Live Longer by Reversing Thymus Aging - Part II
The TRIIM (Thymus Regeneration, Immunorestoration and Insulin Mitigation) Trial caused a lot of excitement when it came out. The first study in humans to show a reduction in the most accurate clock of biological age, our epigenetic clock. The 9 volunteers had a 2.5-year reduction in their age on measuring epigenetic age from the study protocol taken for one year. The Protocol was simple: Growth Hormone, DHEA, Metformin, Vitamin D, and zinc taken for one year with MRIs of the thymus gland to watch its regrowth and serial blood testing to monitor immune response.
Aside from increasing the size of the thymus gland, there were remarkable changes in immune functions that are worthy of note. There was an increase in the production of new T-cells, a core process of a fully mature function thymus gland that decreases with aging. They also documented three classes of new or “naïve” T-cells that increased. Because new T-cells survive and function for years, then these new T-cells (immune traffic cops) will continue to protect after being turned on. That increase could be monitored by measuring the Lymphocyte to Monocyte Ratio: LMR. It increased. There are many studies that demonstrate a reduction in cancer and all-cause mortality with an increased "LMR" ratio.
What is it about monocytes? Well, most of them carry an enzyme called PD38 that degrades NAD. Aha! The link with your epigenome. NAD is the fuel that sirtuin proteins must have. Degrade NAD and your sirtuins won't work. Your sirtuins are the caretakers, the gardeners if you will, the lifeguards of your epigenome. They depend on NAD for their energy supply. More monocytes, less NAD.
It wasn't just immune function as measured by LMR that tipped. The study showed a pretty dramatic improvement in cancer protection by stimulating a reduction in PD-1 expression on cytotoxic T-cells. The PD-1 receptor is used by many cancers to trick your immune system to giving the cancer cell a pass. With that receptor, the cancer keeps growing right under your immune system's nose. The heavily advertised drugs, Keytruda and Optivo, both work by blocking the PD-1 receptor.
Finally, they also showed that the PSA, free PSA ratio all improved quite dramatically: PSA dropped and Free PSA increased. Again, a reduction in risk.
All of these effects are broad-based in their impact and have important implications for overall health. You can summarize it down to just a few key talking points. 1. ) This strategy increases your thymus gland function of manufacturing youthful, active lymphocytes, changing the LMR (lymphocyte to monocyte) ratio.
2). Too many monocytes are not so good for you because they gobble of NAD.
3). You really do need NAD to maintain a youthful epigenome and turn on the right genes when they are needed, and turn off the wrong genes when you don't want them - actions that require NAD. 4). You turn off PD-1 and that doesn't let cancer out of the bag. Keytruda is not cheap. Cancer is not friendly. You want less PD-1.
www.What will Work for me. I've got it. The link between NAD and David Sinclair's brilliant book,Life Span, and immune function comes to focus. We should all be on NAD and Metformin, DHEA, zinc, and Vitamin D. Now, Growth Hormone is pricey at some $ 2500 a month but CJC/Ipamorelin isn't so expensive. The challenge is to get these markers available to us ordinary folks so we can keep ourselves "younger" and measure it to prove it. MyDNAge.com does a pretty good job of telling you your epigenetic age if you want to measure it.
1. What is your epigenome? Answer: the markers on the outside of our chromosomes that manage the expression of our genes. We pass many of those markers on to our kids, so the epigenome acts somewhat like your genes as an intermediate layer. It is managed by your sirtuin proteins, that run on NAD only.
2. What happens to your epigenome with the TRIIM protocol? Answer: In one year of following the TRIIM protocol, your epigenome gets 2.5 years younger.
3. That beneficial effect is modulated by several synergistic effects. Can you name several? Answer: a) Increased thymus size (last week's letter), b) Increased fresh new T cells, c). Improved Lymphocyte/Monocyte Ratio. d). Reduced PD-1 receptor activity e) Increased NAD, f) reduced PSA and increased free PSA, g). reduced CRP.........
4. What is the link between thymus aging and your genetic resilience? Answer: When you make fresh, young T cells, your monocytes decline and they tend to degrade NAD. With more NAD, you have the fuel to keep your sirtuin proteins energized, and they take care of your epigenome, and keep it functioning vibrantly and protectively.
5. Can you name the compounds/elements taken in the TRIIM trial? Answer: Growth hormone, metformin, DHEA, Vitamin D and zinc.
This Column was written by Dr John E Whitcomb, Brookfield Longevity, Brookfield, WI (262-784-5300)
Reverse Thymus Aging - The TRIIM Trial
Your thymus gland, just behind your breast bone, is the nexus of your immune system. By age 50 it is basically all composed of fat and non-functional. Without a properly functioning thymus gland, your immune system starts drifting toward "lack of balance" with many indications that you are becoming vulnerable to disease. Aging. We can measure aging by the calendar, and indeed, we sing Happy Birthday to you every year.
But, a more accurate measure of your frailty is your epigenetic age. Your epigenetic age is now acknowledged by most aging scientists as the best marker of your biological age. Your epigenome is the library of methylation and other markers on your DNA that indicate to you "when to hold 'em, and when to fold 'em", when to turn on genes and when to silence them. That whole system is maintained by your sirtuin proteins which are nourished and fed exclusively by NAD and not ATP. Your epigenome has its own energy system and its own repair system. Repairing and maintaining DNA had to be the first function of the first cell on planet earth, so sirtuins and NAD are found in all cellular life.
