 Thank you very much and good morning's pleasure to be here. I assume at this point about a third of you are sleepy or going to sleep, okay? Probably a third of you are texting other people, okay? And probably a third of you are either having sexual fantasies or waiting for lunch, okay? So my job is to try to get at least two-thirds of you on the same page I am and see if we can find some interest. So I want to make two bold predictions. One of them I'm going to make now and one of them I'm going to make at the end of the talk, okay? And if I put this down and you can't hear me, tell me to raise it up, okay? So my first bold prediction is at the next ancestral health meetings that at least one day of the meeting will be completely devoted to mitochondria, okay? Mitochondrial biogenics, bio-energenics, dietary supplements for mitochondria, how do you make ATP, generate ATP, what's the role of mitochondria in aging? You could go on and on, you could really have a whole three days on mitochondria. So prediction is it's really important. My job here today is to turn all of you into mitochondriacs. So when you come back next year, you'll be addicted to mitochondria and you'll want to do great things with that. So with that sort of background at the end of the talk, I'll give you one more bold prediction about what we can do in the course of a year to make mitochondria really important in our lives. Okay, so I'm going to start and do a little pass through the history of the universe, talk about the present and what we can do about the future. I'm going to name a lot of things. I tend to think of things in biochemical terms. So there'll be a lot of strange names, PGC1 Alpha, NF1, NF2, UCP3, CERT1, things like that. I don't think it's so important that you know exactly what they do, but you should remember their names because as we go through the next couple of years, they'll become more and more interesting, more and more popular, things that you'll want to know in terms of what we do. So just as a full disclosure, yes, I did dance for New York City Ballet. I forgot to mention that. That's not important. I am a scientist by training. I'm a pharmacologist by a chemist studied medicine all in one place at the University of Virginia. For years, my profession was making drugs, the evil empire to some of you. I would say to you that drugs do save lives, and that's important, especially if you're on the life saving end of that. However, drugs rarely if ever treat disease, and this is something that we discovered quite late in the 1990s. We had enough information about functional genomics as post molecular biology, post genomics into functional genomics. We learned enough to know that we did not know enough to ever treat any individual chronic disease with a single magic bullet. Therefore, we're up against this challenge that drugs don't actually work very well. So is there an alternative to long-term health and longevity? Well, we think so. That's why we're here, and it doesn't have anything to do with making a drug, but it really has to do with don't get sick. If you don't get sick, you'll obviously be healthy. The healthcare system will love you, and you'll love yourself and you'll live a long time. So is there a way to avoid getting sick? And what do we think might be some of the important things? Well, I would say the first-line therapy in your life should be exercise. Exercise is the key to health. You should all exercise as much as you possibly can. You should never let it be secondary to anything else. And we'll make this case, particularly in the case of mitochondria, why exercise is so absolutely important to mitochondrial health and well-being. So exercise is number one. Number two is diet. Now, we're here. We're all believers in the paleo diet. I would submit to you that any diet works if the biochemistry of your body is right. So that means there's one thing you could measure. You'd want to measure hemoglobin A1C. Anything above 5.5, your pre-diabetic or diabetic, anything below, you're considered healthy. I would argue you should be down as low as you possibly can. You should be down at five if you can get down to five. If you can maintain that, whether you're a vegetarian, a vegan, a paleo person, if your A1C levels are down, you'll be healthy. That'll take care of your cytokine issues. It'll take care of your fasting glucose levels. Take care of your fasting insulin levels. Just do that. So the importance of diet is the diet needs to meet the biochemical principles of health. And there's always a place for supplements. Exercise first, diet second. Choose a diet that keeps your A1C levels down. Take supplements that work. This is a big deal because most supplements don't work. They don't work because the ingredients are not in sufficient quantities to make something work. There are homeopathic elements in there. That means on a dose-response curve, effective dose for