Genomic Instability - Hallmark of Aging #1
"Please, please write your newsletter about the Hallmarks.....I want to know," asked one of my clients. I couldn't rattle them off by memory, so here is one of them. Genomic Instability is listed as the first Hallmark. This idea of Hallmarks of Aging has been proposed in 2023 and caused a great stir in the research world. The twelve initially proposed hallmarks are genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis. Sounds like jargon. I want to turn it into understandable English.
Each cell in our body has enough DNA to reach about 6 feet in length. The process of duplication of cells, activation, and deactivation of genes, and reproduction, all in an environment of toxins and radiation that breaks DNA means a prodigious amount of DNA repair must occur. Any given cell has to decide as to where their energy is going to be allocated: repairing DNA or living longer and reproducing. Sex always wins. We have to reproduce, which means our DNA has to get old.
With all the means of damaging DNA around, our DNA ends up with point mutations, deletions, translocations, telomere shortening, single- and double-strand breaks, chromosomal rearrangements, defects in nuclear architecture, and gene disruption caused by the integration of viruses. I didn't even mention transposons. (What are transposons? That's the process of taking a whole segment of DNA and inserting it into another organism. CRISPR is basically transposon methodology turned into medical intervention)
Once you have taken care of nuclear DNA, you discover there is a whole universe of DNA pieces floating around in the cell water, the cytosol. That cytosolic DNA is not meant to be there, and it arouses an innate immune response called "sterile inflammation". That is inflammation set off without an invading bacteria.
We are meant to have repair mechanisms. Our sirtuin proteins are just that, the caretakers of our epigenome (the markers on the surface of our chromosomes.). The very, very first cell had to have several key elements. DNA that could duplicate itself, some means of assembling a membrane, some means of generating energy, and some means of repairing broken DNA. Every order of living beings on planet earth has sirtuin proteins. Fasting turns them on. Metformin turns them on. Metformin activates SIRT 1 (the first of 7 sirtuin proteins in humans) that essentially mimics the same pathways as calorie deprivation. SIRT1 is energized by NAD or niacin.
Hence, the combination of metformin and niacin helps everyone live a little longer. Provided they get enough NAD. NAD (otherwise known as Vitamin B3 or Niacin) declines with aging. NAD+ declines with age largely due to the activation of CD38, an enzyme activated by the inflammation produced by senescent cells – cells that no longer grow or replicate. In a feed-forward cycle, the decline of NAD+ by CD38 induces the spread of more senescent cells and inflammation.
Genomic instability is a deep rabbit hole with many publications and journals covering it. It's a great way to spend a rainy afternoon if you don't like golf.
www.What will Work for me. I'm on metformin and niacin. I do my intermittent fasting too. I'm surprised to learn that one of the Hallmarks of Aging fits so well with David Sinclair's concept of everyone being one metformin and niacin. David Sinclair has started a large placebo controlled trial to work this out in scientific rigor. It's going to take 7-8 more years to get results. Now I want to know the other Hallmarks and see how we can incorporate their physiology to our advantage. Stay tuned.
References: Cell, Curr Genomics, Cell, NAD.com,
Pop Quiz
1. What are the Hallmarks of Aging? Answer: So far 12 interconnected processes that demonstrate degredation with aging. If we can understand how they fall apart, we gain insight into how to address them.
2. What are the problems with Genomic Instability? Answer. Duplicating DNA and turning genes on and off takes a many stepped process that is intricate to the extreme. Any mistake breaks DNA that has to be repaired. That doesn't always go well. Then there are viruses that insert their DNA into ours. Then there are chomosomes that swap genes back and forth with each other. We are still discovering all the ways it goes wrong.
3. What is "sterile inflammation"? Answer: Our DNA is kept in the nucleus of the cell in a tightly controlled place. When a piece of DNA ends up outside the nucleus in the cellular water, it elicits an immune response. We get inflammation without bacterial invasion...so called sterile inflammation.
4. What are the proteins tasked with caring for our epigenome, the markers on the outside of our chromosomes? Answer: Sirtuins. The most ancient and preserved of all proteins.
5. What does metformin do that helps aging? Answer: Turns on the production of sirtuins, just like fasting does. (Nice to find a way to get around that obnoxious fast.)
Anti-Aging Pills Mature: Here is Your Suggested Portfolio
Aging has not been considered a disease state, at least not yet. It has been considered "natural" or "inevitable". Yet, most folks over age 70 have at least one chronic condition or diagnosis that limits their life-style or productivity. Because there are so many of "us", it's a high burden for society to bear. Anti-aging is another whole way of thinking. Phrased positively, it is reaching for optimal health. That would be a state in which you have the ability to do what you want to do, without being limited by disability, chronic pain, loss of vision, mobility, or cognitive problems.
The battle is over each of the Hallmarks of Aging, if you want to delve into them. Read the link here in the journal Cell in detail. You will find cell senescence as one of the Hallmarks. A senescent cell has lost its vitality and function and no longer responds to perform in its intended fashion. If it's a muscle cell, it doesn't pull as hard. If it's a pancreas beta-cell, it doesn't make as much insulin as it once did. Senescent cells are effectively zombies in that they are hanging around and spewing out all sorts of messaging compounds to make the cells around them senescent.
Healthy cells are called "quiescent". They are alert, waiting to be called on, and capable of doing their duty. Like soldiers on the parade grounds, they are standing in place, uniform spotless, alert, rested, armed, and quietly waiting for orders. That's opposed to the zombie cell that's like soldiers in the barracks playing poker in their underwear, having a fourth beer. They aren't able to march double time into battle.
Can I move a zombie senescent cell back towards quiescent? Well yes, to a tiny degree. Chinese researchers just published a report on a compound extracted from grapeseeds called procyanidin HC-1 that kills of senescent cells and encourages those that are thinking about it to go back to quiescence. Mice given procyanidin HC-1 live 9% longer.
Rapamycin, an antibiotic made by an actinomycete from Easter Island (Rapa Nui), also reduces senescent cells. It is not available as a prescription drug Sirolimus and can be prescribed to take once a week.
