Uncategorized

The Secret Life of Mitochondria with Joe Evans, PhD

by Deanna Mutzel, DC

101 comments

 
Mike Mutzel: I just got a text message. Let’s go ahead and get going. Thanks so much for joining us tonight. This is Mike Mutzel and Bettina Newman. We are grateful that you could be on the webinar. We have a fantastic presentation lined up here with Dr. Joe Evans. Before we kick it off, our functional medicine consultant here, Amy Salerno, is going to do a brief background about the conference that she’s putting and really tell that the impetus for doing this off our webinar series that we’re doing every Wednesday night in the month of October. She’s doing a great job in organizing a fantastic event that she can tell you about every shortly, and also getting all these great speakers lined up for about the webinars here and the live event. So Amy, thanks so much for joining us tonight.

Amy Salerno: Thank you Mike so much, and of course the Xymogen for making these awesome webinars possible. Again, this is Amy from New York, Xymogen functional medicine consultant, and I want to invite everyone listening to one of the foremost leading edge conferences of the year, the “2013 Vanguard Conference” that will be held on Sunday, November 10th. It will be presented by leading pioneers in their respective fields. I’m going to skip to the next slide. Mike, I’m not able to move the slide for some reason.

Mike Mutzel: Alright. Let me… There we go.

Amy Salerno: There we go. So, we have pioneers and speakers, Joseph Evans, PhD presenting at the live conference Vanguard Mitochondria: Power, Sex, and Suicide; he’s also our webinar presenter tonight, which we’ll get to shortly. We have Allan Warshowsky, MD presenting Vanguard Endocrinology: Messengers of Stress – Adrenal and Thyroid Hormones. We have Tania Dempsey, MD presenting Vanguard Methyl-Genomics: Breakthroughs in Methylation and Detoxification; and Dr. Susan Blum presenting Vanguard Immunity and Autoimmunity with a Four-Step Program for Restoring Immune Health; and finally, Dr. Richard Horowitz, MD presenting Vanguard Lyme Disease: Solving the Mystery of Lyme and Chronic Disease – although it doesn’t mention it here, it’s with an emphasis on inflammation and detoxification. Each of these presenters are authors and their part of our webinar series, which we’ll mention those specific dates this month. But just to go back to the live event that’s being held on Sunday, November 10th, it’s being held at the beautiful Mohonk Mountain House Resort. If we could skip to the prior slide so that everybody could see the picture of Mohonk. It’s a beautiful castle on top of a sky lake of the New Paltz, New York. This hotel is a national historic landmark in the Catskill Mountains, rated No. 1 resort spa in the United States by Condé Nast Traveler Magazine, so it’s an amazing new spa facility, as well as a hotel and conference center. We have supersaver overnight rates to make it a weekend event, or if you’re just attending for the day conference on November 10th, we want to make this a memorable event merging business and pleasure so you can network with other practitioners, learn about various topics such as methylation, mitochondria, hormones, immunity and autoimmunity, and Lyme disease. The hotel has many amenities; if you bring family members just to enjoy over the weekend, there’s boating, hiking, horseback riding, swimming, golf, tennis, and of course, a full-service spa. There are special overnight rates that we’ve arranged with the hotel, especially a supersaver overnight Saturday rate. We’re also having a dance party Saturday night at 9 pm, so that should be a lot of fun. If you’re interested in registering for the conference, you can also book directly with the hotel. You register it with the conference through me. The hotel – the number is there: (845) 255-1000. Mention Xymogen for the special rates. You would call me to register or email me on the number on the screen at (914) 393-0513. Also, the hotel is conveniently located only 30 minutes north of the Newburgh Airport for those traveling from out of town, about 60 minutes from the Westchester Airport, and about 90 minutes or so from the New York major airports. We had a conference there in May with over 110 practitioners from all over the country. Someone came as far as Belgium. So, it’s a great place to visit and it will be definitely worth the trip, not only for the presenters (which you can skip to the next slide again, Mike), but also for the location. These presenters will be also part of what Mike said, our webinar-author series over the month of October. Just want to give you those preview dates. Each presenter’s going to be presenting a preview to the topic that they’re discussing in more depth at the live conference, and they’ll be giving you clinical pearls that you could take away from the webinars if you attend those on the date such as – well, we know Joe Evans will be presenting shortly tonight, and I’ll be doing an introduction with his background in a moment. But also, Wednesday night, October 23rd (just going down the list), we have Allan Warshowsky back to back with Dr. Tania Dempsey; that’s at 8:30 pm, Wednesday night, October 23rd on selected topics. Wednesday night, October 30 at 8:30 pm, we have Dr. Susan Blum discussing her topic. Next week, we have Dr. Richard Horowitz, which is going to be a great one on Wednesday night, October 9th at 8:30 on Lyme disease; he’ll be discussing his new book launch, and he has a book special about how to get a free book as well, and hopefully you can preorder that before the conference. All these books, as well, will be available at the conference for book signings and for purchase at the conference, and to learn more about during the webinar series. So, that’s the story.

Just want to introduce Joe for tonight’s webinar. Joe Evans will be presenting mitochondria – “The Secret Life of Mitochondria,” which we know as power, sex and suicide. That’s the topic of his book, and it’s available as an eBook, which I’m sure he’ll mention. We’ll be giving out free copies at the live event, so there will be book signings for that as well. His background is that Joe is an internally renowned scientist, author and speaker. Joe has focused his career on the discovery, development and commercialization of safe and efficacious interventions for the metabolic, cardiovascular and inflammatory diseases. Joe has played a major role in the development and commercialization of a first and class controlled-release information about alpha lipoic acid for individuals with type-2 diabetes, also a first and class nitric oxide generator product for the sports and nutrition industry, and a first and class nutritional intervention designed to enhance mitochondria biogenesis, which we’ll be learning about tonight and which have also products affiliated through Xymogen available. Dr. Evans has served as a peer reviewer for more than 30 scientific journals. He’s published approximately 50 peer-reviewed scientific papers, review articles, book chapters, and has U.S. patents; he’s also a part of the Xymogen Board of Advisors, and we’re happy to have him. And again, Dr. Evans is author of the book, “The Secret Life of Mitochondria,” so I introduce our speaker tonight. I think Mike’s going to mention the products associated with our specials.

