Hallmark of Aging 5 - Decreased Autophagy

Hallmark of Aging 5 - Disabled MacroAutophagy


Here is another mouthful to learn about. MacroAutophagy, or just autophagy for short. It's how we get rid of the big stuff. In everyday life, your regular garbage goes out in the trash can. If it's too big, you call the company and ask for the big truck to take your ....old freezer, washing machine, or whatever, away.

In your cell, the big garbage truce is called an autophagosome. It is a separate little entity in the cell, designed to surround or envelop old, used-up parts of the cell that need recycling. That autophagosome then fuses with a second entity called a lysosome that is basically a package of digestive enzymes you wouldn't want running loose inside the cell. Whatever is in there, it gets chopped up and all the amino acids, fats, and sugars come out as their basic selves, ready for building something new.

Old mitochondria, broken proteins (often misfolded), bits of misplaced DNA or RNA, and even bacteria and viruses are all chopped up and reprocessed. At least that's how it's meant to work.

Then there is the city dump you can take stuff to. In your cell we call that an exosphere, which is basically a membrane containing the junk to be reprocessed that is packaged up, spit out of the cell into the blood, and destined to be chewed up and digested by white cells called macrophages that envelope it, take it in and digest it. They do it the same way. They have packages of enzymes that fuse with their internal package of "garbage". All neat and tidy.

All these disposal mechanisms give the cell leeway to clean itself up. If one pathway doesn't do it, the next can pick it up. Until it doesn't. There is clear evidence that decreased macroautophagy is a problem. In multiple experimental models, animals with good macroautophagy live longer.

Reduction of autophagic flux may participate in the accumulation of protein aggregates and dysfunctional organelles, reduced elimination of pathogens, and enhanced inflammation because autophagy eliminates proteins involved in the inflammasome and their upstream triggers.


You begin to realize there is a whole universe of research going on into autophagy with several journals dedicated to its discovery. We need it to keep generating fuel when we go through famine, as our bodies selectively break down cellular elements to keep us fed. Mice with knock-out autophagy genes die of hypoglycemia because they can't generate glucose. The list and nuances merit a whole afternoon of reading if you want a rabbit hole to go down.


On the other hand, when garbage accumulates, old, dysfunctional organelles like mitochondria, instigate inflammation. Just like keeping compost in your kitchen starts making a smell and cockroaches move in, the breakdown of autophagy leads to cellular inflammation and eventual early demise.

www.What will Work for me? This gives another reason for some sort of fasting behavior. It sharpens up all your internal tools of autophagy. And one more time, we find an interplay with the Nrf-2 antioxidant controlling system and autophagy. There is a cross-talk and shared enzymes between the two. I can take the supplement PB-125 from Pathways Bioscience because the food extracts in PB-125 stimulate the Nrf-2 system, under which autophagy is at least partially controlled. I pay my village taxes to have my garbage taken each week. I need to restrict calories in some fashion to do the same internally.


References: Cell, Cell, Autophagy, Frontiers Cell Devel. Biol.,


Pop Quiz


1. What is autophagy?                                    Answer: The internal garbage disposal system inside each cell.


2. What is its function?                                Answer: Several key issues. Getting rid of broken intracellular proteins, DNA, and organelles that will induce inflammation is one point. But having the ability to hunker down and reprocess parts of the cell to make fuel in time of lean nutrients is also key.


3. If you knock out an autophagy-controlling gene in mice, what happens if they are deprived of food and go through a spell of starvation?                                 Answer: They die of hypoglycemia.


4. What is the system controlling autophagy?                              Answer: We may not have the whole picture but the Nrf-2 system certainly has overlaps. It is the central controlling system for all inflammation.


5. Is there any one thing I can do to induce better autophagy?                           Answer: Yes, intermittent fasting, forcing your cells to be a bit hungry, induces the internal repurposing function and keeps the enzymes tuned/sharpened. Besides taking PB-125 from Pathways Bioscience.


Hallmark of Aging 4 Proteostasis

Hallmark of Aging 4, Proteostasis


Whew, I bet that pulls you up short. Can you pronounce that? Do you have a clue why it would be on the list? Or what it even means? Proteostasis. It all starts with your "proteome". That's the universe of all your proteins. Just like the genome is the measurement and stage of all your genes and the metabolome is the whole sum of all your metabolic products made by your genes, the proteome is the universe of your proteins.


Proteins are delicate little creatures. They have to be folded into just the right shape. It can take two or three chains of amino acids to make the final protein. They get tricked out with all sorts of extra sugar molecules and an atom of zinc, or selenium, or cobalt, or whatnot. They have lots of little additives pasted and glued in place. Then, after all that, we ask them to do impossible things incredibly quickly. We take that all for granted. Many enzymes take various compounds and break them into pieces, or add a piece on.

This is not a trivial issue. The accumulation of beta-amyloid occurs in Alzheimer's because of the inappropriate activation of wrong proteins. ALS is associated with mutations in proteins that render them intrinsically prone to misfolding and aggregation. That saturates the mechanisms of protein repair, removal, and turnover that are required for maintenance of the healthy state.