Metformin, discovered as an extract of the French lilac flower keeps popping up in multiple studies showing that those on it live longer compared to matched populations that aren't on it. It appears to work by upregulating 5-6 of the Hallmarks. One of them is its effect on sirtuin proteins that are the caretakers of your epigenome. Your epigenome is composed of some 20 million markers on the outside of your chromosomes that modulate the activation and deactivation of your genes.
Nrf-2 activation is likely part of an effective strategy. The Nrf system is the master controller of inflammation and plays a leading role in all the Hallmarks. Various combinations of foods reflect potent Nrf activation strategies as measured by TBARs testing. TBARs measures malondialdehyde, the best measure of plasmalogen depletion and damage. PB-125 is the best in class Nrf activator.
The question arises as to whether we should all be on these supplements/prescriptions. Should we? Well, yes, to a degree. I think metformin is a must. Rapamycin is probably useful. Should procyanidin HC-1 be added to the list? How about quercetin? How about pycnogenol? PB-125?
www.What will Work for me? How about plasmalogens? The biggest bang for your buck is likely plasmalogen normalization and monitoring. That hasn't risen to the level of widespread acceptance, at least not yet. But Goodenowe's graphs from the Rush Aging studies show plasmalogens to be the far and away best predictors of risk of dying, even up to age 95 where a person who is 2 standard deviations above the norm has the same risk of dying as a 70-year-old 2 standard deviations below the norm. I take metformin, sirolimus, PB-125 and plasmalogens. I suspect each of us has to make that decision as to how many pills can you add to your list.
References: BBC Science Focus, Nature Metabolism, Cell, Frontiers Endo,
Pop Quiz
1. Is aging a disease? Answer: It is if it kills you.
2. What are the Hallmarks of Aging? Answer: Twelve (maybe 15) different means by which our finely tuned system falls apart.
3. What does cellular senescence mean? Answer: A senescent cell no longer performs its function, and damages the cells around it.
4. Where did Chinese researchers find an anti-senescent new compound? Answer: In grape-seed extract.
5. Has metformin been proven to prolong life in normal folks? Answer: Not yet but multiple studies are getting started or recruiting aging folks.
Microplastics Increase your Risk of Heart Disease and Stroke
This is a huge finding. Published in the apex journal of American Medicine, The New England Journal of Medicine, is a groundbreaking study looking at the relationship of microplastics to heart disease and stroke.
Carried out in Italy, the authors looked at the atheromas excised out of carotid arteries in folks who had that surgery for the usual indications such as a TIA or stroke. Microplastics and nanoplastics were quantified by the use of superheated–gas chromatography–mass spectrometry, stable isotope analysis, and electron microscopy. In other words, the authors pushed the boundaries to find evidence of the micro-nanoplastics any which way they could. Inflammatory biomarkers were measured with enzyme-linked immunosorbent assay and immunohistochemical assay.
Sixty percent of the atheromas had detectable evidence of micro/nano plastics. That's huge, particularly when you consider that those who had detectable micro/nano plastics were 4.5 times as likely to have a stroke/heart attack in the subsequent 39 months as the controls who didn't have any detectable plastics.
Half of Western society folks, men and women, are dying of vascular disease. It doesn't matter if it's a heart attack or a stroke, both kill you.
This finding rewrites the atherosclerosis story. The rise of microplastics coincides with the "epidemic" of vascular disease. Association does not causation make....but smoke sure suggests something is smoldering if not burning.
We have been barking up the cholesterol tree for some 60 years, ever since Eisenhower had his first heart attack in the White House. Certainly, there is cholesterol accumulating in an atheroma. But blaming it as the cause is sort of like blaming trees for causing a forest fire. Certainly, the trees burn, but I'm more worried about the lack of rain and lightning strikes or discarded cigarettes than the trees. And the recent discovery that folks live longer with a total LDL of 135 or total cholesterol over 210-240 has eroded the confidence that the cholesterol hypothesis is the root cause. Taking a statin is sort of like cutting down the whole forest to stop forest fires. Yup, it sort of helps.
Now, with the discovery of low plasmalogens and endothelial dysfunction being the root cause and the better predictor or heart disease than cholesterol, we can offer up a better hypothesis. Microplastics certainly cause excess oxidative stress. That essentially means mitochondria are struggling and not able to hang onto electrons. Electrons escape the mitochondria, get turned into peroxide by catalase to get the "hot potato" out of the cell. That peroxide then attacks any plasmalogen molecule with its precious vinyl ether bond. That chemical reaction neutralizes the peroxide. It releases malondialdehyde in that chemical interaction. At the end of the day, that depletion of plasmalogens causes the endothelial cells to retract and separate from one another.
Is malondialdehyde elevated in coronary artery disease? Yup, yup, yup. We've known this for over 7 years.
Oxidative stress depletes plasmalogens in the arteries. Gaps appear in the wall of the artery. White cells then attack because it looks like a damaged cell that needs to be cleaned up. Oxidized, sticky LDLs begin to accumulate. That's all true. But blaming the LDL is a little late to the party.
Microplastics aren't the only cause of oxidative stress. Visceral fat, diabetes (probably caused by visceral fat), smoking, sitting too long, other toxins, sugar, and ultra-processed food are all candidates eagerly raising their hands to take credit for killing us by slow oxidation. But microplastics might have just "bucked in line" pretty close to the front. Jerks!
www.What will Work for me? What we need to be measuring are markers of oxidative stress, not cholesterol. Malondialdehyde is available as a test kit but is not available to use in the commercial sphere just yet. But each of us can reflect back and consider the last time you drank water from a plastic bottle. Was it earlier today or yesterday....? Hmm??? How about the takeout you heated in the microwave? How about the leftovers you put into a plastic container? The organic yogurt you bought in the plastic container? The deli items you bought in Styrofoam? This is a total bummer. On taking plasmalogens, my total cholesterol finally cracked 200. My HDLs are now 56, for the first time in history. At least I'm repairing my plasmalogen deficit. And I just ordered Nitric Oxide for a refill. All these supplements add up but having a stroke adds up more.
References: NEJM, Jr Cardiovasc Thorac Res., Medical News Today,
Pop Quiz:
1. Where did the authors of the above-referenced study find microplastics? Answer: In the "atheroma" (cholesterol pool) excised surgically out of carotids in people who had TIAs and strokes and ultrasounds on their necks revealed critical narrowing.
