nick Jikomes 36:31

like acid or something leaking out of a battery. And that's chewing things up. Yeah, that's, and that's where any accidents come in.

Martin Picard 36:37

Exactly. So antioxidants are, are meant to buffer those reactive oxygen molecules that kind of don't know what to do with their extra electron. And when, yeah, they're different conditions when mitochondria can produce a lot of reactive oxygen species. So that's one thing that they do as a function and the reactive oxygen species are not just bad stuff. And if there's a lot of it that can cause oxidative stress, right, and that's why the theory, the theory behind consuming antioxidants, right, and why that's useful. But the reactive oxygen species are actually very important signaling molecule, right, we just talked about one way that mitochondria talk to the nucleus, they can ship genes there and then change the nuclear genome, they also produce reactive oxygen species that can diffuse change a redox potential, right, so if there's reactive oxygen species, you can damage something, but you can also use their reactive oxygen species and kind of the, their electrochemical environment or state to, to convey information to convey information. Yeah, so then information can be conveyed between the mitochondria and the nucleus. Sure, by shipping pieces of DNA that might not happen kind of on a second by second basis, maybe every few months or years, there's like beasts of DNA that are transferred integrated in the genome. But the reactive oxygen species communication, you know, probably happens every millisecond, right in every cell of the body. And there's also other forms of myonuclear communication that happens via the production of reactive metabolites. And we could talk about the epigenome, right the the layer of information that sits on top of genes that can turn on or turn off certain genes. So that's a whole area of biology that mitochondria play a very critical role. And that's probably an important way in which the nucleus and the rest of the cell became good neighbors, right and good roommates, the mitochondria and the nucleus became good roommates because they learn to speak the same language. And that involves like the epigenome and the the metabolic intermediates that mitochondria can produce and reactive oxygen species. So they're all of these things that mitochondria can generate and produce as signals of communication. So communicating, you could lump as a big function coming back to your question,

Nick Jikomes 38:58

I mean, are there so when you disrupt any of these mechanisms of community, intra cellular communication between the mitochondria and other mitochondria or the or the nucleus or just other components in the cellular milieu? What happens like I imagined experiments have been done where you somehow do a loss of function, you disrupt some some signal the mitochondria produces, what are the negative consequences of that, that start to tell us? What's what's going on there? And what that communication is for

Martin Picard 39:27

likely and what was important, right? So definitely experiments have been done, you can target things to mitochondria, and then you can block a process or you can like activate a certain process and then ask, well, what does this do? Right and to the cell? And what's the normal state? What's the normal role of communication between the mitochondria in the nucleus? So we did an experiment like this and others have done variations of this kind of experiment before where we took cells that were all derived from the same clone. So that's An experiment were, you take a special kind of cancer derived cell that has the same genome, so you can make clones of it. Right? So that's kind of the the ideal experiment. And, you know, in the biology where you have eight monozygotic, identical twins, right? It's a slightly different experiment, because you took a cell, and then you just produce different clones. And then what you can do is play a little trick with the mitochondria. If this cell comes from someone who had a mixture of normal, kind of wild type and mitochondrial DNA molecule, and then this, some people have mitochondrial DNA mutations, right, and then that causes mitochondrial disease. And that's a whole area we could talk about, if that's of interest. So if you take someone that has some of those mitochondrial DNA mutations, what you find is that in one cell, let's say there's 500 copies of mitochondrial DNA, well, out of the 500, there could be, let's say, 400, that are normal, and then 100, that has the mutation, right? So that gives you 20%, mutant mitochondrial DNA, and then 80%, normal or wild type mitochondrial DNA. So that's a normal state called heteroplasmy. heteroplasmy is this mixture of two different kinds, or more different more kinds of mitochondrial DNA in the same cell? So that's what if you take you know, a piece of muscle or piece of skin from someone with mitochondrial disease, you will find this heteroplasmy Almost all the time. I see. So what we did in that experiment, when I was a postdoc in Doug Wallace, his lab, you know, had the chance to work with the cells that had to start with, like 60% heteroplasmy. And then someone took those cells and made different clones with the same, they're all derived from the same cell, right? So theoretically, to have the same nucleus, but they have different levels of heteroplasmy. So one of those cells had 0% heteroplasmy, right. So only normal mitochondria. And then one of those cells had 100% heteroplasmy. So all the mitochondria are mutant, so those mitochondria, and those cells cannot consume oxygen, right? So they cannot make ATP. And they cannot build a membrane potential inside of their mitochondria, because if you don't have the mitochondrial DNA, you don't have those 13 important genes, those 13 genes, or components of the electron transport chain that carries the electrons pump protons, charges the battery, right. So those cells with 100%, mutant mitochondrial DNA don't have the ability to transform energy and the mitochondria, they still have mitochondria. And the cells can survive, if you provide them everything they need.

Nick Jikomes 42:36

I see. So you have to constantly just give them the right stuff.

Martin Picard 42:39

Yes, you'd have to supplement them do, you know, they're, they're handicapped in a way, right. And if they are, of cancerous nature, so they've reverted back to their ancestral, you know, prokaryotes, self, then they can kind of live without, you know, mitochondrial energy production, but they need mitochondria for other things, right. There's other things we can talk about more. And then you have in the same system, cells with no mitochondrial DNA cells, sorry, cells with all normal mitochondria, right cells with all mutant mitochondria that cannot make ATP. And then you have in between clones in between one with 2030 4050, and the 90%, heteroplasmy. So you have a graded kind of system with increasing mutation load, and increasing degree of oxidative phosphorylation, defect, right or deficiency. And then in this experiment, this is also a weird cell that with no mitochondrial DNA, so no mutants, no normal, which is kind of a trick you can play again, in cancer cells, if you supplement cells with, you know, the right thing. And then in that experiment, you can ask, okay, like, here, you have a system, you change one thing, which is the proportion of normal and mutant mitochondrial DNA, you change heteroplasmy. What does that do? Yeah, right, what effect does that have on? And then depending on what your inclination, as you can, you know, ask whatever question you're interested in. And in this case, we use RNA sequencing. So you can look at all of the RNA molecules that the cells are making, which tells you which gene is on and then which gene is off. And how much is each gene expressed, right is expressed a lot or not a lot. And just with RNA sequencing with the profile of gene expression, you can tell if you're looking at a neuron or a liver, a liver cell, or like a heart cell or a skin cell, right? So there's enough information in what's called the transcriptome and the transcript are the RNA molecules that are made from the DNA. Just looking at the transcriptome, you can tell like, what's the cell up to right? What is it trying to do? And what's, what is it attempting to do? I think that's the best way to look at the transcriptome. So we ask what is the transcriptome, right of the same cell line? All of those clones, but with increasing levels of mitochondrial oxidative phosphorylation defect, and what we found was that 67 percent of all of the 25,000 genes in the nucleus, were either up or down in response to this graded, you know, mitochondrial DNA.

Nick Jikomes 45:08

So the first observation is just a lot changes. Yes, it's

Martin Picard 45:11

the majority of the genome, the majority of the human genome seems to be under mitochondrial control.

Nick Jikomes 45:17

And that's presumably not all just energy homeostasis stuff.

Martin Picard 45:21

No, and those, you know, I mean, two thirds of the genome that covers probably like everything, but what we found like most dramatically different or like, communication proteins, like proteins that allow cells to talk to each other, like anchoring proteins, and all sorts of proteins related to growth, right, and the cells, we looked at all sorts of things, you know, to characterize those cells with increasing levels of, of mitochondrial DNA mutation and oxidative phosphorylation defects, and the size of those cell changes, right, we did electron microscopy to look at what did the mitochondrial look like if they have 20% 30% 50%, and so on, the mitochondria look different, right? The nucleus even you know, could shrink and expand based on the, the heteroplasmy, and the, and the mutation load. So just changing the mitochondria is sufficient, right to change the expression of a really large chunk of the genes and the nuclear genome. So those kinds of experiments, I think, are really powerful, and illustrating how much control mitochondria can have on on the on gene expression, right? And gene expression, I think many of your viewers are going to know what Dr. Cellular identity and you know, cell leader decisions, right? Or how a cell goes from being a stem cell to differentiating into a heart cell or into a brain cell and neuron rates are into different kinds of cells?

Nick Jikomes 46:39

Yeah, so So for those that don't know, right, so every nuclear genome that we have in our bodies has the same set of genes. And what makes the brain cell the brain cell and not the muscle cell is just which combination are turned on and off. Mitochondria apparently play an important role in deciding what that combination of on and off is. Can you talk a little bit more about how the mitochondria actually regulates gene expression in the nuclear genome?

Martin Picard 47:03

Yes, so there's a few, a few different ways that people have mapped. And that's an active area of research. So I don't think we've figured most of it yet.

Nick Jikomes 47:14

And they're not they never get into the nucleus, right? They're all always in the cytoplasm. There's

Martin Picard 47:18

one old paper that I know of that, where they found mitochondria actually in the nucleus. And in those weird, you know, the cells with the mitochondrial defect, I think we might have seen some as well.

Nick Jikomes 47:30

So it's rare, but maybe it does happen sometimes, maybe.

