Ketones Turn on Uncoupling

Ketones Turn on Uncoupling

Your body has two fuel sources. Carbohydrates and fat. You could add protein but generally speaking, protein is used for muscle building and extra is broken down into glucose. If you have any carbohydrates (glucose) around, your body will naturally default to running on that first. Here is the catch. You only can store 1500 calories of carbohydrates. Every pound of fat is 3500 calories and given that the average woman is 30 percent fat, she has 40-50 pounds of fat or 140,000 calories of fat. That is the reserve she needs to make it through winter, pregnant.

Back to carbs. When we eat a meal, we fill up our carb tank first. That gives us about a 12-hour fuel source during which our body burns glucose exclusively. You can prove that for yourself by measuring your own ketones. Ketone meters are widely available (Keto-Mojo is on Amazon). They measure beta-hydroxybutyrate (BHB). Six hours after a meal, your BHB level is zero. Twelve hours, it is 0.1. Sixteen hours, 0.4. Almost like clockwork. If you do "intermittent fasting" and skip breakfast, thereby going 16 hours with no food, your BHB will start to climb as your body begins to switch over from glucose/carbs to fat. If you do a 5-day, fast mimicking diet of 800 vegan calories, <8% protein, and 50% fat, your ketones will keep rising until by day 5 you are at 4.0. If you eat three meals a day, 5-6 hours apart, you will never have any ketones in your blood.  Never. 

That's what civilization has done for us. By giving us "food security", and manufacturing delicious, prepared carbs in easy packages, we eat meals three times a day with sufficient carbs in them to always have a topped-off tank of carbohydrates, and never ever burn off our glycogen/carb stores.  So we never access our fat stores.

Inside our cells, our peroxisomes never get challenged to chop up fat and make ketones. Because of that, they wither. Literally. Without any demand to make ketones, the peroxisome doesn't petition the nucleus of your cell for the enzymes it needs to make ketones. The effect of that is easy to measure. You go on a "diet" and cut down on calories. But you are unable to burn fat. Your glucose declines and you become hypoglycemic. Without any fuel around, your brain goes into panic mode and you feel awful. You have to eat. Your diet fails.

You want ketones. Their presence means you are burning fat. But ketones are much, much more than that. They turn on uncoupling of your mitochondria. That means they induce your mitochondria to burn some calories as heat. Suddenly, you aren't just burning fat, and losing some weight. But the fat you are burning is being used as heat, so you are getting an extra 20-30% boost in fat usage. So much for the adage, "A calorie is a calorie is a calorie". And ketones act as very powerful hormones on many tissues in your body. They turn on the messages for your mitochondria to multiply. That means you can make more energy and burn more calories. That heat production is mediated through "uncoupling proteins" that basically let extra high energy proteins escape the mitochondria by giving up their energy as heat instead of making ATP fuel.

Why would they do that? Think back to 10,000 years ago, before agriculture. You are huddling in a cave in November in Europe (Or China, or India, or Peru), the beginning of winter. There has been a frost and all the plants you used to munch on are dead. You only have animals for food. (It could be Africa, at the beginning of the dry season. Again, no plants for the next 4-5 months.) You need to make heat to keep you warm. You are eating the fat from the animals you catch. Your body senses the lack of plant foods, carbs. You start pulling on your stored fat stores and putting out ketones. That turns on uncoupling protein and that makes you warmer. The teleological explanation makes perfect sense for a hunter-gatherer. Our planet Earth was much, much colder for some 100,000 years during the ice ages. We needed to stay warm to survive.

But you want to lose weight and you are trapped by feeling too awful when you cut your calories. Now you know why you feel awful. You need to induce your cells to learn how to burn fat into ketones. Not only that, you want to supercharge your mitochondria and burn some extra calories as heat.  You can't do it all at once. It takes a week or so to turn on the cellular messaging from your peroxisomes, your ketone manufacturing organelles, to your nucleus and get the mRNA back to manufacture your necessary enzymes. And as you do that, you make brown fat. Brown fat is fat cells full of mitochondria, uncoupled, and making heat. A calorie is now being burned for heat.....sort of like in your home. You can use energy to make electricity or heat. Carbs make electricity, but you also need heat, and uncoupled mitochondria, brown fat, make heat. You lose weight.

www.What will Work for me. I'm trying to explain this concept from several angles so that I get the concept in my head. I learn better when I have a lot of various angles to get a better handle on the idea. My current fascination is with ketones from ketone esters. Eating ketone esters routinely blunts your appetite while turning on uncoupling. The price of ketone esters has just dropped 75% so they are now almost affordable. Juvenescence is much cheaper than KetoneAid (the first on the market). This may mean you don't have to starve to get your uncoupling, you just have to have ketones around. Instead of not eating to get BHB, you can just swig some ketone esters. I'm going to try that for a couple of weeks, 4 times a day: one capful. See what happens.

References: FASEB Journal, FASEB Journal, Annals of Neurology, Obesity, Keto-Mojo,

Pop Quiz

1. Your body makes ketones every day, naturally. T or F. Answer: Trick question. It would if you went more than 12 hours without food but in America today, we never go 12 hours. We eat every 8 hours. So, False. True if you intentionally skip breakfast.

2. How many calories of glucose can you store? Answer: 1500.

3. If you skip breakfast and don't eat for 14 hours, how certain are you that ketones will be in your blood? Answer: 100%

4. Ketones in your blood means what? Answer: You are beginning to switch over to burning fat. Aka, losing weight.

5. Ketones do what to fat tissue? Answer: they act as a hormone and turn on the multiplication of mitochondria, changing white fat to brown fat, chock full of mitochondria and burning fuel to make heat. That gives you a 20-30% boost in your calorie consumption. Helping you lose weight faster.

Uncoupling Proteins - Sometimes a Calorie is Not a Calorie

Uncoupling Proteins - Or A Calorie is Not Just a Calorie

"A calorie is a calorie is a calorie". You have heard this bored into your head a thousand times. You don't believe it. And you are right. You can't lose weight and you are certain "Something is amiss." It is. Sometimes a calorie is much, much less. I'm serious. If it gets "uncoupled", you turn calories into HEAT instead of ATP energy molecules. And that makes some calories about 70% of a calorie. Put another way, you can make yourself burn 30% of your calories by how you conduct your life. Want to learn more? But if you can't uncouple, you are stuck with a metabolism that won't give anything away.

