Alzheimer's, Homocysteine and Methylation Engine

Alzheimer's Disease, Homocysteine, and the Methylation Pump

All of us are on the path to cognitive decline. No kidding. All of us. It's just whether you want your turn to show up at age 73 or at age 297. We are all on that path. It's a path that is becoming better understood, which means we may be able to lower the slope, the rate at which it is occurring if we understand its driving cause. Let me give it a try.

Your neurons in your brain have a few problems. They are each attached to some 4,000 other neurons by long, fragile axons. That gives us some 4 quadrillion links (synapses) between axons (that's quadrillion, with a Q). We are diagnosed with cognitive decline when we have lost some 75% of those links, because our brain has amazing redundancy and hence resilience. Each axon can lose a certain number of synapses and still survive, but there is a threshold beyond which it can no longer make it. The problem with 4000 synapses is that they all have to be energized, supplied with fuel, and they tend to have that need a long way away from the core cell, the nucleus wherein resides the instructions manual and manufacturing facilities. Think about it. The neuron has so ship mitochondria to make energy, and many neurotransmitters, proteins, and such all the way down those axons. That is no small distance. In your brain, from one side to another it's some 5-6 inches. But your spinal cord to your feet is.....3-4 feet. A little bitty neuron has to ship enough neurotransmitters 3-4 feet!

There is a second problem. Your brain has to have neurotransmitters to function. Some 70% of your neurotransmitter need is acetyl-choline, made from choline. What happens if you don't have enough choline? Well, your neurons have to have it. No questions asked. They must have it, or you are dead. So, they take it. They borrow from Peter to pay Paul. They steal choline from their own membranes, wherein reside plasmalogens, made from ethanolamine or choline, both of which can be robbed to make acetyl-choline. The axon is made from some 70% plasmalogens, so you have a big reservoir, but not an endless one. And plasmalogens think they can fill several shoes. They are the only lipids that can shapeshift in your body, allowing them to merge membranes and secrete neurotransmitters. And they are the only lipids that have a precious "vinyl-ether" bond, a bond that can neutralize peroxide, the universal oxidant. We live in an oxidizing world that also acts to deplete plasmalogens. Big problem.

The third problem is getting new plasmalogens, new neurotransmitters, new mitochondria out to the tippy tip, tip of the neuron. We now know that that is another unique "engine" in the cell. Like in mitochondria, where we know that the final step in making ATP is a spinning protein that acts like a miniature engine, you have a second rotary engine in the neuron that pumps fluids down the neurofibrils of your brain. Much like the Mazda rotary engine of yore, your brain's neurons pump organelles like mitochondria and packets of neurotransmitters down the conveyor belts (microtubules) of your neurons. To properly do that, they need methylation of proteins to activate the turning proteins.

And that's the rub. What happens if you have your methylation system all mucked up because you are using too much of it to make creatine for your muscles? Or you don't have enough methyl groups because you haven't taken enough B12 or folate? Your neuronal rotary engine can't pump. You accumulate broken tubules in your brain, and we call those neurofibrillatory tangles. (Classic for Alzheimer's). What’s step #1? Probably the loss of plasmalogens.

Did you get all that? It sounds complex and the question arises as to which is the most important. But they are all part of the same ecosystem. We can measure your "methylation demand" by measuring homocysteine. A low enough homocysteine level is an indicator that you have enough methylation to make your "pump" in the neuron work. A sufficient plasmalogen level means you have enough choline for your neurons to shape-shift, to protect themselves from peroxide, to keep your membranes fluid and rapidly functioning. A sufficient choline supply means you have reserve. No one is the most important, they all interact and work in concert.

And we can now measure and fix all of those deficits.   It just takes measuring and identifying the deficits and replacing them before you have used up all your redundancy.  Replacing isn't some arcane, toxic drug that is foreign to your biology.  It is just the right foods and micronutrients.  

www.What will Work for me. I'm totally fascinated by the fact that our bodies run on teeny, tiny, little mechanical engines. The first one, ATP synthase, we found was in the mitochondria where we attach a phosphate to ADP to make ATP. The protein that comprises that tiny engine actually mechanically turns as the proton crosses the membrane of your inner mitochondria. Now we have a second engine that pumps the transport system in our brain. The tau protein in our neurons actually spin and push organelles down the axon. And all of that is tied up with methylation signaling. Hence homocysteine, the universal marker of sufficient methylation capacity measures the ability of that engine to pump. I now believe that we can all adjust and modify the rate at which we decline. The tantalizing vision is that we can actually halt and reverse some of that decline if we catch it in time. Your brain always wants to rebuild redundancy. If only it is provided with the tools to do so. And that's why I am supplementing all of them for myself. It's worth it.

References: Nat Rev NeuroSci, Frontiers Molecular Neurosci., Neuron, J NeuroSci.,

Pop Quiz

1. Each neuron in our central nervous system is attached to its neighbor next to it by wires. T or F. Answer: Arrgh. False. It sends wires out to some 4000 distant other neurons, thousands of cells distant. In fact, several feet distant in some cases.

2. Those connections are filled with what? Answer: A transport system built on microtubules that carry mitochondria to make energy and other organelles to function properly.

3. How does that transport system work? Answer: So glad you asked! It's an amazing little circular engine that pumps fluid out the axon, carrying mitochondria and etc.

4. What is the key to make the pump work? Answer: sufficient methylation capacity, indicated in your blood by a low enough homocysteine.