Your thymus gland and your epigenome have a curious intersection. The aging of the thymus gland results in a reduced population of naive T cells that can be programmed by the thymus to balance many components of the immune system. Thymic involution leads to the depletion of critical immune cell populations, resulting in a collapse of the T-cell receptor (TCR) repertoire in humans after the age of ~63. Immune aging turns on many populations of cells that cause trouble, and your epigenome can't help out, because it too is degrading. That creates a curious nexus between your epigenome and your thymus aging. To fix one, we have to fix the other.
The question arises, can we reverse this? Well, yes! Turns out growth hormone helps regenerate your thymus gland. But growth hormone has a nasty tendency to nudge you towards diabetes. So, the TRIIM trial(Thymus Regeneration, Immunoregulation, and Insulin Mitigation) decided to counter that with a combination of Growth Hormone, DHEA, Metformin, 3000 iu of Vitamin D, and 50 mg of Zinc. Nine men, ages 51-65 were recruited who were given this cocktail, and then had their thymus gland measured by MRI every couple of months.
What happened? Voila. After one year of treatment, the men were 1.5 years younger by epigenetic testing. That means a -2.5 year gain on aging. Their thymus glands grew back dramatically. The study was widely talked about and has been rated in the top 5% of research papers ever scored.
www.What will Work for me. Well, I've measured my epigenome once and I know understand the combination of growth hormone, NAD, metformin and Vitamin D. After promoting Vitamin D for 15 years, I feel vindicated for that. Now, Growth Hormone is expensive. But the technology of growth hormone has leapfrogged into the world of peptide sciences. It is much cheaper, more effective, and safer to get your boost from the peptides that stimulate you to make your own growth hormone. And last but not least, it is also helpful to see the impact of DHEA and its importance. Just about everyone over age 55 has a dramatically lower DHEA than they had at age 20. This study is so important, that we will do more on it next week. This is enough for my aging brain to soak up in one week
1. What happens to your thymus gland with aging? Answer. Fades into the sunset.
2. Is there an acknowledged age where it seems to hit the final wall? Answer: Yes, age 63.
3. Your "biological age" can be measured more accurately than your calendar age? T or F. Answer: True
4. How? Answer: Your epigenetic age. We can now measure and count that.
5. Remind me, what is your epigenome? Answer: the complex markers on your histone proteins, your DNA coating, that instructs your cell about activating and inactivating your genes in response to environmental changes.
This column was written by Dr. John Whitcomb, MD, Brookfield Longevity, Brookfield, WI, (262-784-5300)
Yale Can Image Your Brain and Define Your Cognitive Function
The long-standing sign of Alzheimer's is a shrunken brain. In fact, brain shrinkage is so common in all of us, that radiologists will often make offhand comments that an older person has mild shrinkage, but within normal limits. We have presumed that loss of linkages between neurons, called synapses, is what is happening but hard proof has been difficult to come up with. That means we are all on the path to getting Alzheimer/s, just with some getting it sooner and some later. Hmm.
A little bit of basic science. The estimate is that you have about 4 quadrillion synapses in your brain with each active neuron connected to some 3500-10,000 other neurons. You have so much redundancy and resilience that it is thought that you have lost at least 50% of your synapses before you demonstrate cognitive decline. You can function at 50%. You have just lost the ability to immediately remember where your car keys ended up.
Therein lies the dilemma. This has all been "presumed" but not proven. What is called "mild cognitive impairment" (MCI) or otherwise shrugged off as "senior moments" is actually part of the same process, just earlier in the journey. Treating the disease called Alzheimer's is fruitless. It's too late. You can't bring back the lost neural connections. Preventing it depends on knowing early and reversing the conditions that are setting it off while your brain can still tap into the biological process of rebuilding redundancy. And preventing depends on having some means of quantifying early disease in a credible fashion.
And that is what Yale just proved. Researchers at Yale have now measured early cognitive decline. A PET scan using a new glycoprotein called SV2A gave the researchers a measurement of metabolic activity in brain synapses of 45 people diagnosed with mild to moderate Alzheimer's disease. Each person was then tested in five key areas: verbal memory, language skills, executive function, processing speed, and visual-spatial ability. The loss of synapses or connections between brain cells was found to be strongly associated with poor performance on cognitive tests. There you have it. It's not widely available yet, but it will be coming. The loss of synapses correlates directly with loss of cognitive function. It makes perfect sense.
And this correlates exactly with the plasmalogen evidence that effectively says the same thing, but at the molecular level. Let me repeat that metabolic explanation! Our synapse membranes are 70% plasmalogen content. Plasmalogens are using choline as part of their structure. For our brain to function, it must have acetyl-choline to communicate across the synaptic cleft. If your synapse gets a little short on acetyl-choline, it can make some more by borrowing choline from its own plasmalogen membranes, in effect self-cannibalizing. That's the problem. You can't borrow from Peter to pay Paul forever. The ultimate Ponzi scheme. Enough "borrowing" and the synapse collapses. Now, you only have 3 quadrillion, 999 trillion, 999 billion......you get the point. This process is going on for decades. Lose a synapse here and there and you lose the neural network that retrieved where your keys were.
And that, my friend, is how we will conquer this cognitive decline epidemic. If we measure and quantify your plasmalogens, which we can do, and we repair your methylation system, your inflammation system, and your mitochondrial health, all in the same package, which we also can do, we can give your brain the tools to repair itself. Fundamental to all biology, cells will repair themselves if given the right tools and building blocks and removed from the environment of reductive deficiency. Likewise, your brain will rebuild redundancy and resilience if it has the proper building blocks. And now we have a PET scan coming that will provide the precise details to assure you that you are making progress. Cool, Huh?!
