Monthly Archives: October 2018

Mitochondria Primer 6: PQQ, Stardust, and Mitochondrial Sex

References: AgingLife ExtensionMitochondria and the Future of MedicineLife Extension 2018J Biol ChemCell MetabolismLinnane NY Acad Sci,

All right. You know that mitochondria supply your energy in each cell. You know that they have their own DNA and can divide. You know that your mitochondria come only from your Mom. If the DNA goes bad and “curdles”, we call that cancer and you know that mitochondrial damage may be the defining defect of cancer. By age 90, 95% of our mitochondria are damaged. And you know that as mitochondria decline, the whole organism suffers and gets less energy. Hence, you want to know how to get more mitochondria. That’s called staving off aging.
Muscle cells have about 200 mitochondria. Heart cells have 5,000. Ditto for brain cells. Liver and kidneys have 2-3 thousand. When you exercise, you get more mitochondria. That’s called getting in shape. Exercising is so effective at holding off aging,it effectively halves mortality if you exercise daily over age 60.
But what is the key nugget that mediates mitochondrial duplication? That’s where PQQ comes in. It is an extremely unique compound. It is so stable that it is present in interstellar dust. (Cool, huh?) But more importantly, it isn’t degraded chemically when exposed to extra electrons. It is so stable, it can accept and pass on loose electrons 50,000 times, making it thousands of times more effective than vitamin C as an antioxidant. CoQ10 plays the role of routine loose electron processing in the mitochondria (three weeks ago). PQQ plays a role too. It turns on the genes that make mitochondria multiply.

In fact, PQQ is in all plant food. It’s found in mothers’ milk. But we can’t make it. That makes it a vitamin, for all practical purposes. Animal research has shown if deprived of dietary PQQ, animals have stunted growth, compromised immunity, reduced reproductive capability, and most importantly, fewer mitochondria in their tissue. Give PQQ back and those negative effects reverse.

Apply that to humans and we get this week’s featured study where PQQ is demonstrated to turn on the genes inside mitochondria that initiate and control mitochondrial duplication. If you want to do a deep dive into mitochondrial duplication, you can read Zhong. This article shows that PQQ activates a signaling protein known as cAMP-response element-binding protein called CREB. It wakes up the CREB gene is known to be key in embryonic development and growth. It also interacts with histones, the proteins around DNA that monitor and protect genes. Those two effects appear to result in the growth of new mitochondria. Other important genes are PGC-1α and DJ-1.
I know it sounds dense, but the nugget to take away is the insight into aging being a function of your mitochondria going sour. You can nurture and feed them with CoQ10, acetyl-carnitine, alpha lipoic acid and such, or you can tell them to get in shape and make babies. Get new mitochondria. Exercise, do the fast mimicking diet, or take PQQ. Better yet, do all three.

WWW: What will work for me. I’m getting pretty good at the fast mimicking diet. I’ve completed 9 rounds of it and have a smaller waist to show. I spent all weekend cleaning up the yard getting as exhausted as I could imagine. That’s the exercise. Should I start taking PQQ? I checked on Bredesen’s program. Sure enough, there it is. Along with CoQ10, NAC, and Alpha lipoic acid. Hmmm. So I did.

Pop Quiz

  1. What are the three things that make new mitochondria?                     Answer: Fasting, exercise, and PQQ
  2. What percent of your mitochondria are damaged by age 90?             Answer: 95%. You might call that 1% per year. Take your current years,,
  3. Why can mitochondria multiply?                                                               Answer: They have their own DNA. 10 copies of it in each mitochondrion, right next to the electron transport chain
  4. Why do mitochondria get damaged?                                                       Answer: They have no protective coat of histone proteins. The DNA copies are naked. It makes them incredibly responsive, and incredibly vulnerable to damage and mutation.
  5. CoQ10 and PQQ both do one similar function, and PQQ does one other. Which? Answer: Similar is soaking up loose electrons to protect the DNA. Different is PQQ goes further and plays a signaling role to a bunch of genes that then turn on duplication of more mitochondria.