5. What is the connection of all this to plasmalogens? Answer: they are all integrated into the same system. You need the plasmalogens to make your neurons protected from oxidation, to shapeshift and excrete neurotransmitters, and to allow that to happen rapidly. You make plasmalogens from choline, that need 4 methyl groups to be made, driving methylation demand. That competes with making sufficient neurotransmitters.

COVID is Inhibited by Eating Natto

COVID Inhibited by Nattokinase

Someone has to explain just why the prefecture of Fukushima (north of Tokyo, and the center of Japan's natto consumption) only has 47 cases of COVID per 100,000 whereas Tokyo is over 230 per 100,000). There may be a clue in recent research done at Tokyo University of Agriculture and Technology on the traditional Japanese food, natto, and viruses in petri dishes. Please note that this research was in a lab petri dish, and not in humans but it might just give us a clue.

Thestudy had three parts. In the first part, the researchers took an extract of natto and applied it to the COVID-19 virus and to cow herpes virus in cell cultures. The viruses were unable to infect the cells. In the second part, they exposed the natto extract to "protease inhibitors" and that restored the infectivity of the viruses. This suggests that a type of enzyme called a protease must be involved. As a general rule, proteases digest proteins at various sites as a way of activating them or deactivating them. Finally, they heated the natto extract (which would unfold and inactivate the enzyme) and the viral infectivity returned.

When the researchers looked at the viruses after being exposed to the natto, they found the spike protein missing or severely degraded. There is something called the RBD (receptor binding domain) that is a segment of the spike protein that has the ability to hook onto your cells and then inject themselves into the cell.

This has been taken pretty seriously in Japan. Natto consumption has dramatically increased to the point of a 15% increased import of soybeans to Japan. Unfortunately, natto is a bit of an eccentric taste and not everyone really likes it. In Japan, it is typically eaten as a breakfast food. It is the highest food source of Vitamin K2, which may be why its consumption has been recently associated in a BMJ study with an overall 10% reduction in mortality. In fact, natto consumption just a few times a week has been shown to have measurable improvements in carboxylated osteocalcin (healthy bones). But the star of the show is likely nattokinase, an enzyme found in natto and known to play a beneficial role in preventing blood clots on airplane flights.

www.What will Work for me. I've been trying to get to like natto. I've made my own batches of it by purchasing natto starter off the net, and soybeans. It's not too difficult for a "home fermenter" to do. I believe the K2 is spectacularly good for me. And the nattokinase, ditto. But the taste...... I got my COVID shot to prevent COVID. Eating natto might slow it down, but is likely not sufficient for this virus. I believe the Japanese thought it was a valid tool and were caught with a low vaccination rate for which they are now paying a terrible price.

References: Biochem Bio Research Comm, NIID Japan, Forbes, BMJ, J Bone Mineral Metab., RxList,

Pop Quiz

1. What is natto?                                                                                         Answer: fermented Japanese soybean dish, unique to northern Japan around Fukushima.

2. Eating natto might lower your risk of COVID-19? T or F.                 Answer: True. Not enough to take to the bank but Fukushima prefecture has about 1/6th the infection rate of Tokyo right now.

3. Japan has paid attention to this effect of natto with what measurable result?                  Answer: 15% increased soybean imports. Pay attention to the commodity tables!

4. Did natto protect Japan from COVID?                                                Answer: Not enough to prevent the current terrible spike they are having right now, much like our current spike.

5. Could something come of this research?                                          Answer: Yes. This is how research works. You observe a biological process and then try to make a simpler method to do the same thing. Might there be a similar effect that can block that spike protein.....? Stay tuned. Get your vaccination while waiting.

Ever Heard of an Exercise Snack

Ever Heard of an Exercise SNACK?

You hate to exercise. It's hard to be committed. You can't get the time to do it. Ok, so you need some sort of strategy to get yourself the benefits of exercise. Consider an "exercise snack." Dr Gibala, from McMaster University in Canada, did just that. He got 27 young men (average age 27 +/- 8 year) and had them do three little bursts of biking exercise interspersed with more casual biking using minimal energy. Total time: 10 minutes. He then compared that to 50 minutes of traditional, good hard training. Twelve weeks of each and presto: no difference in the two groups. Both got better and have markedly improved insulin scores, glucose sensitive, etc. That was nifty.

He liked that idea so much, he tried it out with even a shorter time frame of exercise. He recruited inactive young adults to do 20-second bike "sprint snacks" in which they pedaled as fast as they could. Repeat three times a day. Just 20 seconds. After six weeks, their cardiorespiratory fitness improved by 9, about the same as the 13% increase the control group got by doing the same sprints for 10-minute cycling sessions. That was just published last week in the European Jr of Applies Physiology.. The exercise snack was born

This builds on another study Gabala published in Medicine & Science in Sports & Exercise found that sedentary and untrained but otherwise healthy women improved their fitness by doing just 20 seconds of vigorous stair climbing three times a day for three weeks. Triglycerides, insulin sensitivity all got better. He's been on this streak for a while.