2. What percent of folks had plastics embedded in their atheromas? Answer: 60%. Majority.
3. What was the risk those microplastics conferred? Answer: 4.5 times increased rate of some sort of atherosclerotic disease. Huge!
4. What is the source of those microplastics? Answer: Just look around your kitchen.
5. What do we do next? Answer: No mean feat. It's up to you. Figure it out.
Plasmalogens Predict Heart Disease Better Than Cholesterol
You have to understand statistics. When you take large populations of people and follow them for mortality against cholesterol, you find that folks who live the longest have total cholesterol between 210 and 240. Let that soak in. Folks below 200 live shorter lives. Got that? Now, measure how long those folks with higher cholesterol live, despite being put on a statin. Yup, yup, yup. Despite the statin, they still live longer than their controls. That means there was no benefit. What really happened is the statin didn't change anything.
What that means is slightly convoluted, but bear with me here. Exporting cholesterol out of a cell is a crucial feature. It requires nice, healthy, high levels of plasmalogens in the cell membrane. A healthy cell exports more cholesterol, because it has enough. The only way to get rid of cholesterol is to export it back to the liver and excrete it in bile. By itself, cholesterol is indigestible to human cells and must be disposed of through the bile. Carrying the cholesterol back to the liver requires HDL particles. Hence, nice high plasmalogens will result in higher total cholesterol in the blood, in part because there are higher total HDLs, and in part because the LDLs become large and fluffy.
What's the cholesterol, heart disease risk connection? Aha, that's key. We've said this before but it bears repeating again and again because so many people are being pressured by their family doctor, their cardiologist, or their internist, to get on statins because their total cholesterol is over 200. (They don't mention to their patients that American Heart Association quality assurance guidelines support paying bonuses to doctors who reach a threshold of statin prescriptions. Those guidelines were concocted by a committee of doctors paid by the statin industry.) How to you get to a cholesterol over 200? You have to have high HDLs and your LDLs become large and fluffy (and harmless), but make for higher volume. Hence, higher total cholesterol.
You can prove this to yourself by stopping all flour, sugar, and alcohol for a month. Add 5 servings of vegetables every day (or more). Top it off with intermittent fasting, compressing your calories into 8 hours. Presto! Your triglycerides will drop into the <75 range and your HDLs will climb. Now add plasmalogen supplementation (Prodrome Glia and Neuro) for 3 months and your HDLs will be 50% higher than they were before. That means your internal membranes are healthy, and cholesterol export is healthy. And you aren't developing heart disease.
Or you can read the Atherosclerosis article here attached that also proves it. High levels of plasmalogens predict future heart disease risk more accurately than cholesterol. The higher the plasmalogens, the lower the heart disease risk.
What is the actual sequence for heart disease? (I know, this is a repeat) Start with some sort of inflammatory spark (visceral fat qualifies). That will begin to deplete plasmalogens in the membranes of your endothelium, the lining of your arteries and capillaries. You can measure endothelial dysfunction with all sorts of new tests now. The endothelial cells in the arteries retract their membranes, exposing naked basement membrane below. Oxidized LDLs can now stick to that membrane, as can white blood cells. Then, you start to accumulate cholesterol in your artery. That is about step seven. Lowering cholesterol is like telling the crowd at a foosball game to go home. Yeah, it makes a difference to the players to not have adoring fans screaming for them, but it's not the main game. The main game was the inflammatory stress, depletion of plasmalogens, with the resultant deposition of cholesterol following
And that, my friend, you can measure and repair. You can turn off the source of inflammation by losing your poochy tummy that reflects visceral fat. You can stop eating sugar and white flour that overwhelm your mitochondria and force more peroxide to be made. You can take plasmalogens to replenish and repair what you lost by that trip to Culver's ice cream.
Finally, you can add NItric Oxide lozenges from www.n1o1.com twice a day to regrow your glycocalyx and Diosmin to support that process.
Why is this strategy compelling? Statins are poisons. Too many people have muscle fatigue and cramps. Brain fog and memory issues are enough of a concern. But more importantly, we need cholesterol. It's good for you. Your cells need it. Folks with the lowest cholesterol demonstrate more cancer. Folks with higher total cholesterol 210-240, live longer. I rest my case.
www.What will Work for me? If I didn't get asked this question every day, I wouldn't have to repeat it. Heart disease kills 50% of in. Did you know that the ratio of heart disease to breast cancer in women is 10:1. Yes, heart disease is a deadly event. We all need to take it very seriously. But the supplementation with plasmalogens and NO and loss of visceral fat is the real path forward. I went and got the first MRI in Milwaukee of visceral fat. I was the test case to run the software. I think of myself as fit and slender. My MRI showed that that self-image is a mirage. I have a moderately high level of visceral fat. That explains my high CRP that I've had forever. It's a wonder I haven't had a heart attack yet. At least I'm on the plasmalogens and the NO. With the introduction of plasmalogens, my HDLs went from 28 to 58 in just a few months. What a victory.
References: BMJ, BMJ Open, Lipids in Health Disease, Atherosclerosis, Scand Jr Primary Health Care, Jr CardioVasc Thoracic Res,
Pop Quiz
1. What's the FIRST STEP of heart disease? Answer: Some sort of "oxidative stress" from inflammation. That could be too many calories, trans fats, smoking, sedentary lifestyle. Whatever it takes to damage the mitochondria so electrons escape and peroxide is present.
2. What is the SECOND STEP of heart disease? Answer: Peroxide destroys plasmalogens everywhere. That results in a molecule called malondialdehyde which you can measure and that accurately predicts coming trouble from vascular disease, just like low plasmalogens. They are basically measuring the same phenomenon.
3. What is the THIRD STEP in heart disease? Answer: The cells lining your arteries (called the endothelium) which are rich in plasmalogens, lose a lot of their natural function and can no longer be delicate and slender. They pull back their membranes and look more like a fried egg. Exposing basement membrane.
4. What is the FOURTH STEP in heart disease? Answer: White cells stick to the damaged basement membrane and oxidized LDLs (formed by oxidative stress) also stick and start accumulating. Note, this is not the root cause.