Mitochondrial Primer 5: Beta-hydroxybutyrate, The King of Ketones

References: Front Mol MedWikipediaPerfect KetoAm J PrimatologyPeer JBiochemical Journal,

When you burn fat (the stuff that’s in your belly and cellulite and second chin) you produce two ketones primarily. Ketones are what we make from fat burning as we break down stored energy and ship it around the body. The primary one is called beta-hydroxybutyrate, or BHB. The other is called acetoacetate (ACAC). ACAC is what you measure in your urine to show ketones but can be changed to BHB, and thereby not show up in urine. Hence, measuring urine for ketones is iffy and can have false negatives. BHB takes a blood test and is more reliable.
Now, what I find interesting is the enzyme that switches ACAC to BHB and thence into the electron transport chain is actually in the wall of mitochondria. Ketones are such an important part of normal metabolism that mitochondria have all the normal enzymes to incorporate ketones into our energy flow. Did you get that? Our body has all the tools to burn ketones, all the time. It is built in. Through all of human history, ketones were our main fuel source to fall back on in lean times.

What happened in our rich, 21st-century environment? We never, ever run on ketones. There are no lean times. We always run on carbs. We store up what and corn in giant silos, formulate them into delicious foods and provide them to ourselves three times a day in exquisitely flavored recipes. And our body has a default switch that has us burning and running on carbs preferentially. It’s the universal signal to turn on fat making, storage.
This is the key to weight gain and weight loss. Our natural tank of carbs is only 1500 calories. That’s it. Anything over that and we signal our hormones that we have too many carbs. That means it must be September or October when carbs ripen – at the end of the growing season. Our blood sugar rises. We turn on insulin. Insulin switches everything into storage mode. We make triglycerides in our liver and ship those extra fats all over our body in little lipid bundles called LDLs. LDLs then deliver that newly manufactured fat to storage warehouses called your butt, your chin, your muffin top.

Think this through teleologically. We had to be designed like this to survive in a world where carbs show up suddenly, just before the starvation season. We would then evolve a hormone to store those calories when they showed up in abundance. (That’s where insulin comes in.) And we would be favored to have sweet flavor in the middle of our tongue so that we seek carbs avidly, whenever we find them.
But most of the year, we should be running on ketones. Normally. When you are surviving through winter, you are meant to be burning your fat stores. That’s ketones. When you eat green vegetables (present from April till August), your colon turns spinach into ketones. Gorillas, eating 15 pounds of green leaves a day turn those into 70% ketones.
Now there is a whole raft of websites touting the increased performance of athletes on ketogenic diets, how to induce ketogenesis etc. But most importantly, we are proving that inducing ketosis turns on stem cells. It’s so important to run on ketones, Bredesen is insisting we all do it every day for 12 hours and every month for 5 days. Gundry has jumped on board. The tide is changing.

Ketones, otherwise known as Beta-hydroxybutyrate (BHB), are your main, proper food source. BHB rules. It’s the boss! And teaching your body, encouraging your body, forcing your body, manipulating, managing, teasing…..whatever you want to call it…..but do it. Get your body to run on ketones. That means, no grains, no sugar and lots and lots and lots of green vegetables.
WWW. What will work for me. I’m wrapping my head around this technology. I’ve done the Fast Mimicking Diet 8 times and found that it jump starts me into ketosis in three days. I’m going to try taking some Beta-hydroxybutyrate supplement the next time and see if it eases me into ketosis with a little less stress. What I do believe is that this is the pathway forward. Our bodies are aching for us to break our addictive habit of carbs. It just wasn’t meant to be so. The only time we were meant to gorge on carbs was at the end of the growing season when getting ready for winter. Brings a whole new meaning to Halloween candy. Doesn’t it? So, we ended up at the Pancake House for breakfast. I ordered the Eggs Benedict with spinach on the side. Didn’t eat the English muffin. Double spinach please, no potatoes.

Pop Quiz

  1. The human primary fuel is?                                             Answer:  Beta-hydroxybutyrate. The ketone you make from burning fat, your colon digesting green vegetables, the ketone you make from digesting coconut oil, olive oil, avocado oil……
  2. Exposed to carbs, your body will switch to what fuel? Answer: Glucose. Instantly. The microsecond you put out insulin. Three french fries will do it.
  3. Running on insulin instantly is incredibly important. Why? Answer: Because through most of human history, carbs were rare, and present just before the lean, starvation system. Remember, pears and apples ripen in October; right now. So sugar is on our tongues as our preferred taste so we gorge, turn on insulin, store calories and then…survive through winter.
  4. How big is your carb fuel tank?                                                   Answer. 1500 calories, called glycogen. Fill up that tank with…….one plate of pasta, rice, flour.
  5. And what happens to green vegetables?                                 Answer. Your colon bacteria break them down into beta-hydroxybutyrate. The King (or Queen) of Ketones. BHB rules. You’ll have BHB anytime you fast 12 hours or more. You will have a blood level of 3 and more if you do the fast mimicking diet for 3+ days. The Fast Mimicking Diet: best way yet to get you in ketosis.