Mike Mutzel: Great. Amy, thank you so much. That was awesome. Joe, I’m going to pass it over to you. I just want to mention folks that you do want to write down this special – 24 hours special only on these products. This is over 300 different individual capsules than one box and so it’s a great savings of up to 25% off. So, without further ado – Joe, I’m going to go ahead and make you presenter, and thank you so much for joining us tonight.

Joe Evans: Thank you very much, Mike. Thank you, Amy. Thank you to Xymogen for allowing me the opportunity to present tonight and also at the Mohonk event, which if you’ve never been to Mohonk, I really encourage you to visit there and to take in the theory and the great scientific presentation, which I’m sure will be a memorable event. So without further ado, these are the required disclosure statements and the disclaimer statement.

So, what we expect to mitochondria – we’re going to have to take a global look at mitochondria, take a step back to look at some of the functions you may not think about mitochondria, and most importantly, really try to put them in our sight in terms of functional medicine at an earlier stage in terms of mitochondria have been linked to a number of different disorders. We’ll go through them just briefly and throw them an introduction to a fuller description at the local workshop.

Here are some factoids about mitochondria. The word has a Greek etymology to Mitos (thread-like) and Khondros (grain or granule). You’ll be able to see the reason for that on the next slide. Obviously, we are really interested in mitochondria because they produce approximately 90% of the cell’s ATP, the energy molecule, “adenosine triphosphate.” Mitochondria are found in most, but not all cells, typically a few hundred, but some cells really have been metabolically active – have a high number of mitochondria including brain, skeletal/cardiac cells, cardiomyocytes, and the liver and kidney. These cells can contain up to thousands of mitochondria. Sperm cells have less than 100 mitochondria. And according to Enzo Nizoli, where we got a lot of these factoids from – mitochondria’s comprise is actually 10% of our body weight, and they do kind of possess their own DNA (mitochondrial DNA).

Very similar structure evolutionarily – it’s thought that the bacteria really once had a symbiotic relationship with other cells, and so these bacteria-like structures evolved to produce the energy. You could see that these are similar in structure to some sort of primitive bacteria. But these are the mitochondrial cristae; these are the thread-like structures. Double membrane – this is the matrix inside, and they have an inner mitochondrial membrane and outer mitochondrial membrane. Depending on the cells, they have different structures. Of course, we have a different amount of mitochondria in the different cells.

This is the criteria indicating some of the most important mitochondrial function including ATP synthesis at the top of the heap, but mitochondria are also regulating cell death – the programmed cell death – the “apoptosis.” They are really very important in that process. They’re also very, very important in cell proliferation, heat production or thermogenesis. They regulate the level of calcium. Calcium mitochondrial are very important in that process, and a number of other processes.

So, with regards to mitochondria and ATP production, this is probably the most well-known function of mitochondria with all the electron-transport system complex I, II, III, IV – you can have the progressive movement of electrons down the electron-transport chain. The production of the hydrogen ion, which the gradient of the hydrogen ion produces the energy to drive the conversion of ADP to ATP in the complex V or the enzyme ATP synthase. A number of the raw compounds – a number of toxic compounds – have been shown to inhibit various complexes and these essentially have the effect of reducing the organism’s ability to produce energy and that’s why they are considered toxic compounds. Mild inhibition of this complex is actually shown to be somewhat beneficial if you can deal with the therapeutic window. For example, the most widely used anti-diabetic drug, “Metformin” is a mild inhibitor of complex I. So, as we go to pursuit of the creation of the compensatory production of ATP because of the mild downregulation of complex I. It’s not necessarily an absolute that if you inhibit one of these complexes that it’s going to be a toxic compound. That’s an interesting aspect of the electron-transport chain. Along mitochondria and thermogenesis – as I was mentioning, you have this gradient in the intermembrane space with regards to the hydrogen ion, so in addition to being used as the energy gradient, this proton pumps to drive the ATP synthesis. These protons can also greatly – what they call an “uncoupling protein” with the core, so it allows then to come back in, reestablish this gradient and to give off heat in the process. So, you’re not producing ATP when these neutrons come back in and they’re producing heat, and many organisms find that as beneficial depending on their environmental condition. This also has been sort of a strategy in terms of weight loss. You try to increase the thermogenetic properties of an organism by increasing thermogenesis, by upregulating the uncoupling proteins and therefore not really generating energy, but running the fuel as heat instead of generating ATP. The presence of these uncoupling proteins, and they’re giving various meds depending on the tissue, and there are some tissue selectivity in terms of the UCP1 and UCP2, but again, they’re also – and basically, the purest of proteins that allow the hydrogen ions to get back into the cytosol of nature.

Mitochondria, as I mentioned, are very, very important in calcium regulation. If we look at the physiological agonist stimulation, these calcium channels – there’s a great deal of interaction between mitochondria and the endoplasmic reticulum – very, very important cellular process. However, when there’s a huge amount of calcium overloading the dysregulation or a number of degrees that you have increased calcium overloading production of reactive oxygen species within the mitochondria, and this is one of the triggers of programmed cell death (the apoptosis) when calcium regulation is becoming dysfunctional, but basically, under normal conditions, there’s a ton of association between calcium octoate, intracellular levels of calcium, and mitochondrial regulation of them.

Cell death – this is when certain diseases, certain infections, and a number of different triggers for apoptosis. The way this triggers is focused on the mitochondria. There are a number of enzymatic processes involved – activation of these caspases. There’s a whole family of caspases. Again, calcium is one of the key signals of doing this whole process, but mitochondria play a predominant role in regulating cell death, and when this regulation is altered, some of these cells become resistant to apoptosis, and so they are not that easy to kill off. This happens when a number of different types of cancer that the mitochondrial apoptosis becomes dysregulated, and therefore, overall, the tumor is resistant in many patients to normal cell death.