5. Who lives the longest, those with total cholesterol from 210-240 or those with total cholesterol from 150-190? Answer: 210-240. You need cholesterol.
Maillard Reaction - The Devil in Your Food
Of course, it was described first in France! The Maillard reaction is all about flavor and "browning". It's the "roux" of fine French dining. The chemical reaction is simple. Sugars (carbs) and amino acids (meat) combine with all sorts of odd reactions that add flavor and pleasing aromas to food. Most chemical reactions are facilitated and controlled by enzymes. The Maillard reaction is "non-enzymatic", facilitated by heat. There are hundreds, if not thousands of them. Making gravy is basically mixing some butter or fat with some flour and then gradually stirring it while heating it. Voila! Gravy! Maillard.
America was founded on the "gravy" culture whereby every ounce of fat off the animal was combined with ground-up corn or wheat to make stews or gravies. We have now perfected the Maillard reaction with the barbecue grill. Take some meat, slather it with a sugar coating called barbecue sauce, then flame it with the grill on high heat.
You see, nature never did this. Wild animals don't cook. Nor did humans have access to sugar in great quantities until the 20th century. It was expensive and rare. Fuel has always been precious and carefully used. Many indigenous peoples used hot rocks to cook food very slowly, at lower temperatures. Then, we discovered oil and nuclear power, and electricity and gas became common. Factories could manufacture food in quantity with high pressure, high heat cooking. This is all a formula for mass Maillard. The problem is, it is so complex that it's hard to get a handle on it.
That picture is becoming more clear. It's been right before our eyes. Cancer. Dogs and cats, living in our homes, are dying of cancer at many times the rate compared to decades ago. What are they eating? Canned dog food. Maillard reaction soup. Both dogs and cats are descendants of carnivores, who age raw food. When they captured game, what did they eat first? The liver and internal organs. That's where the real nutrition lies. And they ate it raw.
The process is actually quite well-known. Maillard formation can be divided into three major stages depending on colored products. At the first stage, sugars and amino acids condense, and following condensation, "Amadori rearrangement and 1-amino-1deoxy-2 ketose" form. (I warned you: it's complex) In the second stage, dehydration and fragmentation occur to the sugars. Amino acids are also degraded in this stage. Hydroxymethylfurfural (HMF) fission products such as pyruvaldehyde and diacetyl are formed in this intermediate stage. This stage can be slightly yellow or colorless. In the final stage, aldol condensation occurs and finally, the heterocyclic nitrogenous compounds form, melanoidins, which are highly colored. Brown gravy. Grilled meat. Processed sausage.
If you just focus on one, acrylamide, you will find a highly carcinogenic compound. It is formed with just 60 seconds of microwaving. It is pervasive. And it's not just meat. Soybeans, a major foundation of many food products, has oil, protein and carbohydrates all in one little bean. What happens with high-pressure heating and "extrusion" of the oils and proteins? You got it. All sorts of Maillard products with names like furosine.
How about dairy products, produced with high-temperature pasteurization? How about pasta making? Traditional pasta processes were low temperature and took 3-4 days to complete. Modern machinery accelerates that to minutes with high temperature and guess the result. We can go on.
www.What will Work for me? I've had four dogs, two died of cancer at age 8. I've seen, it with my own eyes. I've seen dogs improve from mangy, malnourished animals to sleek, shiny, buff creatures on a raw food diet. I have walked through the pet store and seen the proliferation of freeze-dried raw meat products for dogs which our new puppy scarfs down like she has seen heaven on earth. If this is what the veterinary industry is turning to for our animals, what on earth are we humans tolerating all this Maillard reaction stuff for? I've measured my own acrylamide and was stunned to see how high it was. We so cheerfully eat those French fries, cooked at 400 degrees in soybean oil. No more! We eagerly look forward to our summer grilling and dig out that delicious barbeque sauce. Am I willing to go raw? Or at least lower-temperature cooking? I don't know. Change has to start with knowledge. But my achy heart for the death of our last loved dog from bladder cancer is being assuaged by the delight of a new cocker puppy, even if it involves waking at 2 am for a potty trip outdoors. And I'm buying her raw food. Simple.
References: Food Chemistry, Int Jr of Food Sci, The Grio,
Pop Quiz
1. What is the Maillard reaction? Answer: the abnormal chemical bonding of sugars to amino acids facilitated by high temperature.
2. Can you name some foods that have Maillard reaction products in high concentration? Answer: French fries. Anything grilled. Processed meats. But don't forget the pasteurized dairy, the high-temperature pasta, and the ultra-processed foods that sound so good for you.
3. What's the answer to reducing Maillard products in our food supply? Answer: raw food can be interpreted as more salads, and more vegetables. Cooking can be changed to lower-temperature stews and casseroles. This may explain some of the damage caused by "ultra-processed" foods, all of which are made with high-pressure, high-temperature foods.
4. Why haven't we heard more about this before this? Answer: There are 20+ amino acids and dozens of different sugars making for thousands of different combinations. The complexity is daunting. That inhibits the research. We humans are restless and don't eat the same food often. We like variety. Studying just what we eat is a very tasking process. That makes for long-term population studies, that are expensive and slow.
5. Name one chemical that can now be measured that is a product of high-temperature heating of potatoes and soybean products. Answer: acrylamide.
A2 Milk is a Better Milk
It all started with an alert pediatrician in New Zealand who wondered why children from Samoa never had insulin-dependent diabetes until they immigrated to New Zealand. One of his partners conjectured, "Well, they've got brown cows and we've got black cows." A quick little study in their practice revealed that observation to be accurate.
It took a couple of years of investigation to find that black cows, Holsteins, have a casein protein sequence with a single amino acid change at position 67 on the protein leading to an indigestible, 7 amino acid fragment that is different from brown cows. It was called A-1 casein. In fact, A-1 protein is present only in black cows. All other cows in Africa, India, and brown cows in Europe have the A-2 gene. Actually, all mammals including humans have the A-2 or other casein subtypes, but not the A-1 gene.