Now, remember, you make your body weight in ATP molecules every day, Your mitochondria, (10% of your body weight) turn the low energy molecule ADP (diphosphate) into ATP, (triphosphate) and that is the universal energy molecule for all your cells. Your mitochondria can make 38 ATP from a single glucose molecule. And out comes CO2 and water in exchange. And each ATP molecule gets regenerated some 10,000 times a day.

There are some challenges your body must face that no one ever really put together. What happens if you are a newborn with a huge body surface area to volume? How do you keep that little tyke warm? What happens when you have a lion charge you and you have to go from sitting to sprinting a 10-second 100-meter dash? What do you do if you just stuffed yourself with a feast and are just bloated with turkey and dressing, sweet potato pie, and cheesecake, and ice cream.....? Each of those circumstances requires massive, rapid changes in your metabolic pathways. Each of them involves uncoupling. We'll explain.

Your mitochondria are what you have to respond to that challenge. They must take a resting muscle to a sprinting runner in 1 second, increasing their output by some 40,000 fold. They can do that. But they also need a release valve, almost like a steam engine that lets steam out of the system. That's called uncoupling. You make heat instead of ATP. Your body needs to learn how to do that.

For all that to happen flawlessly and rapidly, we need to have some metabolic pathways in place, working fluidly. One of the most important pathways that needs flexibility is the ability to flex-fuel from glucose (carbs) to fat (many kinds). Your body defaults to running on glucose anytime glucose is around. That's because glucose used to be rare, showing up only once a year during fruit season, or the rare finding of honey. Repeat that. Glucose, for most of human history, was not the default fuel, eaten three times a day. It was rare. The rest of the time, our food was green leaves (think spinach and dandelions, broccoli and kale) or animal products. Green plants get fermented by your colonic biome to make short-chain fatty acids, most notably beta-hydroxybutyrate (a ketone). Fat gets used up, but only after all glucose stores are depleted. If glucose is around, you put out insulin and store any excess calories as fat. That makes insulin your storage hormone that prepares you for winter by storing excess glucose as fat.

Now, with the discovery of agriculture and growing grains just 7,000 years ago, we have carbs year around. With modern farming, we have carbs and sugar at our fingertips 24/7. Hence our metabolism is always running on glucose. Without any demand to burn fat, the enzymes that chop up and prepare fat for our mitochondria are not needed. If not needed, we don't ask our DNA for them to be made. Our peroxisomes, those little organelles next to our mitochondria that chop up fat to present to the mitochondrial furnace, are diminished. They don't have enough to do. Our mitochondria keep getting glucose because we keep eating every day, every 8 hours, and snacking in between. If you go on a diet, and you are glucose addicted, your peroxisomes will not chop up fat and make beta-hydroxybutyrate for you. You become hypoglycemic and feel awful. Your diet fails.

This is a journey that will take you a few weeks to master. I want you to understand how to uncouple your mitochondria and turn on uncoupling proteins. But to do that, you have to start with the basic mechanics of how your energy flow works.

That we feel hypoglycemic when we don't get our regular carbs is another clue. But when you heat a huge meal like Thanksgiving and find yourself hot and sweaty at two in the morning, you are demonstrating uncoupling. That heat is coming because your mitochondria are getting way too many calories thrown at them all at once. They can't manage the overload and to let the steam out of the system, they pull out UCP3, uncoupling protein 3, and say "Let er Rip" and just waste a ton of calories in heat instead of metabolizing it in a proper, orderly fashion. You do gain weight from that dinner, but the heat you felt at 2 am was the even more weight you would have gained had not your mitochondria been uncoupled. The reason for doing that is complex. We'll explain.

Isn't this interesting? Don't you want to know more? We'll get to it next week. This is enough for this week.

www.What will Work for me. This is the fourth of July. You don't want to eat so much that you feel like a furnace and get all hot at 2 am. If you do feel that way, recognized the warning sign. Your mitochondria are begging you to please, not overload the system too fast with so many calories. I'm fascinated with this uncoupling idea. The best way to get yourself able to uncouple is to first get your mitochondria responsive to fat and glucose. The way to start doing that is to let yourself burn off all your carbs every day. To do that, you have to go at least 12 hours without eating. That's when ketones will start to show up in your blood. (You can prove it to yourself by buying a ketone meter from Keto-Mojo and measuring your ketones. After 12 hours of no food, you will have 0.1 mg beta-hydroxybutyrate in your blood. Your peroxisomes are beginning to burn some fat. Now, extend that to 13 hours, then 14, then the time you get to 18 hours, you will have accomplished step one in getting yourself to uncoupling. Your peroxisomes have "petitioned" your DNA to provide the programming to make fat chopping enzymes. You are making ketones, and they are the key. We will explain that next week.

References: Wikipedia, Frontiers Physiology, PNAS, Circulation, PLOS One,

Pop Quiz

1. What is the best sign that you are carb addicted and unable to make ketones?                       Answer: You get hypoglycemic and feel woozy when you go more than 4 hours without food. The woozy feeling of hypoglycemia is your brain complaining because it is metabolically unable to make and run on ketones. It needs to be trained to do so. And that is possible.

2. What happens when you flood your mitochondria with too many calories all at once (like a milkshake, hamburger and large fries)?                               Answer: Pay attention. You feel sleepy and you feel hot. That hot feeling is uncoupling. Adrenaline will also turn on uncoupling. So when you are embarrassed and your face flushes and you get all hot.......there you have it.

3. What is uncoupling of mitochondria?                                 Answer: The letting off of excess calories into heat instead of ATP to escape the calorie overload.

4. How much of my metabolism can I affect by uncoupling?                              Answer: About a 30% swing if you believe the animal research.