Mitochondrial Primer 4: Role of CoQ10

References: Mitochondria and Future of MedicineMortenson JACC Heart FailureLangsjoen Biofactors,

You should know what CoQ10 is by now. It is in every mitochondrion, in every cell in your body. Ubiquitous. It sits between Complexes 1,2 and 3 and passes on electrons, thereby playing a critical role in the electron transport chain. About 2% of electrons escape the electron transport chain, and CoQ10 soaks those escaped little electrons up before they can cause damage. You make lots of it when you are young. You make much less when you are older. It was discovered in 1957 and in 1972 the level of its deficiency was linked to congestive heart failure. Many cardiologists got interested in it and it became a widely used supplement, particularly with statins and muscle pain.

Initial studies of it were not exactly positive, perhaps because lab measurements were not as precise or available as they are today, thereby leading to inconsistent doses. But the Mortenson JACC study showed that 100 mg three times a day compared to conventional drug therapy alone reduced CV mortality by 42%, and all-cause mortality by 44%. That caught people’s attention.
Dr Sinatra has been one of its most prominent advocates and claims that the threshold of effectiveness is 2.5 ug/ml, and that one will not see much clinical benefit below that. He laughs off older studies that do not mention or measure blood levels. I personally see most folks with levels of .7 and 1.2 with very few above 1.5. Hmmm. As we age, we are all deficient.
The other controversy about CoQ10 is whether one should take the common cheap form, ubiquinone, or the fancy expensive stuff, ubiquinol. They do switch back and forth in the body quite easily, but the -ol form is a more potent anti-oxidant. The manufacturer claims that the expensive form is worth it and backs it up with a very small study of 7 people who had failed with the -one. In that study, the average ejection fraction went from 22% to 39%, and their average New York Heart Association CHF class dropped from IV to II. Very impressive. A very small study, not blinded so open to lots of problems.

The number two reason to visit a doctor is “fatigue”. If your mitochondria are weakened by low protection secondary to low CoQ10, one will have decreased heart pumping which will mean decreased delivery of blood to muscles. In muscles, the same low CoQ10 level will result in reduced muscle ability. We call that fatigue.

www.What will work for me. What I think is going on is that most folks never get to the threshold of effective therapy. With random dosing of CoQ10 from variable sources, I suspect some folks just aren’t getting enough, and some folks are getting knockoff CoQ10 that isn’t even the real drug. With the ability to measure its level, we can now really check. A starting dose should be 100 mg 3 times a day. And then ask your doctor to check the level. You are looking for a level of 2.5. Nothing less will do. If less, double your dose. Check again.

Pop Quiz

  1. What is the role of CoQ10 in the mitochondria?                      Answer: two roles. 1) Passing on electrons between complexes in the electron transport chain, and 2) catching loose ones that get away from the electron transport chain.
  2. What happens to CoQ10 levels as we age?                               Answer: Drop precipitously.
  3. How much will a heart’s ability to pump increase if you get a level above 2.5?            Answer: Mortenson’s study showed over 40% reduction in mortality and a very small study of the reduced form showed a 22-39% increase in cardiac output.
  4. What blood level of CoQ10 do you want for yourself?             Answer: 2.5 and above
  5. And what is the dose you need to get that?                               Answer: Start with 100 mg 3 times a day. Then test and then double the dose.

Mitochondria Primer 3: How It All Goes Terribly Wrong with Cancer

References: Mitochondria and Future of MedicineNatureThomas Seyfried on Youtube,

We now know that mitochondria use proton pumps to store potential energy in the form of an electrochemical gradient, and then harnessing that energy as it comes across a membrane to create chemical energy. Every form of life on earth uses this process. Seriously, it’s ditto in plants too, just going the other way: storing instead of burning. Instead of being called mitochondria, we call them chloroplasts. Same process. Generate and store energy, in plants case, from the sun.