You have time. This is a long, persistent issue. But don't discount that "senior" moment. Take it as a warning that you have lost some function you used to have and you want it back.
www.What will Work for me. Having now measured plasmalogens for over 18 months and seen folks come back and say they feel improvement, I'm sure we are on the right path. The issue is whether we can prove it and quantify it. That should be the goal. I want hard data. Someone in a memory unit with severe dementia has lost so much function that rebuilding redundancy and resilience is a much higher burden. I take my plasmalogens every day.
1. What was the imaging technique they used at Yale? Answer: PET scan
2. For cancer, a PET scan uses high glucose use to indicate unusual activity. In this scenario of cognitive decline, the imaging compound was what? Answer: Glycoprotein SV2A
3. Did the research report say much about amyloid plaque or tangles, some of the old criteria for Alzheimer's? Answer: Nope
4. What is the key engine driving cognitive decline? Answer: loss of synapses, or links between neurons.
5. And what is the key nutrient missing that makes you lose a synapse? Answer: choline plasmalogens.
This column written by Dr. John E. Whitcomb, MD, Brookfield Longevity, Brookfield, WI 53045
HDL Cholesterol Relates to Insulin Resistance, and THAT's the Heart Disease Engine
We have known since 1977 that it's low HDLs that are the real risk of coronary artery disease. What we didn't realize back in the 1970-90's was the dimension of insulin resistance overlaid on HDLs. For folks with insulin sensitivity, higher LDLs have virtually no risk at all. It's the binding of LDLs to the vessel wall, their subsequent oxidation that then drives them to be gobbled up by macrophages that deposit the lipid pool in the artery. And that process is driven by insulin resistance.
Each of us has about 1000 LDL particles per cell in our body. Per cell. There are a lot of LDLs. Their job is to deliver cholesterol from the liver to cells to help make membranes. HDLs are much smaller, and there are 10 of them for every LDL, but they never get sticky. Their job is to take leftover cholesterol individual cells don't need and take it back to the liver. They don't have the APOB molecule on their surface, so they can't stick to the vessel wall. It's sticky LDLs that stick to the vessel wall. How do they get sticky?
Ah! That's the issue we need to understand. Stickiness comes about because of insulin resistance and subsequently higher blood glucose. Any given LDL particle becomes more likely to be bound to proteoglycans in the intimal space when it is enriched with the apolipoprotein ApoC III—a process that occurs during states of insulin resistance.
Then there is the added dimension of ceramides, the waxy fats that make our internal organelle membranes much more rigid. We develop with when we eat too much sugar and saturated fat. With too many ceramides in our membranes, they get too stiff and can't export HDLs. Ceramides also point straight at fructose.
And how many of us are insulin resistant? That's the million-dollar question. If you take the most recent guidelines about waist circumference, A1c, BMI etc, you will find that only 12% of Americans are metabolically healthy. The rest have some degree of insulin resistance. And they are making arterial plaque. Using the most recent guidelines, metabolic health was defined as having optimal levels of waist circumference (WC <40/34.5 in for men/women), glucose (fasting glucose <100 mg/dL and hemoglobin A1c <5.7%), blood pressure (systolic <120 and diastolic <80 mmHg), triglycerides (<150 mg/dL), and high-density lipoprotein cholesterol (≥40/50 mg/dL for men/women), and not taking any related medication.
Obsessing about total cholesterol misses the point, almost completely. Our guidelines for administering statins are off the mark badly. What we want is healthy arteries. And the proper guideline is Insulin < 5, HDL, 40/50 (men/women), BP below 120/80.
And that brings up back to our HDLs. HDLs are the garbage trucks of our bodies, carrying leftover cholesterol back from cells that don't need it. Healthy cells have healthy peroxisomes and healthy levels of plasmalogens in their internal membranes. If you eat too much fructose, your make more ceramides, the waxy fats that make membranes more rigid. Your mitochondria and peroxisomes get damaged and you have trouble exporting HDLs, proportionately to your falling HDLs and rising ceramides. Low HDLs mean metabolically damaged cells with insulin resistance. High ceramides mean lower plasmalogens. So, if you think there is a correlation between insulin resistance and Alzheimer's, you got it right.
You can reverse all that. Sugar is such a powerful engine to drive trouble, first and foremost, you must get sugar consumption down. Your waist to hip ratio, your HDL, your insulin, and your blood pressure will all reveal to you your metabolic health. Key to all your efforts is losing weight. There you have it. It's not total cholesterol, it's insulin resistance. Weight loss and control of body size is our metabolic story.
www.What will Work for me. I've been on a three-month streak of wearing a continuous glucose monitor. I'm humbled by what I have learned. Yesterday, in the middle of a 16-mile bike ride without having eaten any lunch, I felt a bit washed out and tired. There was a Clif Bar, chocolate, in my bike bag, leftover from last fall. 6 months old. Frozen in our garage all winter. Wow, it looked good. 250 calories, 17 grams added sugars. My glucose by my monitor was 77. Down went the Clif Bar. 15 minutes later, glucose 145. Whew. It dropped back down pretty fast because we were biking. But for half an hour there, I was glycating my LDLs. That's what is happening to all of us. No more Clif bars for me.
1. What is the job of your HDLs? Answer: Picking up excess cholesterol and take it back to the liver. (That means your cells are healthy, have enough cholesterol and the internal membranes are robust and replete with plasmalogens, low on ceramides.)
2. A healthy cell with healthy membranes can be demonstrated by what? Answer: the ability to "efflux", export, cholesterol, so HDLs have to go up.
3. Insulin resistance can be measured and defined by insulin level. T or F. Answer: True. You want a level below 5. Average American is 12. "Normal range", or what is seen in the population is 2-29.