5. You mean that a calorie is sometimes only 70% of a calorie?                       Answer: Yup.

If You Love Custard Ice Cream - Don't Read this Column

If You Love Your Milwaukee Custard Ice Cream, Don't Read This Column

Sepsis is what kills the most people in hospitals. It is when uncontrolled infections take over in a runaway spiral of inflammation. Most of that inflammation is driven by the lipids off of the surface of gram-negative bacteria from the bowel like Pseudomonas, Proteus, or Klebsiella species called lipo-polysaccharides (LPSs). Now, did you know that if you have a slightly big tummy, a bit of high blood pressure and slightly high CRP you likely have "metabolic syndrome", and the connection between lowgrade metabolic syndrome and the release of LPS is pretty high? LPSs are wicked little devils that wreak a lot of havoc. They basically come off the wall of bacteria from your colon, coming through "leaky gut" into your blood. No wonder Steven Gundry calls LPSs, "little pieces of s..t". They are. And they cause you harm.

Now, if you want to study animal models of inflammation, you take mice and inject their foot pads with LPSs. Makes for a dandy experimental model. But it's not so easily controlled. It would be oh so convenient if we could find a standardized method of inducing inflammation that could be precisely controlled by dose. Now, we have known since the 1980s that you can get precisely calibrated inflammation of mice footpads with carrageenan injections into their footpads. You don't have to deal with all that messy stool bacterial gunk.

Wait! Did I just say carrageenan? Didn't I see that on a list somewhere of ingredients in Culver's Icecream? What is carrageenan? Well, Wikipedia will tell you that it is used as a food additive to make ice cream creamy and smooth. It has been observed as having NOAEL (no-observed-adverse-effects-level) in rats at levels that would be about 1/2 pound a day of it for humans. Ok? But is it really safe?

Here is the conundrum. We extra carrageenan with alkali from seaweed. So far so good. But when we expose it to acid, it turns quickly into poligeenan, a substance known to cause cancer. Guess what carrageenan is going to find in your stomach! Acid! Oh, dear. And there have been a slew of animal studies showing that carrageenan exposures results in changes to bowel wall similar to that seen in inflammatory bowel disease. For example, 30 days of carrageenan given to guinea pigs makes 100% of them get gut ulcerations.

It should be distressing that we know it causes trouble in animals in many models but we say it is safe in humans because we haven't studied it enough. But that is where we are today. No clear evidence that it is safe. Lots of smoke. No obvious fire because we haven't looked at it enough. And goodness gracious, do we love our Milwaukee custard, 100% of which has carrageenan in it? Did you know that inflammatory bowel disease is the #1 reason for admission to Children's Hospital of Wisconsin? Lots of smoke.

www.What will Work for me. Ice cream is something I can't have in the house. I like it. A lot. Sugar and fat sure work for me. But I also have a stubborn CRP that I can't find the cause of. Carrageenan sounds like a possible culprit. But it's not just in ice cream. Did you know that carrageenan is found in coffee creamers, soy milk, sliced turkey, canned soups, microwave dinners......ouch. Now you know what that ingredient you didn't know about stands for...maybe it's time to reconsider eating it.

ReferencesJr of Innate Immunity, Frontiers in Immunology, J Vis Exp, Feder Pro, Culver's Ingredients, Wikipedia - Carrageenan, EFSA Journal, Medical News Today, Frontiers Pediatrics, Gut,

Pop Quiz

1. Carrageenan is extracted from....?                        Answer: Red seaweed by an alkaline extraction process.

2. What happens to carrageenan if it is exposed to acid?                              Answer: It makes a different compound called poligeenan. And it is not safe by everyone's consensus.

3. What environment does food meet when you eat and swallow it?                           Answer: Acid

4. In animal models, like guinea pigs, what happens to the GI tract when given carrageenan for 30 days?      Answer: 100% of the guinea pigs got gut ulcers.

5. Carrageenan has been proven to be safe? T or F.                              Answer: There has been no study in humans to prove it and no one has dropped dead from eating it, in the short term. But there are no meaningful studies in humans that are long-term or look specifically at gut health. You might wonder why. Huge industry pressure to leave your hands off.

Melatonin, your Nighttime Mitochondrial Repair Tool

Melatonin, Your Night Time Mitochondrial Repair Tool

You thought melatonin was your "sleep hormone" that you made every night. Well, that was how it was discovered. And that is still true. But did you know that it is much, much more? Both plants and animals make it in mitochondria and chloroplasts where melatonin plays a primary role in protecting the electron transport chain from OH molecules, which are incredibly toxic. In fact, melatonin plays a more important role in anti-oxidant function than vitamin C or E, and as opposed to those two vitamins, it doesn't deplete glutathione.

You can actually call melatonin your mitochondrial repair hormone. You can call it your uncoupling hormone. Or you can call it your heat production hormone. All three of those monikers are true when you understand the role of mitochondria in your body. At night, when you fall asleep, your mitochondria have a chance to slow down and repair themselves, getting themselves back into tip-top shape. They can clean up the damage from all the extra calories they had to burn during the day and petition the nucleus to send them out some extra repair proteins.

Now, that has huge implications for cancer. Cancer is essentially a "broken mitochondria disease", if you subscribe to Seyfried's description. Seyfried made CT scans of mitochondria in cancer and showed that the inner membranes of mitochondria are all disrupted and broken. Those mitochondria can't make ATP, so the cancer cell has to invade other cells to get food. Melatonin repairs that initial damage that starts cancer cells down that journey. Folks with decreased melatonin from shift work have more cancer. And, with over 3,000 published studies on melatonin and cancer, there is increasing evidence that the scale is tipped in the direction of benefit of taking melatonin if you have any cancer. Life Extension just published a nice review of melatonin's benefits that lists some of those benefits.

It is in the repair of your mitochondria that melatonin probably plays its most important role. That repair process happens during the night when you are asleep. So sleep and melatonin are associated together, but they aren't the whole show. It is the process of uncoupling the production of energy, making heat instead of ATP, that allows mitochondria to take a deep breath and regenerate themselves.

We will explore this topic in the weeks to come. Repairing your mitochondria, uncoupling, ketosis, weight loss, cancer therapy, and brain health are all tied up in this topic. Rather than overwhelming, let's just bite off one little chew at a time.

