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. MyDNAge.com 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)


Loss of Synapses is the Engine that Drives Cognitive Decline

Yale Can Image Your Brain and Define Your Cognitive Function


The long-standing sign of Alzheimer's is a shrunken brain. In fact, brain shrinkage is so common in all of us, that radiologists will often make offhand comments that an older person has mild shrinkage, but within normal limits. We have presumed that loss of linkages between neurons, called synapses, is what is happening but hard proof has been difficult to come up with. That means we are all on the path to getting Alzheimer/s, just with some getting it sooner and some later. Hmm.


A little bit of basic science. The estimate is that you have about 4 quadrillion synapses in your brain with each active neuron connected to some 3500-10,000 other neurons. You have so much redundancy and resilience that it is thought that you have lost at least 50% of your synapses before you demonstrate cognitive decline. You can function at 50%.  You have just lost the ability to immediately remember where your car keys ended up.

Therein lies the dilemma. This has all been "presumed" but not proven. What is called "mild cognitive impairment" (MCI) or otherwise shrugged off as "senior moments" is actually part of the same process, just earlier in the journey. Treating the disease called Alzheimer's is fruitless. It's too late. You can't bring back the lost neural connections. Preventing it depends on knowing early and reversing the conditions that are setting it off while your brain can still tap into the biological process of rebuilding redundancy. And preventing depends on having some means of quantifying early disease in a credible fashion.


And that is what Yale just proved.  Researchers at Yale have now measured early cognitive decline. A PET scan using a new glycoprotein called SV2A gave the researchers a measurement of metabolic activity in brain synapses of 45 people diagnosed with mild to moderate Alzheimer's disease. Each person was then tested in five key areas: verbal memory, language skills, executive function, processing speed, and visual-spatial ability. The loss of synapses or connections between brain cells was found to be strongly associated with poor performance on cognitive tests. There you have it. It's not widely available yet, but it will be coming. The loss of synapses correlates directly with loss of cognitive function. It makes perfect sense.


And this correlates exactly with the plasmalogen evidence that effectively says the same thing, but at the molecular level. Let me repeat that metabolic explanation!  Our synapse membranes are 70% plasmalogen content. Plasmalogens are using choline as part of their structure. For our brain to function, it must have acetyl-choline to communicate across the synaptic cleft. If your synapse gets a little short on acetyl-choline, it can make some more by borrowing choline from its own plasmalogen membranes, in effect self-cannibalizing. That's the problem. You can't borrow from Peter to pay Paul forever. The ultimate Ponzi scheme. Enough "borrowing" and the synapse collapses. Now, you only have 3 quadrillion, 999 trillion, 999 billion......you get the point. This process is going on for decades.  Lose a synapse here and there and you lose the neural network that retrieved where your keys were.


And that, my friend, is how we will conquer this cognitive decline epidemic. If we measure and quantify your plasmalogens, which we can do, and we repair your methylation system, your inflammation system, and your mitochondrial health, all in the same package, which we also can do, we can give your brain the tools to repair itself. Fundamental to all biology, cells will repair themselves if given the right tools and building blocks and removed from the environment of reductive deficiency. Likewise, your brain will rebuild redundancy and resilience if it has the proper building blocks. And now we have a PET scan coming that will provide the precise details to assure you that you are making progress. Cool, Huh?!


You have time. This is a long, persistent issue. But don't discount that "senior" moment. Take it as a warning that you have lost some function you used to have and you want it back.


www.What will Work for me. Having now measured plasmalogens for over 18 months and seen folks come back and say they feel improvement, I'm sure we are on the right path. The issue is whether we can prove it and quantify it. That should be the goal. I want hard data. Someone in a memory unit with severe dementia has lost so much function that rebuilding redundancy and resilience is a much higher burden. I take my plasmalogens every day.


References: Alzheimer's Dementia, Yale News, Apple News, Science Daily, NeuroSci Letters, Science Daily


Pop Quiz

1. What was the imaging technique they used at Yale? Answer: PET scan

2. For cancer, a PET scan uses high glucose use to indicate unusual activity. In this scenario of cognitive decline, the imaging compound was what? Answer: Glycoprotein SV2A

3. Did the research report say much about amyloid plaque or tangles, some of the old criteria for Alzheimer's? Answer: Nope

4. What is the key engine driving cognitive decline? Answer: loss of synapses, or links between neurons.

5. And what is the key nutrient missing that makes you lose a synapse? Answer: choline plasmalogens.


This column written by Dr. John E. Whitcomb, MD, Brookfield Longevity, Brookfield, WI 53045


HDL Cholesterol Relates to Insulin Resistance, and That's the Heart Disease Engine

HDL Cholesterol Relates to Insulin Resistance, and THAT's the Heart Disease Engine


We have known since 1977 that it's low HDLs that are the real risk of coronary artery disease. What we didn't realize back in the 1970-90's was the dimension of insulin resistance overlaid on HDLs. For folks with insulin sensitivity, higher LDLs have virtually no risk at all. It's the binding of LDLs to the vessel wall, their subsequent oxidation that then drives them to be gobbled up by macrophages that deposit the lipid pool in the artery. And that process is driven by insulin resistance.