That's three studies that all show the same thing. Tiny bits of exercise improve your fitness. We are just asking for 20 seconds. Three times a day. Stairs will do. What's happening? In the first twenty seconds, you don't even breath harder and you are actually running on lactate from burning local glucose. Your breathing is still just starting to increase. You make a teeny, tiny amount of acid making lactate around your muscleswith that 20 second burst. And that makes your muscles grow bigger, your ability to keep sugar lower gets better, your lipids look better, your insulin level gets lower because you become more insulin sensitive. All good.

www.What will Work for me. I have a wooden cube in my office to test fitness. It's a high step to do. But there it is. I tried it for 20 seconds right after seeing this research. I like it. Felt good. Didn't get sweaty. I'm going to do more. Want a cube for yourself? Made of nice hard butcher block. I have a carpenter if you call the office. Custom made. Exercise snack, almost comparable to sweat. Now, with the pandemic, I've been biking a lot. I don't go very hard or very fast. Good joggers occasionally over-take us. But most of our routes have little hills that take 20-30 seconds to overcome. Biking three times a week and three little hills, no wonder I feel in better shape.

References: PLOS One, Med Sci Sports Exercise, Bioscience Horizons, McMaster University,

Pop Quiz

1. To get the benefits of exercise, you have to go at least 20 minutes and get your heart rate up....yes or no? Answer: No, go back and read the above articles. You get about 70 % of the same effect with tiny little bursts of peak exercise.

2. Can you name a simple equivalent that women can easily do? Answer: Sure, just two flights of stairs. Or get a block of wood or a step and do some stair stepping.

3. How many times a day do I need to do this? Answer: Come on, if you didn't get that, go back and read. 3

4. What might this be kicking off that induces the beneficial effect. Answer: you run off lactate in the first 30 seconds of exercise. That lowers your muscle pH and kicks off a tiny bit of stress.

5. For the 5 million years we were hunter-gatherers, what might this be the equivalent of? Answer: Scamper up a tree to escape the hyena, dodge the lion, capture the springbok, get out of the rain.....we are suited to put out little bursts of energy to get something we really want. That does not include a race to the fridge.

Bicarb and Ketone Esters Help You Run Marathons

Bicarb and Ketone Esters Help You Run Marathons

Or any rigorous sports activity. Do you want to get sweaty and get the full strength out of your muscles? Going for a 25-mile bike ride? Swimming a mile? Suiting up to play high-level tennis? Football? Any sport! Take some ketones and some bicarb! Alka-Seltzer Gold will do it. A couple of potassium citrate capsules will do it too! Bicarb? Why? This is totally cool and explains some very interesting observations.

It all starts with ketone esters being used in sports. Ketones, the breakdown products of fats, and what you naturally make when you access your fat stores, are actually more energy-dense than carbs. And they get into you about 10% faster. That makes the use of ketones explosively popular in high-energy sports....(chess, maybe not so much) after Cox and his group showed, in 2016, that ketone esters burn energy more efficiently and conserve glucose in muscle.

Hence, if you want to wear the yellow jersey in the Tour de France, you better be using ketone esters. And then there is the contrary evidence with studies suggesting that ketone supplementation may not be all that it's hyped up to be. So, the use of ketone esters isn't completely resolved but has opened a fascinating door to how your energy systems work. (Nice review by Harvey).

This has appeared to be a paradox because it has been thought that you only access ketones when you have exhausted your glycogen stores. And you don't bounce back and forth easily between "carb mode" and "ketone mode". With insulin around you are automatically in carb mode and your fat cells won't let you have any fat to break down into ketones. How does this "bio-hack" work? What is the clever metabolic trick that's going on? Not every exercise physiologist thinks ketones are what they are cracked up to be....despite the Tour de France.

So, accept that pure ketones aren't by themselves a great help in intense exercise. Why? Probably because they are slightly acidic and cause subtle shifts in cellular potassium, glucose transport, blood pH, etc resulting in no net gain. But, add a touch of bicarb, enough to raise your pH that 0.2 range that the ketones lower, and voila, 5% better exercise performance. Five percent doesn't sound like much, but at high-level sports decided by 0.01 seconds, it's everything.

It makes sense. We evolved eating a primarily alkaline diet, based mostly on vegetables and plants though certainly happy to get animal when we could. As we have become wealthier, we have chosen more acid-producing animal-based foods. Our core metabolism and excretion mechanisms are preferentially based on an alkaline basis. We can repair the loss of muscle mass in elderly by encouraging more vegetables and fruits (that is code for more alkaline foods).

www.What will Work for me. I keep trying to move my calorie choices to whole plants. Sugar and white flour are substantial adversaries, as just about everything in our society provides processed, grain-based products. Stick with it. I can take potassium citrate for my bones. Perhaps it's for my muscles too. And then when I do a bike ride, I'm getting 5% better performance. Woo hoo.

References: Med Sci Sport Med, Cell Metabolism, Cycling Magazine, Sports Med, Nutrients, APPS J., Dr. Seeds,

Pop Quiz

1. What are the fuels we use for exercise? Answer: (Not fair, you didn't cover this). In the first 30 seconds when we are escaping from a lion, we burn lactate. In longer exercise, as our breathing and oxygen catch up with our exercise, we switch to carbs. But we only have 1500 calories of glycogen in us and a marathon burns some 2500 plus calories. That has to switch to fat-burning, hence ketones.

2. What is a ketone? Answer: It is a four-carbon fatty acid made in your liver as it chops up fat.

3. What is a ketone ester? Answer: It is the combination of two ketone molecules bound together in a unique oxygen connection called an "ester" bond. (Curiously, it gets into your blood and mitochondria much faster.)