Mitochondria and their relationship to health have really been brought to the forefront to research and to two different areas. One of the areas is nutrition, and specifically, caloric restriction. Second area of research has been the role of mitochondria in aerobic exercise. These two behavioral interventions are the two primary interventions, which lead to increased mitochondrial production – that is mitochondrial biogenesis or the formation of new mitochondria. And so, we first got interested in this area where we are looking at the different behavioral and nutritional factors that promoted health and longevity. Caloric restriction is one, and exercise is another, but there are a number of other factors that have been shown to promote health and longevity, including stress reduction, positive thinking, healthy relationships, religion, and a couple of other areas. So, we’ve assessed that these were the two primary factors that could be exploited biochemically, and in turn were really affecting out what was going on – caloric restriction and exercise. The health benefits of both caloric restriction and aerobic exercise are well-established. Both of these decreased the incidence and onset of age-related diseases. Both caloric restriction and aerobic exercise improve cardiovascular health; they improve metabolic health; they improve neurological health. They have been shown to improve defenses against the certain types of cancer, and perhaps related to that, they improve the entire immune system. So, very, very important benefits have been linked to caloric restriction and aerobic exercise.

The question generally is, “Why is caloric restriction good for you?” and “Why is aerobic exercise good for you?” Well, in statistic trends, the answer is they both increase mitochondrial biogenesis – the production of new, healthy mitochondria. This can occur in both young individuals; this can occur in over individuals. The effect is not limited to get new mitochondria in muscle or exercise. These interventions can increase mitochondria in a number of different tissues, not just skeletal muscle.

Some of the benefits of increased mitochondrial biogenesis include the reduction of reactive oxygen species, and overall, reduction in oxidative stress; an increase in metabolic function; an increase in energy level; increased exercise performance (perhaps being part to increase ATP levels and overall metabolic function); reduction of body fat (So, individuals that have improved mitochondrial biogenesis have a lower percent body fat and increase in lean muscle mass. This is a repartitioning effect.). It’s been shown that increased mitochondrial biogenesis is linked to improve cognitive function and overall decrease in age-related deterioration or age-related diseases. It’s not known if increased mitochondrial biogenesis can increase lifespan, but certainly, it’s been shown that increased mitochondrial biogenesis increases healthspan, which perhaps, most of us are more interested in.

So, the mitochondrial dysfunction and aging. This is the natural process of deterioration of mitochondria with age. In a very healthy mitochondria, we have a very efficient process where the intake of precursors and nutrients – they’re metabolized to a certain extent in the cytosol of cells. The metabolism of these nutrients occurs in the mitochondria, and the mitochondrial matrix can do the electron-transport chain in itself. The really efficient process in enjoying a healthy mitochondria – you have an abundant production of ATP with a relatively low-level production of free radicals. However, over time, this situation deteriorates, and nutrients and oxygen, even the same amount. Basically you’ll yield less ATP due to the inefficiency of the production of ATP and you’ll have a higher level of free-radical production. And so, mitochondria are not the only site of production of free radicals and reactive species. They’re really at the ground zero due to their basic cellular function. So, they produce the vast majority of free radicals, which have been linked to many diseases. In such, as the process of nutrient metabolism deteriorates, you’re going to have a lot more free-radical production simply because of the function of mitochondria. Over time, the accumulation of free radicals – their inability to get rid of the free radicals leaves the oxidative stress. Of course, we know that oxidative stress is positively correlated with a number of chronic diseases including neurological diseases, and depending on the tissue where the excess amount of free radicals occurs, either the heart or the vasculature, you’ll have different types of diseases. We can look at excess free radicals in the joints – this has been linked to rheumatoid arthritis, and so on.

Mitochondrial dysfunction and disease – what has been known and what has probably most widely appreciated is the actual diseases that are of genetic origin in related to the mitochondrial genome. Well, we have defects in mutation in the mitochondrial gene; however, mito function – over the last five to 10 years – has been linked and more widely appreciated to be involved in a number of other diseases including the metabolic diseases, cardiovascular disease, neurodegenerative diseases, and certainly, cancer. Less appreciated is the role of mitochondrial dysfunction in some of the diseases that were not normally linked to, including autism, bipolar disease, certain autoimmune disease, chronic fatigue; and there’s some evidence in Lyme disease, and others. And I’ve been reading Dr. Horowitz – his book on Lyme disease discussing the role of mitochondrial dysfunction in Lyme disease.

So, if we look at these just briefly the role of mitochondrial dysfunction in diseases starting out with the typical mitochondrial disease. These are the mitocopies. The mitochondrial genome is the smaller genome compared to the nuclear DNA. It only codes for 37 genes, 13 proteins, and a couple of RNAs. This genome is maternally inherited. It’s only from the mother, so if there’s a mutation or mitochondrial dysfunction that’s carried in the maternal mitochondrion, then it’s a sure bet that the offspring or children in this family will also inherit that. Originally, mitochondrial diseases were linked to mutations in the mitochondrial DNA. Now, it’s well-known that the definition has expanded greatly due to mutations and nuclear genes involved in oxidative phosphorylation, in transport and assembly of mitochondria protein, in the synthesis of the mitochondrial membrane lipids, and also the temporal localization to other organelle – these are targeting proteins and such. So, the definition of mitochondrial disease is not limited to defects in mutations in mitochondrial DNA. You can also see evidence of mitochondrial disease with mutations in the nuclear DNA.

These are some factoids from one of the mitochondrial disease foundations. This is from MitoAction. You can see that it’s a significant burden to the individuals that have the disease in their family. One thousand to 4,000 children in the U.S. are born each year with some type of mitochondrial disease. It can be either primary, as we discussed related to genetic mutation; or secondary due to some other infection or some other cause. As I mentioned before, the mitochondria are unique because they contain their own DNA unlike any other organelle, and it’s inherited only from the mother.