effect, they're below zero. It means whatever is in there is not helping you. You need to at least be at the ED50, hopefully the ED100, and I'll pull me at ED120 to take care of polymorphisms and human variability. It's very, very important when you think about this that you have to have a supplement system that works for you and brings pharmacologic strength to a product. Therefore, you can actually get health benefits from it. Now, why am I talking about all this stuff? Because all of these things impact how mitochondria work for us. I'm going to submit that mitochondrias are actually the key to wellness and longevity. They provide us life functions. They also prove the death functions. This is what makes them so interesting. Got that right? Here we go. This is not a political statement. This is a statement about how our cells came together that life actually did not take over the globe by combat but by networking. If you think of your own body, you have all these organs and organ systems and cells and endocrine systems and they must all cooperate with each other. If they don't cooperate with each other, then we don't function right. So it's an interesting quote that I think we could apply to our daily lives. Now, I want to go back to the beginning of time. Yesterday there was a talk on mitochondria so I'm going to skip over some of the early stuff. I'm going to do that more in summary by Tim Gershmer. What we know is mitochondrion 1.8 billion years ago lived all by themselves. They were probably highly unusual cells because if they really do what they do today, they must have been the most amazing cells alive. We talk about them being captured by another cell but maybe they captured the other cell because they certainly had more energy and power to do that. Basically, they were primitive cells. They were free functioning. They were called prokaryotes. Somehow, in some sort of magic, amazing step, probably by random accidental effects, they barged into another cell, somehow got engulfed into it and became a part of somebody else's cell. This imparted to the other cell a huge amount of energy generation. That was the beginning of where we got it. It flashed forward another 600 million years. It had multicellular cells. From there, it's all history. That's how we came into being. They were derived from proteobacteria. These bacteria, some of them are still alive today. The process was called symbiosis or endosymbiosis. When we get down to the bottom line, it's humans who are composite of human genetics and mitochondrial genetics and probably other bacterial genetics which we haven't fully well defined as well as what we refer to as the extracellular microbiome. Now, what's the case to prove that? I just said that mitochondria were free-living spirits and then they became symbiotes. The rationale for thinking that has to be based on something that we can hold true. Mitochondria are very similar to bacteria. They have porans which are transport proteins. These are only found on the outer membrane of mitochondria and they're only found in bacteria. These two types of creatures have one thing in common. Another very important component is something called cardiolipin and it's found in the inner mitochondrial membrane and it's also found in bacterial cell membranes. Cardiolipin is a very important element we're going to come back to and talk about later. In terms of DNA, our DNA is helical. We're all aware of that. Mitochondrial DNA is circular. Very different. And the chromosomes in our human nucleus actually contain genes that were originally only in mitochondria. So there was a gene transfer conservation of knowledge. You didn't need it in two places. The mitochondria decided to give it to the nucleus so it became a part of the nucleus in the cell. They lost that thing. The last thing is mitochondria really do still have this independent spirit, if you will. They have a double membrane. So they're kind of isolated from other things in the cell so they're a lot more interesting than a Golgi body or a ribosome or an ion channel because they do some really interesting things and we're going to talk a little bit more about those. So this is how it works. Genes that were redundant were transferred to the host nucleus. So now the little mitochondria and the mighty mitochondria only has 37 genes left in most of those code for proteins. Now, this, I think, I find this fascinating to me. So when we go through, an anthropologist looks at skeletons around the world and we determine that Homo erectus, people who stood upright or creatures that stood upright, evolved and became prevalent all over the world about two million years ago. However, we're not related to them and it's kind of odd why they would all die off. There was like spontaneous generation of free standing up, standing up straight creatures that looked like humans two million years ago. Apparently they all died off. So our