That 7 amino acid fragment is not benign. It has the ability to bind to the morphine receptor in the gut and brain. The morphine receptor is not there for the purpose of making the cow mellow, it is part of the immune system. When you block it, you are activating the immune system. Rat studies show that newborn rats, susceptible to developing diabetes with A-1 milk, will not get diabetes if given naloxone (morphine blocker) prior to A-1 milk, thus blocking the morphine receptor. Rats aren't humans but there is some biological principle here.
It's not just diabetes. There is equal concern around mental health, schizophrenia in particular. It's been noted for decades that folks with schizophrenia do better when on a diary-free diet. There are trials underway trying to parse the issue out, but there is not big money behind it so studies are slow and small. The FDA does not permit A-2 milk to advertise that it might be better for mental health, diabetes, or schizophrenia. The only claim that can be made is for "better digestion". Well, that too is now pretty well proven.
New Zealand has taken that data with serious focus. They have bred the A-1 gene out of their cow herd completely. Australia has followed suit. Keith Wolford, the professor of dairy science and author of the book "The Devil in Milk" details all the nefarious politics around trying to hide the damaging risk of A-1 milk and the desire to maintain New Zealand's "brand" of standing for pure, clean agricultural products. The US has paid virtually no attention to the topic and the American dairy herd, predominantly Holsteins, is heavily A-1. (Not every cow is. It takes genetic testing and then some 10 years to clean a given herd of the gene)
A-2 milk has shown up on the grocery store shelf in Wisconsin in the last five years. But what about yogurt, cheese, butter, cream cheese, ice cream, and any other product with A-1 protein it it. How about milk collection systems? A milk truck picks up milk from several farms and mixes them all together. That's no good. Any given milk truck doesn't know where it is ending up at the end of the day. What cheese maker is calling for product? Hmmm,...Illinois? Collecting A-2 milk has to be clean and separate from A-1. It requires its own collection system and separate cheese-making, yogurt, and ice cream-making. That's tricky.
And that's what has changed in Wisconsin. One brave dairy farmer has stepped out and is now making A-2 cheese and has a herd of A-2 cows. Milkhaus Dairy will ship you A-2 cheese and is thinking about Ice Cream. Woo Hoo!
Where there is smoke, there is usually fire. Enough, serious scientists are on board with this for me to believe there is enough to take seriously. The huge differences in incidence of diabetes in different societies speaks to some sort of environmental influence. Holstein cows are incredible milk machines and have been adopted all over the world. As that has occurred, insulin-dependent diabetes shows up.
www.What will Work for me. I pleaded with my children to raise my grandchildren with A2 milk. That's not hard in Switzerland, where the cows are mostly "Swiss". California is an early adopting state and there are several "Brown Cow" dairys. If I had an autoimmune disease, I would avoid A1 milk. Goat milk, sheep milk, buffalo milk, donkey milk, and camel milk are all fine. It's just those pesky, efficient black cows. I did order some cheese from Milkhaus Dairy. There is no doubt that human infants benefit by good, healthy, protein. Older adults do too. Just don't mess with my immune system.
References: Frontiers Nutrition, The Devil in Milk, Nutrition Diabetes, Indian Jr Endo, Nutrients, Trials, Milkhaus Dairy, Nutrients,
Pop Quiz
1. What is A-1 milk? Answer: A genetic variation of the beta-casein protein at position 67 where there is a proline for histidine (two amino acids that are in all proteins and share two of the three codons. A single mutation allows the switch. The result is a 7 amino acid fragment that is indigestible and which proceeds to activate the morphine receptor. The fragment is called BCM-7 for Black Cow Milk-7. You don't want A-1 milk.
2. What kind of cows have A-1 milk? Answer: All black cows come from a common ancestor. The mutation is thought to have arisen some 10,000 years ago. The resultant cows may have been more mellow and easier to handle. The penetration is only 80-90%. Not all black cows have it.
3. How much A-1 milk is there in India or Africa? Answer: None. They have brown cows (A-2), buffalo (A-2) and goat milk (A-2). Recently they have been importing Holsteins, and getting diabetes to show for it.
4. Is all this science conjecture or is it proven with hard fact? Answer: It's a bit of fact, and a bit of pattern recognition. Hard, irrefutable facts take a lot of money and there is precious little to support this type of research.
5. If you measure the urine of autistic children, do you find more or less BCM-7 in their urine? Answer. No fair. Not covered. But google it. Guess what you find? Yup, more BCM-7 than in normal kids.
Plant Nitrates from Vegetables, As Essential As Vitamins
Life probably couldn't have started without lightning. You see, lightning creates the energy to break the nitrogen bonds of atmospheric nitrogen and make nitric oxide. That step introduces nitrogen into the food chain and starts the production of amino acids and DNA. Now, we have the ingredients for life. That nitrogen is precious. One of the key ingredients from lightning was NO, nitric oxide that is very reactive and can go in multiple directions.
That same role is now played by dietary nitrates from vegetables. It takes a circuitous route to get back to NO. Nitrates from vegetables are concentrated in your saliva, and then a particular, unique biome of bacteria in the crypts of your tongue convert the nitrates to nitrites. Upon swallowing, those nitrites are converted to NO in the stomach, which affects the whole body.
There are two, critical choke points in that process. Salivary conversion of nitrates to nitrites is erased with mouthwash of any kind. That's number one. Drugs that neutralize stomach acid block the final conversion to NO. That's number 2. Both stop the production of NO, almost completely.
NO, once made, turns on an enzyme called soluble guanylate cyclase or just chemically alters many proteins to generate all sorts of endocrine effectors. Those effects are life-giving. Oxygen can penetrate tissues. White cells can kill viruses. Blood can flood smoothly through responsive blood vessels. NO is the real deal. And it drops by 12% per decade. Add that up and if you are over 60, you are deficient.
Under conditions of exacerbated physiological stress such as chronic inflammation, the enzyme responsible for endogenous NO production in endothelial cells, endothelial nitric oxide synthase (eNOS), may generate reactive oxygen species thus decreasing NO production. This change in enzymology is termed eNOS uncoupling. That explains the missing link between chronic inflammation and how it plays out in making us worse off. Sick!
Just about every known disease is associated with low NO. For example, studies have reported a decrease in whole-body NO synthesis rate of 31% with high blood pressure, 61% in renal failure, 73% in heart failure, and 40% with hypertension. The list goes on. That's the science that's being filled in now. Studying NO is so complex because it is so fleeting and nuanced in its effect, that no one fully grasped the scope of its importance. Well, important it is.