4. What's another way to get ketones? Answer: Easy. Don't eat for 12 hours. The switch happens automatically, but slowly. By 16 hours, there they are. You can measure them yourself by buying a ketone meter. You will be at 0.4 in 16 hours. If you stick with that and do a fast-mimicking diet for 5 days, you will be above 3.0. If you do a 10-day water fast, you will be at 7.0

5. What else is bicarb good for? Answer: There is abundant evidence that being a little akaline will repair your bones. You can research this yourself by searching the net for potassium citrate and osteoporosis. Bones, muscles, exercise.....our bodies like that.

Berberine and Your Peroxisomes

Berberine and Your Peroxisomes

It was an innocent question. "Should I still be taking berberine for my diabetes?" Berberine has been used for some 3,000 years in India, China, Assyria....for a whole variety of conditions. It is no mild drug, and certainly has a whole host of beneficial effects for diabetes. Now, I had a client who had wanted to lose weight years ago and had been taking an over-the-counter form of berberine for years. There is clearly benefit for diabetics to use berberine. It has a beneficial effect on fatty liver, cholesterol, glucose levels. So, "Yes, keep taking it."  

But wait! There's is so much more. Cholesterol levels are all about peroxisome function and right now, we are consumed by a pandemic of COVID-19. The folks most at risk for COVID-19 are diabetics. There must be an overlap. And indeed, there is. In fact, this thread is stunning. It gets right to the central nugget of cell metabolism. Follow this thread and enjoy the ride! Maybe you will protect yourself a little from COVID!

First of all, for a virus to get into a cell, it has to attach to something, and then fuse with the membrane of the cell. Plasmalogens are the lipids that have the ability to "shape-shift", allowing a membrane to fuse. Plasmalogens are made in the peroxisomes, adjacent to mitochondria and often attached to the outer membrane of the cell. One of the key features of diabetes is plasmalogen dysfunction, resulting in high blood cholesterol.

Just to remind you what a peroxisome is. It is the organelle in the cell that is the mitochondria's partner. It chops up fats and feeds the pieces into the mitochondria to generate energy. It duplicates in partnership with the mitochondria, and indeed, is passed onto subsequent cells when a cell divides, much like mitochondria. It gets most of its proteins from the nucleus of the cell but otherwise acts like an independent little body, doing its own thing. And it makes plasmalogens, those most precious of lipids that play a pivotal in many diseases of aging. In fact, low plasmalogens predict heart disease better than cholesterol. They predict death better than any other single marker and their repair and replenishment might be the single most beneficial health function we can do in our "middle years".

So what is the berberine connection? Aha! Berberine is a potent PPAR agonist. PPAR? Sounds like Greek. PPAR is Perixosome Proliferator-Activated Receptor. Berberine turns on the proliferation of peroxisomes. Ah! And AMPK. That's the signal that Metformin turns on....that activates your peroxisomes. Berberine activates AMPK too.

So, berberine is no shrinking violet. We have a superhero supplement here that turns on all the most basic mechanisms in our bodies. Peroxisome function plays a spooky role in COVID, raising the specter that it might be beneficial as a strategy, but that hasn't been studied or proven. But healthy plasmalogens come from healthy peroxisomes. And healthy peroxisomes are stimulated by berberine.

www.What will Work for Me? A better strategy than berberine to fix your peroxisomes is actually ketosis....intermittent fasting. Skip breakfast and exercise instead. You will burn up all your stored glycogen and then nudge your body into ketosis. That is the best signal to make more and healthier peroxisomes. And that is the better strategy to fix your diabetes. Ultimately, weight loss and blood glucose control come from those strategies.....and those strategies come from avoiding processed foods.

References: Frontiers Pharm, Front BioSci., Biochem Pharmacol., J Cell Sci, Trends in Endocrinology, Biochem Biophys Acta, Trends Microbiol., DNA Cell Biology, Diabetes, Cell Host and Microbe, J Clinical Invest., Eur J of Pharm.,Innate Immunity, Frontiers in Physiology,

Pop Quiz

1. What is Berberine? Answer: An easily purchased supplement with very impressive effects on lipids and blood glucose for those with borderline diabetes. It has been used in traditional medicine from Babylon to Beijing to Mumbai for over 3,000 years.

2. How come my doctor never prescribes it? Answer: Too cheap, not advertised, and not regulated. You get almost the same thing with all the other PPAR agonists like Actos (pioglitazone).

3. What is the benefit of berberine? Answer: it stimulates your peroxisomes to be more efficient and manage cholesterol better.

4. What else do healthy peroxisomes do? Answer: Make the most important lipids in your body, plasmalogens.

5. So, you might argue that berberine is the first "plasmalogen" drug? Answer: Yup. Been around for 3,000 years. Now we know why it works.

Your Brain and Lithium

Lithium and Your Brain

You probably knew that lithium has been around for a long time as a treatment for manic-depressive disease. What you may not have known is that psychiatrists observing patients on long-term lithium have noted that they appear to live longer, and have less cognitive decline. And studies in Japan and Texas have found that the level of lithium in drinking water correlates with negative mortality. Aka: living longer.

If you want to get to the heart of it, lithium inhibits one enzyme called GSK-3 which you might consider your age acceleration enzyme. GSK-3 stands for glycogen syththase kinase-3. Its action is to add a phosphate group onto threonine and/or serine amino acids of the enzyme glycogen synthase, thus lowering your storage of glucose as glycogen and raising your blood glucose. Inhibition of GSK-3 then does the opposite. You lower your blood glucose. You wouldn't be surprised to know that GSK-3 plays a big role in diabetes, but curiously, also in Alzheimer's. But that's not all, you also modulate apoptosis with GSK-3, or natural cell death, innate immune responses. And lithium slows that modulation down, helping cells live longer, lowering chronic inflammation. These are good things.