Then there is the whole system of properly recycling old proteins that need to be broken down and their products recaptured. The field of protein maintenance is actually quite complex with whole fields of study in all the details.


Finally, there is the Nrt -2 system (nuclear factor (erythroid-derived 2)-like 2) and its effect on proteostasis. The Nrf-2 system was thought to be the master regulator of inflammation but it's turning out to be much more. It is a a key component of the transduction machinery (mobilizing the right DNA in order to activate a process) to maintain proteostasis. In a sense, the Nrf-2 system is a hub that compiles emergency signals derived from misfolded protein accumulation in order to build a coordinated and durable transcriptional response. (Did you get that?). Whew.


www.What will Work for me? I can do something about the Nrf-2 system. We've talked about that before. The Mediterranean diet and the Okinawa diet explained because the vegetables and green foods commonly eaten by them induce Nrf-2 activation. Our Nrf-2 system declines as we age and doing something about it is now possible. The first introduction to that market is the product from Pathways Bioscience called PB-125 that you have to buy directly from them. It's not on Amazon. Buy it. Take one a day. It's just the spice rosemare with luteolin and ashwaghanda. Those three plant foods are synergistic in their Nrf effect. Your proteins will appreciate it.


References: Cell , Redox Biol,


Pop Quiz


1. Why is proteostasis so complicated?                                   Answer: Because every process of life is run by proteins which have thousands of different forms, shapes, means of being folded, extra components, and then exposure of toxins, poisons, oxidation, not to mention recycling and disposal


2. Just what does proteostasis mean?                            Answer: maintaining the state of proper function of all your proteins. That's life itself .


3. How does the Nrf-2 system interact with proteostasis?                                 Answer: Ah! It appears to be the master controller of turning on the right genes to keep your proteome in tiptop shape.

 

4. How can I fix that?                                      Answer: Here is my pitch for PB-125. I don't have any financial relationship with them. I just take it myself.


5. Any other suggestions on how to maintain my proteome?                               Answer: It's a massive topic with huge research going on. Taking plasmalogens allows your membranes to function better. We're going to see more research on that.


Epigenetic Alterations - Hallmark of Aging 3

Epigenetic Alterations, Hallmark of Aging 3


Can you define the "epigenome"? It's not your DNA. It's not the genes tucked into your mitochondria. It's not even DNA. It's the markers on the outside surface of your chromosomes that curiously pass on some of their information to subsequent generations.

For example, two famous famines, in northern Sweden in early 1900 and in Holland during World War II, the offspring of those who suffered through those starvation times can be shown to still have metabolic abnormalities into the third generation. Another example, emotions that pass on in families reflecting generational trauma or even just cultural trends have some of their roots in epigenetic measures. Is that what drives the persistence of racism and its painful recurrent generational trauma?


Another example is likely the means by which all animals pass on their advice to their offspring. Fear of predators and safety of groups appears to be ingrown. Yet deer, living in safe places (our suburbs) become so accommodated to humans they are brazen in their nibbling on our flowers. The elk of Estes Park in Colorado are famous for their virtual occupation of the town. They have no fear. Town is safe. Their DNA has not changed. What passed on their behavior? Likely epigenetic changes.


Your epigenome is the markers on the outside of your DNA that instructs your body when to hold 'em and when to fold 'em. When to activate DNA and when to shut it down. There are some 20,000,000 of them on your chromosomes in complex web. You can attach a one-carbon signal (methyl group) or a two-carbon signal (ethyl group) to DNA or to the histone proteins. Each has separate signals.

Then there are the Sirtuin proteins tasked with caring for your DNA. Humans have 7 of them. Single-celled primitive life forms only have one sirtuin. The sirtuins are the groomers and repair specialists of your epigenetic system. They run on the NAD energy system instead of the ATP system. It's much less efficient and much more primitive, suggesting that sirtuins have been central to cells duplicating themselves since time immemorial. NAD declines with aging.


Hence, David Sinclair in his awesome book, Lifespan, argues that you need to take metformin, the diabetes drug at a 25% of effect (500-800 mg a day) to stimulate the production of more sirtuins, and NAD (otherwise known as niacin or Vitamin B3) in order to power them. This is all in the service of caring for your epigenome.

The frontier of cancer care now is all about measuring the detectable alterations in your epigenome that lead to cancer risk (marked reduction in markers). There are even companies offering cancer screening with high rates of specificity for some cancers. It's very complex because the 20 million markers aren't written in plain English, but pattern recognition is beginning to take hold.