We get nitrates from our food. Only. We can make some NO from animal products but that process is pretty unwieldy and the best evidence we have is that most NO comes from the plants we eat. Clearly, prepared meats have measurable, harmful effects on human health, but the nitrates themselves may be beneficial. All that fuming about the nitrates in ham is misplaced. However, you can't put in the nitrates without making other secondary products. They are the problem.
The conundrum comes with too much nitrate intake, as shown in cardiovascular disease. A U-shaped curve of benefit shows up that demonstrates "tolerance" or adaptation to high doses that erases the benefit. Something is amiss. Like the three bears, you want your porridge "just right". Same for NO. Not too little. Not too much. And vegetables provide that. The convoluted, complex pathway through our saliva and gut is fragile.
There is clear evidence that the natural nitrates in vegetables have a demonstrable beneficial effect on cardiovascular health. It's the nitrates that do it, at the level vegetables provide when eaten. And irony upon irony, organic vegetables have dramatically fewer nitrates in them. That's what fertilizer is. Our depleted soils are so lacking in nitrogen, we are now dependent on the addition of artificial nitrogen. Lightning just isn't keeping up.
And that's how we get to the call for nitrates in vegetables to be considered a conditional, "essential" nutrient, almost a vitamin.
www.What will Work for me? My take-away. If you are over 60, you likely need to be on some sort of program of nitrate enhancement, in addition to 5 servings of vegetables a day. The path to healing cardiovascular disease, our number one killer in men and women, is founded on sufficient NO in our arteries. No questions asked. Nobel Prize for that one. My cardiac calcium score is not zero. I'm taking NO lozenges every day. It's my only "candy". Nice, lemony flavor. I just baked 3 packages of Brussels sprouts with lots of black pepper and a tract of paprika and olive oil. I've ditched the mouthwash and I'm flossing with grim determination. The average American eats 1/2 serving per day of vegetables, only if you count french fries as a vegetable. Buck that trend.
References: Science Direct, Cell, J Animal Sci Tech,
Pop Quiz
1. What is the original source of nitrates? Answer: Lightning.
2. Where do we get most of our modern nitrates from? Answer: Artificially making nitrogen-based fertilizers. Then through plants.
3. How much does NO production decrease per decade? Answer: 12%
4. What are the odds I die of heart disease? Answer: 50%.
5. Hmmm. Las Vegas odds for NO versus heart disease? Answer: Don't be a sucker. You need the NO. I know it's expensive. Death is worse. And more certain.
Ultra-processed Food is a Real Problem
This has been a slippery question. What are ultra-processed foods and do they really make a problem? This column first reported the Brazilian studies that kicked off the discussion and identified ultra-processed food as an item of concern. There have been some studies refuting its risks.
This week's report is on the first meta-analysis (statistical distillation of all studies) of studies looking at the topic. Of over 4,500 articles, only 25 were found to have sufficient scientific rigor to be included. "A consistently positive association between high UPF intake and increased risk of developing diabetes (37%), hypertension (32%), hypertriglyceridemia (47%), low HDL cholesterol concentration (43%), and obesity (32%) was observed, even if the quality of evidence was not satisfying." It appears the tilt is developing, confirming the Brazilian's identification of risk.
What is the definition they used for ultra-processed food? Ultra-processed foods are: ready-to-eat or ready-to-heat industrial preparations made largely or entirely with substances extracted from food, often chemically modified, with additives, and with a small proportion of whole food. Therefore, the term "ultra-processed" includes soft drinks, packaged snacks, sugared breakfast cereals, cookies, processed meats, and packaged frozen or shelf-stable meals, but also flavored yogurts, low-calorie or low-fat products, breakfast cereals, and products "fortified" with beneficial nutrients. Oh dear. Sounds like the whole grocery store.
More simple definitions include: more than 3-4 ingredients, more than 2 steps away from the native food, wrapped in paper/plastic, added sugar, and processed fats. For example, fresh yogurt is minimally processed but cheeses have become ultra-processed because of the added salt, colorings etc. Whole grains are ok. You are allowed to remove the inedible husk of wheat, oats, rice. But once you grind it into flour, bread becomes ultra-processed. (I'm particularly annoyed at salted nuts being "ultra-processed) NOVA (not an acronym but the name given by the Brazilians for the food classification system) classification is pretty clear.
What might be the physiological problem that this is trying to capture? There is now little debate about the risks. It's the rush of too many nutrients overwhelming our metabolic capability to properly process the calories. We get too much, too fast. It forces us to manufacture visceral fat, develop fatty liver, fatty pancreas, fatty heart. Visceral fat has been shown to be the driver of uncontrolled inflammation, yielding us with heart disease, cancer, arthritis, dementia and most of our degenerative diseases of aging. Bummer. Eating our modern, ultra-processed foods is the first domino of what has been an elusive search for causation. It's not the single item, it's the whole ecosystem. Our mitochondria are wonders of nature for their ability to convert food into metabolic fuel. But they are touchy little engines and get overwhelmed when we provide too much fuel, too fast, because we made it so concentrated, pure, varied. Too bad it tastes so good. Ice cream is on the list.
www.What will Work for me? How on earth am I meant to go on a road trip and not pick up McNuggets and a milkshake on my drive? I can't take a sandwich? I can't pick up a sub on the way? What this explains to me is why my grandparents, who kept gardens into their later years, eating most of their food from their own little plot, lived so well, so long. My father was planting his beans into his late 80s. If I look in my fridge, I have 3 containers of yogurts (at least two of them are simple, fresh, no additives) but I'm shamed by all the cheeses, ketchup, whipped cream in a can, soda....my fridge is a battlefield. Nature made me to eat foods in a fashion that we just aren't doing anymore. I'm in a sulk.
References: Advances in Nutrition, Public Health Nutrition, Curr Devel Nutr., World Nutrition, Am Jr Preventative Medicine,
Pop Quiz
1. Define in your own words what is an ultra-processed food? Answer: More than one step away from the plant, with any additives, particularly sugar or salt.