actual ancestors came into being somewhere around 150 to 200,000 years ago and we know that because we all carried the genetic footprint of their mitochondria and that all came through the female egg, not the male sperm. So one is able to follow the genetic drift all over the world from East Africa all over the world and we can actually find subpopulations. So why is this possible is because if the mitochondrion had had a major mutation then the mitochondrion wouldn't work and we would all died off. So only tiny mutations were allowed so that the energy generation of the system could remain in place. So it's a very interesting way to know that we can follow our lives through all of that. So interesting the female Homo sapiens that we are members of carry the females carry the mitochondrial DNA. That's and we can follow that throughout the entire world and so only subtle mutations were allowed. That allows us to follow where things are. So the bottom line here is ladies you rock right. You made the energy that we use and interestingly the female egg destroys eats the male mitochondrion. Sort of a mean thought that's the way it works. Okay so let's talk about the two major functions of mitochondria. The one that we think the most about is it's an ATP generator. You add a little bit of oxygen. You add a little bit of sugar, salt, proteins, fats and the next thing you know you have ATP. So ATP is a cells version of E equals MC squared. So the energy of the biological system is energy equals ATP. Now why is that important and what makes adenosine triphosphate? That's what ATP stands for. What's the big deal about this? Why this molecule not other molecules? It's not so much that it's an energy giver. It's a phosphate giver. So phosphate giving through a high energy bond is really energy giving because our whole cellular system works on a phosphorylation defosphorylation system. That means enzymes are in an inactive state or less active. They're phosphorylated and they become more active. Ion channels work the same way. Everything in our body is phosphatase, meaning phosphates removed inactivated or phosphorylated through kinases, meaning activation. And all of that goes through the ATP system. So we're going to talk more about that because that's really important. The other thing that mitochondria undo which is really sort of key to aging and to cell death and apoptosis is mitochondria also induce cell death. And there's a pathway where they do that. So the mitochondria are very, very responsible for both providing the energy for life and destroying the cell and destroying life. So these two things quoted by Voltaire with great power comes great responsibility. Ironman also made the same quote and I'm sure if mitochondria Eve could speak she would say the same thing. Okay, so let's talk about aging and then we'll get back to the mitochondria. So aging is an interesting process that basically our genetics is designed for procreation, not for aging. We do not have aging healthy genes that are out there. Our job in life is to make more of us not live forever. So our bodies are not designed to live forever but they should be and they can be. So it's very important to understand that distinction. Now in addition to that there are all the other things that really are oxidation induced death. And the things that are kind of fun to think about here is things that you can't avoid. They're like the wear and tear of the body over a lifetime would be the accumulation of random environmental unchecked mutations. Yes, this happens. This can be through internal oxidations. It can be from cosmic rays. It can be from a lot of different things. Result of oxidative damage followed by non-functional enzymes and an overreactive immune system. This is a common thing that we call pro-inflammatory signals. So oxidation today can occur on the cell surface. It produces an immune response. This immune system overreacts, destroys the cells and that's what inflammation is all about. Inflammation leads ultimately to bad karma and death. Okay, so not a good thing. Now the result, the other sort of interesting hypothesis is the telomere tail. The DNA has a tail and the tail is called a telomere. Every time a cell divides, a little piece of the telomere is chopped off. You get to a certain place in life and the cell decides times up, starts a poptotic sequence and dies. Okay, so this is sort of like the, is this the end of it? Is this how we have to go? It's one theory, yes, but there are other theories which would counter that. Another long approach here is a loss of stem cell repair mechanisms. So as you go through life, you can think about some of your older family members, Uncle Joe last year, he was a picture of health, didn't see him for a year, went back and oh my god, Uncle Joe has aged like not one year, but like 100 years. Uncle Joe has finished. So what happened? Uncle Joe ran out of stem cells. So