Melatonin Turns Down Your Stress Response

Melatonin Turns Down Your Stress Hormone Response


We know melatonin is our sleep hormone. And we know it plays a role in changing the Warburg metabolism that favors cancer through its effect on the PDC complex. But did you know that it also plays a big role in changing your metabolism of catecholamines, your stress response hormones? That is an interesting story.


Where that inhibition takes place is its own curious biology. Our adrenal glands make cortisol and catecholamines, epinephrine, and norepinephrine. We need cortisol to mobilize glucose and have an alert, awake brain, so it has also been included in the "stress response" portfolio. Cortisol also has a powerful diurnal pattern surging some 5-10 fold between 3 am and 7 am. That is the opposite of melatonin which surges with the onset of darkness and the dropping of cortisol levels.

How does melatonin turn down the production of catecholamines? Clearly we see melatonin go up as cortisol goes down. This is where the complexity and interwoven nature of our biology is so interesting. A whole family of peptide hormones called bone morphogenetic proteins, discovered around bone growth and actually being used clinically to help repair long bone fractures and recalcitrant dental problems, appear to be active in the core of the adrenal gland, where you make your stress hormones. The investigators in this study measured the messenger RNA of the rate limiting step of catecholamine synthesis, tyrosine hydroxylase and found that melatonin turned down its production. A bone-modulating protein, collaborating with melatonin to alter the production of catecholamines! Wakes you up in the morning. Puts you to bed at night.

The technology to elucidate all this intricate web is the same tool molecular biologists are using to examine COVID's effects on our immune system and that Shoemaker is using to examine the downregulation of mRNA in mitochondria secondary to CIRS and mold exposure. It's the measurement of tiny variations in messenger RNA, being sent around the body in the blood to activate and produce new protein. The enzyme, Polymerase Chain Reaction, can copy DNA and RNA and can make millions of copies. When you do that, you can amplify and study it and demonstrate increases and decreases in messaging that is happening in the human cell. And hence we can learn the subtle shifts and machinations of our own biology, and the intertwining effects of hormones.


www.What will Work for me. I'm taking 20 mg of melatonin at bedtime now and feel like I sleep pretty well. Could I be a bit more mellow from doing so? This paper suggests that my stress hormones are all downregulated by my melatonin dose. In the middle of the night, when monkey chatter wants to take over my brain, that effect may be what keeps me asleep. We do know that our production of melatonin has dropped by some 70% from childhood by the time we reach 60-70 years of age. So, I'm going to keep taking it.


References: Jr Ster Biochem Mol Bio, Wikipedia


Pop Quiz

1. Melatonin is known to reduce catecholamine synthesis. What are catecholamines?                       Answer: Your fight-or-flight hormones: epinephrine and norepinephrine.

2. How does it do that?                         Answer: Very complex interaction with BMP, bone modulating protein in the core of the adrenal gland. For a deep rabbit hole experience, read the Wikipedia entry on bone morphogenetic protein.

3. Does this make sense to you? If you are very angry, or frightened, common feelings with high catecholamine synthesis, can you sleep?                        Answer: Ah. No.

4. How did bone morphogenetic protein get involved in all this?                          Answer: This is just another example of the incredible, nuanced web of hormonal mechanisms we have yet to fully appreciate. We can't explain it. We can observe it.

5. I should take more melatonin?                     Answer: Probably. No harm, no foul.


Melatonin Turns off Your Cancer Switch

Melatonin Turns off the Cancer Switch In Your Cells


In 1931, Otto Warburg got the Nobel Prize in Medicine for elucidating cellular respiration, and how and where cells burn glucose. He noted that cancer cells could survive without oxygen, provided they had enough glucose. All cells have the capability of chopping glucose into two halves without using any oxygen and thereby getting two ATP molecules. For many cancer cells, that is their principal source of energy, making them dependent on other nutrients. Cancer cells are very inefficient and have to parasitize their hosts, spreading like crazy. Indeed, Thomas Seyfried, at Yale, has made a CT scanner of electron microscopes and demonstrated that mitochondria are broken in all cancers and cannot digest fat and ketones, proving Warburg's hypothesis.

Efficient cellular metabolism needs more energy than that. Glucose needs to be turned into pyruvate, then shuttled into the Krebs cycle inside mitochondria where one molecule of glucose can make 38 ATP instead of the measly 2. That takes oxygen and healthy mitochondria. That represents a 19-fold increase in energy from a single glucose. That's efficient and the basis of all cellular biology.

In a healthy human cell, glucose is made into two pyruvate molecules which are then transported into mitochondria and irreversibly converted to acetyl coenzyme A by pyruvate dehydrogenase complex (PDC). That is the nexus of metabolism. Making Acetyl CoA is the penultimate step before the entry into the mitochondria where 36 ATP follows. Turning on and off the PDC complex is akin to the circuit board on a computer or your fuse box to your home. Central, first, and important.