4. What percentage of Americans are metabolically healthy? Answer: 12%
5. Slender women with a total cholesterol of 230 and an HDL of 70 should be on statins. T or F. Answer: False. That's why our cholesterol guidelines are broken.
Where Are We Exposed to Oxalates?
Last week we learned that oxalates have no role in humans except as a breakdown product of two amino acids. We make about 25 mg a day. Plants, however, use oxalates widely, mostly as poisons to keep themselves from being eaten by other creatures like insects, etc. And, oxalates allow plants to live in adverse environments with high burdens of toxic metals. Oxalates bind and chelate many heavy metals.
We also learned that it is possible for humans to die from oxalate poisoning. There are rare but famous examples of folks who have eaten rhubarb leaves. The toxic, pre-lethal dose is considered to be 500 mg/meter squared body surface area. That appears to be a lot and there is quite a bit of space between the 25 mg a day our body makes and excretes, and the lethal dose. Or is there?
Just about every health website has a page listing high oxalate foods and admonitions to be cautious if you have kidney stones. WebMD has a nice page listing spinach where a half cup of cooked spinach will give you 750 mg of oxalates. One cup of soy milk, or soy yogurt will give you 336 mg. One ounce of almonds gives you 122 mg. Baked potato, 97 mg. Beets, 152 mg per cup. Beans, 76 mg. How about a nice, "healthy" smooth cleanse? Well, put in a couple of cups of spinach in your smoothie, add some soy, some nuts and you could have yourself a lovely oxalate rush. If you had gastric bypass, a known method to induce higher oxalates, and got yourself a smoothie cleanse, you could go into renal failure, and end up on dialysis, as proven by one case report.
Is all this exposure a problem? Well, yes! Here is one example. Did you know that you can show a link between oxalate exposure and the calcifications in breasts that are the early sign of breast cancer in women? And if you then inject oxalate into mouse footpads, a common method of measuring toxicity, you can demonstrate the growth of cancers that appear similar to breast cancer in humans.
Another example. Folks with decreasing kidney function are known to have high oxalates in their urine. Recent research has shown that there is marked activation of the inflammasome pathway of progressive inflammation linked to oxalates.
What happens if we eat foods high in oxalates? Well, research has been done on that. Let's take the iconic wonder food, chocolate. It's pretty high in oxalates. Take 6 volunteers and have them eat 100 grams of chocolate. That's quite a lot, but a goal most of us can stretch to reach. That dose of chocolate will raise your blood level of oxalates to the same level as someone with the genetic defect, primary oxaluria. Voila, you have made yourself potentially ill for a couple of hours. Now, do that every day.
Just about every oxalate website out there says the nutritional quality of high oxalate foods balances out the risk of the oxalates, which become high risk only rarely. Paul Saladino, in his book, The Carnivore Code, says you are playing with fire. Bruce Ames explains how in his "triage theory" that posits the short-term effects of mild deficiency, or excess is not noticed. Only severe deficiency becomes apparent in the short term. But long-term, low-grade deficiency, or excess wears you down. "Death by a thousand cuts." Oxalates are little tiny cuts. And we expose ourselves to them at our own risk.
www.What will Work for me. I really wanted to learn about oxalates and internalize the details. It's the gradual decline in kidney function that I see in so many people who are essentially vegans that I worry about. The number of women with mammograms showing microcalcification, and who are heavy plant-eaters.... All of these examples haven't really been studied as the long-term effects are too expensive a research project to do. I am an "n" on only one. I'm not a randomized controlled trial by myself. I don't have medical research to guide me. But I eat a lot of vegetables, spinach included. I love "saag paneer", Indian spinach curry. I have it about once a month. Bruce Ames is suggesting that the "long game" of long-term health is an important consideration. There are some plants that are low oxalate that I love. Hurray for black and blueberries (raspberries are pretty high). Kale is low. Ditch the spinach. (WebMD has a nice list of Low Oxalate Foods...many sites do too)
1. What food might be the highest oxalate food? Name a couple: Answer: spinach, almonds, soy, potatoes, raspberries, chocolate
2. What percent of Americans have kidney stones? Answer: Somewhere around 7-10%. Most of them are oxalate-based.
3. What percent of American women have microcalcifications on mammogram? Answer: Somewhere around 10-15%
4. How much oxalate does my body make every day? Answer: 25 mg.
5. And how much oxalate can I get from a green smoothie with spinach in it? Answer: Ooooh! Ten times your minimum. Same with 100 grams of chocolate.
Oxalate, the Poison You Didn't Know Much About
Oxalic acid. Tiny little molecule we humans make as a byproduct of digesting glycine and hydroxyproline, two amino acids in protein. We have no use for it. It is an end-product of metabolism and just needs to be excreted. We get rid of about 10-30 mg a day. A few folks have a genetic problem with it and they have higher excretion rates (100-600 mg a day) and have many kidney stones, kidney failure. We call that systemic oxalosis. It's rare. The toxicologists say that 5 grams is a lethal dose and 500 mg per meter body surface area is dangerous. Ok, that means it is a bona fide poison too, at high levels.
But lots of plants use oxalate as part of their operating system. Like lectins, plants use oxalate to poison animals and insects so that they don't get eaten. In plants, the molecule is actually manufactured in the process of photosynthesis and is used in chelating many minerals to help maintain cellular levels in a constant range. Plants can grow in otherwise toxic soils with too much lead or cadmium around because oxalic acid binds up the minerals. Oxalic acid is useful to plants.