the stem cells are those little progenitor cells. They go out there and repair everything for you. As long as you have those guys, you can actually repair your body, your heart, your liver, almost every system in your body can be repaired. So this is really an important way we maintain our lives is through stem cell repair. Now, the one that I want to talk about is apoptosis induced induction by deteriorating mitochondria. And this happens when mitochondria release cytochrome C from the inner mitochondrial membrane and back to the cytosol. Now, functionally, I should say from my own experience, going back almost 40 years, I did a clerkship with Professor Robert Haynes, who was one of the original mitochondriacs. And so in those days, this was pre-molecular biology. So we were really physiology and biochemists and pharmacologists. We didn't know a lot about anything beyond that point of view. But we began to study mitochondria in different situations. We'd give them change their energy source. We'd change their oxygen number. We'd do all those things. And what you could see is, and we do this in animals and we do it in cellular systems, what you'd see is when a mitochondria gets sick, it becomes round. A healthy mitochondria is almost rectangular. It takes energy to be rectangular. The easiest state of less energy is roundness. So when a mitochondria rounds up, it's sick. So when you look at disease states, you look at ischemic myocardium as an example. When you take a punch biopsy of a heart, you will find multiple ischemic mitochondria because they're rounded. They're non-functional. And that rounding process is where cytochrome C has left the state of redox cycle that makes mitochondria make ATP. It's left the mitochondria and where did it go? It went back into the cytoplasm. So that's a really important thing, but we didn't understand why at that time. But what happens when that happens, you'll see, I'll tell you about the calcium hypothesis of disease in a minute. What happens is this begins the apoptonic sequence. And if you just think about from the time one is 20 and you have your very active cells have a lot of mitochondria, that'd be like your liver, muscle cells, heart cells. They're packed with mitochondria because anything that's working hard needs a lot of energy and therefore there's more mitochondria. But any of us who are over 60, that's just me and one or two other people in here, I have half the mitochondria that I had when I was 20. And that said, that means I can only make a certain amount of energy. I only have two choices here. I can somehow find a way to have my mitochondria work better, biogenesis, or work better, or make more of them. So I have two choices here. But at this point, my ATP theoretical capacity to make something is one half. So cytochrome C, let's go back to here. So this is an essential component of the electron transport chain. So the way mitochondria make energy is through oxidative phosphorylation. It's a reduction oxidase called a redox system. The faster that cycles, the greater the rate of turn of that, the greater the amount of ATP that can be made per minute per second. It's really the most important aspect of the system. So cytochrome C undergoes oxidation and reduction, and it's very important in the whole process. It's also a very highly conserved protein. It's similar across all species. That means mitochondria in all species kind of work the same way. It makes sense because they are bacteria and they got into other things. They didn't just make humans and made everything under the sun, so to speak. So it's very conserved. It binds the cardiolipin, remember I mentioned cardiolipin before, which is in the inner mitochondrial membrane. So this is how it binds there, it stays there, it works there. Now reactive oxygen species, better known to me as free radicals, these are unpaired electrons which are highly active and will insert themselves into anything and destroy anything or become a part of it. These reactive species oxidize cardiolipin and then cardiolipin breaks out from the mitochondria and it goes into the cytoplasm. Now cytochrome C has its own pharmacology. So it induces calcium release from inside the cell where calcium can be stored and this causes a massive increase in calcium from outside and inside the cell. So as the calcium levels rise, this activates a series of proteolytic steps called CAP-PACE. CAP-PACE is 9 and 3 in particular. That's so important to know the numbers except to understand the process. Gytochrome C comes out, calcium goes up, proteolytic enzymes become active and they digest the cell. So when that happens, the cell gets destroyed. Now this whole process obviously destroys the mitochondria and destroys the cell. So you have one less cell, you have less mitochondria and this seems to be the general path towards aging and towards cell death. Now there are certain things that change this and