Focus on that PDC enzyme. In cancer cells, the PDC enzyme gets inhibited, shifting the cell into "Warburg" metabolism. You don't need to know all that nerdy stuff but it has some advantages for cancer cells because a pentose phosphate pathway makes more DNA molecules for rapidly growing cancer cells. A healthy cell wants to "dis-inhibit" the PDC complex, shifting metabolism back to healthy ATP production, making energy, and closing down the pentose phosphate shunt. And that's what melatonin does. Signaling molecules that "dis-inhibit" the PDC complex usually do it by inhibiting hypoxia-inducible factor-1α which then leads to PDC disinhibition allowing for the intramitochondrial conversion of pyruvate into acetyl coenzyme A. There are several levers of control that wax and wane inside the cell and melatonin is one of the most prominent. In summary, melatonin swings the cell away from the cancer model and towards the healthy cellular model.

This might explain why melatonin is being found to be beneficial in the prevention of many diseases. Everything from metabolic syndrome to COVID in addition to cancer appears to be beneficially affected by melatonin.

It all starts in healthy mitochondria. And the PDC complex.


www.What will Work for me. Whew, heady physiology that comes down to a simple summary. Our melatonin levels drop dramatically as we age. It is safe and easy to buy. There are now multiple authors suggesting that 40 mg a day for cancer is reasonable, and there are more aggressive "thought-leaders" in functional medicine advocating for 200 mg a day of melatonin for anyone with active disease. I haven't found much evidence of toxicity, despite some anxious websites that quote out-of-date references.


References: Int Jr Molecular Sci, BMC, Trials, Frontiers, Oncotarget, MoleculesMDPI,


Pop Quiz

1. What is the "PDC" complex in the human cell?                               Answer: The metabolic switch the makes the last step of molecular preparation before the cascade of the mitochondria. I've likened it to your home's fuse box.

2. In cancer, what happens to the PDC complex?                        Answer: It gets inhibited, so instead of energy molecules with complicated names going into the mitochondria, they head off in directions that help cancer cells grow faster.

3. What does melatonin do to the PDC complex?                         Answer: Aha! Turns it back on. "Dis-inhibits" it.

4. You mean to suggest that higher doses of melatonin might turn cancer off?                  Answer: Yup, yup, yup.

5. If you google and look up cancer care around melatonin, what is the highest dose you might find?                 Answer: 200 mg a day is not hard to find.


Melatonin - Your Mitochondrial Protectors

Melatonin - Your Mitochondrial Protector


You likely thought of melatonin as your sleep hormone. Indeed, it is. Its secretion clearly rises with darkness and results in your feeling more drowsy. Young children appear to have the most of it, with blood levels of 150-350 picograms or so and then it gradually declines, losing about 10% per decade. That means a normal 60 year old will have 60% less melatonin.

It turns out melatonin plays a much bigger role inside the cell than in your blood. Not just inside the cell, but inside your mitochondria. That's where the vast majority of it is made and used. The pineal gland happens to have mitochondria that are a bit different than other cells. It exports melatonin to the whole body, whereas every other cell uses its own melatonin internally. What for?


This is where it gets very interesting. Your mitochondria are your energy factories. They are making the energy molecule called ATP which is the currency of energy function in your cell. Each ATP is made and remade about 10,000 times a day - and the daily production of ATP is about your body weight. Impressive! The conversion of food in the form of glucose or fat into ATP comes down to making an electrical gradient of protons across the inner membrane of mitochondria. Separating electrons from protons is a hazardous task because of the Heisenberg principle of uncertainty of quantum mechanics. We can't tell if an electron is a particle or a wave....or just where it is. Our mitochondrial proteins tasked with the burden of making energy can't hang on to them perfectly, and some get away. Some get away. The Achilles heel of cellular energy production is the escape of a few electrons that spin out and make reactive oxygen species (ROS). Those ROS's are terribly damaging. In the best of circumstances, they get rapidly neutralized and gobbled up. That's what melatonin does.

Melatonin is now being recharacterized as your mitochondrial protector par excellence. We repair our mitochondria when we sleep, and in fact, it may be why we have to sleep. Our brains are so critical to our being multicellular organisms that every creature with a nervous system has to sleep in one fashion or another. It is doing so so that the brain can be flushed out of its accumulated toxins and regenerate itself. It is notable that our brains also have more mitochondria than any other organelle (other than the female egg).


The protection process is actually a whole portfolio of integrated actions, all of which stem from and support soaking up those escaped electrons and ROSs. It sounds arcane but key to the cell coping with too much energy is the ability to inhibit the mitochondrial permeability transition pore (MPTP) thus supporting mitochondrial membrane potential (Δψ) . This gets really nerdy but inhibiting that pore helps keep your membrane potential intact so that the mitochondria keeps making energy properly. But to let off the extra steam melatonin also turns on uncoupling protein, thereby making heat instead of ATP. All to keep the flow of energy moving smoothly and efficiently. It's as though your mitochondria is the engine on a supercharged drag racer, just screaming and roaring, and melatonin is the skilled engine mechanic tweaking and nursing that engine along to peak performance without it burning out. You want your melatonin.


www.What will Work for me? The conjecture in all the current literature on melatonin is that it plays a major role in keeping our cells safe, and it declines by that dreaded, inexorable 10% per decade. I am now 7 decades down. Hmmm. My cells can't repair or regulated their mitochondria in any fashion that they used to. It gets even more interesting when we realize that cancer, a disease of aging to a large part, is a mitochondrial disease. That's next week. For now, at least take some at bedtime. I would urge you to consider at least 10 mg at bedtime. Just about every study on night workers who have horribly disrupted melatonin shows that they have more cancer. Maybe we need much, much more. That's next week.