And that is melatonin, a miracle-working hormone that you likely need more of. It is your sleep hormone, but so much more. You probably need to gradually raise your dose if you aren't on any. And consider eating those foods that come power-packed with melatonin naturally built-in: pistachios and mushrooms for starters.

www.What will Work for me. I love pistachios. Mushrooms are showing up in farmer's markets all over the place now. I'm trying to get into the habit of eating them in my eggs, my salads, or in just about every stew or casserole I make. I've been advocating for 10 mg of melatonin at bedtime for years. I'm going to raise that for anyone with cancer. William Falloon now advocates up to 50 mg a day with pretty good evidence for its safety. Your blood level of melatonin when you were a tiny tot was 200 pg/ml and drops by an order of magnitude over your lifetime.

References: Clinical Nutrition, Nutrients, Seyfried, Chirurgia, Life Extension, Cells, Int J Mol Sci, JCEM

Pop Quiz

1. What is melatonin? Answer: Trick question. It was discovered as your sleep hormone, with which it is related, but probably should be known as your mitochondrial repair hormone.

2. How does melatonin keep your mitochondria safe? Answer: Complex answer. It is your best antioxidant, protecting your glutathione levels. And it activates decoupling proteins, letting the steam out of your metabolic kettle.

3. Name a disease for which broken, disordered mitochondria is central to the pathophysiology? Answer: Cancer

4. Can melatonin help prevent cancer? Answer: Yes

5. What happens to my melatonin as I age? Answer: You have less than 10% of what you used to have as an infant.

You Want to be in Ketosis

You Want to Be in Ketosis

Yup. Every day. You want to be in ketosis! What is ketosis? What is a ketone? Let's explain. A ketone is a carbon-oxygen double bond that is naturally made whenever your body shifts into "fat-burning". But it is so much more. It turns out to be a critical signaling compound that turns on anti-aging in many ways. The question is how to make them and how to lead a lifestyle that encourages their production. Note, we are not talking about the terrible ketoacidosis of uncontrolled diabetes that occurs in the vacuum of no insulin.  The "house of medicine" has been misled, thinking that all ketosis is a prodrome to that condition, when in fact we are talking about a natural, in fact, beneficial state of physiology.

So, let's start with that. First of all, you have two major fuel sources to burn. Your fat stores, of which you are likely at least 20% fat and possibly as much as 50%. And carbs, which we eat every day. Now, consider that you can only store 1,500 calories of carbs. Anything more gets pushed into fat for longer-term storage. Fifteen hundred calories will only last you about 12 hours or so. Eat supper, and top off your carb tank. That's 7 pm. Now, 12 hours later, it's 7 am and you do a finger stick for ketones. Your level will be 0.1. You are beginning to turn on ketones/fat burning. Primarily a ketone body called beta-hydroxybutyrate (BHB). It's a 4 carbons long molecule. But you eat breakfast and have a carb source: cereal, toast, orange juice.  You have a rise in glucose in your blood, and an insulin response.  Ketones disappear upon the presence of insulin. But if you skip breakfast, have only black coffee, by lunchtime, your BHB will be 0.4. 

If you then continue to never fill up your carb tank and only eat 800 calories a day of which 50% is fat (this is the foundation of the Fast Mimicking Diet) for 5 days, your BHB will rise daily until on day 5 you will be at 4.5. You do that because your body needs 2,000 calories a day, and you are only getting 800 so you have to draw on your fat stores to make up the deficit. You are in full fat-burning mode and losing weight. More importantly, your ketones have dramatically turned on your anti-aging mechanisms, and folks who do that 4 times a year will add 16 years to their health span. 16 years. Probably the singularly most powerful antiaging tool we have. (Read Longo's book: The Longevity Diet).

Prior to civilization and growing grains as crops, we were hunter-gatherers. We didn't have carbs year around. The natural cycle of nature was that we had 8-10 months of adequate food sources, but every year 1-4 months of food scarcity during which we had to switch to our fat stores. We only had carbs for the few weeks than any particular fruit was ripening. We had a much better chance of survival if our metabolism could switch back and forth from fat to carbs. 

But that is a hard diet to do for most folks because they have been on carbs for so long, they have not stimulated the enzymes to make ketones in their peroxisomes. It's even more difficult if we are insulin resistant and thereby have elevated insulin all the time. (Insulin instantly turns off ketone production.) Folks who are insulin resistant (88% of us) try it, can't make ketones, become hypoglycemic and feel too awful. They quit and fail. Once your are ketone competent, your glucose can be 45 and you have no symptoms of hypoglycemia.

Is there a way around that to teach your body how to get back to "flex-fueling"? Yes. The key is breakfast and the timing thereof. At 7 am, everyone, always, is in nascent ketosis. 0.1. You have made the first timid step. So, we now know unequivocally that you can make some. We just want to wake up your DNA, and make more enzymes to manufacture more ketones. It takes a week or two for your DNA to get that done. Start a process of stretching out breakfast to 8 am. Then 9. Then 10 until you make it to noon. You will be in ketosis for 6 hours. Your enzymes will develop and you will feel the effects of that for yourself. You will find it to be easier, and finally easy.

How well does that work for weight loss and longevity? Groundbreaking work on monkeys and mice in Madison and the University of Texas on diet and fasting was completed just a few years back that showed that calorie restriction worked in prolonging life, but calorie compression worked just as well, regardless of the calories. Mice fed in a 3-hour window, versus 24/7, were remarkably healthier. They lived longer. They weighed less. The exact same calories over 24 hours led to weight gain. Same process has been proven in every animal species ever studied. Can you compress your calories into 12 hours, then 11, then.........6? What was more amazing is that it didn't matter what type of calories the compressed timing mice ate. (Unending chocolate ice cream?)

What you have done is to activate your "metabolic gym".  You have turned on all the genes that make the enzymes for you to make ketones.   Your metabolism can switch back and forth between carb and fat burning. Your brain learns to run on ketones, as do your muscles, your gut, and your kidneys...... And your body starts bathing in the wonderful, metabolic effects of ketone magic. (Read next week)

Now, there is a lovely little trick you can do to keep nudging yourself into ketosis. You can have coffee with a tablespoon of MCT oil in it. What is MCT oil? Mid Chain Triglycerides. It is a byproduct of coconut oil with carbon fat chains that are only 8 and 10 carbons long. Those are liquid. They go directly into your fat cells and can only be broken down into ketones. Add a tablespoon of MCT oil to your coffee (they have no flavor) and your blood ketones pop right up. You will feel the energy boost and very likely also feel your thinking to be a bit clearer.

www.What will Work for me. I've learned to do this and am now finally, at the point of feeling confident that it is not too hard. The bottle of MCT oil is finally empty, after using 1 T a day. Most importantly for me is that my average blood glucose has dropped some 20 points and my waist size has dropped two notches on my belt. I have been using Ketone Esters, another nifty trick to make ketones, regularly when I feel a little woozy and thing I'm short of fuel. They are amazing for giving you your energy back in 5 minutes. Two molecules of ketones, bonded together in an ester bond, gets into my blood faster than any other food source, and raises your ketone level very rapidly without turning on insulin. Try it.