The problem is that we humans eat plants and don't think much about it. We just sort of assume it's safe for us to munch on. Hmmm. Did you know there have reported deaths from eating rhubarb leaves? Yup. Sad but true. How about kidney stones? Nine percent of Americans have them. 75% of kidney stones are oxalate in composition.
Then there are crystals of oxalate in our tissues if you go looking for them. For example, one autopsy study found that 79% of thyroid glands have oxalate crystals in them. The same study also found crystals in the thymus, blood vessel walls, kidneys, testicles, brain, eyes....it appears we deposit the crystals in an asymptomatic fashion and they accumulate over a lifetime. Could all those crystals be annoying our immune system sufficiently to set off an autoimmune response?
Is there any connection to disease? Well, yes. Kidney stones are common. But it is frequently taught that the mystery disease, vulvodynia in women, is best treated with a low oxalate diet.
It's not the disease state per se that is the problem, it is the low level of exposure that makes for long-term, chronic "annoyance" that just adds up. Could there be evidence for that? Bruce Ames, functional medicine pioneer extraordinaire, posited the "triage theory" that basically says we are limited by what's extreme at the moment, but maybe not be being just borderline deficient in the immediate sense, but accelerated in the chronic time-frame. The reverse of that is what is in action here. We are poisoned in the short term by what is extreme, but what is going on when we are chronically exposed to something noxious? Gundry has made a point of positing lectins as being the root of many autoimmune diseases. Could oxalates be another class of problem makers we haven't made widely known? We do know that low levels of many chemicals like PCBs, dioxins, DDT, etc play havoc with us. Those are man-made problems. But plants are also trying to avoid us. We are their "pests" and they make their own "pesticides" to keep us away. And just where do we get those oxalates (aka, "human pesticides") from? Heck, to be a real mid-Westerner, you have to have a rhubarb patch in back. And I do. Next week we'll talk more.
www.What will Work for me. Dr. Saladino in his book The Carnivore Code has written one of the best treatises on oxalates I have seen. He relates to his personal story of getting his own eczema exacerbated every time he ventures into eating some high oxalate foods. I'm trying a weight loss regimen based on his teaching and so far, I've got my glucose averaging below 90 most days by following his advice. I'm eating a lot of fatty animal products. And a lot of fish. I would love to find a simple measure of oxalate other than a 24-hour urine collection. But I now know that 30 mg should be our upper limit.
1. What are oxalates? Answer: a metabolic byproduct of digesting glycine and hydroxyproline, two amino acids.
2. How much do we naturally make? Answer: about 30 mg a day
3. Plants make oxalates for their own purposes. Examples? Answer: they use oxalates to inhibit them being eaten by poisoning caterpillars, as one example. And by binding heavy metals so that the plant can grow in otherwise heavy metal laden soils.
4. Human can get in trouble with oxalates. Can you name one example? Answer: Yes, you can drop dead from a salad of rhubarb leaves. Then there are kidney stones. It goes on.
5. Can you name the upper limit of safe oxalate? Answer: Cheap trick question. Bruce Aimes claims, in his triage theory, that low level of deficiency will manifest itself only when extreme and then changes your fate immediately, but at low levels may accelerate the process of aging. But the deficiency may be modulating your fate without your being aware. Reverse that and you have low level of toxicity modulating your fate, and you aren't aware. So, there may not be a "safe upper limit" by that metric. Until now.
Ceramides are the Missing Link to Diabetes and Insulin Resistance
Who cares? I never heard of ceramides. Why would anyone waste their time worrying about something I can't even pronounce? Ah, therein lies the truth. This is one of the metabolic keys to how we get sick. Ok, explain!
First of all, what are ceramides? They are membrane lipids that play a huge role in making your cells' outer membrane more rigid and firmer. They have a waxy component to them. You actually start life coated with a waxy ceramide covering, the vernix caseosa, that newborns have covering them at birth. We wipe it off. Your cornea has a ceramide coating to keep it from drying out. Your skin is the same. It gives us a protective coating that creates an effective barrier. So, we need ceramides for all sorts of valuable structural components in our bodies.
But it's the metabolic effects of membrane-chemistry of ceramides that is the new cutting-edge frontier. Of all the causes of diabetes, it is the sphingolipid ceramide that is the main culprit that combines a plethora of too many nutrients (notably saturated animal fat) and inflammatory cytokines (such as TNF-alpha) to the progression of insulin resistance. That's step one. Step two evidence is that
hypertrophied adipose tissue, after fat cells exceed their storage capacity, neutral lipids overflow and begin to accumulate in non-adipose tissues, inducing organ dysfunction in many organs. Fatty liver, for example. Fatty muscle is another. Finally, being overweight is linearly related to the development of chronic inflammation and the release of cytokines directly from adipocytes or from macrophages that infiltrate adipose tissue. And its ceramides playing a key role in each of these stages.