References: Int Jr Molecular Sci, Exp GerontolScoliosis ,


Pop Quiz

1. Melatonin comes from where?                         Answer: Trick question. What's in your blood comes from your pineal gland but the majority of it is produced and used locally inside the mitochondria, inside the cell.

2. When you take melatonin at bedtime, how do you feel?                   Answer: Sleepy.

3. What happens during sleep?                     Answer: We now know that you turn on your glymphatic drainage of your brain as it squeezes down some 15% of its volume. That rinsing process is paired with melatonin secretion. Proven connections to follow.

4. What has been proven so far about mitochondria and melatonin?                        Answer: Nerdy stuff. Mitochondrial membrane potential (Δψ) maintenance and uncoupling protein activation.

5. What happens as we age to our melatonin level?                         Answer: 10% per decade down. Think that might be a problem?


Plasmalogens Can Cure a Rare Genetic Brain Disease

Plasmalogens Can Cure A Genetic Brain Disease


Ok, so RCDP is rare. Very rare. Only 2-3 children a year in all of North America and Europe. It is a genetic defect in the critical proteins that make plasmalogen precursors in your peroxisomes called RCDP2 and RCDP1,3. The resulting disease, RCDP or Rhizomelic Chondrodysplasia Punctata, has several forms. The severe form shows terrible problems within months of birth with the affected children dying by age 12. The milder form still has mental retardation and requires lifetime care. Terrible diseases. Why are they important for us to know about?

RCDP is essentially a mirror image of Alzheimer's, much accelerated. That's why.


Here is some core biology. A baby's brain is filled with wires, called axons, between cells up until about 20 weeks. Those fetal brain cells can't talk to each other until those connecting axons get insulated by oligodendrocytes. The insulation material are plasmalogens. The links, called synapses, are also 70% plasmalogen. Starting at week 20, a fetus needs huge amounts of plasmalogen fats. Mom gets a big drain on her supply of plasmalogens to provide that hungry fetus's brain. At birth, a newborn is severely plasmalogen deficient just because of the demand of the rapidly growing brain. Guess what the best source of plasmalogen lipids are? You are right! Mom's breast milk. Breast milk from humans has 10 times the plasmalogen content of cow milk. Formula has none. A baby's brain is growing at a tremendous rate for the first 6 months-2 years, which is why breastfeeding is so beneficial for infants.


That's when RCDP kicks in. Without a plasmalogen source, the baby's brain can't keep developing after birth, and even more, after weaning, RCDP infants start showing symptoms. Without plasmalogens to supply the building blocks to their neurons and axons (cells and wires in between), the affected infants descend into endless seizures and disability.


Why is this a mirror image of Alzheimer's? We now know that you can simplify Alzheimer's to the loss of plasmalogens over years resulting in the loss of synapses or links between brain cells. Our working memory is embedded in the complex web of synapses laid down over time. The human brain actually keeps accumulating total mass and volume of plasmalogen fats and synapses up until age 50. Yes, a 50-year-old brain is just about the most developed. From age 50 to 70, the average person will have lost 20% of their brain plasmalogen density. The human brain has so much redundancy and resilience that it can cover up that decline and hide it with "work-arounds". This column referenced a Yale study from this year in which cognitive function perfectly mirrors synapse density and plasmalogen density. RCDP occurs as the brain is growing and expanding and runs out of supply. Alzheimer's occurs as the brain is shrinking from the gradual loss of supply. As your plasmalogen supply declines, your synapses decline and you working memory declines.


Guess what happened just this last month to the first child suffering from RCDP treated with Prodrome GLIA! It took some 30 days before much change was seen but here is an entry from his mother's dairy on day 34. "His drooling has improved so much and he is chewing on his shirt way less (it has been a sensory thing for him). We used to need to change his shirt a couple of times per day because it was so wet. We don't change it at all anymore.". Next entry. "I will never in my life forget tonight. The joy they all felt playing together for the FIRST TIME ever. T understood cognitively how to interact and how to PLAY with his siblings".


This is the first case of RCDP that has been treated and has shown immediate repair. The genetic error of RCDP is so rare, there aren't a lot of kids to work on. But this illness is catching a brain disease right at the most vulnerable point of plasmalogen need. Alzheimer's comes much later after a mature development has occurred. Supplying the building blocks to rebuild the missing 20% of your plasmalogen supply, gives your brain the tools to start rebuilding redundancy and resilience and get back to learning and remembering.


www.What will Work for me. I'm all in. There is now increasing evidence that we can fix one disease of plasmalogen deficiency. And we now are getting more sophisticated at measuring our plasmalogen "ecosystem" with Goodenowe's test. The price of Prodrome Glia just dropped by 50% this month. Hopefully Prodrome Neuro can be produced more cheaply soon - that is supposedly the plan. A plan is in the works to start a study with autistic kids. There is some hint that may be helpful too. Wow!


References: Am J Med Gen , Neurology,


Pop Quiz


1. You can measure an infant's brain for synapse density. T or F.                                  Answer: True

2. What is the disease RCDP?                                Answer: We don't expect you to remember what the acronym stands for. Just that it is an inborn error of metabolism that can't make plasmalogens. Very, very, rare.