Martin Picard 47:33

And there's some reasons you know, why that that might happen, and why that never happens, or almost never happens. So one way that I mentioned earlier was those reactive oxygen species, right. So there's some proteins that are called transcription factors. And what their role is, is to go into the nucleus, bind a specific area of the genome, the the beginning of a gene that's called the promoter. And then when the transcription factors bind that region, it's basically signaled to say yes, turn on this gene, right. And then there are other proteins that can come, then the polymerase can come in attached, kind of piggybacking on the transcription factor, and then it will start to move along the gene and then turn on the gene in a way and then make the RNA the transcript, and then that eventually, that makes a protein. So that transcription factor is plays a big role in determining whether a gene is turned on or turned off. And then you can ask, Well, what makes a transcription factor go into the nucleus and bind to that gene, right. And one of the things that triggered is movement, it's called the translocation of the transcription factor from the cytoplasm to the nucleus can be this redox status. So the if you have a few reactive oxygen species, not too much, that it's just damaging the hell out of everything, but enough to change the redox, you know, status of a certain protein. So there are little disulfide bonds and proteins that can kind of change slightly the shape. So if you have a transcription factor that looks like an open doughnut, yeah. And then if there's a bit of, of reactive oxygen species, the redox status change, it will close a doughnut, right? And now we have a closed doughnut. This is, let's say, for this protein to perfect configuration to perfect shape to get in to get in the nucleus, right and then boom to bind to a gene promoter.

Nick Jikomes 49:18

And presumably, what happens next is the cell is going to initiate protective mechanisms to deal with the oxidative stress or something like that. So that's

Martin Picard 49:27

a beautiful example that's been very well mapped. If there's too much reactive oxygen species, then you have not only those transcription factors that are sensitive to slight redox potential, but transcription factors that are sensitive to oxidative stress, right, then those go into nucleus turn on very specific genes that have like the genetic sequence, where those transcription factors can bind those oxidative stress responsive transcription factors, and then that turns on genes, not any gene, but those genes that encode for enzymes that can detoxify, right can play an anti detox

Nick Jikomes 50:01

detox genes. So yeah, so that the mitochondria literally produce proteins that can get inside of the nucleus, switch genes on or switch them off. And the way that happens, at least in some cases has to do with this the level of reactive oxygen species that the the cell in the mitochondria are sensing what

Martin Picard 50:20

they produce, they produce. You said produce proteins that can go into the nucleus, they produce signals like reactive oxygen species, IC, and other metabolic intermediates

Nick Jikomes 50:31

I see that affect transcription factors that were produced elsewhere, right, I see. They might

Martin Picard 50:35

also produce proteins. That's a whole area of you know, biology, it's very recent, still still some question mark? Yeah, some small proteins that are kind of hidden in the mitochondrial genome that can be made and then traveled to the nucleus, and they play a role there.

Nick Jikomes 50:48

And, you know, with hundreds of millions of years of evolution behind it, the the response to the increase the intrinsic response, that's that's evolved to the increase in reactive oxygen species is presumably pretty damn good at doing its job. So this is maybe a weird question that's just coming to me. When we talk about antioxidants, you know, ingesting compounds in the diet that can that can presumably help with these reactive oxygen species. Is it a fact that antioxidants are doing what most people think they're doing? Or is that a presumption? And I guess the the related question there to the mechanism you're describing is, if you start, say, ingesting a lot of antioxidants, and you sort of disrupt this sort of communication to the mitochondria in the nucleus, could that actually have negative consequences? Because then the cell's own detox mechanisms don't come online.

Martin Picard 51:39

Yes, right on. And there's a few good studies that actually showed in clinical trials and people, let's get people to really hide those antioxidant, and see what it does, right. And at baseline, there's, I think there's mixed evidence for what it does and different like disease states and so on. There was one really powerful paper published in PNAS 2014 I think, where the, the authors did a exercise training program, right, so they evaluate the effect of exercise training on mitochondrial biogenesis. And some people, you know, Will, may know that if you exercise, right, what you ask of your body is to transform more energy. And that's why when you move, you go up to a flight of stairs, or you train for a marathon, anytime you run, or you bike or you swim, or whatever you do, you breathe harder, right. And the reason you breathe harder is because you need to bring more oxygen into your lungs. And the reason you need to bring more oxygen into your lungs is because your blood is more depleted of oxygen. And the reason to blood is depleted is because the oxygen is being pulled and consumed by the mitochondria to charge their membrane potential, right. So the whole being out of breath and your heart's beating up when you exercise is because your mitochondria need oxygen, right. So your you breathe harder to feed your mitochondria. So what happens during exercise, acutely, right, within seconds, and minutes, you breathe harder and your heart accelerates, and so on. But what happens inside the muscles that say that you using for exercising is that those muscles say whoa, a lot of energy is being required to do this thing that we're doing like running or biking. So in order to prepare for, you know, the next time you do this, what cells do is that they make more mitochondria. And there's a whole communication there, right? Like the cell perceive there's not enough energy, mitochondria produce signals that go to the nucleus and say, We're insufficient here, like, there's not enough of us do provide, you know, the energy that's necessary. So there's a whole number of signals that converge onto the nucleus. And then the nucleus turns on a genetic program that basically drives mitochondrial biogenesis. So the genesis of new mitochondria, and then one cell can go from having, let's say, 500 copies of mitochondrial DNA to let's say, 800, or 1000, right, you can double the number of mitochondrial DNA copies in your muscles, let's say and also the mass of the mitochondria and the muscle by doing exercise. So if you go from being couchpotato, to training for a marathon, you can double how many mitochondria your cells have. And then what that does is that it improves the ability of that cell with double the number of mitochondria to transform a lot more energy. So you can make a lot more ATP and therefore consumer, much more oxygen. So that's the that's a normal adaptation right to exercise in that study what they did going back to your antioxidant question. In that study, they said, Okay, we'll have people do this exercise training program, I forget how many weeks it was when something like eight weeks, typically four to eight weeks, you have people training really hard for three or four days a week, and that is sufficient to increase mitochondrial biogenesis and to improve fitness so you can measure how much oxygen the whole body can consume.

Nick Jikomes 54:57

And this is endurance training, weight training. Wondering what happens either way,

Martin Picard 55:01

you know, the exercise that makes you breathe really hard. So the endurance training, treadmill or bicycle, or rowing or swimming and these kind of exercises. And then what they did was to take a piece of muscle, the muscle biopsy, before the training after the training, and then they asked, What are the training induced exercise adaptations. And the healthy adaptation is that you make more mitochondria, right, then you increase the oxidative capacity of the working tissue. So that's healthy, that is kind of a necessary survival, adaptation to doing more exercise. If you feed people a really high dose antioxidant in this study, I think it was vitamin E, you completely bluntness.

Nick Jikomes 55:43

And that kind of actually makes sense, given what you've, you've told us so far,

Martin Picard 55:47

it makes sense. If one of the signals right for the cell to know like, I need to make more mitochondria is this oxidative stress signaling, reactive oxygen species? And it seems like it is. So you can blunt mitochondrial biogenesis training induced or exercise induced training biogenesis with antioxidants, so that tells us that probably this reactive oxygen species signaling just plays a normal role in physiology.

Nick Jikomes 56:15

Yeah, and I guess this can become pretty intuitive and common sensical. When you just think about so many different things in life, you know, stress, you don't want stress, to be extreme, and to be life threatening, but you don't also want you don't want to be absent, either. You actually need those signals to grow and learn and do the things that we do in life. And apparently, this is true at that sub cellular level.

Martin Picard 56:40

Yes, yeah, those kinds of things, you know, you're tapping into a concept, right? That or principle, that is true, kind of at the level of human psychology, right? There's this concept thing, that's what you're referring to, if there's a bit of stimulation, a bit of stress, then you can reach optimal performance. And if there's too much stress, then you crash. And that's true of, like athletic performance, but also, like, best, you know, yeah. And so it's true at that level, that it's also true at the level of physiology. And it's also true at the level of you know, sub cellular communication. So I think that increases the likelihood that you're, you know, tapping into a principle, a conserved principle across the level of biological organization, that is true, you know, too little stresses is not good. That organism, you know, can't be at his best, but too much can be damaging.

Nick Jikomes 57:29

Yeah. So like, when you think about things like diet, you know, one core principle, I guess, that I always come back to that I'm not like a diet expert, but everyone needs to know enough about diet to be healthy, is, you know, you don't want to have a deficit of anything. But that does not mean that you just want to consume as much as possible of all of these quote unquote, good good compounds, you know, you can't just consume, you can, you can overdose on and have too much of a good thing, in essence,

Martin Picard 58:00

yep. And either that good thing in excess becomes toxic thing, that's one way in which the system can, you know, not benefit or suffer from excess of a good thing. Or by supplementing the organism with too much of a good thing, you might end up suppressing the natural, the endogenous pathway in your body that makes that good thing, right. And if you suppress that, then if you ever stopped taking the supplement, now this pathway has been turned off, let's say for years, right, if you're on this supplement, now the body develops kind of a dependency on an exogenous source, as opposed to kind of having the natural, you know, balance of processes that produce most of what we need in you know, in addition, in addition to good, healthy balanced diets for for all of the minerals cofactors. So there's a lot of things that the body can make. And then we also, you know, eat some, and if you don't eat, you know, very much of this, the body can crank up the production. If you eat a ton, you'll shut off, you know, this production. So there are these two sources of potential, you know, imbalances that you can produce, probably by over consuming certain things.

Nick Jikomes 59:10

So you you answered already, one of the other questions I was going to ask, which is, you know, when you think about fitness and exercise and building muscle or building endurance, what happens to the mitochondria? Well, you've told us, you literally make more of them. And that makes perfect sense. I would also expect that there's definitely going to be some important role for mitochondria to play in states of deprivation. So when people are in a fasted states, and they're not eating for days or weeks at a time, they go into ketosis and things like that, what's going on with the mitochondria? When our when our diet changes and the way that we're transforming energy or the source of like the raw materials actually changes? Are they are they switching the way that they're generating ATP or anything like that?