Epigenetic modification mechanisms are still being discovered. There are all sorts of messenger RNA including circular mRNA and micro RNA particles that aren't coding for proteins that have epigenetic actions. If you want a really deep rabbit hole, type in retrotransposons and aging. (DNA segments that can get up and move their place in chromosomes and wreak havoc.). They play a role in cellular senescence, a cardinal sign of epigenetic exhaustion.


www.What will Work for me. I have used epigenetic markers to measure my biological age compared to my calendar age. I have used epigenetic markers in my clients to look for cancers, with satisfying responses. I'm taking metformin and NAD to care for my epigenome. I'm stymied about the complexity of it all but I do know that simply allowing my body to get into ketosis helps most of this. Prolonged starvation is such a drag, but a bit of induced starvation (skipping breakfast) or manufactured starvation (energetic exercise) likely accomplish the same thing, without the death part.


References: Cell, Oxford Handbook of Emotional Dysregulation, Overkalix Study-Wikipedia, American Jr Biolog Anthropology, Lifespan by Sinclair,


Pop Quiz


1. What is your epigenome?                     Answer: The markers on your chromosomes that indicate when to activate and when to silence genes.


2. Do you actually pass those genes on to your kids?                   Answer: Yes, to some degree. How, we don't quite know yet.

3. What are those markers?                       Answer: simple one and two carbon compounds, methyl groups and ethyl groups.


4. What are the proteins tasked with caring for your epigenome?                   Answer: The sirtuin family, stimulate by metformin and powered by NAD.


5. Can you name one dramatic effect of metformin and NAD?                        Answer: No fair, this answer takes reading Sinclair's whole book. But here it is. Recently menopausal women may get their period back when starting metformin and NAD. Some may not think of that as a major leap forward.


Telomere Attrition Hallmark of Aging 2

Telomere Attrition, Hallmark of Aging 2


Do you know what a telomere is? Yes, it's the cap or end of the chromosome that doesn't code for any protein. The enzyme that duplicates DNA has to have a fixed number of base pairs inside the protein to do its work of copying the DNA. When it gets to the end of the chromosome, it has those base pairs inside it but unable to be reached. Those final base pairs get lopped off. The chromosome is a tiny bit shorter. That is a rate-limiting step on how many times that cell can duplicate.


This isn't the same phenomenon as "genomic instability", Hallmark #1 because of the action and function of an enzyme called telomerase. It can lengthen the telomere and there is research in mice and humans on how to do just that. In some cancers, the activity of telomerase actually helps lengthen lifespan and kill off the cancer faster. That makes telomere lengthening and shortening a separate phenomenon. The inexorable march of that shortening explains the observed phenomenon called the Hayflick Limit that predicts how many times our chromosomes can duplicate, and therefore how long we can live.


Yes, you can lengthen your telomeres. There is a 6-protein complex called shelterin that makes the repetitive sequence of base pairs TTAGGG. That sequence is what is repeated in telomeres. When there are enough of those sequences, shelterin can attach and in just the right circumstances, stimulate telomerase to make longer telomeres.


One clinical example is a study in thejournal Lancet on 25 men with prostate cancer compared to 25 controls. The prostate cancer group was put on a plant-based diet, nudged into more exercise, provided with extra social support, and given stress management exercises. In just three months, their telomeres were longer compared to the controls whose telomeres had lengthened.


The NHANES study, the largest, ongoing study of adults in America reviewed every 10 years with comprehensive dietary analysis, shows that for every 10 grams of extra fiber per 1000 calories, your telomeres will be 83 base pairs longer. That translates into 4-5 years extra lifespan.


We can now quantify telomere length in the research lab. There are also companies that will measure your telomere length for a fee. Just type in Telomere measuring and you will find a raft of companies providing the service. Consider pledging to yourself extra exercise and more fiber and see how you do. Add some meditation and stress management to the mix and you will replicate some of the process that has been done in research labs elsewhere.


www.What will Work for me? I measured my biological age last year and did a test on myself. I reduced my biological age by some 9 years by taking Tartary Buckwheat and metformin. This is something that is within your reach to do too. It's a fascinating rabbit hole to go down and I'm mesmerized by the concept. One more time, exploring the Hallmarks of Aging reinforces the lifestyle methods you can follow that can be measured and documented with tests that are now coming online. Those tests aren't to be found at your regular family doctor who is examining you for the presence of disease. If you have to get a tattoo this week, consider making it TTAGGG, just to remind you to have the salad instead of the pizza.


References: Cell , Cell Metabolism, Nature Review, Nutrients, Wikipedia, Lancet


Pop Quiz


1. What is a telomere?                            Answer: Aw, come on. That's a softball. It's the "Nonsense DNA" on the end of your chromosomes that gets shortened with each duplication of your chromosomes.


2. Is there a name for the result of all that shortening?                           Answer: Yes, the Hayflick Limit.


3. Can I lengthen my telomeres?                      Answer: Yes.


4. Name one strategy you can add to your lifestyle that will help you lengthen your telomeres.              Answer: Exercise, fiber, stress management, plant-based diet, social support.


5. Can I escape the Grim Reaper doing all those things?                  Answer: Well, maybe 5 years extra. Adding plasmalogen supplementation may add more.


Hallmarks of Aging 1 Genomic Instability

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 Portfolio

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

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

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.


The Maillard Reaction: The Devil in Your Food

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.


A-2 Milk Really Is a Better Milk

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.


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