3. When is an infant's need for plasmalogens the greatest?                        Answer: Right at birth, when the brain is growing the fastest.

4. What are the plasmalogens used for?                              Answer: They are the building blocks to make the insulation wiring of the brains and the synapses.

5. Oral replacement of plasmalogens in the first case has now demonstrated what?                           Answer: Within a month a dramatic reduction of repetitive, dysfunctional behavior and the reinitiation of play and social interaction.


Limit Your Methionine and Live Longer

Limit Your Methionine and Live Longer


When your body codes for a new protein, it has a "start button" that signals "begin protein synthesis". After that start button, the protein construction begins by interpreting different codons of three DNA base pairs to add a new amino acid to the lengthening chain. That very first start codon is the same for methionine. Methionine, one of 8 essential amino acids we don't make on our own, is one of only two that have sulfur in it. Sulfur is a very active ion that plays a huge role in sucking up extra electrons, leading to glutathione (made from methionine) being so important as your natural, internal antioxidant. And sulfur ends up making your urine acidic. Bottom line: All protein synthesis starts with methionine. You can't make any new proteins without methionine. That's a given.

Curiously, we are now finding that methionine restriction plays a role in turning on your longevity genes, much like calorie restriction. The beneficial effects of calorie restriction that can be demonstrated in all mammals kick in strongly at the 40% calorie reduction mark. The problem with methionine restriction is that you likely have to get to some 80% restriction to get the same threshold of effect. That's harder to do. But methionine restriction likely explains why we should eat more plants and fewer animals. Plant-based proteins, just like animal proteins, all start with methionine but have a lot less of it. So plant-based diets are usually alkaline whereas animal-based diets result in a net acid milieu. Now, frozen peas only have 0.47%methionine whereas roast beef has 2.68% and eggs have 2.90% methionine. Likewise dairy and fish all have 2.5-3.0% methionine and similar effect on acidification.. Then there are Brazil nuts at 6%. The more vegan you eat, the less methionine you get (except for the Brazil nuts).

Is that a problem? Paul Saladino (author of the Carnivore Code) claims that it is not. He argues that methionine toxicity is overcome by having sufficient glycine (the simplest amino acid that is present at about 8% in meat and tendons). In other words, the whole animal, not just the meat. If you eat a pure cut of meat, he argues you better get some bone broth or eat some collagen to make of for the "gristle" you didn't eat. Then, the glycine repairs any "toxicity" of methionine and explains why you need to eat the whole animal, tendons and bones included.

The real key of methionine restriction may also come from understanding its roles in multiple downstream effects. For starters, methionine restriction appears to increase autophagy (eating old, garbage cells) due to the suppression of mechanistic target of rapamycin (mTOR). Secondly, it also decreases reactive oxygen species production in mitochondria. It plays a big role in methyl group donation and in that context, that opens up the whole field of our epigenome management and homocysteine balancing. Finally, it increases the production of hydrogen sulfide a molecule that has its own biology of lifespan extension.

But the final key may be the increase in glutathione production. Glutathione, the natural line of defense against free radicals, might be the most important chemical in your body. You make it from methionine but reducing methionine intake results in more available glutathione. Sounds paradoxical, but there it is. You want higher levels of glutathione to live longer and have less cognitive decline.


www.What will Work for me. I'm a bottom-line kind of guy. I'm finding more and more folks who have high levels of environmental toxins in them, which basically indicates inadequate glutathione production. We can now measure glutathione levels and I'm adding that to my testing of folks who are intent on keeping their brains safe. The low methionine idea is not practical. We can't eat an 80% reduced methionine diet, which is what it takes to induce measurable enhancement of longevity in animal models. We have enough challenges in calorie restriction. No one can do 40% calorie restriction, and maintain normal function. And, methionine "toxicity" is reversed by sufficient glycine. I'm back to chewing on the tendons and connective tissue in my steak. But we can choose to tilt the slope to more vegetables. Ok, that I can do. And now I have a good, concrete reason why that is helpful. Less methionine, more glutathione. More vegetables. Or more tendons. I have a hunch the more glycine hypothesis explains a lot.


References: Biomedicines, Fight Aging, Josh Mitteldor, Innovation in Aging, Saladino: Carnivore Code, Aging Cell

Pop Quiz


1. What role does methionine play in protein synthesis?                            Answer: It is the first amino acid in all proteins and is the starting point. And it acidifies urine.

2. Methionine starts many cellular pathways. Can you name one?                             Answer: It is the compound that balances homocysteine and regenerates it. It plays a role in stimulating autophagy, the natural process of taking out the garbage of old cells. It helps build glutathione and make H2S which is a longevity inducer.

3. What foods have the lowest methionine content?                          Answer: Vegetables

4. Is there a nut that has very high levels of methionine?                              Answer: Brazil Nuts at 6%

5. Is methionine reduction really necessary?                              Answer: if you listen to Paul Saladino, he argues cogently that no, you simply need to add glycine which is the most abundant amino acid in beef at 8%, and even higher in bones and cartilage.