Martin Picard 59:58

So they're switching So I'm not an expert in, you know, diet, internet dietary interventions and, and, you know that area of the science but what's clear, if you don't eat too much for let's say, if you eat a lot of sugar, right, then cells can choose, you know, to some extent right to your there are two main pathways for transforming energy, you can flow carbons, you know, from glucose down glycolysis, and then that the end product of pyruvate either can enter mitochondria, then you do oxidative phosphorylation, and do this thing of carbon oxygen separation and producing membrane potential and so on, you can also decide to flow the pyruvate into lactate. And so that can all of this can happen without oxygen, right, this is kind of the ancestral and aerobic way of transforming energy, which yields, you know, less ATP molecules per molecule of glucose. And then in the beautiful organisms, you know, they have multiple different kinds of organs like us, this lactate then will go into the bloodstream, and then like they can go into the liver and then the liver can take the lactate, bring it back into glucose, and then the glucose boom is shot back into the blood. And then the glucose comes back, let's say to the muscle and then this can happen again, that's called the cori cycle. So yeah, to some extent, right, you could live on a very high carb diet. And that is probably the least, that you put your organism then and the condition that is the least stimulating for your mitochondria. Because then mitochondria end up playing, you know, a kind of a secondary role, where some tissues can can feed not all tissues, but some tissues can feed without engaging too much their their mitochondria. There's some tissues like the brain, for example, right? That need, they cannot burn other things in glucose. But the majority of other tissues have this flexibility, they can choose kind of what they eat. And there's some things that cells will eat consume, for energy that require absolutely mitochondria. So for example, lipids, right, if you're going to burn fat, you cannot do this through glycolysis, because they're the only substrate that can be, you know, burned through glycolysis, or, you know, transformed is the entry point is glucose. But if you come in with a fatty acid, then the fatty acid needs to be chopped. All of this happens through another pathway called beta oxidation. And there's several of the enzymes a bit oxidation that are in the mitochondria. And then what you when you do better oxidation, the path from chopping and burning lipids to making ATP is mitochondria dependent, right? And then you need to rip up the electrons flow them charge your battery and then use that potential to make ATP. Same thing with ketones, right? And so then if you go on a no sugar, like a ketogenic diet, right, and I think a lot of people are going to be familiar with this where you you eliminate all of the sugars from from your diet, then you end up burning almost exclusively fat and proteins. And when you burn fat and proteins, there's no way you can do this without your mitochondria. So if you take a little micro centric approach, and you say what diet is going to be most stimulating to the mitochondria, right? And so that would be eating, you know, fats and proteins.

Nick Jikomes 1:03:24

So if you were if you were doing let's I know people who have done or do ketogenic diet for weight loss, fat burning reasons, based on what you're saying earlier about the ability of cells to increase mitochondria and responsive endurance training, would you actually lose? Would you burn fat faster if you went on the ketogenic diet? After you were already doing endurance training? Because your cells would have more of them to do that?

Martin Picard 1:03:50

If you continue the endurance training, I would say probably yes. Right. If you continue to exercise more, probably, you know, cells are really quick to adapt in the most beautiful way, right? Like they don't, they don't hold on to things that they don't need. Unlike humans, they don't get attached to their mitochondria. So if a cell makes a lot of mitochondria, because you're running, right, let's say, an hour every day, then do you need more mitochondria. But if you stop running an hour every day, then the cells of your legs, you know, your muscle cells are going to get rid of those extra mitochondria. So I think probably if you have a bigger pool of well functioning healthy mitochondria, you're in a better position to to adapt and maybe to burn fats, your to more efficiently. And I think the same thing happens if not only you change your diet, but you change when you eat, right like time restricted feeding is something that some people have tried. I tried that once and I thought it was it was very cool. I have a good friend who tried that recently and who's she's in her 50s and she said it pretty much changed her life. And she has so much more energy now that she does time restricted feeding, which is basically you don't feed the whole time you're awake, you choose a certain period of your awake time, and then you only eat then. So when you wake up in the morning, you don't eat and you don't eat until, like, 2pm. Yeah, and then you eat only between two and 6pm, we're right some window of time, six hours, I think is typically what people do. So if you allow to eat only for those six hours, then there's, you know, an abundance of food substrates that come in, you can use them, but then there's a very big chunk of time, like 18 hours, the rest of the day where you're not eating, and then the body's needs to switch into that mode of, I need to depend on my mitochondria for energy. I can't rely on you know, the rapid influx of sugars that, you know, you'd be having, if you ate, you know, three plus meals, you know, what's next? In the day. So this intermittent fasting, or this time restricted feeding regime, in a way, I think is an is a

Nick Jikomes 1:05:59

way of stimulating, it works out your mitochondria. Exactly. Yeah.

Martin Picard 1:06:03

Or gives them purpose, right. I think if you're only feeding on on refined sugars, then mitochondrial the purpose, if you think about mitochondria, as little social creatures that need to be around for to serve a purpose and the organism, then they kind of lose that.

Nick Jikomes 1:06:23

Yeah, I don't know if I want to get into this, or maybe we'll circle back to it later. But just as an anecdote to share, like, I've done some amount of like fasting and time restricted feeding, and for me, at least anecdotally, like if I don't eat for 24 hours straight. I mean, I go through, I go through the waxing and waning of hunger, as you would expect. And in the beginning, like, yeah, I'm really hungry for a while, and maybe I'm irritable, and, but then it kind of goes away. And that cycle is a couple of times. But after I get towards the end of it, maybe two thirds or three quarters of the way through that 24 hour period. There's an actual psychoactive effect, I feel more awake and focused. And there's, there's kind of a mild euphoria. And I don't know what the basis of that is, but there is some kind of metabolic change that you actually feel, and then that you would think, right, when you get to the second half of the 24 hour fast, you're gonna be hungry or because you've gone longer with food. But once I get towards the end, it was actually the opposite for me, I sort of just lost lost track of the feeling of hunger.

Martin Picard 1:07:21

Yeah, so this can probably be explained physiologically, as you know, the first phase, you're going through withdrawal. And then you have cells that that are, you know, a bit in panic mode and the body because they they're maybe not equipped, or like they weren't expecting that to happen, right. And then the hunger is like, whoa, suddenly, we're away from the setpoint, which is like how much how many calories we need to be taken, taken in. So the hunger is almost like a little emergency signal. But the hunger that we experience subjectively is coupled with, you know, hormonal neuro endocrine signals that are then you know, being released. And then once those signals are released, that triggers adaptation. So now you have some transcription factors, right, that detect the fact that there's not enough energy that goes into the nucleus, they turn on some genes, and you have some new proteins that come in, let's say, for the cori cycle, right, so you can take something, turn it back into glucose. So after several hours, now you have the systems that are you know, more adapted, and now you can start to actually feel good again, because the system is, you know, in a, in a more stable place, and you're not kind of in an emergency mode. I think being hungry once in a while, is a really healthy thing, that maybe we lose a bit when your fridge is plentiful. And when we have, you know, psychological drivers and social drivers, an addiction, you know, due to food and to plentifulness.

Nick Jikomes 1:08:48

Yeah, and I mean, the ancestral state was, was a state of higher food uncertainty, certainly for most of our evolutionary history. So, in my mind, it would have to be true that the body is in some sense, adapted to not having constant consistent food availability.

Martin Picard 1:09:07

Yes, yeah, definitely. And then the body cams, you know, the studies that have been done, it's really hard to when you start time restricted feeding, like if you're used to having breakfast, lunch and dinner, and you start to say, you don't do breakfast, you know, in your first day, that first day is really rough. The second day is also rubbed the third and the fourth, and then after that, you know, you get into a rhythm and people then don't report terrible hunger in the morning. Yeah, they look forward to eating right. And then it becomes a real a real joy. When you haven't eaten in 18 hours, and then you you have a meal this like feels really good. So yes, there's a psychological component to this. And then once the body is in this new adaptive state, which potentially it was the state we were in like 10 20,000 years ago, where you don't eat for a large chunk of time and then boom, right? You eat or sit for several days maybe. So there's a few reasons to think like this is probably Probably more adapted behavior, right time restricted feeding or yeah, that kind of behavior that to our history or evolutionary history.

Nick Jikomes 1:10:12

I want to zoom back in and talk about the health of the mitochondria themselves. So you sort of maybe hinted at this earlier, you said the mitochondria age, there's old ones and young ones. Presumably that means I would guess that the old ones don't quite behave as well as the young ones. I'm interested in exploring that a little bit more, I know that you've, your lab and others have worked with something called the mitochondrial health index. So how is that actually measured? And what does it map to? What does an unhealthy mitochondria doing compared to a healthy one?