2. Is bread ultra-processed? Answer: Count the steps: Grind the flour (1), mix with yeast, sugar, preservatives, and bromine. (2). Put butter on it. (3). Yup. It's Ultra-Processed.
3. My yogurt with fruit is bad too? Answer: Count the ingredients. What's in my fridge has 13 ingredients. I don't know what two of them are.
4. What is happening in my body when I eat this stuff? Answer: It is so refined and so purified, it rushes into me, overwhelming my ability to digest it in the fashion nature designed. My metabolism wants those calories delivered more slowly. Fiber helps. That "overwhelming" results in oxidative stress, and fat accumulation in problematic places. That visceral fat is the secret inflammation engine that drives degenerative aging.
5. How do I get rid of visceral fat: aka, that poochy tummy of mine? Answer: No processed food. Just about all successful dietary plans start that.
LDLs Play Little to NO ROLE in Heart Disease
Half of us are dying of heart disease so this is no trivial matter. Our obsession with cholesterol started with President Eisenhower who had multiple heart attacks while in the White House, with a stroke thrown in for good measure. He finally died of congestive heart failure in 1969 at age 78. He went on a low cholesterol diet and his blood cholesterol went up. He was miserable. Lesions in the heart that plug up the heart are filled with cholesterol so it was just assumed you had to eat less cholesterol. It was there, it must be the cause. That started the obsession with cholesterol. It's been misplaced.
To fix a disease, you have to understand what is causing it. We have had multiple studies in the last few years that reflect an alternative reality. Bathum's study in Scand Jr Pri Health Care is one of the best, among many. In that study, over 118,000 adults, over age 50 were followed for LDLs, Triglycerides, HDLs, statin use, and mortality. With over a million human years of data, their data showed what many other studies have shown: LDL cholesterol has no impact on mortality. In fact, low cholesterol (< 190) has higher mortality than a total cholesterol of 270. For example, for ages 60-70, total cholesterol of 193-232 has 0.68 of the mortality of cholesterol below 193. And 0.67 of the mortality if their cholesterol was between 230 and 270. That's a 32% reduction in mortality, having a cholesterol way above what we consider normal in America, being < 200. We are advising people to lower their cholesterol into a range that is associated with a higher mortality.
Now, confounding all that is that folks on statins had lower mortality as well, somewhat in the same range, some 30%. That confirms the irrefutable benefit statins provide to heart disease once one has had a heart attack. Hmmm. But is the cholesterol lowering effect what actually makes the benefit. That hasn't been proven. And the people who were started on statins were all those with higher cholesterol and therefore lower mortality to start with. So, maybe, just maybe, there is NO BENEFIT.
The authors concluded that only high triglycerides were associated with higher mortality, at least in women. HDLs are protective, yes. But LDLs appear not to be the main problem if any problem at all.
Are we barking up the wrong tree? It is unequivocal that cholesterol accumulates in artery walls. That is proven and clearly apparent. But what is making the cholesterol accumulate?
Ah! There is research to show just that. If you do metabolomic studies of the lipids that predict future heart attacks and strokes, it's not cholesterol that comes out on top, it's plasmalogens, at low levels. Remember, metabolomic studies measure everything, without bias, and then observe what statistically holds up to benefit. That study called the SCORE Study, followed 1852 adults for 16 years and obtained blood levels on 1,228 metabolites every year. They then did the number crunching for statistical validity of what predicted future trouble.
Yes, cholesterol was in the mix but it was low plasmalogens that emerged as most predictive of future unstable angina and heart attack. Whoa! Once again, high cholesterol didn't predict future trouble. Low plasmalogens did.
Here is the probable sequence. Oxidative stress releases a flood of peroxide and the -OH ion. Plasmalogen lipids, present in the endothelial cells of arteries, are the only lipids to contain a vinyl-ether bond that soaks up those peroxide and -OH ions, neutralizing them. That depletes the plasmalogen molecules which are critical for playing a key role in membrane function. Without plasmalogens, membranes get stiffer and have a hard time secreting cholesterol, so HDL levels fall. Endothelial cells shrink their footprint, exposing the basement membrane for LDL particles to stick to. Without that loss of plasmalogens, the endothelial cells would maintain their coating of the artery, protecting them. So LDLs are at the party. They play a huge role in making trouble with accumulations of cholesterol, but they aren't the core root cause. It's fixing the root cause that will prevent the disease.
It's the oxidative stress, probably most prominently driven by the sugar and white flour we eat, and the visceral fat we then develop. That depletes plasmalogens and cells start to separate with membranes that get stiffer and less functional. THEN, and only then, do LDLs start to accumulate.
Got it? It's not the cholesterol that is the root cause. It's that tummy fat, that sugar, that ice cream that starts the ball rolling. We lose plasmalogens. We can measure that. And their loss is the single best predictor of future heart disease. If you want to see into the future for your #1 risk, measure your plasmalogens.
Then, there is the inexorable loss of Nitric Oxide with aging. That is the other prominent wild card in the mix. Eat all the vegetables you can.
www.What will Work for me? Now, here there is some hope. We can now measure and replace missing plasmalogens. I have personally been tormented for years with lousy HDLs and I have done everything but stand on my head to get my HDLs up. I have never been successful, until this last year when I started taking plasmalogen replacements. From an HDL of 28, I am now up to 58. I'm thrilled. Combine plasmalogen replacement with Nitric Oxide replacement as the means of regrowing your glycocalyx and giving your arteries their natural coating, and we can really get to the heart of your heart. How interested is BIG Pharma and BIG Health Care in cutting your risk of heart disease, the #1 health-spend in America? You are interested. But you may not get help. Should you be on a statin? They do reduce mortality, but not for the reason you think. The cholesterol effect is irrelevant. They likely are playing a role as antiinflammatory, reducing the oxidative stress, and reducing the loss of plasmalogens. That research is waiting to be done.