A little bit of "overweight" results in a little bit of stress on your pancreas. Your beta cells have to crank it up and make more insulin to keep the fat cells responsive and keep glucose in check. Your insulin level rises. (Anything over 5 is risky. You may get away with 7. But 12 is the average American insulin....and goodness, are we ever in trouble. Our pancreas glands wear out and we simply run out of the capacity to make sufficient insulin to keep our stiff, rigid, ceramide-laden fat cells taking up glucose. Intramuscular fat typically made up of ceramides is actually more predictive of insulin resistance than waist-hip ratio or BMI. (Think of marbling in human muscle instead of steak. Your cows are equally ill-served metabolically when you look at your juicy, marbled steak at the grocery store. That cow was also developing diabetes, given time and too much corn. )
It gets more and more complicated as the intermingling of multiple metabolic pathways all pitch in. But that's the nugget. Saturated fat causes insulin resistance. Plain and simple. Ceramides in your cell membranes make up the net mechanism by which that saturated fat carries out its demon effects.
www.What will Work for me. Aha! Here is the conundrum. I want to lose weight. If I eat bacon (the epitome of saturated fat food,) I feel full and don't eat too much. And I can lose weight. Turns out getting into ketosis and burning off all that fat in your liver, your muscles, your heart, your pancreas....all the places that fat has accumulated as you stuffed yourself with corn chips, and donuts and rice and bread....is the means to reverse the metabolic damage. So, a few months of bacon and saturated fat will reverse your metabolic ceramide disaster. Getting slender has a goal in sight. If your glucose is below 86, your insulin below 5, your A1c below 5.5 you are likely in good shape. Now, keep it there. The ability to measure ceramide levels is coming on the market and is included in the Prodrome test of plasmalogens. We finally have a lab that is including it in their panel. We just need to start using it.
1. What are ceramides? Answer: waxy fats that provide membrane stability to our cells, so crucial components of the structure of our membranes.
2. How do ceramides cause trouble? Answer: Ah, the nugget. Too much saturated fat forces us to make too many ceramides and our membranes get goofy. Not sure exactly where or how, but those ceramides are stiff and rigid, making membranes that are meant to be more fluid dysfunctional.
3. What is the simplest way to measure the metabolic dysfunction of too many ceramides? Answer: Insulin level. Get it below 5.
4. How can I reverse my ceramide damage? Answer: cut the flood of carbs, lose weight, get your fat cells smaller, and allow your body to burn off all that extra stored fat that is crammed into every niche in your body.
5. And what is the easiest way to lose weight without being way too hungry? Answer: have a diet of omega-3 rich animal products and get yourself into ketosis. That allows your insulin level to get to 2 and your fat cells to open up and share their calories. Over a couple of months, you will drain your liver, your muscles, your pancreas, your heart....and return to metabolic stability. If you could find pure grass-raised meat, and ocean-caught fish, you would be perfect, but perfect is hard to find in our modern world. And you can only eat so many wild-caught sardines.
How Saturated Fat Wreaks Its Damage on You
Saturated fat is bad. Right? Well, not so fast. Lots of nuance here.
First of all, what is saturated fat? It is fat with all the carbon bonds filled with hydrogen bonds, maximizing the energy content. As a general rule, what you have in calorie storage around your middle is saturated fat made with mostly 16 carbon (palmitic) and 18 carbon (stearic) acids. When you add a double bond and "desaturate" it, you lose two hydrogens in making the double bond and add a 30-degree angle in the molecule. Instead of being straight, and packing tightly into a lattice, the molecule is bent and can't pack tightly. It becomes more liquid. Hence, olive oil has one double bond and is liquid. Fish oil is a rich mixture of DHA and EPA which have 5 double bonds with 5 bends of 30 degrees each. That makes it a spiral that really can't pack tightly and makes membranes very fluid. Hence, plasmalogens have a DHA molecule on them, giving them their fluidity and utility in your central nervous system.
Grass-raised animals don't have much saturated fat in them. It is only when they are stuffed full of corn and beans on feedlots that they generate "marbling" of their meat, and make the meat juicy and tender so you pay more for it. Wild-caught game is largely composed of omega-3 fats, just like wild-caught fish. Humans' diet has been mostly wild-caught game and seasonal edible plants until about 5000 years ago. And fatty parts of the animal were favored. Plants were "starvation food" or when rare, ripe fruit was around. It was only the last 150 years that we developed fine white flour and coffee shops and donuts, making human feedlots where we stuff ourselves with so many calories that we too make saturated fat and marbling of our muscles and livers.
Saturated fat is bad for you. It sets off inflammation. As part of it, we do know that the cell walls of gut bacteria break down and get into our blood. We call them LPSs and they are clearly inflammatory. Here is the synopsis of how saturated fats wreak their havoc. It starts with too many calories arriving in your mitochondria all at once. Our mitochondria are designed to eat one nutrient at a time. Give me a fatty meal, or a protein meal, or a carb meal and I'll do fine. Don't fry my protein and my carbs and combine too many calories and flood my mitochondria with too much energy all at once.
The biochemical pathway is now better understood. Eating lots of saturated fat turns on inflammation in a novel way. Researchers from Arizona found that saturated fat activated the innate immune system with a novel pathway requiring metabolism of the fat to ceramide and activation of PKC-ζ/mitogen-activated protein kinases. Did you get all that? Eating saturated fat activates your innate, built-in immune system. There is a potent amplification of monocyte/macrophage innate immune responses through saturated fat that gets altered and changed into ceramides. Ceramides are then the nexus of trouble, but it started with the full combination of saturated fat in the diet, too many calories, too big a tummy.
Simplify it! Fat was our food of choice in our "pre-history", hunter-gatherer diet. It was a rich source of omega three fats then. Now, animal fat is different. Our animals are overfed. Saturated fat was rare in our "pre-history" food chain. Now, with feedlot animals it is common. We magnify its wicked effect by eating too many calories and exposing ourselves to too many things that turn on gut inflammation and leaky gut (NSAIDs like ibuprofen, wheat, dairy, nightshades, lectins.....). Then, the party begins and our fat tissues spew out inflammation.
www.What will Work for me. Bummer. It's hard to look at our modern food chain and see all sorts of wicked, saturated fat in it. But I believe we are beginning to parse out the details. My belief is that the real engine that drives trouble is insulin resistance that goes hand-in-hand with obesity and big tummies. It is not the cholesterol that's causing the problem. It is the glycation and oxidation of our cells caused by high blood sugar that activates our immune system. Then we have saturated fats on top of it and away we go. I'm wearing a continuous glucose monitor to measure my own glucose excursions. Very interesting. Rice from the Indian Restaurant will give me a blood glucose of 240 in 20 minutes. Now, that's a real bummer.