Lower Your Own Uric Acid

How To Lower Uric Acid by Yourself


It's quite a surprise to find that uric acid is not just a passive chemical that represents the final step of purine digestion. It is an active hormone, a part of your metabolome, that plays a big role in altering the direction of your core metabolism. Oh yes, and too much of it causes gout. Let's not forget.


If you conceptualize how that came about, you can consider the most pernicious cause of uric acid comes from eating fruit. The sugar fructose isn't regulated in its entry to liver cells, and floods the liver cell, depleting it of ATP, your energy molecule built on the chassis of the purine called adenine. Your free ATP falls as adenine gets digested off into uric acid. And you develop fatty liver. But it's fruit season, just before the dry season when there are no calories. Your body needs to build up fat stores to make it through the relative starvation of dry season. Research on orangutans shows just that. They gorge on fruit when it is available, gain 40 pounds, then coast on their boring diet of green leaves until fruit shows up again. That is the teleological engine driving natural selection to make uric acid participate in getting fat.


Today we don't eat fruit with fiber, we drink orange juice which is basically yellow-colored sugar water. And we guzzle "Big Gulps" of sugared soda, replete with high fructose corn syrup. Our intake of fructose has skyrocketed, and boy, do we get fat! Today we don't eat fruit with fiber, we drink orange juice which is basically yellow-colored sugar water. And we guzzle "Big Gulps" of sugared soda, replete with high fructose corn syrup. Our intake of fructose has skyrocketed, and boy, do we get fat!

But that leads us to understand how to lower uric acid all by ourselves. It's simple. First and foremost, stop eating/drinking fructose in all its forms. We know that sugared soda drinkers have higher uric acid. So that's easy. But you need to also be a Sherlock Holmes regarding all the foods that have sugar added to them. Some 80% of American prepared foods have extra sugar added. Ah, so watch out for those baked beans, and ketchup and learn the 50 names for sugar by which the food industry hides it. (Agave syrup, barley malt, blackstrap molasses.......)


Then you can add some targeted supplements that do a good job of lowering uric acid. Quercetin, for example, is a star. 500-1000 mg will do. Luteolin, an ancient yellow dye, derived from plants also lowers it. Vitamin C, 500 mg a day will do it too. A fifteen-year-old study of men shows a 44% reduction in gout by taking C. Ha! Then add some fish oiland cherries and live gout free.


www.What will Work for me. Well, I just bought my own uric acid home-measuring device. It works like a charm. A finger prick and $ 37 are the only barriers. I wasted two tests learning how to do it, then read the instructions and did it right. I still have 22 tests to go for that price. I came in at 4.8. Men should be below 5 so I'm a bit close to the top. I stopped taking Vitamin C a couple of months ago out of supplement fatigue, but I'll add it back.


References: Eur Jr Int Medicine, NIH News, NBC News, Arthritis Rheum, Br Jr Nutr, J Trad Compl Med, Archives Int Med, Arthritis Rheum, Ther Adv Musc Dis, ProMax Nutrition,


Pop Quiz


1. What is uric acid? Answer: The breakdown end product of purine digestion/metabolism.

2. What is the most common purine molecule that gets digested and wasted, thereby making your uric acid go up? Answer: Our energy molecule, ATP. That A stands for Adenosine, a purine.

3. What role does uric acid play in a "natural world"? Answer: during the season of fruit abundance (end of the growing season and just prior to the starvation season), extra fructose in fruit would have been useful in helping shift our entire metabolic system to calorie storage. Hence, a tiny bit of fructose helps you retain and save calories. That used to be useful. Now, I tiny bit shifts your metabolism and helps you get fat, and fatter. And in the extreme, get gout.

4. The food industry knows you are trying to avoid sugar. It changes the name it puts on packages so it doesn't have to list sugar as the first ingredient. Can you name all 50 alternative sugar names that are, in fact, sugar? Answer: No. I can't. But I know how to look them up.

5. Can you name 5 supplements that help lower uric acid? Answer: Quercetin, luteolin, fish oil, cherries, Vitamin C, and fish oil.


The Newfound Danger of Uric Acid

The Dangers of Uric Acid


Do you know your uric acid level? Have you ever had it checked? Do you know why it is important, or what it causes? Well, I'm going to argue that it is as important a test for you to know as your HgbA1c, your cholesterol, your blood pressure.....you name it. It should be in your premier list of known numbers. Why, because uric acid is not the mild little leftover of purine metabolism that causes gout. Indeed, it causes gout, but it turns out to be a central player in the core disease of our time, metabolic syndrome. The confluence of diabetes, insulin resistance, overweight, high blood pressure, high CRP, kidney failure and big waistline is metabolic syndrome, and uric acid drives that bus. It is intrinsically causative and implicated in its genesis. Here is how. 

It actually all starts with fructose. Fructose, the sugar made by many fruits and is about 4-6% of that fruit, is pretty benign in that context because you eat the fiber with it. What is not benign is high fructose corn syrup in sugared sodas and hundreds of other products whereby you get 50-80% fructose in a sudden rush. We have never had fructose in such concentrations before until the 1970s when we learned how to manufacture it from corn by the enzymatic wizardry that turns corn glucose into high fructose corn syrup. That fructose is now 10% of our calories, every day.