The tissues affected by mitochondrial dysfunction include brain, nerves, muscles, kidneys – I mean, this should be obvious because mitochondria are present in nearly every cell type, and so it’s not surprising that they can affect one organ. Some selected symptoms of mitochondrial dysfunction include poor growth, loss of muscle coordination, visual or hearing problems, respiratory disorders, increased risk of infection – a wide variety of different clinical manifestations of some mitochondrial dysfunction.

Less appreciated is the role of mitochondrial dysfunction and some other diseases, although this has really come to the forefront in the mitochondrial research over the last five years or so. There are a number of metabolic similarities between obesity, impaired glucose tolerance, type-2 diabetes, and metabolic syndrome. At the cornerstone – some of the common denominator between all of these is the insulin resistance. All of them, to some degree, cause dyslipidemia, reduced mitochondrial content, and also reduced mitochondrial function.

The possible molecular mechanism in linking mitochondrial dysfunction to insulin resistance has been proposed. And a lot of what I’ve been saying is discussed and outlined in the book that Amy mentioned, “The Secret Life of Mitochondria,” and I have that listing in the reference for a lot of these slides. So, chronic nutrient overload – whether that would be in terms of micronutrients, such as fat and carbohydrate, can really lead to beta-oxidation in the mitochondria, the accumulation of long-chain fatty acids, and also the accumulation of this intramyocellular lipid especially in skeletal muscle. So, this produce a proinflammatory diacylglycerol molecule, which activates protein kinase C, and protein kinase C has been linked to the activation of a number of substrate leading to insulin resistance. In addition, chronic nutrient overload in mitochondria increase the production of the reactive oxygen species; these molecules trigger the activation of inflammatory kinases, which also result in insulin resistance. So, it’s a very simplistic presentation of how mitochondrial dysfunction is linked to insulin resistance, but is backed by a large body of scientific evidence. And so, targeting mitochondria for improving metabolic health is not out of the room of possibility. We know that mitochondrial improvement can be achieved through exercise and caloric restriction. We have been thinking about and have developed a number of interventions really that try to exploit the biochemical pathways of exercise and caloric restriction to an attempt to mimic these interventions at least partially, and so the end result really is to try to reduce overall reactive oxygen species, increase mitochondrial function, and then increase mitochondrial biogenesis. All of which lead to improved insulin sensitivity and improved cardiometabolic health.

If we look at mitochondrial dysfunction and neurodegenerative diseases, we can see that neurodegenerative disease can result from mutant proteins interacting with mitochondria leading to decreased deficiency in the electron transport chain, lipid consequence of increasing reactive oxygen species overburdening the neurons leading to neuronal necrosis given an amount of specific cellular gas, and the mutation of neurons is related to neurodegeneration. In addition, this reduction in the electron-transport-chain deficiency will lead to a decreased ATP production, which impairs the calcium regulation, and so this will then lead to triggering of the intracellular apoptotic signals or the triggering apoptosis – the programmed cell death. So, this is considered a nonspecific, non-programmed death, and the apoptosis is really a sequential, very regulated process. The end result of both of them is neurodegeneration, which is one of the hallmarks of degenerative disease.

If we look at the link between type-2 diabetes and Alzheimer’s dementia and vascular dementia, we can see that there are some similarities and increased risk of Alzheimer’s dementia on the top and vascular dementia on the bottom in individuals with type-2 diabetes. This is the relative risk, and you can see that for varying degrees in these various studies have shown that type-2 diabetes really increases the risk for these other neurological diseases. And so, it’s been proposed that the mitochondria may provide a link between diabetes and for example, Alzheimer’s, where you have abnormal glucose metabolism really driving mitochondrial dysfunction perhaps through the production of reactive oxygen species, certainly through the production of AGE. This concept is really talked to in Dr. Perlmutter’s new book, and so I invite you to take that in consideration because he really talked about that in great detail – this proposed mitochondrial link between type-2 diabetes and Alzheimer’s dementia. Here is another possible interplay between diabetes and dysregulation of calcium levels triggering apoptosis and eventually, Alzheimer’s disease. Again, there is some common link, and the research is very supportive of this that if we can really target the mitochondria early on before we have the manifestations of the late forms of these diseases and also their cardiovascular and other consequences, we may have better patient outcomes. So, the point I’m trying to make is consider mitochondrial dysfunction early on.

Here in this table are some examples that have been shown to be mitochondrial-targeted interventions for neurodegenerative diseases. So, we’ll finish up with the role of mitochondrial dysfunction and diseases with the discussion of cancer. For those of you who really want to get into the details, this is a wonderful poster produced by Dr. Wallace. It’s freely available on Nature Reviews Cancer; this was produced in 2012. It’s not really readable, but I just have it up here as a reminder that if you want to look at the role of the mitochondria in cancer cells and metabolism, going back to the observation of the increased glycolysis, increased production of lactate, there are a number of different defects in the mitochondrial metabolism that are very common in cancer cells and have been led to really a number of rationales for targeting the mitochondria for cancer therapy. This is the number of companies in the biotech and pharmaceutical area. I’ve really been trying to pursue this to varying degree of success. So, the mitochondria are really a prime target, not only for mitochondrial disease, but also for the metabolic diseases, the neurodegenerative diseases, and also as a cancer therapy.

There are a number of laboratory tests that can affect mitochondrial function. A lot of times, they usually give an overview especially of mitochondrial-dysfunction-based oxidative stress. One way is to looking at glutathione – the ratio of reduced to oxidized glutathione. There are some other ways of looking at the markers of oxidative stress including 8-hydroxy-2’deoxyguanosine, looking at isoprostanes, and SOD levels – these are all can be markers for overall mitochondrial function. There are a number of other ones, and so we will be talking about them in more detail at the Mohonk workshop. If anybody is interested, they could contact me directly in terms of other specific attestments of mitochondrial function.

Nutritional interventions for improving mitochondrial function and mitochondrial biogenesis – this is some of the practical applications of one of the research that I presented. We’re all doing good to really focus on these pathways and the role of mitochondria, but if there’s any way other than aerobic exercise and caloric restriction that we can really exploit and improve mitochondrial function and mitochondrial biogenesis.