In every form of animal life on earth the energy extracted from the electron transport chain is used to move protons across a membrane. It is so universal, pumping protons across a membrane is the central signature of life on Earth. It is the key, the nexus, the whole kahuna. Complex cells require this to work. It is a miracle. The miracle of complex life on our planet. But not a perfect miracle. This is the model that arose and all life came from. And it has some flaws. Evolution has had several billion years to try and clean those flaws up with different trials and experiments, but some flaws remain.
Here is one example. In order to be extremely flexible to energy demands and flow, mitochondria must have the ability to manufacture their own critical elements. Hence, mitochondria have 5-10 copies of their own DNA still inside them. That allows them to duplicate themselves when there is demand, and increase the number of electron transport chain units (up and down from 10,000 per mitochondria). The vulnerable point is that the DNA is sitting right there next to the sites in the electron transport chain where electrons can escape and damage the DNA. Mitochondrial DNA is surrounded with a puffy coat of proteins like nuclear DNA. Free electrons make “free radicals” that can get in and damage the DNA.
Ok, now we know that the core defect in cancer is that there are broken mitochondrial membranes in every cancer cell. In fact, one could make the argument that cancer is not 500 different diseases but rather broken mitochondria in 500 different tissues. What you see in cancers is that their mitochondrial membranes look like curdled milk instead of ordered arrays of organized membranes. It is not the sole defect, and cancer cells depend on some residual mitochondrial function to live, but it is certainly a signature defect in cancer. And cancer cells can’t extract the extent of energy from glucose and fat that a healthy mitochondria can. Cancer cells depend on the very primitive and limited chopping of glucose in half, to get 2 ATP instead of 38. To fix cancer, to prevent cancer, we have to understand just where in mitochondria that first broken mitochondrial membrane came about. But mitochondria damage remains central to the defect of cancer.

What’s the core defect? DNA damage in the mitochondria because of electron transport chain proximity to naked DNA. Result: cancer. Cure: reduce the incidence of free electrons escaping. How do you do that? Next week or so.

WWW: What will work for me. I’m determined to master this knowledge base. I know that healthy mitochondria love to run on fat, and injured ones can’t use fat at all. Hence, a high-fat diet, or at least a high beta-hydroxy-butyrate diet, helps mitochondria burn fuel smoothly. Where does BHB come from? Vegetables. We know vegetables get turned into beta-HB. We had roasted Morrocan cauliflower for dinner last night.

Pop Quiz

  1. What is the key to complex life on planet earth?                               Answer: The pumping of electrons and protons across membranes and then the miracle of ATP-synthetase, or Complex 4, theworld’s smallest machine, that converts electrical energy into chemical energy with a spinning wheel.
  2. How many sets of mitochondrial DNA are there in a mitochondria?      Answer: 5-10
  3. What is the vulnerability of mitochondrial DNA?                             Answer: it’s naked and close to the production of escaped electrons which form damaging chemicals.
  4. What is the core defect in cancer?                                                  Answer: Broken mitochondria.
  5. What reduces your risk of cancer?                                                  Answer: Running on fat from plants, known as beta-hydroxybutyrate. AKA, more spinach and broccoli.

Mitochondria Primer 2 – The Electron Transport Chain

References: Mitochondria and the Future of Medicine, Youtube, ATP-Synthase on Youtube,

This is heavy science, so hang in with me here. I’ll try to give you the simplest analogy that allows you to understand what is happening in your mitochondria. It sounds arcane, but this is the nugget of how long you live, what diseases you have when you die. All those little details, which may be of interest to you. 

In essence, they extract the energy inherent in high energy hydrogens that are attached to carbon atoms (what we call food: fat or carbs), and reattach the hydrogen atoms to oxygen and extract that high level of energy into activated ATP molecules. That makes water and carbon dioxide as end products. It’s as though the hydrogen atoms are spinning faster around carbon atoms and have more momentum. When they get attached to oxygen to make water, they are spinning slower and have lower momentum, or less energy. The extraction of that energy is very elegant as it transfers the latent energy that plants made by capturing light rays from the sun and storing energy in the form of carbs, fats or proteins. Animals can then extract that latent “momentum” energy back into usable fuel. The molecule ATP, adenosine-tri-phosphate has 3 phosphate atoms on it which pick up that latent energy and use it as the universal currency of energy in your cell. Whew. If you got that, you’re good. 
The extraction process happens by separating the electrons of hydrogen from their protons and moving the protons across the inner membrane of the mitochondria, thereby building up a pool of high energy protons in a reservoir that then cascades downward, activating ATP-synthase as they do so.