1. Saturated fat causes inflammation? T or F. Answer: It actually potentiates it if there are other things present. Like too many calories. Life leaky gut and LPS molecules in your blood.
2. You can measure a unique intermediate metabolite that appears to be the smoking gun nexus with saturated fat activation of inflammation. What it is? Answer: Ceramides.
3. You mean, if I eat coconut oil (a short-chain fatty acid mix) and a life eating only coconuts and fish on a Pacific Island, I might not get in trouble. Answer: Yup. (No fair - not mentioned in the column above.)
4. If blood glucose is the problem, then weight loss and reduction of blood glucose reduces the amount of fat in my gut, and reduces the LPS particles in my blood, and that may reduce more risk than not eating bacon? T or F. Answer: Whew, long question. Yes, it is more important to lose weight and control your tummy fat than to avoid bacon. If bacon helps you lose weight. Go for it.
5. Close your eyes and imagine the one food you can add to anything you eat that makes the food MUCH better. What is it? Answer: Bacon. I find it interesting that the food we all yearn for is fatty animal food. Suggests that is what we have been eating for 4 million years. That must be true because I found a pound in the back of my fridge that looked at least that old.
The column was written by Dr. John E Whitcomb, MD at Brookfield Longevity, Brookfield, WI (www.livelongmd.com) or 262-784-5593
Meat and Scurvy
"If you only eat meat, (Animal Products), you will not get the vitamins you need. You will die of scurvy. (Vitamin C deficiency)" was what was said to Stefansson and Anderson when they returned from living with the Inuit for 5 years. Well, they hadn't died. They came back from northern Canada looking trim and fit. The scientific community of New York was convinced they were scientific fraudsters and refused to acknowledge their findings. Vitamin C had just been discovered and it was considered to be critical to life. After all, all those English sailors died on sailing ships unless they got their limes (hence the name 'Limies').
To prove their point, Stefansson and Anderson agreed to live solely on meat for a year, living at Bellview Hospital and providing a urine sample every morning to prove they were in ketosis and had not eaten any carbs. Well, they didn't die. They walked the streets of New York and did just fine. No diabetes, no weight gain, no scurvy. These were exactly the findings they had reported on the Inuit from Greenland and Northern Canada.
Ok! How? What's going on?
Studies done during World War II on conscientious objectors showed that you could induce scurvy in about two months by withholding Vitamin C. Doses of 10, 30, and 70 mg of Vitamin C. All three doses worked to cure the scurvy in equal amounts of time. Did you get that? Ten mg a day is enough to cure scurvy. You don't need much Vitamin C to cure scurvy. And further studies measuring the anti-oxidant effect of Vitamin C in the blood show no added benefit at higher doses.
The answer is that you don't need Vitamin C at all if you eat just "animal". It has Vitamin C in it, despite most nutritional tableslisting animal products as having zero vitamin C. In fact, at about 16 mcg/g in grain-fed meat and 25 mcg/g in grass-fed meat, you get plenty of Vitamin C from "animals.". More importantly, it's the digestion of carbs that needs more vitamin C to accomplish, so you don't need that much when you eat just animal products. Hence, Stefansson returns from Northern Canada, healthy and trim. He reported that some Innuit in Greenland were developing scurvy, but only after being provided with "nutritional assistance" in the form of wheat and corn products, carbs.
Now, there is a whole discussion about saturated fat as being bad for you. I think there is nuance there for another day. Animals raised on grass just don't have that much saturated fat. Our modern, feed-lot animals, stuffed with corn and beans are chock full of saturated fat. Just like we humans. The overabundance of carbohydrates forces our metabolism to become insulin-driven, supersaturated with fat we have to rush into storage. Our cows and pigs put on weight. So do we. If we are to be meat-eaters and avoid the perils of saturated fat, we need to have pasture-raised animals, eggs, cheese, milk, fish, shrimp, oysters, sardines.....
There you have it. The question remains, how did that come about? Well, we humans began to evolve a larger brain some 5 million years ago and shifted to eating more animal products to support our energy-hungry brain. We started hunting and cooking, all of which supported our enlarging brain. We had so much Vitamin C in our diet and needed so little, there was no dietary need for more Vitamin C. There was no evolutionary penalty to the loss of the ability to manufacture it for ourselves, because, by eating meat only, we simply got enough. Same with B12. You don't get B12 from plants. It was only 5000 years ago that we started shifting back from hunting and eating meat to settling down and eating plants. That's not enough time to recover the need to make Vitamin C.
www.What will Work for me. I used to believe you had to have Vitamin C and took a gram of it every day for years. That was while I was being a foodie, following all the admonitions to eat mostly plants. "Eat Foods, Mostly Plants, Not Too Much" was pretty much a mantra. I've read the book Carnivore Code by Paul Saladino. He makes a pretty strong argument for reconsidering our fear of animals. As I've watched my gradual waist line enlarge, I've been discouraged with the metabolic mess eating just plants seems to lead to. I've been wearing a glucose monitor for a month now, eating animal only. It's mind-boggling. Next week.