Here’s a shortlist of the nutrients that there is evidence that they either improve mitochondrial function or mitochondrial biogenesis. Some of these are well-known to you. Some of these are less well-known to you. Lipoic acid is one ingredient that’s found on both sides; it’s been shown to improve mitochondrial function and also mitochondrial biogenesis. Resveratrol – there was a link paper out just in time by the Translational Medicine showing that the metabolites in resveratrol can be related to tissue; they can be modified and converted back into resveratrol, and so now, this is a very, very exciting finding – really supporting some of the earlier work showing the beneficial effects of resveratrol even despite the fact that it has poor pharmacokinetics. Pterostilbene is a form of resveratrol – the methylated form – and has been shown to increase mitochondrial biogenesis, along with quercetin, berberine, and hydroxytyrosol (one of the compounds in olive oil extract); omega-3 polyunsaturated fatty acids have been linked to improved mitochondrial biogenesis, and some dietary intervention such as the ketogenic diet, branched chain amino acids, and caffeine. These are some research tools that have been shown to increase mitochondrial biogenesis.

When we were putting about this whole process and how to exploit the beneficial effects of exercise and caloric restriction, we focused on three ingredients that were known to intervene and intersect in biochemical pathways that were also upregulated by aerobic exercise and caloric restriction including nitric oxide pathway, the SIRT1 pathway, and the AMP kinase pathway. So, what we tried to do was – there’s a nutritional formulation and really mimic and facilitate the biochemical signaling pathways leading to the activation of a transcriptionally activated PGC1-α, which is the major approach in the cell responsible for increasing mitochondrial biogenesis. So, this is our ultimate target, and these are the pathways that we wanted to activate, and these were the three nutritional ingredient that we put together to really presume this line of working and really invent this nutritional approach. These would be the most target outcomes that we are attempting to achieve.

So, the first ingredient that’s part of this nutritional intervention is the ALAmax; this is 600 mg of controlled-release alpha-lipoic acid, and this is designed to target the AMP kinase pathway. The next component of this intervention is the Resveratin Plus; this is 75 mg of the trans-resveratrol, 250 mg of quercetin, and approximately 62 mg of the pterostilbene – and so these three ingredients combined with Resveratin Plus – and were designed to be included in the formulation to activate SIRT1. And finally, the N.O.max ER, which is an analog of arginine – the naturally recurring arginine, “alpha-ketoglutarate” – about 2 gm in three capsules; in addition, it also contains whey peptide fraction, “Actinos,” which is another activator of the nitric oxide system; so, these are all the ingredients that were designed to increase nitric oxide. So, we’re targeting the AMP kinase pathway, the nitric oxide pathway, and the SIRT1 pathway. And so, these have been combined conveniently in the Mitochondrial Renewal Kit, which has been available through Xymogen and as mentioned at the beginning of the presentation.

I’m going to show you the result from Dr. Desmond Ebanks in Connecticut at his clinic where he evaluated the four-patient case studies the effects of the mitochondrial renewal kit on aerobic conditioning and body composition. These four subjects (3 males and 1 female) were instructed to take two packets per day of the kit for three months. So, two packets a day for three months – and all subjects were instructed to maintain their pre-study diet along with their pre-study level of physical activity. I’ve listed here what they have been taking at that time. So, the mitochondrial kit’s been added on top of these other supplement regimens. And so, what Dr. Ebanks’ recorded was that the individuals on the kits improved on exercise performance as judged by exercise intensity. These are the individual improvements. So, these are the values at baseline and the post-treatment, and this is exercise intensity measured in watts. This is the change from baseline for the individual subjects, and this is the average change and increase in 18 watts, and so the change from baseline, which corresponded to about an 8% of change. So, the ability to exercise more intensely. In addition, there’s the reduction of body fat. These are the subjects; these are the values at baseline; these are the values post-treatment; and this is the change from baseline – the individual subjects; and this is the average, so approximately a 2.9 change in percent body fat, which corresponds to an overall change from baseline of about 13%. If we look at the lean muscle mass, we see – from varying degrees – that lean muscle mass increased. If you look at the change from baseline to the individual subjects, the overall change from baseline was 3.2, and the percentage change from baseline corresponded to about 2.2. If we look at the questionnaire – the overall wellness portion – this is a quality-of-life scoring system where the subjects were asked to really give themselves an overall rating on various different aspects of their personal lives – a great deal of improvement from baseline to post-treatment. Each of the individuals reported an improvement; this is the base from baseline and the score, and percent change from baseline.

This is sort of a snapshot of what has been recorded for the last three or four years – five years having along a product that’s been on the market – very good feedback and a lot of positive stories from subjects and the divisions that have used this product.

This is the summary of the mitochondrial biogenesis triumvirate. This is our ultimate target to try to activate nutritionally through the AMP kinase pathway and lipoic acid, through the nitric oxide pathway and the L-arginine nutrient, and finally, through the SIRT1 pathway using resveratrol and related compounds.

So, targeting mitochondria for improving healthspan – we see that nutritional intervention can be used to mimic the effects of exercise and caloric restriction leading to the reduction of reactive oxygen species – mitochondrial function and mitochondrial biogenesis increases. All are related to improve the insulin sensitivity, which is then have been linked to improve cardiometabolic health, improve cognitive health, improve immunological health, and we’re both getting the anti-cancer defenses.

The key takeaways from the presentation – hopefully, we’ve gleaned these. So, mitochondria are much more than just cellular powerhouses. They’re involved in a large number of critically important cellular processes. Mitochondrial biogenesis is linked to the health benefits of exercise and caloric restriction. Mitochondrial dysfunction is not limited to the mitopathies, but clearly is linked to the chronic diseases of aging and many other diseases. Mitochondrial dysfunction can have genetic etiology, but can be triggered by the environment. Importantly, laboratory tests are available that can assess mitochondrial function and dysfunction, and that nutritional interventions are available that can improve both the function of mitochondria and in stimulating the increase in mitochondrial content – the number of mitochondria. And finally, we believe that mitochondrial function and dysfunction should be emphasized and really considered early on in the diagnosis and intervention stages of functional medicine.