References: Science News , Cell Metabolism, Ketones - The Fourth Fuel, Unlocking the Ketone Code, J Lipid Research, Jr Lipid Research, The Longevity Diet

Pop Quiz

1. What is a ketone? Answer:                      The "Fourth Fuel". It is the fragment of a fat molecule that is the common pathway of fat burning, or weight loss. Carbs, fat and protein are the first three.

2. What does ketosis mean?                  Answer: That you have turned on making ketones.

3. How do you do that?                  Answer: By not eating for 12 hours and burning out your carb tank of glycogen.

4. Can you do it faster than 12 hours?                            Answer: Of course. That's why exercise is so good for you. It uses up your carb tank and switches you over to ketones.

5. Can you raise your ketones faster than sitting around waiting for hunger?                            Answer: Yup. Just a tablespoon of coconut oil will do it. Put it in your coffee and call if Bullet Proof Coffee.

The Diabetes Risk Assessment for the 92% of Us Who are Insulin Resistant

The Diabetes Risk Index: A New Predictor of Future Diabetes Risk

Diabetes is the human Achille's Heel. Getting it is bad. Being overweight correlates highly with being diabetic. The problem is that nature wants you to be fat. We evolved in ecosystems where food was not plentiful year-round, and prolonged periods of calorie deficiency (winter in Asia and Europe, dry season in Africa) were the norm. Putting on weight needed to happen when easy calories were abundant. At the end of the growing season, many plants have fruiting bodies like seeds, nuts or fruits that were seasonally available, so we ate them as fast as we could, and gained a little weight. Today we have those delicious foods available for us year-round. The tightrope of calorie control is too hard for most of us to navigate. Our calories are too easy. We get fat and diabetic.

The definition of diabetes started out in Hippocrates' time as "sweet urine" that ants would migrate to. We know we spill glucose into our urine when we exceed a blood glucose of 180. Ok. With the advent of lab medicine, we refined our definition of diabetes to being two measurements of fasting blood glucose of 126. We learned that absolute deficiency of insulin was one type of diabetes, but insulin resistance was the far more common and insidious form. Type II. Lots of insulin around, just not working well. And that also turns out to be a continuum of risk.  The first crack in the wall came with the Whitehall Study out of England showing that a glucose of insulin 86 was the threshold for finally being rid of diabetes risk.  


The definition of Type II diabetes has also been evolving. We switched from the definition of Type II being a high blood glucose to the Hemoglobin A1c. A1c stands for the percent of hemoglobin molecules in a red cell with a glucose attached. Red cells live 100 days or so, so the A1c reflects the average glucose over the last 100 days. That's much more stable than the wildly swinging blood glucose. Even the A1c reflects a continuum and has been refined. The Institute of Medicine, our nation's arbiter of guidelines, used to define the target for optimal health of A1c as 6.0 and type II diabetes as an A1c of 6.4. Those goal posts were changed to an optimal A1cof <5.7 about three years ago. Medicare pays extra to health systems to get their patients' A1c below 7. Out of control folks will be 8, 9, or worse. Getting to 12 and 13 is lethal. 

The final step of discovery was recognizing that insulin is actually the key. If we can make enough insulin, we can control our blood sugar. But we can't. We only have the capacity to make some pre-determined quantity of insulin, and then our pancreases poop out. That means there are two variables, glucose and insulin, and insulin eventually runs out of steam. Then, we become "diabetic".

Ok, we have the definition of Type II diabetes down pat. But we recognize that it is a continuum which generally gets worse as we put on more weight and become insulin resistant. Can we look into the future and predict who is going to get worse? That's the key.

So, now we have developed two tools to do just that. The HOMA-IR(Homeostasis Model Assessment of Insulin Resistance) has been around since the 80s but not widely used. Do you know your HOMA-ir score? You should. It's easy to calculate. The formula is = fasting insulin (microU/L) x fasting glucose (nmol/L)/22.5. A score of 1 is great. Anything above 2 is suspect for early insulin resistance. There are lots of websites that will calculate it for you. You just need an insulin level. 

But the evolution of diabetes risk continues. It's not just the glucose level that is going astray. Curiously, the branched-chain amino acid levels in your blood are strongly predictive of the development of Type II diabetes. Finally, the advent of laser measurement of lipid subfraction particle sizes allowed precise size measurement of lipid particles in the blood. And they predict future diabetes even better!

Can we combine the two? Aha, Labcorp has done just that. The DRI, Diabetes Risk Assessment combines the lines of evidence: the LP-IR score, a measure of insulin resistance based on the Women's Health Study and Branched Chain Amino Acid levels. It measured the size of HDLs, VLDLs, and LDL particles which correlate strongly with insulin resistance.

The PREVEND study was published in August of 2020. It followed 6134 subjects for over 8 years and measured these variables to develop the new index, the Diabetes Risk Assessment. They found a 12-fold predictive variability from the top to bottom 20%. The DRI is more predictive of future diabetes risk than any prior measurement, including the HOMO-IR, the BMI, or individual scores.

This is a huge advance. We can now look prospectively into the future. With data, we can catch and measure and find trouble early. The vast majority of folks don't know any of this data. And the majority of folks I've measured it in didn't have a clue they were in trouble.

www.What will Work for me. Well, I measured my HOMO-IR and DRI with Labcorp. My Homo-IR used to be above 3. I'm now down to 1.9. What a relief. That took me a couple of years to get there but I keep chipping away. My DRI came in at 33, but that was after I spent four months wearing an insulin monitor and changing my eating habits quite dramatically. The goal is to be below a score of 50 for men, 40 for women. Higher than 65 is serious trouble. So, I've taken my risky genetic profile and been able to nudge it down into the safety zone. You may want to consider doing the same. Ask for the Diabetes Risk Index test from Labcorp. I'll order it for you if your own doctor won't.