Living longer isn't that important if your brain isn't working, so brain health is important. And lithium appears to do that. It increases the activity of BDNF, the peptide that instructs your neurons to connect with each other. And it decreases the accumulation of amyloid, one of the cardinal features of Alzheimer's. 

And heck, this isn't all that new. Lithia Springs in Georgia, a site with high lithium in the water was visited by Mark Twain and 4 US Presidents. All long before PubMed and Randomized Trials. They just noted that they felt better, thought better, and appeared to live longer. Medicine the old-fashioned way, by the seat of their pants.

Read the Life Extension article.

www.What will Work for me. I've been taking lithium on and off for years when I've seen earlier posts along these lines. I think I'm resolving that 1000 mcg a day might be on my long-term list. So, not just for my car or my deck blower, but for my brain as well.

References: Life Extension Magazine, Wikipedia, Amer J Psychiatry, Canadian Jr of Psychiatry, Appl Phys Nutr Metab.,International Jr Mol Sci,

Pop Quiz

1. What is lithium? Answer: a very light metal that has some curious properties to it. It is great for rechargeable batteries, and as such may help us slow down our climate change issues. But maybe even better, it's good for your brain.

2. How does lithium work on my brain? Answer: It inhibits GSK-3, an enzyme that is at the nexus of glucose metabolism.

3. Does lithium have any toxicity. Answer: At the low doses we are talking about, no.  Clearly, you can take too much. Folks with mania need their levels to be checked to make sure they don't get too high. There are some concerns about kidney function when taken at too high a dose.

4. How long is it safe to take lithium? Answer: There are many thousands of folks who have taken it for their entire lives.

5. What happens if it is naturally in the water in your town? Answer: you can mine it for battery use, or you can market it to people to come to the healing waters and make a spa.

5-amino-1mq, The Ultimate Weight Loss Drug

5-Amino 1 MQ - The Real Key to Weight Loss

Have you noticed that as you get a bit older, you have put on a few pounds around your middle? Can't get rid of it? You have hit on the nexus of middle age and weight gain. The teeter-totter of energy-burning versus energy storage has started to tilt the way you don't want, to uncontrolled storage. Details? Well, for one, we don't make as much NAD, starving our sirtuins and dismantling our epigenome. But we have covered that in the past. That's why we take metformin and NAD.

To understand what's happening in this context, you first have to learn some jargon for human physiology. There is an enzyme called NNMT: nicotinamide N-methyltransferase. It is the fulcrum in this discussion. It is also one of the key enzymes which modulate energy balance. In biological chemistry terms, it regulates nicotinamide and S-(5′-adenosyl)-L-methionine within a couple of intracellular pathways that deal with cellular energy regulation. Basically, it ships off NAD into breakdown products. What happens when this cellular energy balance becomes unbalanced? It starts the domino effect; one thing leads to the next. In aging humans, a little extra weight can lead to a little extra NNMT enzyme which leads to worse fat cell metabolism which leads to increased fat cell energy storage. That's called weight gain. On a more sinister note, it sets you up for diabetes, heart disease, stroke, cancer, dementia.... What happens if we reverse that by blocking NNMT? We tilt the teeter-totter back in the right direction. First, fat cell metabolism is rebalanced. Rebalanced means fat cells won’t grow. Finally, decreased NNMT means we lose weight because the fat cells shrink. Healthy aging, in part, is weight control.

What is equally interesting is how it was discovered. Researchers at the U of Texas, trying to find a key to helping folks lose weight, used "structure-guided design and binding calculations" to find a whole raft of molecules that would inhibit NNMT. That means looking at an enzyme with a supercomputer to see the shape of its active docking station. Then, make a chemical that will fit into that docking station in just the right way. Instead of having to trial and error millions of compounds, you get right to the heart of it by having to examine only those that would "fit". 5-amino 1 MQ popped out as having the highest IC50, the ability to inhibit the enzymes 50% with the lowest dose. And with that discovery, the blogosphere of body shapers was off to the races. "Miracle weight loss."

And just what energy increase happens? Well, by inhibiting the enzyme, you remake your vital internal energy molecule NAD instead of the molecule falling apart and being repurposed for other uses. NAD is critical to providing energy to all your SIRT proteins, the little fellas tasked with keeping your epigenome maintained and your DNA healthy. Raising your internal NAD is one of the Holy Grails of anti-aging research. NAD is the only source of energy for the SIRT system, so this inhibition and recycling by 5 Amino 1 MQ is a huge "Two-fer", two wins with one effect.

Is this drug safe? How do we know? It's only been discovered 3 years ago in mice. There are no human studies. But just spend a minute on the internet and you can find any number of blogs saying it is the best weight loss drug around. That's why I include the blog by Jay Campbell as a reference. But there are many others. It has shown no toxicity to date that I could find, but this is pretty early in its discovery curve. There are known risks to being overweight too.

www.What will Work for me. I am utterly intrigued. I know of one person who has taken it and improved their weight and A1c rather dramatically in just a few months. I find no sign of toxicity. This is a topic we need to keep watching with great interest. The NAD side of the equation captures my fancy as much as the weight loss side. If you are interested, call us up.