With that, I just wanted to put up here, “The Secret Life of Mitochondria.” This is available for purchase as an eBook at both Amazon and Smashwords. You just have to get these links; they’re kind of long, but my name’s in the book of the book. A lot of these concepts have really been detailed a little more clearly in the book. It’s fully referenced, but it’s easy for many patients who are interested to go through it. And, I would like to get a plug for one additional book. It’s a book by Nick Lane, and that book is entitled, “Power, Sex, and Suicide,” and it’s truly a history of mitochondria – a very, very so academic description of mitochondria, and that was the inspiration for a lot of this information.

With that, I think I should turn it over to the organizers and take any questions if there are any questions.

Mike Mutzel: Alright, Joe. That was fantastic. We have quite a few questions here. I just want to dive into that. Again, we do have a special promo here – 24 hours only – on some of the unique products that Joe did mention and their combinations. Joe – this has been one – I know you have time to get in for us. It’s been fantastic. This is a recreational asset myself; I really noticed. If I don’t take my Mito Kit before I work out or take a few days break, I know it’s one for recovery and endurance and everything else – the weight room, and then also hiking and biking, and various things. Definitely, the thing that folks notice when they’re getting out there on the weekends or after work or whatever, exercising like they should be, so that’s just an awesome formulation. There are some questions, Joe, on the forms of CoQ10 and I know you haven’t talked about this before. Ubiquinol versus ubiquinone – can you get into the differences and what are the key takeaways for practitioners there?

Joe Evans: Absolutely. CoQ10 is well-known and most widely used to enhance mitochondrial function. There are two primary forms. Historically – the ubiquinone – this is the oxidized form of CoQ10. More recently, the ubiquinol – the reduced form – became commercially available. The vast majority of the efficacies studies – these are the clinical studies and there are animal studies, too – have used the oxidized form of CoQ10 – the ubiquinol. And so, that is the form that one should take in. It does get converted back into the reduced form and so, at least in most people. There are some small subsets of individuals that cannot do the conversion properly. And so, there’s been a lot of marketing and a lot pressure to switch over to the reduced form of ubiquinol. To me, the evidence is somewhat convincing that clearly, the weight of the evidence and the clinical trials with regards to the pharmacokinetics and the efficacy, most of the work have been done with the oxidized form. It’s not to say that the reduced form doesn’t offer some advantages. Clearly, it offers the advantage for the individuals who cannot do the conversion. It’s actually a lot more expensive, and it’s not particularly stable. The bioavailability profile is similar. There may be some studies that show a better bioavailability of the reduced form. I personally was not convinced that there is an overwhelming advantage of using the reduced form, but I certainly don’t think it is the wrong balance. It may be equivalent, but I am not convinced at this point that there is any demonstrable advantage in spending the extra money using the reduced form.

Mike Mutzel: Right. Joe, I would agree with you on that note, and also folks, you do know that Xymogen happens to supply you whatever form you want. We do carry the ubiquinone, so we’re not even a fan of that version. The CoQmax (the regular) that we sell – it’s more of a trilipid-enhanced version that is going to increase the bioavailability superior to that of just standard ubiquinol on a milligram-per-milligram basis. There was an article in the Journal of the Mitochondria, Joe, and I can forward that to you. I think you and I just discussed it before. That actually compared all the human clinical trials between ubiquinol and ubiquinone. They found that the conversion of the ubiquinol to ubiquinone – obviously, that occurs inside the mitochondria itself and not on transport chain and so forth. But also, when we’re talking about supplemental forms occurs in the intestine and that’s kind of a stick straight. If you take ubiquinone, it’s going to be converted to ubiquinol inside the intestine before it gets sent around in the plasma, and so that rate is pretty strict and that doesn’t vary across person to person, and with age and such. I know there’s been a lot of marketing, so that you’ll get ubiquinol. Anyway, that was a great answer there, Joe.

So, let’s see here, there are some additional questions on testing. I think you mentioned some advanced biomarkers and oxidative stress primers. Just for the day-to-day office use for practitioners if they’re not going to get into some of these advanced tests, what would you recommend – glucoses or triglycerides? What do you suggest there?

Joe Evans: Well, I would just stick to the most sensitive effective markers of oxidative stress because again, the mitochondria are not the only source of reactive oxygen species production, but they are a primary source. So, chances are there are out-of-range measurements for these markers such as the glutathione ratio, such as the F2-isoprostanes, such as the oxidative markers for DNA. The F2-isoprostanes is a lipid marker of oxidative stress. The AL HCG is the marker for DNA oxidation, and the glutathione ratio is sort of an overall intracellular measurement of oxidative stress including reduced glutathione. So, I would tend to stick with them, and also labs that are going to measure of SOD2 – that’s superoxidase dismutase 2; that is the mitochondrial form of that enzyme. If that’s reduced, chances are that the cells are not able to rid themselves of the superoxide molecule, so that should be a marker. This is sort of the first battery of tests and so they could be followed up by more specific tests such as ATP levels, the ratio of COQ10 to a certain number of molecules, in addition to overall lactate, and like I said, ATP levels. Lactate can be elevated in many different conditions. The lactate is not really a particular sensitive measurement of mitochondrial function.

Mike Mutzel: Great. So basically, we’re looking at oxidative stress as an indirect marker of impaired glutathione function as kind of your go-to assessment.

Joe Evans: Yes. I had a number of conversations with that event. These labs have done a lot of testing for not only oxidative stress, but for mitochondrial dysfunction, and I believe we’re on the same page with looking at these particular markers as sort of like the first line of laboratory assessment, and then being able to move on to other things if required.

Mike Mutzel: Let’s talk about the whey fraction peptide in the controlled-release L-arginine product called “N.O.max ER.” I know you’re familiar with that – the Actinos. Can you talk about why it’s in there and its role?