some of the elements I'll talk about have two functions. In this case, nitric oxide inhibits the reduction of cytochrome C and it actually leads to further oxidation and leads to cell your death. Now we think of anion nitric oxide as our friend. It comes off of arginine, other groups. It's a vasodilator, it's Viagra, it's all those things. So it's a good thing except right here. Now later on I'm going to tell you nitric oxide is really a good thing because it increases biogenesis. So some of the elements we'll talk about do two things. One part that causes the mitochondria to die. The other side they actually cause rebirth. So there's not a clear answer in all places. Another thing I hopefully next year will be talking about is BCL2. This controls the movement of the cytochrome C from the inner mitochondria into the side of the cell through a large pore called a MAC channel. So this is a point of intervention. This is sort of the summary of that. Oxidized cytochrome C leaves the mitochondria via the MAC ion channel and induces capase activation and cell death. BCL2 to be determined next year. Okay, BCL2 is the one element here that prevents that. So if you prevent oxidation, we'll save the mitochondria. If you prevent oxidation in general, you tend to save the mitochondria. Now let's get into some physical forces about what things can we do that we are doing all the time to help preserve our lives and our mitochondria. Endurance exercise, calorie restriction, cold exposure, stress functions, inflammatory stress, ketosis, inflammatory stress, oxidative stress. All these things actually end up increasing PGC1-alpha, okay? Nitric oxide does that. That's good. CERT1 is a one missing here. Deacetylates PGC1-alpha. Why that's important is PGC1-alpha is the one element of the mitochondria and why that's important is PGC1-alpha is hanging out in the cytoplasm. It's got to go inside the nucleus. It's a co-activator for DNA transcription. And when it gets inside the nucleus as a deacetylated form, then it can cause the mitochondria to increase their genes, double their genes, and it can actually, from the nuclear point of view, provide all the symbiosis parts back to the mitochondria so that the mitochondria now has all the elements for biosynthesis. All of these things are kind of linked together. Their common link is PGC1-alpha. Anything that controls the up-regulation of PGC1-alpha controls the energy cell, controls the mitochondria, controls the ATP function. Okay, so there are other ways to do this. Reactive oxygen species induces both biogenesis and apoptosis. The PG1 signal right here is a whole host of other interesting things to talk about. These are next year topics, because one or more of these will be much more important. Nuclear respiratory factors 1 and 2, UPC. All these things ultimately lead to the overexpression of PG1-alpha, and this is a necessary and sufficient condition to increase mitochondrial content. This and this alone. There are other activators like AMP-activated protein kinase. This is an energy sensor. When ATP runs down, AMP runs up, because ATP is three phosphates, AMP is one. When you get down to one phosphate and the ratio changes, this activates the system since we need more energy. So this is an activator and drives the whole system. AMP kinase also decreases with age. This is another point where if we can prevent that AMP kinase loss, we will increase mitochondrial function. So it's a point where things can get done. It's a mitochondrial AMP activator. Okay, and this whole process of AMP decreases with age. Here, nitric oxide is a positive, because it causes the activation. So this is a biogenesis factor that's good. Now, you can think about this. Can you do anything about this in terms of drugs? Probably not. There is one interesting type of process. These things are called thiozolidine diones. These are insulin sensitizers. It means less insulin reduces the right amount of response. So insulin destroys mitochondria through another mechanism called the AKT pathway. But if you use less insulin, it becomes a positive factor. Okay? So I'm going to move along a little more quickly here. So now, let's talk about natural products. This is more along the lines of what we like. So there are six natural products here. And co-emzyme Q10, alphalipoic acid, percitin, and PQQ are all basically functioning as antioxidants. Okay? What's interesting about these is some of these tend to be targeted more to the mitochondrion. So they're more mitochondrion-specific antioxidants. So these are really interesting ideas. Coenzyme Q10 increases redox flux. That's a good thing. They're more ATP, but it is a quinone, and therefore it's an antioxidant. PQQ is a quinone, and it's an antioxidant. Cercitin is an antioxidant that is regarded as an anti-inflammatory, but it's an anti-inflammatory because it's really an antioxidant. Okay? So these are things that are sort of