References: Biochem Pharmacol, Jay Campbell, Dr Lauren Bramley,

Pop Quiz

1. What is 5-amino-1MQ? Answer: a tiny molecule that blocks some key enzymes that reverse the age-related decline in NAD metabolism that shifts energy into storage.

2. Will my doctor prescribe it for me? Answer: Are you kidding? This has had no human trials of any kind yet.

3. Have humans used it without apparent trouble? Answer: Google it and read the blogosphere's answer to that. There are many claims out there that it is the best thing since sliced bread.

4. What's the alternative if I can't lose weight? Answer: That has risks to it, as we all know. Healthy aging can be, in part, equated with healthy weight maintenance.

5. Do you want to know more? Answer: Don't we all. Pubmed lists ZERO references to it. That will change.

Metabolic Problems of Processed Foods 6 Inflammation

Metabolic Problems of Processed Food #6 Inflammation

About 70% of the volume of our immune system is around the gut. Its surface area is some 200 sq meters, much greater than our skin. Starting with the tonsils, there are millions of tiny white cell groupings in the gut that contain immune cells, watching to see what's coming down. The surface lining of our gut is only one cell layer thick, and those cells are maintained with only a few tight junctions. If I told you that wheat creates problems with "leaky gut" because of the production of zonulin, you might take pause. It should be no wonder that modern, processed foods are prone to increased inflammation. Many, many foods contain wheat.

But it's not just leaky gut that makes processed foods deadly. With over 60% of American foods containing extra sugar, we have way too much fructose coming into our systems. Fructose is a curious actor in your liver. We have no means of controlling its ingress into the liver cell, so it floods in. And it stimulates the production of palmitate or palmitic acid. Now, we have another inflammatory agent that is strongly correlated with many chronic diseases.

Now, add in the loss of fiber in processed foods and you are beginning to see a whole complex of problems. Fiber is what gets broken down and processed into beta-hydroxybutyrate (BHB) which is food for the enterocytes. BHB is also incredibly anti-inflammatory. The cross-talk between your biome living in your gut and your immune system is a whole course in biology. With inadequate fiber, your risk of many chronic diseases skyrockets. Processed food, almost by definition, is lacking in fiber.

We can't touch on these topics too long, because we haven't even gotten to artificial sweeteners, preservatives, residual pesticides and glyphosate, colorings, and antibiotics and you can discern the complexity of the topic. With leaky gut, you start getting LPS particles in your blood. They are inflammatory. With abnormal sweeteners, you start getting aberrant insulin secretion and larger, insulin-resistant fat cells. They are inflammatory.

Leave it at that. Processed foods just make for inflammation.

www.What will Work for me. We can measure inflammation with a CRP test, but that misses a lot. You can presume inflammation if you have chronic arthritis, high blood pressure, a bigger tummy, chronic fatigue, a whole raft of symptoms. Whole foods, you make from scratch, without added sugar is what human being needs. Feed the gut, protect the liver. More fiber, less sugar. That's Lustig's condensation of the wisdom in his book.

References:PMC, Frontiers in Immunology, Cell Mol Life Sci,

Pop Quiz

1. Processed food causes inflammation through what mechanisms?                                  Answer: too much sugar, no fiber, wheat, just to name a few.

2. Wheat? Your kidding? How?                                                   Answer: Read the article by Fasano in PMC. And you can measure the antibodies if you want to order the blood test from Cyrex labs.Order their "array" #2 and #3. In my experience, some 50% of folks have antibodies to wheat and leaky gut. You are lucky if you don't. It's not, emphatically not, celiac disease. It's leaky gut, and that's something entirely different, except that it's still caused by wheat.

3. Fructose appears to be a special villain. Is it ok in fruit?                                                  Answer: Yes, in most fruits, fructose is in the range of 6% and comes with a bunch of fiber. In processed foods, say, apple juice, we have removed the fiber and increased the concentration of fructose by so doing. And you can drink a glass in 3 seconds. An apple takes 3 minutes. Some as simple as apple juice is "processed". OJ is maybe even worse because everyone believes it should be part of your breakfast.

4. And what does fructose do metabolically that makes inflammation?                            Answer: It pushes the production of the sugar palmitate that wreaks all sorts of havoc. There is tons of evidence out there that the consumption of fructose will cause metabolic syndrome in just a few weeks if you eat enough.

5. Ok, what is the easiest, most effective way to cut down on fructose?                            Answer: Don't drink it. Get rid of all sugar-laden drinks.

Metabolic Problems of Processed Foods 5 Membrane Integrity

Metabolic Problem of Processed Food Number 5 Membrane Integrity

When I read Lustig's new book, Metabolical, and he listed his eight problems of processed foods, I was stunned by his listing "Membrane Integrity" as #5 on his list. He is the first major author that I have seen to list this. Hurray! It should be on the list, maybe even higher up. Now, he doesn't go into the detail of it all but he gives a decent start. Most importantly, it's on the list. This is the fundamental, main reason, processed food is killing you and me. Let's give the details.

It starts with "membrane science". This is the field of medicine that Goodenowe is introducing in his discovery that plasmalogen deficiency is the prodrome for most of our modern illnesses. How do these two approaches converge?