Joe Evans: Well, yes. That was included in there because that’s been shown – the Actinos peptide fraction has been shown in cellular studies to really produce an increase in the enzyme of the endothelium nitric oxide synthase. It’s there to complement the substrate. So, the idea behind that combination of the ingredients is to provide the apo-substrate, but also to stimulate the activation of the enzyme responsible through producing nitric oxide – the endothelium nitric oxide synthase. These peptides have been shown to cause a dramatic increase in nitric oxide production in the high normal ranges without triggering the activation of the inflammatory form of that enzyme – the iNOS (inducible nitric oxide synthase). So, it’s a very desirable ingredient in the N.O.max ER.

Mike Mutzel: Great. We’re just making sure that arginine goes down the right path. A lot of questions, Joe, on exercising – high-intense, the short-duration burst training in reaching anaerobic threshold and such. In your assessment of the research and clinical expertise, what’s the best prescription for practitioners when talked with patients about how to exercise, the duration and the intensity and all that?

Joe Evans: Well, I think the data are really leaning towards the high-intensity for a shorter amount of time, so basically, which would be not just 20 minutes or 40 minutes at the same pace of cardiovascular exercise. The people that I’m talking to that are experts in the field are really leaning towards the best benefits, the what is called the “high-intensity interval training” where we basically go to 75 or 80% of your Vmax for a shorter time, perhaps a minute or so, and then go back down to 60%. And so, you can repeat this for 20 minutes. What I’m saying is that the trainers and the exercise and overall shorter time, maybe for 20 minutes workout instead of a 40- or 45- or 50-minute workout. That shorter duration is compensated by the fact that it’s more high intensity. So, you’re doing much more. However, that being said – the research, in terms of increasing mitochondrial function and mitochondrial biogenesis – the vast majority of the research has been linked to the some of the older style cardio workout where you’re basically working out for 40, 50 minutes at a fairly regular rate whether that be 50% Vmax. So, we’re waiting to see clearly from a biochemical or a clinical perspective that the benefit of the shorter intensity, but that’s really what I’m hearing about and reading about more. That’s the emerging field. So, that’s what I’m personally focusing on now with my own exercise regimen – to do the shorter duration with a higher intensity.

Mike Mutzel: Yeah. I would definitely agree with that. I don’t know about you, but what I’ve been doing is kind of a one-minute-on-four-off-type approach and during that one minute, it has almost been the last 20 seconds and I can barely – I mean, a lot of pain. So, I really need those four minutes of bio-rest in between. That’s what I’ve been doing and I think it really works. There’s a lot of good data like you said. That’s awesome.

Last question, Joe. A few folks have mentioned that NADPH and the role of mitochondrial function. Can you talk about that and what role that plays clinically in the mitochondria?

Joe Evans: Well, yes. And so, there have been certainly NADPH placement – a very important role when these reducing agents are in lower levels, this can activate the citrinin pathways. So, this really gets activated when you have higher levels of NAD, and so basically, there’s a very delicate balance similar to that enzyme NAMP kinase, which is regulated by the ratio of ATP to ADP. The citrinin pathway and some other enzymes are actually regulated by the ratio of NADPH and ADP. And so, in certain states, they don’t have time to go into it right now, but in certain conditions, you have a dysregulation of this ratio, which in some cases, it may be beneficial because you have sort of a lower level of the reduced form of NAD, so you have a reduced form of it, a reduced level of it – it can activate compensatory pathways that would be beneficial. Sort of what I was referring to when you have a slight inhibition of complex I through the pharmaceutical Metformin, you have this compensation with ATP production, and then that actually is beneficial; it’s almost counterintuitive, but if the inhibition is not prolonged, they’re irreversible, then you actually have physiological benefit, and it’s the same with what you said with NADPH.

Mike Mutzel: Fantastic. Alright, guys. Thank you so much for joining us tonight. Thanks a lot, Joe. This is awesome information. We’ll make the archive available tomorrow morning. Amy did want me to let you guys know that the early-bird special for the conference is she’s bringing on the attempt of the member. It ends here on October 18th. That’s coming up in the next two weeks. But then again, everyone’s invited to join us in October. We’re going to have an awesome webinar by authors in our field of integrative medicine. We have the 24-hour special here: SPWEB and the date today – so, the 2nd of October, 2013.

Joe, thanks so much and have a great evening.

Joe Evans: Thank you, everyone. Thanks Amy.

Amy Salerno: Thank you.

101 Comments

Join the conversation

  1. Hello Web Admin, I noticed that your On-Page SEO is is missing a few factors, for one you do not use all three H tags in your post, also I notice that you are not using bold or italics properly in your SEO optimization. On-Page SEO means more now than ever since the new Google update: Panda. No longer are backlinks and simply pinging or sending out a RSS feed the key to getting Google PageRank or Alexa Rankings, You now NEED On-Page SEO. So what is good On-Page SEO?First your keyword must appear in the title.Then it must appear in the URL.You have to optimize your keyword and make sure that it has a nice keyword density of 3-5% in your article with relevant LSI (Latent Semantic Indexing). Then you should spread all H1,H2,H3 tags in your article.Your Keyword should appear in your first paragraph and in the last sentence of the page. You should have relevant usage of Bold and italics of your keyword.There should be one internal link to a page on your blog and you should have one image with an alt tag that has your keyword….wait there's even more Now what if i told you there was a simple WordPress plugin that does all the On-Page SEO, and automatically for you? That's right AUTOMATICALLY, just watch this 4minute video for more information at. <a href="http://www.2014PandaSeo.com">Seo Plugin</a>