References:J Clin Medicine, News Medical Life Science, Diabetes Care, CDC, Diabetologia, MDCalc, Nature, J Clin Lipidology, J Clin Med,

Pop Quiz

1. What is the definition of diabetes? Answer: It has been a moving target but we now call it a Hemoglobin A1c of 6.4%.

2. What is the optimal level of A1c for longer life? Answer: Less than 5.7%

3. What happens to my lipids with insulin resistance? Answer: the size of various subfractions changes dramatically. Generally, bigger is better. Fewer is better.

4. What are branched-chain amino acids? Answer: the ones we measure are called leucine and valine. They are literally branched in shape. They are more common in animal proteins and legumes and are critical to building and maintaining muscle mass. But too many, not so good.

5. And what do I want my DRI to be? Answer: Less than 50 as a man, 40 for a woman.

Extra Estrogen Protects Against COVID

Extra Estrogen Protects Against COVID-19

Two observational studies have now shown the same thing. The first, published this April, looked at 198,822 adults living in Italy during the first wave of COVID who filled out an online questionnaire. Positive tests and severity of illness were asked about.   6,873 participants had a known result of a nasal swab and they made up the study. They were 47 years old (mean) and were 65% female. According to the multivariate statistical analysis, women were about 75% as likely as men to get an infection from COVID and only 46% chance of getting a severe infection. Then, for the 2, 153 women over age 60 who were getting hormone replacement, their risk of getting a positive test was 46% compared to their age-matched peers. So, there was a 25% advantage to being a woman over a man for infection risk and then a further 54% reduction for women over 60 on hormone replacement for even getting an infection. Sounds like a tilt in favor of estrogen, doesn't it?

Hence, a second study to see if Italians are just like Swedes. Turns out, they are. In this newly published study, 49,853 women who were diagnosed with a positive test for COVID constituted the study group. Of those, 16,693 were aged 50–80 years old. 2,535 were taking hormone replacement therapy and 227 were on estrogen-blocking drugs for breast cancer management. Extra estrogen versus no estrogen. After adjusting for all the confounding variables, they estimated that being on extra estrogen (HRT) reduced the risk of dying by some 53%. (Postmenopausal women will have a serum estradiol level of 6-10 naturally, but once on a blocker, a level of 0-1 pgm. On replacement, they will often be 30-50. Premenopausal women will be 100-200 pgm) Being on estrogen blockers and having no estrogen doubled the risk of dying from COVID, but ended up not reaching statistical significance. As in other studies, age was an additional confounding variable, increasing the chance of dying by 15% for every year over 60. Ditto with "medical conditions".

What on earth makes this remarkable advantage? Why is estrogen so good for the human immune response? The reasons aren't known but it may be as simple as estrogen increasing mucus in the nose where the virus gets trapped and disposed of. Another thread of evidence suggests that estrogen modulates the ACE2 receptor the virus attaches to. Women have dramatic differences in their innate immune system, hence a greater propensity to auto-immune diseases. In the case of viral infections, like COVID, that may be helpful. Stay tuned. But now is not a bad time to be on hormone replacement....and considering all the subvariants of COVID and the likelihood that this virus is here to stay for the foreseeable future, a good reason to stay on it.

www.What will Work for me. Being male puts me off this strategy. We are beginning to have a credible library of choices to make to fight this virus. The best is protection and vaccination. But we are vulnerable human beings who need community and love and human touch. A hug, a handshake, a smile are all parts of our lives that we can't do without forever with a deep sense of loss and isolation. I want every woman I care for to feel encouraged to stay on their hormones. In the complex formula of risk and benefit, this is chalk mark on the benefit side.

References: Maturitas, Medical News Today, BMJ Open, Hormones, Am Jr Phys Lung, Cell Immunology,

Pop Quiz

1. What effect does estrogen have on COVID risk as shown by these studies?                   Answer: Aha, trick question. These are observational studies, and as such, don't constitute "proof". Association does not mean causation. There could be confounding things we haven't considered. Firemen, at the scene of a fire, usually aren't the cause of the fire. But it opens the door for a legitimate question. It's hard to imagine a randomized trial to study it, so the question may never be answered.

2. Ok, if I take it as enough evidence, what is my added risk of having COVID if I am age 67.                  Answer: 15% for every extra year over 60.   7 times 15 =105% or doubled risk over age 60. And then 15% for every extra medical risk: diabetes, etc

3. What is the suggestion of reduced risk of being a woman over a man?                      Answer: around 25% less

4. And what is the suggestion of reduced risk for hormone replacement versus no hormones for women over age 60.                                  Answer: About in half

5. And what is the additional risk for women on estrogen blockers, aka, no estrogen?                     Answer: Another trick question. The trend line suggested doubled risk but this is not statistically valid so needs a double grain of salt. An association study with no statistical validity is really a weak argument. But the trend line is there.  As everything in science, it needs a bigger study.  More infected people.  Not happening. 

LDL's are Not the Cause of Heart Disease

LDLs are Not The Key Driving Problem in Artery Disease

We are obsessed with cholesterol in our modern medical system. Don't get me wrong! 50% of us die of vascular disease in one way or another, so this is an overwhelming epidemic. But we won't cure the epidemic if we don't get to the root cause. The root cause is right before our eyes if we but see it. The science is there. We are just bucking the huge inertia of a massive pharmo-medical-industrial complex with a lot of money behind it. So, let's give it a try.

First of all, we must acknowledge the plain known fact that cholesterol above or below 200 is nonsense. There is unequivocal evidence that people live longer with cholesterol between 210-240. That 200 number was just put there as an arbitrary marketing tool to sell more statins. You want a cholesterol of 230. Just get over it and be happy when you get there.

Second of all, what is cholesterol and why is it in the blood? Cholesterol is a rigid membrane lipid that is useful for cells to make an outer membrane. Its rigidity allows cells to build firm outer walls that hold together (imagine bricks around the outer wall of a house). That way a liver cell looks like a liver cell. A heart cell looks like a heart cell. Only a few proteins can be embedded in the wall to allow just the right things to get in and out. You make cholesterol in your liver and deliver it to your cells with little pickup trucks called LDLs. If your cells are unhealthy and need a lot of cholesterol, your blood level will be lower. If you have plenty, the level will be high. That's what LDLs do, They deliver cholesterol to the cell.