Martin Picard 1:10:44

Yes, you know, health is a really complex problem. So we came up with this mitochondrial Health Index, this MHI as a simplified way to quantify energy production capacity. So if you look at a mitochondria, right, if you could do such a thing, and ask, how much energy can this one produce, right? That's how we defined that's how we operationalized energy production, mitochondrial health, as the ability, you know, to flow electrons through the electron transport chain. So what we did was to basically take approaches that were developed, you know, back in the days to measure energy production capacity and the electron transport chain, right, there's I spoke complex five earlier, the ATP synthase. There's complexes 1234, where the electrons initially come in through complexes one and two, and then flow to three and then four, then at complex four, this is where oxygen comes in. So you can measure the activity to capacity of those complexes biochemically in the lab, right? And then once you quantify this, you can say, ah, you know, if you take a certain number of cells, or mitochondria, and then you quantify how much activity is there, let's say in these 5 million cells, how much activity is there of complex one, or complex four, then that gives you a proxy, right? It's an indirect measure of energy production capacity, by quantifying the the abundance of those of those enzymes and the the functional capacity of those enzymes, then if you take the capacity to transfer electrons, and the electron transport chain is those enzymes, and then you divide this and a simple equation, you divide it by how many mitochondria you you started with, right? So you had 5 million cells, but let's say you had like 100 units of mitochondria, and you quantified, you know, 200 units of electron transport chain capacity. So you have 200 divided by 100, give this give you an mitochondria health index or an MHI of two, right? Let's say you have another person that you also take 5 million cells, and then you count the mitochondria. There's also 100 units of mitochondria. But then this person, if you measure the activity of those enzymes, there's not 200 units. There's like 400 units. Yeah, they're getting more bang for their buck. Yeah, each Mito now can transform more energy, right, so now the MHI goes from two to four. And then you can have the reverse situation where you have someone also with 200 units of energy production capacity, like or first person, but this person to reach to achieve 200 units needs not 100, but they need 200 units of content. So now it's 200 divided by 200. Now your health index is of one, right? So now you have a person like the first person MHI have to now the second person with the same amount of mitochondria, but more capacity had MHI of four, and then the third person with more mitochondria, but less capacity per has an MHI of one. So So that's simple mitochondrial health index was an attempt at quantifying energy production capacity. So we could, you know, measure this in different people and ask, Do people have different kinds of mitochondria different energy production capacity, you know, to explore hypothesis about what makes people different.

Nick Jikomes 1:14:13

Yeah, I mean, it's gotta be true, right? There must be there's a lot of variance, I would imagine. That

Martin Picard 1:14:18

is yes, there's a lot of variance. Yes, not all mitochondria are created equal, you know, within the body. And that's something we're actively thinking about now. But also mitochondria and different people, right, and the immune cells that which is what we looked into are in the muscle and people have very different amounts of mitochondria and then the function that the proteins that are in the mitochondria, different. Different abundance. So yeah, there's large inter individual differences. And there's also over time, that's something that's much less well established, but like the exercise studies that you know, we were talking about earlier, if you have someone exercise for eight weeks, you you train for like a half marathon or you just decide not to be physically active and go from being completely sedentary, you will will you will make more mitochondria and the quality of the mitochondria is going to change also a little bit. So we know there's plasticity within a person. And something we're interested to explore in the lab is how, you know, sure physical activity increases mitochondrial content through biogenesis and other things. So physical interventions that make you breathe harder changes in mitochondria, right? Do do psychological states. And you know, the things that we experience, does that actually manifest in our mitochondria? is a question that is much less understood. Yeah,

Nick Jikomes 1:15:39

I mean, I imagine that that's an area where there's a lot of open questions. But you know, like a very high level, when you start thinking about the brain, or a, like, when you think about mitochondria, you think about energy. That's not all they do, as as we're learning. But when you think about energy, like at least me, you think about muscle cells. So it's like, the muscles probably have a lot of my country because they're very expensive. But then neurons are the same. In that sense. They're very expensive, they require they require a lot of energy to do what they do. And so can you start talking a little bit about the, the mind of mitochondria connection, like, you know, there's so many places to go with this. They're metabolically expensive neurons are, so they presumably need a lot of mitochondria. They don't divide like other cells. And I wonder how that influences how they like regulate their own mitochondrial cycling. So what what would you say is a good place to start when we think about what mitochondria are doing in the brain and for the

Martin Picard 1:16:33

brain? So it at very high level, you're right, the brain is really expensive. And, and, you know, the best estimates is that in general, on a normal human body, the brain is about 2% of the body weight, but it consumes something like 20%, of energy of the whole organism. So the cost per per gram of tissue is quite a quite a lot and the human brain, and we've been doing work comparing mitochondrial content and mitochondrial qualities, what we call Mito types, since there are different cell types. Yeah, so the difference, there are different mitochondrial types or Mito types, and in different parts of the body, different organs, different cell types. And the brain, the human brain, as a lot of mitochondria, if you rank all of the tissues, there's a beautiful database of 55 different tissues in the human body, right, from autopsies. And then you do gene expression. You do RNA sequencing, what we talked about, you look at a transcript on what we were talking about earlier, you look at the proteome, you do proteomics, then you can start to ask, well, how many of those mitochondrial proteins are there, how many mitochondria are there in the brain right there in different parts of the brain, the brain is like beautifully complex, and, and then versus the heart versus the liver versus the muscle versus the kidneys than the the placenta, the testes, the gonads. So the mitochondria are very different in all of those tissues, and the amount of mitochondria is substantially higher in the brain than the majority of the other tissues. So the brain is among the tissues that have the highest mitochondrial content, per per unit of mass. And it consumes energy. Very high, but also very constant, the muscle, in contrast, can consume a ton of energy, that stop, you sleep for, you know, several hours, the muscles barely contract for, for many hours at a time, the brain never stops, it's really amazing, even when you're not thinking, you know, the brain is always going. So there's kind of a very continuous steady state energy requirement that the brain need that other tissues now don't all need. And mitochondria kind of optimized for this kind of study, you know, high level energy production, the oxidative phosphorylation system is really good at this.

Nick Jikomes 1:18:53

I see I see. I mean, how I imagined there's, you know, how dynamic are the mitochondria in, in neurons at at a at a short timescale? Like when you think about the scale of action potentials, like the actual signals that the brain sends, you're talking about milliseconds, 10s of milliseconds, like how, you know, things have to happen in terms of like ion flux into and out of these neurons to allow that to happen. That consumes a lot of ATP at very particular sort of points on that timeline. How dynamic are the mitochondria inside of a single neuron? Yes, that's

Martin Picard 1:19:27

a great question. timescales. And action potentials are like millisecond, you know, level. Mitochondria can turn on, right within seconds, right to less than seconds. Like if you do cool experiments, you can do the lab as you isolate mitochondria, let's say from neurons, right? And you put them into a little chamber, and then in the chamber, there's a little sensor for oxygen, right? A little electrode, and then it tells you how much oxygen is in the chamber. Then you add your mitochondria and then the mitochondria start to consume bit of a bit of oxygen and you see this you know, going down Then you add ADP, right? If you add ADP, like we talked about earlier, ADP is going to come into the mitochondria, mitochondria sense this, then the turbine starts to spin really quickly, you dissipate the membrane potential, right, it all goes through the turbine, then you start to make ATP from the ADP that's coming in. And then if you relieve the pressure from the dam, right, from the transmembrane, potential, now the electrons start to flow like crazy. And that starts to consume oxygen. So under a little trace, you see, oxygen start to drop really quickly, this happens very quickly, you add the ATP, you look at the trace, and right away, it's it starts to, to be consumed. So second, you know, sub second, maybe the you get mitochondria to react very quickly, but not like milli second and the membrane potential will drop and then reestablish, and with very fast kinetics, the kinetics for ADP, you know, production would be much lower and oxygen consumption. And you kind of see this in what's called fMRI, functional, magnetic resonance imaging of the brain, where you see, you know, I think probably everyone has seen a picture like black and white image of the brain, and then they're like blobs of colors. Where like, if you, if you think about something, you plan for the future, there's a prefrontal cortex that lights up. And then if you process visual information, there's the occipital cortex that lights up. So the lighting up is basically increased blood flow, to provide oxygen to those brain regions that are more active, their mitochondria are consuming more oxygen, and then there's more blood that's flowing to those areas. And those are pretty sluggish, right? Like the, you start to process visual information. And then you within three, four or five seconds, right, there's, the signal goes up, and then there's kind of a slow, slow decay, then there are a few reasons it says hemodynamics, we're looking at blood flow, not directly looking at oxygen consumption. But just to give us a sense of kind of the dynamics membrane potential boom, milli seconds, mitochondrial, maybe seconds, and then, you know, a few seconds, and then this a little more slowed down at the physiological scale.

Nick Jikomes 1:22:09

So you do endurance training, you start going running every day, and you can you know, to x, or more potentially the number of mitochondria in some of your cells. Does this type of change happen in the brain as well? Like, can you drastically increase? Like, if you start studying really hard, and working out certain circuits in your brain? Will more mitochondria be created to accommodate that change?

Martin Picard 1:22:35

That is a great question. I don't think that there's a good answer to this interesting. There has not been a lot of comparatively like the skeletal muscle exercise physiology literature is vast. Yeah, a lot of people have done really good work there.

Nick Jikomes 1:22:48

The biopsy Yeah, the brain is harder.

Martin Picard 1:22:52

The brain is harder to access. Yeah. And living people? Yeah. That's a That's a great question. There's one animal study that looked at this, they did exercise training in rats, and then they looked at gene expression for mitochondrial biogenesis in the brain, the and then you could do all the exercises in the muscle, Why would something happen in the brain, but they found the increased, you know, the induction of mitochondrial biogenesis in the brain itself, in response to physical activity.

Nick Jikomes 1:23:22

So getting into the weeds a little bit here, because I just can't help myself. Based based off my history, are there ways to image the activity of mitochondria in vivo, and then are people using optogenetics to, you know, make them come on and off and do different things.