Each of us has about 1000 LDL particles per cell in our body. Per cell. There are a lot of LDLs. Their job is to deliver cholesterol from the liver to cells to help make membranes. HDLs are much smaller, and there are 10 of them for every LDL, but they never get sticky. Their job is to take leftover cholesterol individual cells don't need and take it back to the liver. They don't have the APOB molecule on their surface, so they can't stick to the vessel wall. It's sticky LDLs that stick to the vessel wall. How do they get sticky?


Ah! That's the issue we need to understand. Stickiness comes about because of insulin resistance and subsequently higher blood glucose. Any given LDL particle becomes more likely to be bound to proteoglycans in the intimal space when it is enriched with the apolipoprotein ApoC III—a process that occurs during states of insulin resistance.

Then there is the added dimension of ceramides, the waxy fats that make our internal organelle membranes much more rigid. We develop with when we eat too much sugar and saturated fat. With too many ceramides in our membranes, they get too stiff and can't export HDLs. Ceramides also point straight at fructose.


And how many of us are insulin resistant? That's the million-dollar question. If you take the most recent guidelines about waist circumference, A1c, BMI etc, you will find that only 12% of Americans are metabolically healthy. The rest have some degree of insulin resistance. And they are making arterial plaque. Using the most recent guidelines, metabolic health was defined as having optimal levels of waist circumference (WC <40/34.5  in for men/women), glucose (fasting glucose <100 mg/dL and hemoglobin A1c <5.7%), blood pressure (systolic <120 and diastolic <80 mmHg), triglycerides (<150 mg/dL), and high-density lipoprotein cholesterol (≥40/50 mg/dL for men/women), and not taking any related medication.


Obsessing about total cholesterol misses the point, almost completely. Our guidelines for administering statins are off the mark badly. What we want is healthy arteries. And the proper guideline is Insulin < 5, HDL, 40/50 (men/women), BP below 120/80.


And that brings up back to our HDLs. HDLs are the garbage trucks of our bodies, carrying leftover cholesterol back from cells that don't need it. Healthy cells have healthy peroxisomes and healthy levels of plasmalogens in their internal membranes. If you eat too much fructose, your make more ceramides, the waxy fats that make membranes more rigid. Your mitochondria and peroxisomes get damaged and you have trouble exporting HDLs, proportionately to your falling HDLs and rising ceramides. Low HDLs mean metabolically damaged cells with insulin resistance. High ceramides mean lower plasmalogens. So, if you think there is a correlation between insulin resistance and Alzheimer's, you got it right.

 

You can reverse all that. Sugar is such a powerful engine to drive trouble, first and foremost, you must get sugar consumption down. Your waist to hip ratio, your HDL, your insulin, and your blood pressure will all reveal to you your metabolic health. Key to all your efforts is losing weight. There you have it. It's not total cholesterol, it's insulin resistance. Weight loss and control of body size is our metabolic story.


www.What will Work for me. I've been on a three-month streak of wearing a continuous glucose monitor. I'm humbled by what I have learned. Yesterday, in the middle of a 16-mile bike ride without having eaten any lunch, I felt a bit washed out and tired. There was a Clif Bar, chocolate, in my bike bag, leftover from last fall. 6 months old. Frozen in our garage all winter. Wow, it looked good. 250 calories, 17 grams added sugars. My glucose by my monitor was 77. Down went the Clif Bar. 15 minutes later, glucose 145. Whew. It dropped back down pretty fast because we were biking. But for half an hour there, I was glycating my LDLs. That's what is happening to all of us. No more Clif bars for me.


References: JAHA, Am J of Med, NLM, ATVB, Metabolic Syndrome and Related Disorders,


Pop Quiz


1. What is the job of your HDLs?                                  Answer: Picking up excess cholesterol and take it back to the liver.   (That means your cells are healthy, have enough cholesterol and the internal membranes are robust and replete with plasmalogens, low on ceramides.)

2. A healthy cell with healthy membranes can be demonstrated by what?                               Answer: the ability to "efflux", export, cholesterol, so HDLs have to go up.

3. Insulin resistance can be measured and defined by insulin level. T or F.                                Answer: True. You want a level below 5. Average American is 12. "Normal range", or what is seen in the population is 2-29.

4. What percentage of Americans are metabolically healthy?                                   Answer: 12%

5. Slender women with a total cholesterol of 230 and an HDL of 70 should be on statins. T or F.                      Answer: False. That's why our cholesterol guidelines are broken.


Column Written by Dr John Whitcomb, MD, Brookfield Longevity, Brookfield, WI www.LiveLongMD.com. 262-784-5300


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