Here is the biological conundrum. We don't have any biological means of slowing down its entry into our liver cells. In the liver cell, humans add a phosphate atom to it from an ATP molecule. (ATP is Adenosine TRI-phosphate). On reacting with fructose, it becomes Adenosine-DI- phosphate (ADP), two phosphates. In a normal cell working in normal times, an ADP would go into the local mitochondria and get turned back into ATP. But in a liver cell flooded with fructose, there is no time for that. We need ATP, now! Two ADPs get together to make an ATP and then there is an Adenosine MONO-phosphate left over. Adenosine monophosphate, AMP. And that, AMP, gets rapidly degraded to URIC acid. There you have it. Drink a Big Gulp of fully sweetened soda and your uric acid will go up 2 points. And your adenine supply gets cut in half. Your liver is starving for energy.


And now we know that uric acid is emphatically not just an end product of metabolism. It acts as a hormone, a messenger. It shifts our metabolism from burning energy to storing energy. It turns off leptin (your "I'm full" hormone) and turns on ghrelin (I'm hungry hormone). Its actions show up in every aspect of energy storage. So you get fat. And fatter, and fatter. Obesity then sets off insulin resistance, high blood pressure, kidney damage, inflammation and all the other markers of metabolic syndrome.


The first step to controlling uric acid is to stop consuming fructose in all its hidden forms. It's in sugared sodas, that we know. But just about every fruit juice is also a concentrated form of fructose. Salad dressings, peanut butter....you can spend a weary day looking at food labels and finding hidden fructose. It's everywhere. A full 10% of our calories.  (As an aside, beer has a lot of purines in it so drinking beer raises uric acid too.)


www.What will Work for me. The calories you drink are the calories you store. That adage has been around for a long time. Now we know why. It's a bit complex but the story runs rights through fructose in a concentrated form, what it does to your liver, and then, the ultimate demon, uric acid. I can now measure that. The question remains, what level is safe and good? We used to say up to ranges like 3.5-7.2 because that is the range in which you don't see gout. With the connection to metabolic syndrome, we have to revise that. Now, there are those advocating for 5.0 for men and 2-4 for women. I'm going with that.


References: Perlmutter, Eur Jr Clin Nutr. Int Jr of Cardiology, J Clin Med, Medicine, Arthritis Rheum.,


Pop Quiz

1. What is uric acid?                            Answer: A metabolic hormonal switch that turns on energy storage, and an end product of purine metabolism that causes gout.

2. What is the main cause of uric acid elevation in America today?                        Answer: (If you don't get this one, I'll shoot myself.). Drinking high fructose corn syrup in fully sugared sodas.

3. What does fructose do in the liver?                          Answer: It floods it too fast and drains the supply of ATP, our principal energy molecule. Make uric acid is a byproduct of that, further draining ATP because it reduces the core molecule by half.

4. How do you treat gout?                            Answer: Oh, that's a tale of woe. Queen Victoria soaked in the warm waters of Bath, so everyone else in England followed her. ER visits, rheumatology visits, agonizing toe pain, and joint pains......lots of various drugs......lab tests for lead levels, and other causes. Allopurinol lowers uric acid. Did you know that it, allopurinol, also reduces the risk of cognitive decline?

5. What is the first, most effective thing you can do to reduce your uric acid?                        Answer: Become a fructose detective and rid it from your food chain. Then, work on high-purine foods......(next week).


If You Can Do Just One of These, You will Live Longer

If You Can Do Just One of These - You Will Live Much Longer


Everyone knows that being physically fit is good for you. But just what does physically fit mean? Do you have to get a personal trainer and go to a gym four times a week? For decades we've thought that you can test your future "risk" of death by getting on a treadmill test with a heart monitor and seeing how long you can last as the treadmill gets faster and faster. Want a more accurate tool? Cheaper too?


Get down on the floor and see how many pushups you can do! That's what they did at Harvard. The study, published in JAMA Open Networks was the most read study in medicine in 2019. Middle-aged firefighters (1,104 of them) had treadmill tests and did pushups and were then followed for 10 years. Turns out doing 40 pushups for middle-aged men predicted a 96% lower risk of cardiovascular events compared to those who could only do 10 or less. Any women? Nope. Women have lower upper body strength so the data doesn't work on women at the 40 number, but the principle remains.


Do we have other data that reflects longevity risk? Yup. Walking. The University of Sydney shows that walking at a faster pace (>3 mph) is extra good for you over just a mosey. For those over 60, being able to walk one mile at over 3 mph had a 53% reduction in cardiovascular risk. Just walking a mile regularly provided a 21% risk reduction. They studied some 50,225 walkers to get this data. The same findings come from the Honolulu Retired Men's Study that showed walking 2 miles a day reduced cardiovascular mortality some 50% (27 down to 12 deaths per 1,000 years). We can all walk, and faster is better.


More ideas? Yes! Can you get up from the floor? Cross your legs and sit down on the floor. Then get back up from that cross-legged position. Here is the video. Score yourself by taking off 0.5 points for each time you need to use your forearm, knee, or hand, or need to shift onto the side of one leg before getting all the way up. Also, off 0.5 points if you lose balance. If you score under 8 after starting at 10, you are two times more likely to die in the next 6 years. If you score 3 or less points, you are 5 times as likely to die. Wow! Getting yourself limber and fit enough to get up from the floor matters! In fact, scoring a 6 is lousy, but raising it to a 7 gives you a 21% reduction in mortality. You can work on that. That yoga class sounds all the more attractive. You can practice, practice, practice in the privacy of your own home and get better and stronger at it.