Martin Picard 1:23:43

The first, when I started the lab here at Columbia, the first project that we started was my top dough genetics. So to try to put a channel of adoption inside the mitochondria. And then with light, you could either you know, completely discharged the membrane potential and, you know, bring mitochondria you know, basically kill the mitochondrial battery, or you could use a different kind of ops and then use it to pump protons and actually hyperpolarize you know, hypercharged you the the mitochondrial and mitochondrial membrane. And so we didn't succeed that, you know, it was technically, you know, the molecular genetics there were really challenging. But some people did succeed. And there was a paper published a few years ago showing proof of concept, you can use light to manipulate mitochondrial membrane potential in cultured cells. I haven't seen anything yet on this in vivo, and, you know, this when we try the cells weren't very happy to put this like massive protein. Yeah, you know, inside the mitochondrial inner, the inner mitochondrial membrane. So, so that's for like the optogenetics, you know, approach in terms of imaging mitochondria in vivo. Yes. There's there's a lot of If you go on Google images video and you ask for mitochondrial motility, mitochondrial movement, in vivo, you'll find a lot of stuff and it's amazing the mitochondria. You see them move around like a long axons or a long dendrites, and the shape of the mitochondria, we did a study where we mapped the three dimensional shape on mitochondria in neurons in the mouse brain, in the hippocampus, specifically in pyramidal neurons and the dentate gyrus and then the CA three and other part of the of the hippocampus. And then you can ask, What do mitochondria look like, in those different cells into different parts of the brain. And then also within a cell, within that part of the brain, there's the cell body where the nucleus is, and then like the skin of the cell, the cell membrane around it, and then there's the axon, right that projects to a very distant area of the brain, or to outside the brain. And then there's all the dendrites that can receive inputs from other neurons and glial cells. And the mitochondria look completely different, right there and biology, a lot of things. You can glean information and insight into the function by looking at the morphology, right, so the form and the function tend to be related and deform, the shape of the mitochondria are very different in the dendrites, where they're extremely long and branched and can spend, you know, several microns in length, versus the axons, they tend to be at a small punctate mitochondria. And, and they're much more immortal, and the axons and the dendrites were much bigger and more stationary. And in the cell body, you have this beautiful population, you know, complexity, the same way different humans are different. You have these inter individual differences, and, you know, in height and size and proportions, and skin color, and all of this, so you get the same kind of population diversity. In in the mitochondrial network inside this the same cell body, you know, some are super tiny, some are long, so I'm gonna have these branches, and some are circular. And it's beautiful.

Nick Jikomes 1:27:08

Interesting. I mean, I was going to ask about it, because one of the other things that is interesting, and different in in many ways, for neurons compared to other cell types is their morphology, it's sort of weird in certain ways, they can have these very long shapes, the axons can stretch across the body, in some cases, like the dendrites have these very elaborate shapes. And I would imagine that like, I mean, when you start to think about what neurons do, and where they do it at different compartments in the neuron, right, you've got the nucleus of the neuron might be way over on in one area, and then the neuron is reaching its axon away over somewhere else, you know, there's presumably all kinds of metabolically relevant stimuli that the mitochondria and say the action in the axon terminal, are detecting. And somehow those that information like we were talking about before it needs to get back to the nucleus. How do and that's a lot long distance to span so that the mitochondria literally sort of cross crawl around, or are there actually mechanisms to actually shuttle them fast?

Martin Picard 1:28:09

There are mechanisms. That's called mitochondrial motility. So some people might have seen like the movies of the walking motor proteins, yeah. Dynein are the kind ezines. It's like actin, myosin, as well, the myosin can walk on the actin filaments for the muscles to contract. So there's these specialized motor proteins that exist in every cell of the body. And there, there are some that are then anchored, you know, directly due to mitochondria. So you have a mitochondrion. And then it has the kind of adapter protein and then it's attached to the motor protein, then the motor protein will walk into microtubule. And then that's our understanding of how mitochondria generally move around by walking on cytoskeleton through the those motor proteins. And then there are things that if mitochondria sense, let's say they're moving around along the axon, and then they get to a point where there's a lot of calcium around calcium, there can be calcium gradients in cells and or changes your rapid changes in calcium and there's a lot of calcium, mitochondria will stop moving. And then they will help buffer the calcium. That's one of the functions I see that we didn't talk about earlier, mitochondria will take in calcium can buffer and sequestered is calcium. And generally when there's a lot of calcium around it means there's a need for ATP. So there's also mechanisms inside the mitochondria. That couple, if they take an if there's a lot of calcium out there, they'll stop, they'll start to take it in. And then when as they take in calcium to activate some enzymes makes metabolic activity accelerate and then you flow more electrons, you consume more oxygen, you make it and then you can make ATP. So those processes are coupled in a really beautiful way. So they move around and they respond to their environment. They can stop and restart and move one direction move the other direction as to whether there's mitochondria in the periphery. We, let's say, in the very far end have a neuron, you know, that goes out of the spinal cord, right to connect to, to a muscle, the mitochondria there, right and the neuromuscular terminal. I don't think we know that those mitochondria can make their way up track all the way back up to their cell journey. Yes. So there's actually evidence that the mitochondria and the terminals, it can imagine that everything costs energy, right. So if the organism lives in a way that is trying to optimize how much energy it's spending, and it's trying to minimize that, either you spent all of this energy to bring this mitochondrial all the way back up the axon into the cell body, and in there, you can autophagy right, you can self eat, or my tophatter, you can eat the mitochondrion, let's say it's no longer useful. Or if you lived as a mitochondrion, if you lived in an environment where the cell you're in is buddy with the cell next door, and the cell next door, you know, might be a neuron, the one here, the other one next door might be a phagocytic. glial cell, right, so it can be like a microglia. Yeah, right, that those cells are good, they're like the macrophages of the brain, they can eat stuff up, you know, degrade them, and so on. So one option again, is to travel this, Mito all the way back up, spend all of the energy and then you you eat it up. And then x is the neuron or you ship the mitochondria out to your neighbor. And then you have your neighbor that specializes in this, eat up the you know, the the damaged, you know, dysfunctional mitochondria. And, and there's probably a great deal of the second option happening. Because there's a lot of collapse, you know, yeah. And so there's, there's evidence that cells do this, they share mitochondria, and some cells eat them and some cells make them

Nick Jikomes 1:31:55

I want to, I want to spend some time talking about aging stuff. There's actually quite a quite a bit I want to get to, but when we just think about aging, very high level. I mean, mitochondria have to be involved in a very important way as an aging, it just seems like it must be true given the role that they play in, in metabolism, ATP production, things like oxidative stress. So like how I'll let you guide us as to where maybe we should start this discussion. But what would you say are some of the the best well, well worked out ways that mitochondria contribute to the normal aging process, either preventing the bad stuff associated with aging from happening, or actually maybe facilitating how it happens, or how quickly it happens?

Martin Picard 1:32:41

Yes. So that's a big question. It almost brings us down to why do we age? And people have been at this question for a long time. And at this point, in the history of aging research, there's really good evidence that outputs right signals from mitochondria contribute in a very important way to the aging process. And to kind of the trajectory if we think about aging as a trajectory. And some of the this idea started a long time ago, and you know, the rate of living hypothesis, animals creatures, you know, that have smaller bodies tend to breed faster. So they can and to burn energy much more quickly. And then compared to larger animals. So if you take a mouse, for example, the heart rate of a mouse is around 400 beats per minute. That's 400 Beats from that several beats per second, right? Yeah. What's the heartbeat of a human more like 6070 beats per minute? What's the heartbeat of a whale? Like a very big mammal?

Nick Jikomes 1:33:42

I think it's really low, right? It's

Martin Picard 1:33:43

really low. It's only a few beats every minute, compared to you know, 6070. For us, 400. For demos, and the metabolic rate, you can compute that right? How much energy does a whale burn every minute of life versus humans kind of intermediate size versus a mouse was smaller size. And then you can go even smaller than a mouse like there's a little shrew that's like a gram. The smaller the animals, the faster their metabolic rate. So they burn energy so much faster than you know, larger creatures. And then these we then you can plot this. Yeah. So you have on the x axis, you say how big is a creature? And then on the y axis, you say, how fast is its metabolic rate? How quickly does it burn energy? How quickly does it you know, consume oxygen. And there is a remarkable, you know, inverse relationship there, the bigger creatures have a much lower metabolic rate than the faster you know, smaller creatures. And that's called allometric scaling. And people have talked a lot about this also in relation to lifespan. Yeah, because that is not disconnected from lifespan. Yeah. Yeah. Like a fly, right, which is super tiny. Yeah, it lives like you know, a month or two Max. Yeah. Like Drosophila lives about two months. A mouse lives like two to three years, Arad, which is a bit bigger, there's like three to four years and, you know, monkeys and you

Nick Jikomes 1:35:08

just keep going to Wales and they live for like 200 years up to 200

Martin Picard 1:35:11

years. So there's this scaling how big the body is how much energy to consume. And then you can flip this and say, how much energy to consume and how long they live. So there's this inverse relationship, the smaller you are, the faster you breathe, the quicker you die. And then there are these mathematical relationships. There are some outliers to this. So some people hate these laws, because they're bogged down by, you know, birds don't conform to this law, like birds are like outliers in this in the allometric scaling, for reasons that I think are partially understood and partially not. So there is there is something there. I think nobody really agrees on what exactly is there? And but it

Nick Jikomes 1:35:51

is remarkable. The relationship. I did an entire episode early on with Geoffrey West during his book scale. Yes, yes. Yeah. So for those listening, if you're interested in some of these concepts related to lifespan, and how things scale living things, and nonliving things, he has got a great book, and that's a great episode. But there is sure there's outliers. But when you look at those plots, like that's, that's a pretty concise regression line.