1. Vitamin C is critical for life. T or F. Answer: True (and a supplement if you eat carbs)
2. Indigenous peoples have always chosen animal foods over plant foods? T or F. Answer: True.
3. When you feed bison corn and beans, the fat in the bison becomes what? Answer: In just a few weeks, their fat changes from mostly omega-three fatty acids to saturated fats. Just like with all mammals. Sheep, pigs, cows, camels, humans......
4. The fat in your waistline is mostly what? Answer: Well, you ate corn and beans too.....saturated fat. Call it your feedlot-tummy.
5. Can you prevent scurvy by eating meat. Answer: Yup. It has sufficient Vitamin C
The Fat We Eat Has Changed for the Worse
Fat isn't just fat. There are important differences between types of fat. Last week we learned that humans were apex predators by measuring Paleolithic bones and finding very high levels of Nitrogen-15, an isotope that gets concentrated up the food chain. And the review of "primitive" diets found in residual "First Peoples" reveals that fat has always been the food of choice. Animal organs, brains, and fat stores were the prized food items in virtually every prehistoric food chain. Just what were those fats? What did our paleo-grandparents eat?
What we know they didn't eat was corn, soy, peanut, or any other vegetable oil. Those oils, by and large, require industrial equipment to separate and harvest. We now also know that those oils are rich mixtures of omega-6 fats.
When you examine a grass-raised animal (including cows), you will find that their fat tissues are composed predominantly of omega-3 fats. Wild game is usually around 6-8% omega-3 fats. As soon as an animal (including humans) is fed large amounts of concentrated carbohydrates (corn and beans on a feedlot - or donuts and ice cream at a coffee shop), the mammalian organism will make saturated fat and store that. Humans do it. Cows do it. We like our steaks juicy and tender, and the saturated fat of marbled beef is just that concentrated saturated fat. And it's inflammatory. It's not natural to be in the cow. Nor is it natural to be in us. We never had it in our food chain before.
We now know that the human brain should have a substantial proportion of omega-three fats in it to manufacture plasmalogens, thereby building the axons and synapses to construct a healthy brain. Plasmalogens are the lipids without which a central nervous system could not exist, and DHA, the apex omega-3 fatty acid resides in plasmalogens. It is the fluidity of DHA and plasmalogens that allows our brain to shapeshift and thereby fuse membranes, allowing neurotransmitters to be secreted. It is plasmalogens that allow embedded proteins in the brain and mitochondria to function rapidly. It is no wonder that a mother's milk is one of the richest sources of DHA as a baby's brain is rapidly growing and needs those building blocks.
And we don't have omega-three fats in our food chain. Paleo man did. His/her grass-raised mammoth/deer/moose/rabbit was 6-8% omega-three fats. His walrus, whale, seal were 50-60% omega-three fats in their blubber. We can't compare exactly, but one clue as to changes of DHA in the food chain in just the last 100 years is to compare mother's milk in America to women's milk (0.2%)in more pastoral societies that have more grass raised exposure (0.32%). Close to a 40% drop.
Another means of comparison is to look at the ratio of omega 6 to omega 3. That is the ratio of anti-inflammatory building blocks to inflammatory building blocks. Paleo man probably had a 1:1 ratio. Today, our urban societies have a 10:1 ratio and our inner-city folks with little access to grass-raised animals have a 20-50:1 ratio. That change is largely driven by the seduction of fried foods and fast foods which use large amounts of vegetable oils, these supply huge amounts of omega-6 fats.
We still don't know the full scope of damage caused by the change in ratio. The hints we are getting with the discovery of Alzheimer's and plasmalogens are filling some of the cracks. The impact of omega-3 fatty acids on many mental health measures suggests that our brains are just crying out for more omega-3s. It is no wonder that that nation with the highest omega-three consumption has the least depression, Iceland.
Feedlot-raised animals have their fats change. Those changes are not to our benefit. Their fat becomes largely saturated with little residual omega-3s. It takes about a month to lose half of an animal's omega -3 fats, to be replaced with saturated fat. We can't eat a Paleo diet, where fat is what we are seeking when we pick up steaks at our local grocery. And our expanding bellies have that same, inflammatory, saturated fat in them.
www. What will Work for me? Bummer. I'm trying to find grass-raised animal foods and it's no mean feat. Even a local butcher that claims to have all grass-raised animals has a suspicious amount of marbling in their steaks. My conclusion is to take a tablespoon of fish oil every day. I'm not permitted to shoot the deer in my suburb, and their meat is likely highly contaminated with pesticides. I can buy wild-caught sardines, but not forever. When I measured my Omega 3 to omega 6 ratios, I was ostensibly in the healthy range. I suspect my occasional ocean-caught fish and supplementing will have to be what I can muster. I can monitor my plasmalogens and make sure my brain has enough building blocks.
1. Where do omega-3 fats come from? Answer: Green plants on land or in the sea.
2. Our bodies use omega 3 fats for what purposes? Answer: To make anti-inflammatory messengers/hormones and as building blocks for our central nervous system.
3. Paleo humans preferred fat in their diet. What percent of a Paleo deer would have been omega-3 fats? Answer: Probably around 8%. How about a seal or walrus? Answer: Their blubber was likely 60% omega-three fats.
4. A feedlot-raised animal has how much omega -3 fat in them? Answer: Usually less than 1%. It's all been swapped out for saturated fat. And comes in around 30% of modern meat.
5. How much saturated fat was present in Paleo game? Answer: Zero.
6. And the vegetable oils that are so prevalent today are composed of what? Answer: Rich mixes of inflammatory omega-6 fatty acids.
This column was written by Dr. John E. Whitcomb, MD,Brookfield Longevity, Brookfield, WI (262-784-5300)