 

Final study. Grip strength. Handshake strength. In a landmark study from England published in the BMJ, handgrip strength was strongly, inversely correlated with all-cause mortality. You can test it with a dynamometer. Levels of < 57 lbs in men and 35 in women correlate with trouble. You can fix that too. Start by finding a bar you can hang from and just let yourself "hang out". Can you hang 60 seconds (men) or 30 seconds (women)? That's good. If not, practice it. It will build up your strength. Then, can you do one chin-up? Two? Ten?


We didn't cover peak flow, oxygen consumption, and many others but this is a start. Getting fit matters, and we can measure it in a variety of ways.


www.What will Work for me? Whew, I measured my pushups some 5 years ago and go all the way to 12. I have been at it for 5 years now and I can hit 40 if I give it a go. But one chin up? Getting off the floor? Oh, dear. This falling apart with aging is a drag and keeping ahead of it takes work. Just plain does. I'll encourage you if you encourage me.


References: JAMA Network, Sidney. AU, Eur Jr Prevent Cardiology, Clin Interv Aging, Geriatrics, YouTube,  BMJ, Topendsports,


Pop Quiz


1. You live longer when you are .............?                      Answer: Physically fit

2. You will be 96% less likely to have a heart attack if you can demonstrate your fitness by doing what?        Answer: 40 pushups

3. Easier to accomplish, is walking. What is the best method of walking?                                Answer: Faster. 20 minutes for one mile predicts at least 50% lower risk of heart disease.

4. Can you name two other methods of assessment?                                  Answer: Hand grip, getting off the floor without assistance, peak flow on forced breathing....

5. Can you name the simplest goal with hand grip?                          Answer: Hanging from a bar for 60 sec (men), 30 sec (women). No..not that kind of bar.


Sugar Disrupts Your Colonic Biome and Leads to Metabolic Problems

Sugar Disrupts Your Colonic Biome and Leads to Diabetes


Human biology is pretty complex with multiply interacting components. To make it a bit harder, we don't allow researchers to sacrifice their human subjects to be certain of their results. So, we do research in mice, that may not be exactly the same, but frequently are pretty close. That's what this study showed. The nuance and results fit neatly into other research, so ring true. It's worth trying to understand.


Some 70% of the human immune system is around the gut. The lining of our intestines is just one cell layer thick, so it takes that army of watchful immune cells to make sure bad actors don't get in. And in turn, the host of bacteria living in our gut has a constant conversation with our immune cells surrounding the gut. That's what this landmark study, published in Cell this week, is about. Your gut works best when it has lots of "segmented filamentous bacteria" (SFB) all along its lining. Those bacteria facilitate your having more T-helper cells called TH-17 cells. TH-17 cells reduce your absorption of fat.

When you eat a lot of sugar you induce damage to the gut lining. That sets off inflammation which in turn inhibits the growth of those helpful filamentous bacteria. Like dominoes, when you have fewer FSBs, you get an unhelpful overgrowth of different bacteria, Faecalibaculum rodentium, that appear to be unaffected by the sugar and blossom in the absence of the FSBs.


In this study in Cell, they colonized the mice with FSB bacteria and then fed them a high sugar, high fat diet. The high sugar depleted their FSB bacteria. Their TH17 cells dropped. They gained weight. Without the sugar, they kept their FSB bacteria and TH17 cells and didn't gain weight.

This study was done in mice, so it may not be applicable to humans. However, there is abundant human evidence about TH17 populations in the gut being depleted by sugar. The overgrowth of FSBs is a new finding, however.


The real problem is that we humans in America are eating 310 calories of sugar a day. That is 15% of our daily calories.  Table sugar is a combination of fructose and glucose. Most of that is hidden in foods like peanut butter, ketchup, sports drinks all of which contain sugars to trick you into eating more.


And we don't feed our biome in our colon. Fiber is the foundation of biome nutrition. Some amino acids like glutamine are also helpful. But mostly fiber. Americans average about 10-14 grams of fiber a day. We have many bowel diseases like diverticulitis, appendicitis, gallbladder disease that are all made worse by low fiber diets. Parts of the world where fiber consumption averages 30-40 grams of fiber a day don't have those diseases at all.

To top our health dilemmas off, we take antibiotics way too frequently, damage our colonic biome and lose wide swaths of good bacteria that take months and months to repair.


www.What will Work for me. This study adds to our understanding of the complexity of our interaction between the precious biome in our gut, that acts much like an independent organ, and our immune system. We are all sugar addicts and very vulnerable to the seduction of sweet flavors. I know I am. If I start on sweet, the rest of the day results in eating more food of all kinds. You can observe that in yourself too. See if you can go for a year without any antibiotics, lots of fiber, and less than 1 oz of sugar a day. Just try.


References: Medical News Today,Cell, J Acad Nutr Diet,


Pop Quiz


1. What happens in our gut when we eat sugar?                               Answer: We get a decrease in filamentous bacteria that typically lie adjacent to our gut lining. (If you are a mouse.)