Martin Picard 1:36:13

Yeah, it's hard to ignore some underlying, you know, conserve biology there when you see this across the animal kingdom. Yeah. So we've chose not to ignore this and to try to understand it a little bit. And Gabrielle Sturm, a former student in the lab, who's now at Berkeley, is working on a paper on this with someone from the Santa Fe Institute, Chris campus, who's an evolutionary biologist, ecologist, you know, mathematical mathematical whiz. So he's just wonderful. And so we've been thinking about these things together, and in relation to lifespan in the human system. So you can take cells from the human body, and put them in a dish, and then do an aging study. And we call this a cellular lifespan, you know, system, or so your lifespan model. And what this does is? Well, it's it's thought us two things. One is if you take cells of the human body, let's say you take skin cells, and then those cells, right, they were, let's say, programmed, or they were in the in an environment in the human body, and they were going to live like 80, or 80, you know, so years, 90 years, 100 years, more or less, if you take them out of the human body, and then you put them in a dish. And then you ask, Well, how long are they going to live now? Right? It's almost like a time perception experiment. So you take cells out, you put them in additions, okay, how long are they gonna live now. And then, what Gabriel did was very patiently took them through their whole lifespan. So you grow the cells for a week, and then you take, you know, some of those cells. Because, you know, if you put up a few cells, if you know, a few 1000 cells, then you're going to divide, divide, divide, and that the end of the week, there's much many more, right? So if you put a million cells down, maybe at the end of the week, you have 5 million cells. So then you can take 1 million from at the end of the week one, and you seed them for a week number two, and then you do another week of lifespan, right? So it's the same, the same population, yeah. And then you the formula and cells that you don't need you, you put them aside. And then you can measure things like DNA methylation to us like epigenetic clocks and biological aging, you can measure telomere length, right to the end bit of the chromosomes that shorten as we age, or you can measure, you know, bioenergetics, the, how many mitochondria are there, how many copies of mitochondrial DNA are there are you can also take the media, you know, cells and these experiments, they grow into this liquid that feeds them, right, it's the equivalent of the blood. And then you can measure, you can measure things and you know, stuff that cells will secrete to do understand cellular behavior as they age. So when Gabriel did this, for many months, we went up to 10 months, every week, not missing a week, at the end of the lifespan, right? The cells are, many of them are dead, and those that are left, they're in this state called senescence. So they've entered this kind of end of life stage and they're not no longer replicating, they're no longer dividing. So you can quantify, like, how long did this take? And you know, I said 10 months, right? So cells don't live many more than then this, you know, I've never heard of a fibroblast lifespan experiment. That's more than a year. But humans live more like, you know, 80 plus 100 years. So that's kind of an interesting observation. But what was much more interesting was to look at biological aging markers that people have validated in humans, right? So you can look at telomere length. And then in humans, there's good data on popularly 1000s of people. What's their rate of telomere shortening over time? So if your x axis on your graph is decades of life, and you start with like 10 years old, up to 100 years old, then you have a number of People with telomere length right? And there's some longitudinal data, it's a little scant. But there's some, then you can quantify What's the slope here? Right? How many?

How much length of telomeres? Do you lose for every year of life? So you can actually get a number for this. Now you say, okay, in the dish, what's that slope? Right? How quickly are the telomeres eroding for every year of life? And the answer is that the erosion in the dish is about 100 times 50 to 100 times faster than in the human body. It's okay, that's telomere length. That's interesting. But the cells in addition to or dividing all the time in the body, not every cell is constantly dividing, right? So there are other approaches that are less sensitive to cell division that we've looked at. And we've also showed that the rate of telomere shortening in the dish is not only about cell division, which is kind of something that's fairly widely assumed in the literature, but we've showed if you heard the mitochondria, so you can pharmacologically right, you can put a little poison we were talking about earlier, like antibiotics can, you know, hurt the mitochondria as a as a side effect. So there are a lot of really good, you know, targeted poisons for mitochondria, like Cyanide is, you know, the reason cyanide kills people is because it inhibits mitochondria. Interesting. And there are other, you know, fungi and mushroom derived chemicals that were designed to kill bacteria, right, and this war between fungi and prokaryotes, and all of this. So you can harvest this Pharmacopoeia to do selectively perturbed right or like experimentally manipulate the mitochondria in the dish, and those cellular lifespan studies. And what you find if you do this is that if you heard the mitochondria pharmacologically, right with a very targeted way, or genetically, you can use tools like genetics, or use cells of patients that had a genetic defect in the mitochondria, that, as I said earlier, can cause mitochondrial disease. So you can ask what's the lifespan of those of those cells right with the mitochondrial defect. And what you find is that the rate at which telomere shortened is not just about cell division, the theory is, every time one cell divides, you lose, you know, X number of, of letters and the telomeres, what we find is that if you perturb the mitochondria, pharmacologically, or genetically, the number of telomeres, tell them your bases are, the length of telomeres lost, every cell division is much greater. So it's uncoupling this loss of telomere length due to cell division. And there are other tools like DNA methylation based epigenetic clocks, that some of your listeners might be aware of those clocks work in the dish. And those clocks were designed, right, you take human blood from people that are 10 years old, people that are 100 years old, everyone in between, then you can train an algorithm use machine learning, penalized regression methods to identify some algorithm that will predict someone's age just based on DNA methylation. So you can take a DNA sample from someone's blood. And you can predict with about a three year accuracy how old this person is, just by looking at the epigenome or the in particular, this is DNA methylation.

Nick Jikomes 1:43:14

Is this where these products start to come in that you're seeing out in the world now where you can get your, your, your biological age versus your like, chronologic chronic chronological age. Exactly. And are those would you say that those are accurate and reasonable?

Martin Picard 1:43:29

So the epigenetic clocks, right, so that will quantify biological age are pretty accurate, like scarily accurate, they're almost some of them are almost too accurate. Because if their clock just says, you know, you're 63, and you look at the calendar, and I am 63. And then the clock says, Okay, now, you know, this other person is 22. And they are exactly 82, then the clock is useless, because it's just telling you what calendar time is. Yeah, but there's a bit of variation. And if you're epi genetically, right to biologically older than your actual age, so there's Delta, or you're epigenetically younger, then this might tell you something. So I think this is where the whole industry around quantifying your biological age and and then trying to do stuff, right to reduce your biological age to slow down your your biological aging. So yes, that is exactly this. What Gabriel found three years ago was that the epigenetic clocks work and the dish. So you take these clocks that were trained in human populations, and then you say, Now, okay, I'm not going to apply this to like other human blood samples where it predicts age really well. I'm going to apply this to samples in vitro, right? So you took cells from someone, you put them in a dish, and then you make them you let them age. Then if you take samples at different intervals, then effectively you're creating a longitudinal study where you're tracking the same person over time. And the result here is that on average, first, the clocks work in vitro, which is really cool. Yeah, you can track biological age and and this has convinced us that this model of human aging in the dish is is is not just an artifact,

Nick Jikomes 1:45:07

you have a you have a reasonable in vitro way to study age. Exactly. Yeah.

Martin Picard 1:45:11

Yes. And this shows also quite convincingly, if you heard the mitochondria, the rate of biological aging is much faster this

Nick Jikomes 1:45:17

faster if there is if they're not allowed to freely go, or they would otherwise go.

Martin Picard 1:45:23

either. It's like, you mean the mitochondria? Right? Yeah. So maybe that something about like the movement of mitochondria and where they go, maybe it's something about ATP production, right, and the flux of electrons and the electron transport chain, maybe it's something else your reactive oxygen species production Mitel nuclear communication, there is something that's communicated between the mitochondria where you perturb it pharmacologically, or genetically, there's something changed in the mitochondrial biology that is transduced. Inside the nucleus, which is where the DNA methylation happens, right, which is where the telomeres are that shortened faster. So there's there's information being transduced. And one very simple way to think about this is that the mitochondria, or what allows cells to perceive time. And if you have good functioning, healthy mitochondria, and energy is flowing, you know, kind of at a at a slow pace, then somehow the cells perceive time in a way that will be consistent with our large mammal, right, that has a very, very slow metabolic rate. If you're, if there's energy that's flowing much faster, if your mitochondria were less efficiently, then somehow that kind of speeds up your perception of time. And that's kind of a loose interpretation of the individual findings that we have,

Nick Jikomes 1:46:44

I guess that does kind of start to make sense. Like the, the larger animals tend to live much longer, they tend to have this lower metabolic rate. And they're, they're going through life more slowly, in many ways. And you can do that within a single life, right? Like people who are people who are in very good shape to do certain forms of exercise have lower resting heart rates. And so even though that they they go through these physical exertions while they're exercising, they're almost like, it's almost like that's buying them the slower baseline metabolic rate. And presumably, that has some sort of lifespan payoff. Exactly.