Every cell in your body is encased in a membrane of lipid fats that keep the outside world out and the inside world in. That's what giant soap bubbles are, a huge container composed of a lipid bilayer - two layers of fatty acids. In your cells, you have many embedded proteins recessed in that bilayer that are the passageways or gatekeepers for different nutrients going in or out. The sodium-potassium pump is the most prominent one. It uses up some 10% of your energy just keeping sodium outside the cell higher than potassium and potassium inside the cell higher than sodium. That simple gradient drives most other "pumps" that keep different nutrients coming and going. You don't just have membranes around the cell, you have them inside the cells as well. There is a special membrane separating the nucleus with its DNA from the rest of the cell. You have the endoplasmic reticulum, where proteins are manufactured, folded, sorted, packaged, and shipped out. You have the mitochondria, making your body's weight in ATP daily. You have the peroxisomes, chopping up fat, making plasmalogens, neutralizing peroxide. On and on.

Membranes need a certain level of fluidity. Here comes the rub. All of your membrane lipids are attached to various long-chain fatty acids which give them different qualities. Adding double bonds form a 30-degree bend in an otherwise straight molecule. Olive oil has one double bond. Fish oil, DHA, has 5 double bonds. Each additional double bond makes for more fluidity. DHA is incredibly fluid. It plays a fundamental role in plasmalogens. Those jutting out internal lipids like DHA play a huge role in providing a scaffolding for your embedded proteins to hang on to. Gaining or losing a double bond is no trivial matter. Throwing in transfats becomes a problem, if not a catastrophe. But those double bonds have another more serious vulnerability. Double bonds are very vulnerable to oxidation. That 30-degree bend can be "flipped" into a trans configuration making the molecule straight, more rigid, less flexible.

Here's the nugget of it all. The oxidizing propensity of processed foods trashes our membranes, making them less flexible.  The trans fats common in processed foods compounds the trouble. We overwhelm our ability to neutralize the excess peroxide that is created by too many calories all at once. Plasmalogens get used up trying to neutralize the excess oxidizing capacity. Our membranes get more rigid.

Many problems stem from that shift to rigidity. In our mitochondria, we start exporting more substrate for cancer cells to make their energy supply. In our arteries, we start accumulating plaque. In our brains, we stop being able to ship neurotransmitters and start stealing choline from our depleted plasmalogens.

Clarity into these details is gradually emerging in the bench science world. Lustig is the first to bring to the lay-person marketplace of ideas the danger caused by our processed foods. It's all about the function of our lipid membranes. Processed foods alter the proper mix and throw in wild cards. It's a mess.

The problem is that processed food has emerged because it is what we like. Our food manufacturers make what they make because we buy more of it. Sweet tastes good. Fast food is easy, on the way home. We don't have to cook. It comes in a convenient package. Our burdened membranes are crying for relief.

www.What will Work for me. I'm on vacation in Door County. Every second establishment is selling ice cream. It's cherry season and the trees are loaded with cherries. There are no kids from eastern Europe to provide service jobs in the restaurants and as best we can tell, very few farm workers to harvest the cherries. Our favorite "cherry" place has 900 forms of cherries with sugar and flour added. We were biking on Washington Island and stopped at the Jackson Harbour restaurant. The cherry pie was delicious. Oh well.

References: Lustig's new book Metabolical, Biochem Biophys Acta, Biomed Research, Chem, Medical News Today,

Pop Quiz

1. Every one of your 30 trillion cells in your body is delineated in its boundary with what?         Answer: A lipid membrane. Just like a soap bubble.

2. What makes a healthy membrane?                     Answer. It has to be fluid, meaning it allows proteins embedded in it to move around easily and quickly. (It also has to be strong. That's where cholesterol comes in. Cholesterol makes it more rigid and more sturdy. That's good too, in the right circumstances.). And it has to be made with the right lipids. Fish oil, DHA, is a key ingredient.

3. What makes more fluidity in membranes?                       Answer: the quantity of plasmalogens with their DHA (fish oil) molecule attached to them.

4. What is the core problem with processed food and membranes.                   Answer: Aha! The nugget. Processed food makes for too much oxidation. Too much peroxide. Damaged fatty acids making for diminished plasmalogens and more rigid membranes. But hang on to that thought. This is an emerging science and more information is likely to come out to refine the dangers of "the wrong fats" in our membranes.

5. What is the number one method to cut down on oxidation?                            Answer. Less sugar and less rapidly digested white carbohydrates. Think whole foods you have to actually chew to digest.

The Metabolic Problems of Processed Food 4 Insulin Resistance

Metabolic Problems of Processed Food #4: Insulin Resistance

Adult-onset diabetes is high blood glucose AND HIGH insulin. That's right. High insulin because the core defect in the cell on the path to diabetes is resistance to insulin. That means it takes a higher level of insulin to push glucose into the cell. Insulin is there, it's just that the cellular receptors are acting like it isn't.

Cardinal to this resistance is fatty liver, bigger tummy fat, usually high CRP and other markers of inflammation, higher levels of endotoxin. We can measure those things and see them. If your doctor will measure it for you, you want a level of insulin below 5. That's the level someone is at when they are optimally sensitive and their cells are open to its effects. Now, the "normal" range of insulin in many labs is listed as 2.5 to 25. That is because the lab collects 1,000 samples, discards the top 5% and bottom 5%, and calls everything in between "normal". It's not normal. It's what the population of Wisconsin has. Calling it normal suggests the population is normal. We know it's not. We do know that fully 50% of Americans have fatty liver and metabolic syndrome. They aren't normal. They have insulin resistance. "Healthy" insulin is below 5, when your glucose level is below 85, and your A1c is below 5.5. That is what you want to be.