high-end things. You have 30 seconds. Okay? So I have to move right along and finish this. So how do we make half the mitochondria work more efficiently? Limiting substrates, anti-oxidation reduction cycle. Good. We need to have another process here. We can't rely upon fission or fusion. These are not nuclear things. These are biological things, but these are not ways to get there. So the other process, we'll address that next year. And so ending up here, what's going on here? Most people feel energy deprived, and it's because they have a problem. Okay? They have a psychological problem, and they have an ATP problem as well. And as you get older, you have even greater problems. So older people are truly energy deprived. Energy is ATP. And chronic fatigue, muscle weakness, heart failure, cognition, memory are all ATP-generated things. This is the bottom line. As energy goes down, depth and disease goes up. So last slide. What can we do about this? I think next year, there's enough information coming out from many, many sources that we'll be really addressing. How can we use dietary supplements, natural factors, all the other things that we can do for our lifestyle change. And we'll be at a point where we can enhance our ATP generation and live longer. Thank you. I've seen good studies, as far as I can tell, showing that physiologic levels of fructose consumption are associated with lower ATP levels specifically in the liver, and maybe other tissues as well where liver fructose is metabolized. Well, fructose is an unusual subject because it also has an effect on insulin sensitization. So it's very, very complex. But to ask, to answer the question differently, if you think of congestive heart failure, and you actually do a punch by the eye, so you have a human heart, ventricular muscle, you will find the ATP levels are way down, and the heart is very weak. So from a functional point of view, ejection fractions down, all of those things. So actually, an interesting study was done by Dr. Steve Sinatra, no relationship to Frank. And he's a cardiologist, and he began to explore the view of what could he do to extend New York Heart Class IV patients who are really patients with ejection fractions below 20, therefore very sick. And what he found is coenzyme Q10 alone would increase life expectancy or extend life. He also added ribose. He also added carnitine, and this combination of things allowed the cell to make more ATP, and therefore it recovered a lot of its functions. People lived a longer time. And kind of a follow-up question if there's no one else here. I don't mean to be just a quick one here. Along the hypothesis that a lot of the problem with ATP depletion is kind of... Or is ATP depletion analogous to hypoxia and reperfusion? And we know that reperfusion events often is when you get a lot of oxidative damage in tissues. Sure. Well, reperfusion, reentry reperfusion is a result when you open, for example, the heart, coronary occlusion. And so there you have two things going on. Massive free radicals, therefore, all of that sort of follow-on damage. But you need to reperfuse. You have to have oxygen, as well as substrates, to make ATP. So anything that's oxygen-deprived can't make ATP. Don't have fats can't make ATP. So yes, it all connects. Okay. Thank you very much. Questions. Have you heard of nicotinamide riboside supplements? And what do you think of those? And then also, while we wait a year to hear your advice on what we can do next year, what would you say the top three things... I think I heard you say exercise, but the top three things we can do to extend our mitochondrial health. Okay. Yes, I have heard the first one. Nicotinamide riboside. There's a literature on that, and it's promising. Still trying to understand how it works. But basically, that was the one I left off, the five mOzone nicotinic riboside, because I didn't have time, and it's a whole new story. But yes, I think it's interesting. You should follow that carefully. It might be useful. Okay. Second part was what should we do in waiting for the real answer next year? Okay. Okay. Well, you know, I suggest two things. One, I do favor a low-carb, low-carbohydrate diet because high-carb, high-carbohydrate diet causes insulin overshoot. So we always talk about the bad aspects of insulin overshoot. The things that are really bad that are still not talked about is insulin overshoot activates AKT and PI3 kinase, that causes mitochondrial demise. Okay. So low insulin levels are good. So how do you get low insulin levels if you don't eat high-carbohydrates? So it's close to a ketosis-type diet the better. Keep the fat running in through the mitochondria. You can facilitate fat transfer with carnitine, something like that. Co-Q10 is good, but you have to take a lot of it. It's pretty expensive. Watch out for supplements because they don't really put enough in there to make it useful. Thank you. Okay. Thank you.