Well then, how does cholesterol end up being in your arteries and causing heart attacks and narrowed blood vessels? Aha! The $ 64 billion dollar question.

Here are the steps. LDLs don't cause trouble until they get sticky. They don't stick to the blood vessel wall until they become oxidized and get sticky. The key to that happening is you have to be insulin resistant, which 88% of Americans are. When you are insulin resistant, the proteins on the surface of your cells become sticky, like velcro. With insulin resistance, you produce a protein called Apolipoprotein Apo-C-III that induces that stickiness. ApoC-III equals LDL velcro. With insulin resistance, your blood glucose is higher and more glucose sticks to various proteins, like Apo-C-III. Then, you are off to the races. The little tiny oxidized, glycated, LDLs can stick to the vessel wall and start being transported into the vessel. The LDL particle actually can turn on innate immune system inflammation.

Why does stickiness and damage start in artery walls? Why not in veins? Same blood level of LDLs in both places. Only the arteries get damaged. And when you make bypass surgery grafts with veins, they become clogged with plaque all too quickly too. Why did the artery get damaged, and not the veins? Because of high blood pressure and increased friction on the wall of the artery from the force of that pressure. We now know that high blood pressure and glucose resistance are all part of a continuum.

The LDLs are just there delivering cholesterol to the artery walls, just like to every other cell in your body. But now they are at the scene of the crime. They get sticky and get gobbled up by white cells trying to help repair the damage. Cholesterol pools begin to develop. Just like firemen at the scene of a fire, the LDLs are not the cause. The cause was the friction-based damage to the wall of the artery caused by higher blood pressure, stickier LDLs particles that have glucose on their surface, which signals white cells to attack them and try to remove them from the scene of the crime.

How to reverse all that? How to reverse glycation comes down to reversing insulin resistance. That's weight loss and moving to an ecosystem with less free glucose in it. White flour and sugar are the key enemies. Any food that makes lots of free glucose in your blood: potatoes, rice, and grains are problems. The instant you become overweight, the slope gets more slippery. Insulin resistance climbs. The cardiovascular surgeon with his home on Pine Lake is waiting for you.

How can you tell or measure your insulin resistance? Lab tests: Insulin level below 5. Fasting glucose below 85. A1c below 5.6. Labcorp's new Diabetes Risk Assessment Test level below 50 (men), 40(women).

www.What will Work for me. I'm on my own experiment with this as my HDLs have always been low and I have family history of heart disease. My A1c wants to drift up to 5.8 if I'm not vigilant and my fasting blood glucose stubbornly remains at 102. I've been wearing a continuous glucose monitor now for 4 months and have discovered the foods that make my glucose shoot up. I can see the change with just 5 raisins. My blood glucose will rise 15-20 points. One spoonful of chocolate ice cream will give me a 100 point rise. That indicates insulin resistance. If I do a 5 day fast mimicking diet, my insulin will be 2. But otherwise, 10. I'm there on the cusp, just like the 88% of Americans. I want to explore Lab Corps new Diabetes Risk Assessment Test. Next Week.

References: BMC, Biochem Biophys Acta, Diabetologica, Current Opin Lipidology, Wikipedia, Nature

Pop Quiz

1. What is the real engine that drives heart disease?                             Answer: insulin resistance that leads to stickier LDLs, stickier artery walls and more damage to artery walls from higher blood pressure. Yes, 125/85 is worse than 1115/65.

2. What is the function of LDLs?                               Answer: To deliver cholesterol to every cell in the body to help build its outer membrane.

3. What has to be added to LDLs to make them sticky?                               Answer: Apo-C III

4. How can you raise your ApoC-III level?                                     Answer: Easy, peasy. A trip to a fast food joint with a Big Gulp soda, nice refined bun and a shake on the side. Lots of refined sugar and flour.

5. Is heart disease reversible?                                    Answer: Yes. One step at a time. Fix your insulin resistance. Then we will get to ketones.

Reverse Thymus Aging Part II

Live Longer by Reversing Thymus Aging - Part II

The TRIIM (Thymus Regeneration, Immunorestoration and Insulin Mitigation) Trial caused a lot of excitement when it came out. The first study in humans to show a reduction in the most accurate clock of biological age, our epigenetic clock. The 9 volunteers had a 2.5-year reduction in their age on measuring epigenetic age from the study protocol taken for one year. The Protocol was simple: Growth Hormone, DHEA, Metformin, Vitamin D, and zinc taken for one year with MRIs of the thymus gland to watch its regrowth and serial blood testing to monitor immune response. 

Aside from increasing the size of the thymus gland, there were remarkable changes in immune functions that are worthy of note. There was an increase in the production of new T-cells, a core process of a fully mature function thymus gland that decreases with aging. They also documented three classes of new or “naïve” T-cells that increased. Because new T-cells survive and function for years, then these new T-cells (immune traffic cops) will continue to protect after being turned on. That increase could be monitored by measuring the Lymphocyte to Monocyte Ratio: LMR. It increased. There are many studies that demonstrate a reduction in cancer and all-cause mortality with an increased "LMR" ratio.

What is it about monocytes? Well, most of them carry an enzyme called PD38 that degrades NAD. Aha! The link with your epigenome. NAD is the fuel that sirtuin proteins must have. Degrade NAD and your sirtuins won't work. Your sirtuins are the caretakers, the gardeners if you will, the lifeguards of your epigenome. They depend on NAD for their energy supply. More monocytes, less NAD. 

It wasn't just immune function as measured by LMR that tipped. The study showed a pretty dramatic improvement in cancer protection by stimulating a reduction in PD-1 expression on cytotoxic T-cells. The PD-1 receptor is used by many cancers to trick your immune system to giving the cancer cell a pass. With that receptor, the cancer keeps growing right under your immune system's nose. The heavily advertised drugs, Keytruda and Optivo, both work by blocking the PD-1 receptor. 