Martin Picard 1:47:17

Exactly. That's, yeah, you're tying all of these things together into, you know, a model that's consistent with our understanding, and Herman Ponsor, a Duke has this beautiful body of work, showing that exercise actually, you know, does exactly what you're saying you spend more energy during the exercise, but then after, then the body is in a more, you know, can operate in a more efficient state. And, and ultimately, maybe, you know, the, it's possible, I don't know, it's not a fact. But it's possible that the health benefits of exercise could be derived from this, the fact that you train your body to become more efficient. So we're not exercising, your heart rate is lower. And then you're bringing your body into this, you know, relatively more hypo metabolic state, which has health advantages. So you become, you're bringing metabolism to be more aware, like, yeah, versus if you're stressed out all the time. I was like,

Nick Jikomes 1:48:14

I want to ask you one last question related to that, before we get to the gray hair stuff, which is kind of fun. So based on this, like allometric, scaling stuff, and this relationship between metabolic rate and lifespan, maybe this is not known. But if it's not known, maybe if you think you have a clear prediction. What do you think if you were to measure the average number of mitochondria, per cell per organism, of all of those organisms on on some of those plots where you're looking at metabolic rate versus mass? Whales, monkeys, dogs, shrews, like if you were to measure the average number of mitochondria per cell per animal? Would you expect to see a clean relationship there? Or is it not obvious?

Martin Picard 1:49:05

It's not I don't know. I don't know. It's not obvious. There's a limit to how many mitochondria you can pack in a cell. Yeah, just spatially. Yeah. And it's not just about the number of mitochondria, but it's about how much flux happens through each. So you know, mouse muscle has more mitochondria than human muscle, right? The volume density, just the number of mitochondria to make it simple. In the mouse muscle cell is about double and you know, to triple what humans is. But the difference in metabolic rate is not two to three times it's more like eight times or maybe more. So I don't think that the scaling and even also in lifespan, like a two year lifespan for a mouse a 200 year lifespan for Well, that's 100 fold. There will not be 100 fold difference in mitochondrial numbers between mouse and whale I I don't see this being possible.

Nick Jikomes 1:50:04

So anyways, I did want to ask you about some some work that you've done that is related to aging. And it's also related to something a component of aging that everyone is tuned into, because it's so visible and people, people care about what they look like, you know, as we all know, when you get older, most people to some extent, will have their hair start to turn gray. So what what is that at the cellular level? What's going on? And why does that? Why did Why does our hair turned gray in the first place.

Martin Picard 1:50:31

So the reason are hairs and you know, scalp hair, beard hair, you know, other hairs are colored is because of this protein called melanin that's kind of incorporated in the shaft of the hair. And it's made, there's beautiful biology there, each hair is the product of a little mini Oregon. Like my collaborator Ralph powers at Miami likes to say, the hair follicle, which is like the, the bald right and, and under the skin, from which the hair grows out is like a mini Oregon. And there's there are cells that are that are specialized in making this melanin colored, you know, colorful pigment. And then that gets incorporated into growing hair. So just in humans, scalp hair just grows continuously. And then it goes through a few phases, but it can grow continuously for very long periods of time. So that's a source of hair color. And in graying, then you lose that. Right. So it's just the the pigment is gone. And there's a few, you know, hypothesis and decent models for why this happens. And at this point, I'm not an expert in hair granular Ralph is but we looked at quite a few hair follicles and a lot of, you know, hair strands from from people who participated in our study. And what we found, if you do electron microscopy, for example, you take a white hair and a dark hair from the same person. Right? So it's the same genome, same environment, right, you're exposed to the same stuff, same emotional cycle, social context, all of this. Yet, in the same person, you have some hairs that go gray when you're like 30, and then some hairs that will stay dark until you're like 80. So there's this beautiful diversity in a genetically homogeneous system. Right. So these changes cannot be genetically driven. So that was the initial point of interest for us to be interested in that if we could figure out the reason why some hairs are more vulnerable to aging, and then they turn gray very early, and then some hairs are more resilient. This could be the key to understanding more of the factors that keep some people resilient, and some people you know, less resilient. So the grain is just a loss of the melanin and in the growing hair.

Nick Jikomes 1:52:44

And did did this tie in to mitochondria at all?

Martin Picard 1:52:50

Yes, yeah. So initially, that was probably the only project that we started without having a clear understanding of how mitochondria would fit in the picture. But I, I had read some things when we started to think about hair graying, and the the idea that there could be this, there is this heterogeneity, it could give us a new insight to the variation, the variability in human aging, inter individual variation in aging. And then we started to look in the literature and there is some very nice work showing that the mitochondria produce reactive oxygen species, the stuff we were talking about earlier. And in the hair follicle where the hairs grow. There's something that seems to happen to where the the mitochondria can start to produce, you know, too much reactive oxygen species. And this almost acts as bleach. And then kind of, you know, bleaches the hair, and maybe it has an effect on the melanocytes, the cells that make the melanin. So there's some cool biology there that people have been looking into for, you know, for a number of years. And then there was this particularly, you know, cool paper about mitochondria, and what they call the Ring of Fire, like the ring of oxidative stress that could be involved in the hair growing. So there was some element. But you know, we didn't know and really what was really cool, but thinking about the hair to hair variation, what could be at the origin of this. And then very quickly, I was chatting with my partner who's a neuroscientist by training. And then, you know, going through this reasoning of like, the same body, same genes, right, same genome, same environmental exposures, yet this heterogeneity, how could this be? And then the idea was, well, what if you could find on someone's head, like you pull the hair, and then the tip is dark, and then their route is white? Right? So somewhere, the hair goes from dark, dark, dark, so it's young, right? And then it gets old, and it becomes white.

Nick Jikomes 1:54:48

It's a call to catch it at the time that it's Yeah,

Martin Picard 1:54:50

well, you catch it. The beautiful thing with hair is that it grows and it sticks to your head. Yeah, so maybe that thing that transition from young dark to old white to happen, that's a dream. Want to go back three months and hair time is three centimeters? Yeah. So you know, as long as you have hairs that are a few centimeters long, you can find these hairs that are two colored, or these by color hair. So, you know, that was that was neat, you know, to think about and then we thought what if you could have hairs where the tip is as dark, and then you have a white segment. And then it goes back to dark again. Like what if this was reversible? And and then Mary said, Well, I've I've seen hairs like this before. And then I thought what? white hairs I can go back dark, just like yeah, she went to the bathroom and she pulled two out. So did she came back to the living room is like hey here. So right there, we had, you know, a physical evidence that the hair graying the hair growing in humans is at least temporarily reversible, which which blew my mind. And then that kind of brought us to think about how this could happen. And then we did proteomics. So then we launched a study, it was called the SMA study the stress of mitochondria and aging hair, sma H Study. So in this small study, we started to recruit people. And we use the snowball recruitment method where, you know, you tell someone, then they tell their friends and, and then people were sending Ziploc bags with hairs in them. And, and then, you know, we've developed a method to digitize, you know, the same way you would digitize pictures, you know, old physical pictures, like in the good old days, you put you know, the hair on the scanner, you stretch it, we you know, eyelid is a student who was doing this in the lab, she would iron the hair out, and then you know, tape both ends, then you have the, you know, the hair all stretched out, and then you scan it at super high resolution. So you push the scanner to its max resolution, and that you get several pixels for each millimeter of hair. So you get beautiful spatial resolution, which becomes temporal resolution. Yeah, because errors grow over time. And then we were able to quantitatively for the first time show that here's a hair that's dark, boom, here's the hairs that's that's white, and then who it goes back to being dark again.

Nick Jikomes 1:57:10

And do we know? Do we know how common that is? And what might be driving it at least?

Martin Picard 1:57:16

Yes. So that's, that was?

Nick Jikomes 1:57:19

That might literally be a million dollar question. So it's

Martin Picard 1:57:23

pretty common. This was Shannon rouser, another student in the lab who that was her challenge to, you know, collect all of those hairs and do a study to, you know, see how this changes over time and in relation to stress hormones in relation to like life exposures, and then we developed a tool to map stress over the same period of time, if you have a hair's at 12 centimeters long, then that's about 12 months of time, right? So you have the historical record, or the biological record of this person over the last 12 months, and what happened in the way it's encoded in this hair. And then you can ask the person, you know, to go through their calendar, and identify the period over the past two years, or the past one year, that was the most stressful for most people. That's pretty easy. So yeah, this, you know, last June, broke up with this with my partner, and this happened, you know, I change job or Yeah, pandemic happens. Yeah, and then what was the least stressful point of the past year, and then people are pretty good at identifying this too. And then we ask them to identify another like six points, and then you connect the dots, then you end up with a profile of stress over the past year. It's flawed, you know, from being a retrospective, but yeah, that that was sufficient to identify statistically significant correlation between events of life stress events of grain. And then when the paper was published, demonstrating this, I've received about this point, but 60 emails of people from all over the world, which is amazing people saying, you know, people were thanking me I was crazy, but the I have the hair United States in my fridge if you want it. Thank you for showing that. You know, they're not crazy. So the reversal,

Nick Jikomes 1:59:01

you mean people that had started to gray and then got their color? Black? Yeah, yeah. And

Martin Picard 1:59:05

or, you know, they're, they look in the mirror and say, Oh, this weird here, that's it's white at the tip, and it's dark at the root, how this is not supposed to happen, right? If aging is a uni directional, linear process that we're doomed to go through at a fixed rate, you're not supposed to see aging features reverse. So this kind of, I think that's why it's a little upsetting for people, then some people, you don't react weirdly to this because it upsets the paradigm or the framework from which we work. And I think this data shows hair graying, and probably other features of aging, or more malleable than we used to think.

Nick Jikomes 1:59:44

I mean, did you at least start to get a sense of I mean, what was there a correlation between like, oh, yeah, I had this really stressful period, you know, someone died or I got laid off or whatever. And then something really great happened six months later, and that correlated with the The color coming back.