2. With fewer filamentous bacteria, what happens to our immune system?                    Answer: We have a reduction in TH17 cells. (If you are a mouse.)

3. With fewer TH17 cells, what happens to our weight when we eat an all-American high fat, low fiber, high sugar diet.                       Answer: Our weight shoots up.

4. Americans eat how much sugar a day?                            Answer: About 310 calories. That is between 10-15% of our calories.

5. Bottom line.....if you want to lose weight...do what?                       Answer: Don't eat any sugar. Read the ingredients of everything you eat...and don't eat sugar.


Uncoupling Protein Keeps Your Warm

Uncoupling Protein Keeps Your Warm


Did you know that we start life as babies with a lot of brown fat? About 5% of newborns' weight is brown fat, mostly around their shoulder blades and upper back. Newborns can't shiver and they have a lot of surface area relative to volume, so they have a very high need to generate heat. That's what brown fat does. It is brown because the fat cells are chock full of mitochondria, generating lots of heat. That's what uncoupling protein does: turns on heat production in mitochondria.   The fat cells becomes brown because of all the mitochondria in it, busily making heat instead of ATP.  Guess what hibernating animals have? Lots of brown fat! Same metabolic need: heat.

The finding of brown fat in hibernating animals and infants led scientists to explore whether human adults have it too. They do! It was found, somewhat by serendipity, on doing PET scans for cancer metastases. Adults have it around their clavicles, and like infants, in back between their shoulder blades, in the center of the chest cavity, and along the spine. These are all ideal places to generate core heat.

Hmmm. Think for a couple of seconds. Do you want more brown fat? The answer is the same as to the question, "Do you want to lose some weight?". Of course you do. You want to burn off those calories as heat instead of being stored as fat. Brown fat is full of mitochondria, and they have uncoupling protein going full blast.

How can you turn on the production of brown fat. The concept is easy. White fat (very few mitochondria) can be turned into "tan fat", (a few mitochondria), can be turned into "brown fat", lots of mitochondria. Cold exposure, for one. If you haven't heard of Wim Hof, you need to bone up a little and learn about his ability to swim in ice water and not get cold. He has broken many records for cold exposure and now teaches others how to do it. If he had his fat tissue biopsied, it would be dark brown, because he exposes himself to cold water with incredible diligence.

You can do that too! NIH Research shows that if you expose young men to 66 degrees for one month for 10 hours a night, with just a bed sheet and standard hospital pajamas to sleep, after one month of 75 degrees (that's right, just a 9 degree drop in night temperature), you will turn on brown fat and have a 42% increase in brown fat in just one month. That's cool! (So to speak). Modest cold exposure will do it. Cold bathing will do it. Probably any regular cold exposure will do it. The more you do it, the browner the fat - the more mitochondria in the fat with uncoupling protein activated. That explains why the indigenous peoples of Tierra del Fuego could live in a cold environment with no clothes!


What else will turn on uncoupling protein, hence brown fat? First on the list in the Frontiers article is capsaicin, chilis! Resveretrol, curcumin, omega-3 oils, menthol all activate UCP too.

Ketones! This makes sense. A hunter-gatherer, gets to October and its cold, and carbs are now frozen off, needs to generate heat to survive. Living without carbs means transitioning to burning fat for calories, and that makes ketones. Some of the energy gets diverted into heat! Foods that naturally give you ketones include MCT oil, coconut oil, fiber (that gets fermented in your gut to ketones), goat cheese (has much higher ketone content than cow cheese, vinegar and all fermented foods.


www.What will Work for me. There you have it. Spooky synergy in biochemical processes. Uncoupling protein is good for you in that it protects the mitochondria from too much energy production by letting off the extra energy as heat. That I experience every Thanksgiving night after consuming half a turkey. I'm hot and can't sleep at 2 am. My mitochondria are uncoupled, just to protect me from the calorie excess. But now I get this new idea. I can turn on uncoupling protein, generate a little extra heat on the side by just adding some ketones to my coffee. One T of coconut oil in my morning coffee will do it. And make sure I keep getting fiber in my diet. Goat cheese? Now, that's unique. I like goat cheese.


References: Wikipedia, Hdb Exp Pharma, J Exp Biology, Am J Phys Endo Metab, Wim Hof Method, NIH Research Matters, Frontiers Phys, Quora,


Pop Quiz

1. What does uncoupling protein (UCP) do?                             Answer: Like an old fashioned steam engine, it lets off excess energy as heat instead of forcing it into the ATP production line.

2. When do I experience that excess heat capacity?                      Answer: When you eat too much, like a big holiday dinner. Or any night you have a snack before bed and then wake up at 2 am feeling too hot.

3. What's the upside of UCP?                       Answer: It generates heat to protect you and keep you warm.

4. Where do we see that in nature?                           Answer: Right before our eyes. Newborns, incredibly vulnerable to heat loss, have loads of brown fat. And in anyone who is regularly exposed to cool temperatures. You can do it for yourself by turning the shower to cool / cold for the last 30 seconds.

5. What makes brown fat brown?                               Answer: Loads of mitochondria that have activated UCP, all generating heat instead of making ATP fuel.


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