The concept of a “pool” or “reservoir” requires the sequestration of the high energy protons on one side of the membrane. Think of it like a dam. Your mitochondria pump “water” up into the reservoir and then extract the energy like a dam with spinning turbines extracting electricity.

The downhill cascade of protons makes ATP with the energy from the electron transport chain. It has 4 “Complexes” of proteins. The first two “Complexes” called Complex I and II pass off their electrons via CoQ10 to Complex III that then passes them on cytochrome C, and then to Complex IV to then make water.
Here is the critical rub. Electrons are odd creatures. They are sometimes waves, and sometimes particles. The poor electron transport chain has to deal with these slippery critters and doesn’t always get it right. About 2% of them slip away and wander around, attaching themselves to other molecules. High energy electrons are dangerous. They attach to oxygen and made oxygen radicals that damage and destroy other proteins. Alarm, alarm. This is a big problem.

We’ve had a time figuring all this out. You see, Complex I is actually 46 smaller proteins all assembled together. It pulls out the first 4 electrons to pump upstream and is the primary site of electron escape. This is exactly where CoQ10 either captures or mops up those loose electrons.

But that’s enough for you to know. We need to know that electrons can get away, that they aren’t universally captured by the proteins assigned to process them, that CoQ10 is a critical compound and that ATP is made by all of this process. From there we can understand the problems with illness that happens when those processes don’t happen smoothly. That will be next week.

www.what will work for me. I’ve spent my career combating carbon monoxide poisoning in the ER. Every winter as furnaces go on, various combinations of folks come to the ER with headaches and lethargy. Carbon monoxide plugs up the electron transport chain so that the mitochondria is literally plugged up. Electrons can’t go downhill. The mitochondria dies if the CO isn’t forced back out with high-pressure hyperbaric oxygen. Same problem with cyanide. It blocks the final steps. If your mitochondria die, you follow shortly thereafter. For starters, keep your mitochondria safe by making sure you have a carbon monoxide monitor in your home.

www.what will work for me. I’ve spent my career combating carbon monoxide poisoning in the ER. Every winter as furnaces go on, various combinations of folks come to the ER with headaches and lethargy. Carbon monoxide plugs up the electron transport chain so that the mitochondria is literally plugged up. Electrons can’t go downhill. The mitochondria dies if the CO isn’t forced back out with high-pressure hyperbaric oxygen. Same problem with cyanide. It blocks the final steps. If your mitochondria die, you follow shortly thereafter. For starters, keep your mitochondria safe by making sure you have a carbon monoxide monitor in your home.

Pop Quiz

  1. Carbs and fats, made by plants have latent energy in them captured from sunlight. T or F   Answer: True. The essence of life on earth given from the sun.
  2. That potential latent energy can be captured by sequestering it on one side of the mitochondrial inner membrane, like pumping water up into a holding tank or reservoir? T or F Answer: Precisely. Capturing the energy in reverse to be used in a form of “energy currency” inside our cells.
  3. That name of that energy currency is ADP. T or F                      Answer. False. Ok, I’m being mean. Close. It’s ATP. ATP is Adenosine TRI Phosphate. That’s the energy currency. When it gives one Phosphate away, it becomes ADP or Adenosine DI Phosphate. The mitochondria remakes ADP into ATP all day long. Each molecule of ATP leaves the mitochondria, activates something somewhere in the cell and comes back into the mitochondria 10,000 times a day. Round and round.
  4. The Electron Transport Chain is the mechanical means by which the energy of the electrons is extracted. T or F                                                                     Answer: that’s it. The smallest machine.
  5. It’s a perfect machine. T or F. Answer:                                 False. Electrons are “uncertain” – sometimes waves and sometimes particles (Heisenberg uncertainty principle). That makes them slightly unpredictable. They slip out the cracks. Then all hell breaks loose because high energy electrons in the wrong places cause damage. Oxidants. Reactive oxygen species. Etc. Like spilling gasoline. One match from disaster.