What's going on that makes you insulin resistant? It's actually so complex and so multifactorial that there is intense debate as to the full cause. Fructose, added to 68% of American foods, might be the central lead actor. When you eat any fructose, you have no inhibitory controlling enzymes that limit how fast it floods into your liver. That might be the key tipping point. But not the only one! We do know that there are multiple inhibitory proteins that make you more insulin resistant. PC-1 is a prime candidate. We also know that fatty liver is clearly a player. Just look at what a fatty liver looks like under an electron microscope. If your liver cell is chock full of fatty globules, the fatty globules basically fill up the cell with "dead space" around which the cell has to signal to itself and manufacture the proteins it is tasked with making and digest the food it is tasked with digesting. That's a hard one to prove, but that's where multiple authors appear to be heading in their attempts at proof.

And the same hypothesis would work with your fat cell. As you put on weight, you don't make more fat cells. The ones you have just get bigger. Again, their central space is filled with one, huge, obstructing globule of fat.

There are dozens of inflammatory modulators, molecular signals, chemokines and hormones all of which have impacts, but the action can be best understood with the following explanation. Your fat cells are responsive to insulin when they are small and have only a tiny amount of intracellular fat. As you get fatter, your fat cells become larger and less responsive. You need more insulin. Bigger cells, higher insulin. Again, bigger fat cells, even higher insulin until finally, you can't get your fat cells to respond, even with the insulin level of 45...55....65?. And 45 isn't sustainable. Your pancreas acts as though it only has a fixed amount of insulin to produce and secrete in a lifetime. If you burn up your supply, you eventually are calling for your pancreas to make 50 units, and it can only make 45. Your blood glucose rises to 140. But your pancreas is pooping out. It can only then make 40. Your blood glucose rises to 170. You can then only make 30. Your glucose is 200. ...and on and on. Your doctor can always prescribe insulin shots, and give you a zillion units of insulin. We can finally whip those poor, beleaguered fat cells into submission. But what we can't fix is the damage caused by that high insulin, which is inevitable kidney damage and frontal lobe brain damage.

How does processed food make all that happen? Easy. It's front and center. Refined grains and sugars, the epitome of processing, deliver calories to your liver so fast, it just plain can't keep up. Fructose is the arch-enemy in that regard, as it rushes into your liver with no controls at all. You begin to get fatty liver with one good sugared soda. Processed food is the delivery method of choice to create insulin resistance because it comes with lots of little microtoxins that add to the mix: trans fats, pesticide residues, artificial sweeteners, and just too many calories, too fast.  Too many calories, too fast.  No fiber to modulate your immune response in your gut.  That whole field of medicine is just awakening but Lustig puts it front and center with his motto: "Protect the liver, feed the gut."

How do you fix it? Opposite of processed foods. Whole foods, plain and simple. Fasting for 18 hours a day and compressing your calories draws down on all the stored fats in your liver. Losing weight by fasting, whole foods, avoiding white carbs and sugar, sugar, sugar is the only real cure. Read labels. If added sugar is on the label, you can't have it. You can prove it to yourself by getting a ketone meter and measuring your blood glucose and ketones while you do a 5 days fast mimicking diet (800 calories of vegetables only, 50% fat, very low protein). Your glucose will drop to the 70-80 range. Just 5 days will do it. Keep up the 800 calories and your weight will come off you.

www.What Will Work for me. I do a 5-day fast-mimicking diet every month. I've been doing it for 3 years now and it doesn't feel so hard anymore. I measure my glucose and ketones each time. My insulin, which normally runs 7-10 (not quite what I want it to be, but below the average for men of 14) will drop to 2 on day 5. Last month my glucose hit 59 and my ketones got to 5.1 on day 5. A personal record. I have the genes within me to be insulin resistant and diabetic if I would succumb to ice cream, cookies, and bagels. It's harder to eat whole foods. But that's the journey I'm on. Join me. It's the only means of beating insulin resistance.

References: Metabolical by Lustig, Nature, Diabetes, WebMD, Nutrients, NYT,

Pop Quiz

1. Adult-onset diabetes has very low insulin levels. T or F. Answer: Trick question. In the beginning, very high. Anything over 15 is the sine qua non for Type II diabetes. But as your pancreas burns out, it starts to fall. Eventually, it burns out completely in some folks and they become essentially insulin-dependent.

2. What food group has no effect on insulin? Answer; Fats. Again, a trick question because we didn't go over it in the column above. But that means you can eat fats and not bump your insulin.

3. The only food that stimulates insulin is sugar. T or F. Answer: False. Any form of white carbohydrate, processed so that it is digested rapidly, will boost blood glucose and thereby insulin. But more unknown is that large amounts of animal protein also are potent stimulants to insulin release. The simplest form of "processing" that causes trouble is grinding up grains to first remove their fiber coat that slows down digestion, but then to pulverize them into talcum powder dust that allows them to be digested and converted to pure glucose very quickly. Think whole grains of oats turned into little small circles, stars or animals and coated with sugar.

4. Where do green vegetables come in in regard to insulin? Answer: Aha! Another trick question. The bacteria in your gut digest their cell walls and make beta-hydroxybutyrate, a short-chain fatty acid from green vegetables. BHB is all the craze right now. It's the ketone you measure in your blood. You don't touch insulin when you have BHB on board as a supplement. So green vegetables don't turn on insulin and allow BHB to stay around - meaning your fat cells and all the calories in them are available for use.

5. What is the single worst food you can eat that makes you develop insulin resistance the fastest? Answer: fructose in liquid form.