Martin Picard 2:00:01

Yeah, so the most striking example we have in the paper is a young, you know, Asian participant who said, you know, she finished, she defended her thesis or PhD thesis. And then you know, things were fine for a few months. And then she said, I went through the most stressful two months of my life. And she went through a breakup and you had to travel and, and then she had to decide what she was going to do with her life. And so it was very stressful. For her physiology change. She lost her menses for two months. And then after she decided to take a job in New York City, and she, you know, she moved to New York City and and now things were good. And if you look at her stress profile, right, she finished her thesis, it was like a level two out of 10. And then the most stressful two months speak at 10. And then around the eight, nine for two months, and then another peak at 10. And then boom, down to about one and then one for the rest. The hair graying pattern, is you superimpose it on top of so it's the hair is dark, dark, dark, and then boom, it becomes white for exactly two months of time. Then the stress subsides and then the hair gets its color back. This was amazing. P equal point 007. If you do with statistics on that,

Nick Jikomes 2:01:12

now is this. That's remarkable. And it's totally believable. But at the same time, when you when you just look at people in our life, you don't usually see that right? We don't, we don't really notice that. And so is it just an uncommon thing? Are these unusual individuals who had an extremely high amount of stress but low baseline? Or do you think that this, that anyone could achieve such a thing? Yes,

Martin Picard 2:01:39

I think anyone can achieve such a thing. We've seen this. Now in like, an a nine year old girl from Europe, a she had a white hair that reverted back to dark beard hair from like a 37 year old, male pubic hair from a 37 year old woman. So it happens in all sorts of regions of the body and also to people when you start to look, then you start to to find them. And I think we typically don't see them. I had never seen this. And then when we started, look, you know, we found you over recruited for about two years. And we found 17 people. So it's not a ton, right. And since that paper is published, and there was in, you know, in the media a little bit, so it reached a large number of people out of everyone it reached, there's a fraction of those that you know, noticed that had experienced as the they saw two colored here and there on their head. And 55 of those people kind of found my email somewhere and you know, email me. So at this point, we think it's pretty common. And we ran a survey with my colleague, Ralph, I was in Miami to ask, you know, those people who had, you know, contacted us what, how many hairs did they find in their hair? And was there stress associated with this transition reversal? And so on. So it seems like it's decently frequent. And it's not kind of a once in a blue moon type of event.

Nick Jikomes 2:03:04

Interesting. Well, we've, we've talked about mitochondria for two hours. There's just a lot of fascinating stuff here that connects to so many things. And we didn't even get to all of them. It sounds like I mean, if you think of health and mitochondria centric way, it seems like some of the sort of very basic practical takeaways for people who want healthy, vibrant mitochondria are definitely you need to have some exercise endurance exercise. You don't need to be a marathon runner, but if you're not getting it, there's your mitochondria are not going to be be used in maybe the the best way or the most efficient way that they could be. And also it sounded like if you have an extremely carbon sugar centric centric diet, that would be another thing that's not going to sort of optimize your mitochondria basically.

Martin Picard 2:03:54

Yes, I wouldn't make strong claims based on my knowledge of like the type of diet I think clearly refined sugars are toxic. That's, that's no, there's no magic, they're not eating too much is the way I

Nick Jikomes 2:04:07

would phrase it, right, just just the amount of calories,

Martin Picard 2:04:11

the amount of calories the timing of calories, like we discussed is probably you know, relevant. So to your first point movement, like if you can take the stairs instead of taking the elevator to go to flight of stairs, right? Or you can walk instead of taking the car or like these little details, just physical activity. There's good evidence you don't need to be a marathon runner and to exercise like a maniac to the right of benefits of moving, just moving anything that makes her breathe a little harder is good for you. It's good for your mitochondria, and not eating too much. Yes, it stimulates you know, your your mitochondria gives them a purpose. And there's also evidence if you if you're hungry, right, that actually stimulates processes that get rid of the bad mitochondria. This might toffee gees, like like older mitochondria. So quality control. So when you're hungry, the body kind of goes into this mode of I need to Get rid of the stuff I don't need. And then if you have mitochondria that are on the edge, like are the well functioning or not? If they're challenged, or if the cell goes into this starvation mode mode a little bit, then it will you know, digest the not so useful things, which can include old mitochondria.

Nick Jikomes 2:05:16

What happens if you don't get rid of those old mitochondria? Do they start causing collateral damage?

Martin Picard 2:05:21

That's, that's the idea. Yeah. And there's, there's a few kind of indirect lines of evidence that yes, that's the case, if you fail to, to degrade the poorly functioning mitochondria, they can kind of hurt the the functioning of the whole mitochondrial community the same way that you know, if you have a bad apple in a social context, right, that person can have a negative effect on other people. So if you think about mitochondria as dynamic little social organisms, yes, I think poorly functioning or, you know, damaged mitochondria in that are not getting degraded, could deleterious could have deleterious effects on the functioning of the system as a whole.

Nick Jikomes 2:06:01

And I guess I'll end with you know, I probably I would have liked to dwell on the the mind mitochondria area of discussion a little bit more. Could you maybe end by just describing, you know, with respect to the so called Mind mitochondria connection? What's sort of an exciting area of research that's on the cutting edge? Where do you think we'll also make some real progress in the next few years? What kinds of questions do you think are answerable? But haven't been answered yet? Yes, that's

Martin Picard 2:06:27

a great question. To add to what we just said, like moving stimulate your mitochondria, not eating too much, or being hungry once in a while stimulates mitochondria gets rid of the bad ones. Some of our recent work and the work of others shows that years, the psychological states can actually manifest and in molecular terms in the mitochondria, and change, maybe the function, maybe the content of the mitochondria. And one of her early study in that area of the mind, mitochondria connection showed that woman who felt more positive emotions, right positive mood that's called, so a woman who's you know, on a questionnaire that asked this past, you know, 24 hours today? The answer is in the evening. So today, how much of this that you feel right, and then you have items that are like, today, I felt, you know, love, compassion and trust, right, there are some days, we all feel some of it. And if you wake up, you know, with someone that you love, and then you have some good positive interactions in the morning, or, you know, you see a good friend or right, then you can feel quite a bit of this. And then there's some other days where you don't feel love, compassion and trust. And you feel more things like you know, disgust, betrayed and depressed or sad and downhearted. And so by reading a bunch of positive items like this, you know, being inspired or you know, excited, or more negative stuff like being depressed, then you can get a sense of how positive how negative people feel. And when we did it that first study with the mitochondrial health index, so it's getting at the energy production capacity on a per mitochondrion basis, right. So almost like the quality of the mitochondria. In white blood cells, we found that women who said, I felt positive, right, more positive the day before they gave blood. So if, let's say on the Wednesday, they say, today, I felt really good. The next day, their mitochondria are like 10 to 15% have higher MHI.

Nick Jikomes 2:08:24

The mitochondrial health index was higher when they had a really good day. Yeah, basically, when

Martin Picard 2:08:29

they had a very good positive experience, right, they when they had experienced a lot of positive emotions the day before, and two days before the effect was there also but a little more attenuated and three days before also more attenuated, then you can ask the reverse question, you know, is this connection just bi directional? Or is it that the mood drives right? Or influences mitochondria? Or is it the mitochondria that influences how you feel. And by having this kind of temporal sequence, where you ask people how you how they feel multiple days in a row, and then what their mitochondria look like, or the MHI is, and then you continue to ask them after you measure the MHI. That study provided directional evidence showing that the mood predicted mitochondria, and up to 15%. of you know, higher or lower MHI was explained by mood the day before. But mitochondria me try it on that they didn't predict mood on future days. So that was, I think the first evidence of a directional, you know, connection short lived, right or short lived, or at least, you know, rapid acting within 24 hours, your mood might translate into the function of your mitochondria. So this study needs to be replicated and needs to be done better in a design where you measure mitochondria, you know, more frequently and you know, more often and with, you know, better measures than our early MHI. So we're developing new methods to do this. So this was kind of the first foray into this mind, mitochondria connection that convinced us there's something we're looking at you And we're doing more studies now to understand, well, if your mitochondria change how, why does this matter? Right? Yes, bring you more energy as a change how you respond to stress and how you think and function of your brain and so on? Well, I

Nick Jikomes 2:10:12

mean, the folk psychology here is suggestive, right? We all experience states where we feel like our mind is working better when we're in a relatively good mood. But at the very least, what I'm abstracting from what you just said, is, within a 24 hour period, the this index that you're talking about, about how efficient the mitochondria are, can change 10 to 15%, at least, which is significant, which is enough that it right that that must have consequences for, for how your brain circuits or how efficiently they're functioning. Yes, whatever the details are, it's, you know, on a day to day basis, there's that level of change in the energetic efficiency, basically,

Martin Picard 2:10:51

yes, if you know, 10 15%, more energy or less energy can be substantial. You know, we know this from model systems and experiments. So I wouldn't be surprised if that makes a pretty big difference. If you just think about energy in terms of calories that you eat 10% 10 50% More or less calories every day. That's it. That's a huge difference. And then if we bring this back to lifespan, and you know, how much energy you're burning through, yeah, yeah. If you burn energy much faster, then you know that. So there's likely a connection there at least a good hypothesis that we're pursuing that human, you know, experience, psychological states, get under the skin influences, you know, things like metabolic rate and influences the rate of aging through an effect on mitochondria. Right? So this becomes kind of a mind mitochondria to health axis, and there's, you know, a lot of things to test and a lot of, you know, points to do to confirm along that that axis.

Nick Jikomes 2:11:55

All right. Well, I think that's a good place to end it. Martin, thank you for taking the time and sharing this stuff with with us it was I thought it was really fascinating. Great. My pleasure.

Unknown Speaker 2:12:05

Thank you.

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