References: Scan Jr Pri Health Care - Bathum, Heart Attack and Stroke, JCI Insight, MedRXIV,
Pop Quiz
1. If I measure everything in my blood, every year, for over a decade, what compound will jump out as being the best predictor of future heart attacks? Answer: Plasmalogens
2. What role do plasmalogens play in the wall of the artery? Answer: No fair. Diidn't fully discuss this. But here it is. They are the most fluid of membrane lipids because they are where DHA, fish oil, ends up. That fluidity and the ability to shape shift allows some unique properties. The membrane can stretch and bend. That's very useful for an artery with a pulse going through it. It's also important to allow the endothelial cell of the artery membrayes to be very thin and connect to all their partner cells. Finally, the proteins embedded in the wall of the endothelial cell can shape shift because of that fluidity. All that is degraded as plasmogens are lost. Their achilles heel is the vinyl-ether bond they possess that is the anti-oxidant of FIRST resort, That protection is nice, for a short term event. It becomes a liability with persistent oxidative stress.
3. Who has a lower life expectancy, someone with a cholesterol of 150 or someone with 250? Answer: I'll take the 250 any day of the week.
4. What is the best marker of my artery cells being healthy? Answer: Lower triglycerides and higher HDL. They indicate properly function cholesterol transport.
5. How can I naturally raise my own plasmalogens? Answer: First, stop the burning. This is why you need to cut down on sugar and white flour. Lose the tummy fat. Intermittent fasting and compressing calories into 8 hours turn on peroxisomes to make more plasmalogens. Exercise also deplete glucose stores and switches you to fat burning, stimulating the peroxisome to make more plasmalogens. So, the simplistic phrase "Eat right and exercise more!" holds water. Do it.
Carbon 60 Buckyballs, Are They Good for You?
When you see the following statement, "Carbon 60 is the most powerful antioxidant currently known – over 270 times stronger than vitamin C!", you might think this is something to explore. Is there any validity to the breathless claims that rats treated with it lived twice as long as untreated rats? Or, if treated with radiation showed virtually no toxicity. Where is all this coming from? Is it worth taking a look?
Carbon 60 is a fullerene, the discovery of which garnered a Nobel Prize in 1996 for Harry Kroto. Imagine a soccer ball of carbon atoms (60 to be exact) in which they are constructed to make 20 hexagons and 12 pentagons. The hexagons all have 3 double bonds in them, separated from each other by the pentagons. This is a very elegant structure.
Those double bonds cover the whole surface of the "soccer ball" or fullerene molecule. What do they do? Well, double bonds have a curious affinity to suck up peroxide and the hydroxyl ion. Those two "Reactive Oxygen Species" are the end products of the oxidative stress cascade that happens everywhere in your body when you are exposed to "oxidative stress". By that I mean anything that overwhelms and taxes the mitochondria, leading it to lose its grip on electrons. When you overeat sugar and saturated fat (aka, ice cream, hamburger with bacon and cheese, giant steak, etc etc) your mitochondria are overwhelmed and the normal leakage of 1-2% of electrons turns into a flood. COVID with its unique toxins creates oxidative stress too. As does smoking, air pollution, microplastics, environmental toxins...the whole gamut of bad things. An escaped electron will damage cells without discrimination. To dampen that damage, we have several enzymes to capture that electron and get it out of the cell into the blood in the form of peroxide. Superoxide dismutase (SOD) and catalase are the two loose electron police. Catalase gets induced and you can measure higher catalase levels in folks with Long COVID, Autism, or other brain diseases.
Glutathione is your next line of defense. It gets diminished, battling the flood of electrons. If peroxide overwhelms glutathione, it then converts into the Darth Vader of Reactive Oxygen species and makes the -OH ion, the hydroxyl ion. Both peroxide and -OH will attack membranes and damage them. This is where plasmalogens come in. They have a double bond on the surface of the cell that captures peroxide or -OH and neutralizes it. But you lose the plasmalogen molecule.
With the depletion of plasmalogens, you set off all sorts of other problems. That depletion is actually the engine driving Alzheimer's, coronary artery disease, cancer, and just about all diseases of aging. This column has covered those connections in great detail.
So, this is no ideal question. Could an exogenous form of plasmalogens be a helpful supplement? That's what C-60 is. It is the only molecule that provides a potent source of double bonds that will suck up reactive oxygen species. Double bonds are so fragile, and actually so rare that we have only a tiny supply of them. We can only make a minuscule quantity of them in our peroxisomes. Could we really take them as a supplement and augment our meager supply? Wow? This would become a backup plan for supporting membranes and soaking up reactive oxygen species.
The problem is, they aren't a natural molecule and they don't fit back into the matrix of our cells. We need plasmalogens for many other reasons. Their fluidity and ability to shape-shift give cellular membranes the basis for their function as they allow proteins to also shape-shift, facilitating activation and deactivation.
There is a company, C360 Health, now hawking C-60 as an antioxidant, claiming the sun, moon, and stars in benefits. They have some impressive graphs showing a reduction in inflammatory cytokines. All those cytokines are set off by the cascades of reactive oxygen species made when peroxide and -OH damage those double bonds.
www.What will Work for me. I love ideas from right field that come out of "nowhere" when you weren't expecting it. There appears to be little toxicity to this C60 fullerene, to date. I'm not ready to endorse it quite yet, but I understand the chemistry and it fits into the concept of Membrane Biology as defined by plasmalogen lipids that drive functionality of mammalian membranes. That functionality will reshape medicine and require a rewrite of all of our textbooks. Medicine is going to be radically reshaped as the plasmalogen revolution rolls over our understanding of modern diseases of aging. This cute, little, Nobel Prize Winning Soccer Ball may have a role in there somewhere. It is the only double bond that survives gut digestion. If it is safe, that may be important. To date, we don't have much human safety data. For now, that's a safety warning. Stay tuned. This is interesting.
References: Neurobiology Aging, Wikipedia Kroto, Biomaterials, ResearchGate, C360Health,
Pop Quiz
1. What is C-60? Answer: It is a fullerene, a ball-shaped molecule, like a soccer ball of carbon rings filled with double bonds. Nobel prize in 1996 for its discovery.
2. What happens when you give it to rats? Answer: They live much longer. (This is a mistake. We need something to get rats to live shorter)
3. How does it have its biological effect? Answer: Dramatic reduction in inflammatory cytokines.
4. How does that reduction in inflammatory cytokines come about? Answer: Those double bonds snarf up the reactive oxygen species that set off all the inflammatory cascades.
5. Is it safe to take? Answer: Time will tell for sure.