Finally, they also showed that the PSA, free PSA ratio all improved quite dramatically: PSA dropped and Free PSA increased. Again, a reduction in risk. 

All of these effects are broad-based in their impact and have important implications for overall health. You can summarize it down to just a few key talking points. 1. ) This strategy increases your thymus gland function of manufacturing youthful, active lymphocytes, changing the LMR (lymphocyte to monocyte) ratio. 

2). Too many monocytes are not so good for you because they gobble of NAD. 

3). You really do need NAD to maintain a youthful epigenome and turn on the right genes when they are needed, and turn off the wrong genes when you don't want them - actions that require NAD. 4). You turn off PD-1 and that doesn't let cancer out of the bag. Keytruda is not cheap. Cancer is not friendly. You want less PD-1.

www.What will Work for me. I've got it. The link between NAD and David Sinclair's brilliant book,Life Span, and immune function comes to focus. We should all be on NAD and Metformin, DHEA, zinc, and Vitamin D. Now, Growth Hormone is pricey at some $ 2500 a month but CJC/Ipamorelin isn't so expensive. The challenge is to get these markers available to us ordinary folks so we can keep ourselves "younger" and measure it to prove it. does a pretty good job of telling you your epigenetic age if you want to measure it.

References: Aging Cell, Life Extension, LifeSpan,

Pop Quiz

1. What is your epigenome?                                Answer: the markers on the outside of our chromosomes that manage the expression of our genes. We pass many of those markers on to our kids, so the epigenome acts somewhat like your genes as an intermediate layer. It is managed by your sirtuin proteins, that run on NAD only. 

2. What happens to your epigenome with the TRIIM protocol?                          Answer: In one year of following the TRIIM protocol, your epigenome gets 2.5 years younger. 

3. That beneficial effect is modulated by several synergistic effects. Can you name several?                       Answer: a) Increased thymus size (last week's letter), b) Increased fresh new T cells, c). Improved Lymphocyte/Monocyte Ratio. d). Reduced PD-1 receptor activity e) Increased NAD, f) reduced PSA and increased free PSA, g). reduced CRP......... 

4. What is the link between thymus aging and your genetic resilience?                          Answer: When you make fresh, young T cells, your monocytes decline and they tend to degrade NAD. With more NAD, you have the fuel to keep your sirtuin proteins energized, and they take care of your epigenome, and keep it functioning vibrantly and protectively. 

5. Can you name the compounds/elements taken in the TRIIM trial?                            Answer: Growth hormone, metformin, DHEA, Vitamin D and zinc.

This Column was written by Dr John E Whitcomb, Brookfield Longevity, Brookfield, WI (262-784-5300)

Reverse Thymus Aging - the TRIIM Trial

Reverse Thymus Aging - The TRIIM Trial

Your thymus gland, just behind your breast bone, is the nexus of your immune system. By age 50 it is basically all composed of fat and non-functional. Without a properly functioning thymus gland, your immune system starts drifting toward "lack of balance" with many indications that you are becoming vulnerable to disease. Aging. We can measure aging by the calendar, and indeed, we sing Happy Birthday to you every year.

But, a more accurate measure of your frailty is your epigenetic age. Your epigenetic age is now acknowledged by most aging scientists as the best marker of your biological age. Your epigenome is the library of methylation and other markers on your DNA that indicate to you "when to hold 'em, and when to fold 'em", when to turn on genes and when to silence them. That whole system is maintained by your sirtuin proteins which are nourished and fed exclusively by NAD and not ATP. Your epigenome has its own energy system and its own repair system. Repairing and maintaining DNA had to be the first function of the first cell on planet earth, so sirtuins and NAD are found in all cellular life.

Your thymus gland and your epigenome have a curious intersection. The aging of the thymus gland results in a reduced population of naive T cells that can be programmed by the thymus to balance many components of the immune system. Thymic involution leads to the depletion of critical immune cell populations, resulting in a collapse of the T-cell receptor (TCR) repertoire in humans after the age of ~63. Immune aging turns on many populations of cells that cause trouble, and your epigenome can't help out, because it too is degrading.  That creates a curious nexus between your epigenome and your thymus aging.   To fix one, we have to fix the other.  

The question arises, can we reverse this? Well, yes! Turns out growth hormone helps regenerate your thymus gland. But growth hormone has a nasty tendency to nudge you towards diabetes. So, the TRIIM trial(Thymus Regeneration, Immunoregulation, and Insulin Mitigation) decided to counter that with a combination of Growth Hormone, DHEA, Metformin, 3000 iu of Vitamin D, and 50 mg of Zinc. Nine men, ages 51-65 were recruited who were given this cocktail, and then had their thymus gland measured by MRI every couple of months.

What happened? Voila. After one year of treatment, the men were 1.5 years younger by epigenetic testing. That means a -2.5 year gain on aging. Their thymus glands grew back dramatically. The study was widely talked about and has been rated in the top 5% of research papers ever scored.

www.What will Work for me. Well, I've measured my epigenome once and I know understand the combination of growth hormone, NAD, metformin and Vitamin D. After promoting Vitamin D for 15 years, I feel vindicated for that. Now, Growth Hormone is expensive. But the technology of growth hormone has leapfrogged into the world of peptide sciences. It is much cheaper, more effective, and safer to get your boost from the peptides that stimulate you to make your own growth hormone. And last but not least, it is also helpful to see the impact of DHEA and its importance. Just about everyone over age 55 has a dramatically lower DHEA than they had at age 20. This study is so important, that we will do more on it next week. This is enough for my aging brain to soak up in one week

References: Aging Cell, Life Extension, Aging, Frontiers in Immunology, Journal of Immunology,

Pop Quiz

1. What happens to your thymus gland with aging?                         Answer. Fades into the sunset.

2. Is there an acknowledged age where it seems to hit the final wall?                        Answer: Yes, age 63.

3. Your "biological age" can be measured more accurately than your calendar age? T or F.               Answer: True

4. How?                               Answer: Your epigenetic age. We can now measure and count that.

5. Remind me, what is your epigenome?                      Answer: the complex markers on your histone proteins, your DNA coating, that instructs your cell about activating and inactivating your genes in response to environmental changes.

This column was written by Dr. John Whitcomb, MD, Brookfield Longevity, Brookfield, WI, (262-784-5300)