  2. http://www.burberry-factory.net/
    http://www.shophandbagsonline.com/
    http://www.official-coachoutlet.com/
    http://www.barbour-factory.com/
    http://www.burberry-outlet2014.com/
    http://www.guccibags.us.com/
    http://www.marcjacobsonsale.com/
    http://www.mcmworldwide.ca/
    http://www.guccishoes-uk.com/
    http://www.kate-spades.com/
    http://www.louisvuittonas.com/
    http://www.lv-guccishoesfactory.com/
    http://www.official-mkoutlets.com/
    http://www.official-pradaoutlet.com/
    http://www.michael-korsusa.net/
    http://www.north-facesoutlet.com/
    http://www.moncler-clearance.com/
    http://www.north-faceclearance.com/
    http://www.clothes-mall.com/
    http://www.polo-outlets.com/
    http://www.ralphlauren.so/
    http://www.ralphlaurentshirts.com/
    http://www.ferragamos.in.net/
    http://www.longchampsoutlet.com/
    http://www.abercrombiee.com/
    http://www.barbour-jacketsoutlet.com/
    http://www.michael–korsonline.com/
    http://www.thenorthface.so/
    http://www.beatsbydreoutlet.net/
    http://www.tommyhilfiger.in.net/
    http://www.ralphslauren.co.uk/
    http://www.michaelkors.so/
    http://www.oakleyssunglassoutlet.com/
    http://www.warm-boots.com/
    http://www.woolrich-clearance.com/
    http://www.nike-jordanshoes.com/
    http://www.monsterbeatsbydres.net/
    http://www.canada-gooser.com/
    http://www.bestcustomsonline.com/
    http://coach.mischristmas.com/
    http://www.coach-blackfriday2014.com/
    http://www.coachccoachoutlet.com/
    http://www.coach-clearance.com/
    http://www.coach-factories.net/
    http://www.coach-factorysoutlet.com/
    http://www.coachlosangeles.com/
    http://www.coachoutletstates.com/
    http://www.coach-pursesoutlets.com/
    http://www.hermes-outletonline.com/
    http://www.misblackfriday.com/
    http://www.mischristmas.com/
    http://www.mmoncler-outlet.com/
    http://www.newoutletonlinemall.com/
    http://www.ralphlaurenepolo.com/
    http://www.zxcoachoutlet.com/
    http://michaelkorsoutlet.mischristmas.com/
    http://mcmbackpack.mischristmas.com/
    http://monsterbeats.mischristmas.com/
    http://northfaceoutlet.mischristmas.com/
    http://mk.misblackfriday.com/
    http://coachoutlet.misblackfriday.com/
    http://coachfactory.misblackfriday.com/
    http://uggaustralia.misblackfriday.com/
    http://coachpurses.misblackfriday.com/
    http://coachusa.misblackfriday.com/
    http://coach.misblackfriday.com/
    http://michaelkorss.misblackfriday.com/
    http://michaelkors.misblackfriday.com/
    http://airmax.misblackfriday.com/
    http://michael-kors.misblackfriday.com/
    https://twitter.com/CoachOutlet2014
    https://www.facebook.com/coachoutletstoreonline
    https://www.facebook.com/ralphlaurenoutletonline

  3. First of all I want to say wonderful blog! I had a quick question that
    I'd like to ask if you don't mind. I was curious
    to find out how you center yourself and clear
    your mind prior to writing. I've had difficulty clearing my thoughts in getting my ideas out there.
    I do enjoy writing however it just seems like the first 10
    to 15 minutes are generally wasted simply just trying to figure out how to begin. Any recommendations or
    tips? Thank you!

  4. Howdy! This blog post could not be written any better!
    Going through this post reminds me of my previous roommate!
    He always kept preaching about this. I am going to forward this
    post to him. Pretty sure he'll have a good read.
    Many thanks for sharing!

  5. Definitely consider that which you stated. Your favorite
    justification seemed to be at the web the simplest thing to understand of.
    I say to you, I definitely get irked while folks consider issues that they plainly do not know
    about. You controlled to hit the nail upon the top and also defined out the entire thing without having side-effects , other people can take a signal.
    Will likely be again to get more. Thanks

  6. Woah! I'm really digging the template/theme of this website.
    It's simple, yet effective. A lot of times it's difficult to get that "perfect balance"
    between superb usability and visual appeal. I must say you've done a great job with this.
    Also, the blog loads extremely fast for me on Chrome.
    Excellent Blog!

  7. Woah! I'm really enjoying the template/theme of this blog.
    It's simple, yet effective. A lot of times it's difficult to
    get that "perfect balance" between usability and appearance.
    I must say you have done a fantastic job with this.
    Also, the blog loads very quick for me on Opera. Outstanding Blog!

  8. Please let me know if you're looking for a article author
    for your blog. You have some really good articles and
    I think I would be a good asset. If you ever want to take
    some of the load off, I'd absolutely love to write some content for
    your blog in exchange for a link back to mine.
    Please send me an e-mail if interested. Thanks!

  9. http://www.lespra.com/shoesmarket-d9354.htmlCONVERSE ALL STAR MINIM HI コンバース オールスター ミニム ハイ 32693321 BLACK スニーカー専門店-ナイキ(Nike)、アディダス(Adidas)、ジョーダン(air Jordan)、ニューバランス(New balance)、CONVERSE、バンズ(VANS)、ブーツ、運動靴など人気シューズがが豊富に激安価格で揃っています!全国送料無料!!
    スピードマスター ブロードアロー 腕時計 ウォッチ激安専門通販サイトです 品質保証 OMEGA<br>オメガ 大特価でセール販売中 http://www.watchesdosale.com/オメガ-スピードマスター-ブロードアロー321.10.42.50.02.001-メンズ【50周年モデル】-p-1344.html

  10. http://www.lespra.com/shoesmarket-d5619.htmlナイキ ズーム コービー NIKE ZOOM KOBE VIII BLACK/PURPLE/YELLOW 555035-103 スニーカー専門店-ナイキ(Nike)、アディダス(Adidas)、ジョーダン(air Jordan)、ニューバランス(New balance)、CONVERSE、バンズ(VANS)、ブーツ、運動靴など人気シューズがが豊富に激安価格で揃っています!全国送料無料!!
    ブライ トリング 腕時計 http://www.watchesdosale.com/

Leave a Reply