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1. How do we tie the squabble at AHS to Neolithic disease generation?
2. How does a cell react to acute stress and what results?
3. How does this stress get measured by labs and my doctor?
4. What happens when this stress lasts too long?
5. Why cholesterol is always good for us, but why the surrounding terroir dictates the disease we get?

Let’s continue talking about cellular stress and depletions of things in a cell. We got on that topic because of the macronutrient squabble from AHS. But after following some twitter feeds (@Drjackkruse if you want to follow me on twitter or instagram) about supplement regimes I thought I might try to tie some cellular mineral depletions together with how it causes the cell stress and causes it to affect its cellular terroir and our resultant hormone status. I think this story will help you understand just how important following the trial of biochemistry is.

Any type of cellular stress lowers our stores of ATP and of magnesium (Mg) because they are coupled together by our ATPase enzyme as we saw in this post. This is classically seen in diabetes development as we mentioned there. Another interesting thing also occurs to the cell, that we clinicians can follow on our patients regular labs like a Chem 7. Their carbon dioxide (CO2) levels also fall, while cells become dehydrated, because mitochondria are actively transfer tons of electrons to O2 to make more ATP to replace the deficit from the stress. This causes a simultaneous drop in CO2. The normal cellular response to ANY cellular stress however is rather telling to review for most lay people and MD’s because they may have forgot how that biochemistry works via its connection to the environment. The simultaneous fall in ATP and Mg2+ stimulates the cell to make LDL cholesterol! Yes, you read that correctly folks, the supposedly bad LDL stuff, LOL! It is obviously not bad if the cell is making it for some reason. Let us look why the cell does this. You may want to reread this blog on cholesterol.

The cell responds to all stress by increasing cholesterol production. If you go into an ICU with a patient with an acute infection and draw their lipids (not often done except by a tool like me) you will find sky high LDL cholesterol. And that is both LDL and HDL, but they LDL fraction is much higher. Higher LDL cholesterol stabilizes the inner mitochondrial membrane function during heavy oxidative phosphylation (cellular energy production). And since the cell is trying to recover from a stress it needs a good inner mitochondrial membrane in which to transfer its electrons to make ATP. That is the reason why this occurs. You can review this in this post.

But here is why the cholesterol story tends to trip clinicians up. The cholesterol is needed by the cell for many uses. To be used properly, cholesterol is made to stabilize membranes and make all our hormones. To do this several co factors are also required. If the cells have a lot of toxins around or the use of the cholesterol is too slow it can oxidize and become the real bad stuff called the sdLDL that is oxidized easily (sdLDLox). This is the stuff that can hurt you. How does this happen? Well to make steroids we need an adequate amount of thyroid hormone (T3) and vitamin A around to convert the cholesterol to pregnenolone and then to DHEA. Remember the blog post that spoke of pregnenolone steal syndrome? So if someone is hypothyroid and/or has low vitamin A levels they can accumulate higher sdLDLox and this lowers the HDL level. Remember from the VAP post that a lower HDL means less filtering ability (endocytosis clearing by the liver) in the liver’s portal circulation for endotoxins. That means that the liver is no longer as good a sieve to filter any toxins from our guts to keep the antioxidant burden in our general circulation low. Continuing on, the lowered HDL causes a “leakier” gut too to proteins, toxins and unwanted bacterial toxins that can further oxidize the plasma and even the increased amount of cholesterol the body just made to combat the stress. This is precisely why patients with chronic hypothyroidism tend to have higher levels of heart disease and other neolithic diseases like autoimmune conditions.

They can’t use their newly minted cholesterol fast enough to make steroids or new mitochondrial membranes because they don’t have enough T3 and or Vitamin A. So the excess cholesterol oxidizes and is taken up by the arteries and deposited in macrophages that will later become foam cells and eventually an atherosclerotic plaque that could make your coronary artery blow up or clot and cause a heart attack. Any cellular stressor can do the same thing. Infection, high cortisol levels, obesity,  trauma, even sleep apnea can cause this.

The other affect of hypothyroidism (low free T3) is that it causes decreased steroid synthesis due to pregnenolone steal syndrome. Remember steroids secretion are how the brain maintains control over the twenty trillion cells in our bodies. If you can’t make the chemicals the brain needs (cortisol) to maintain this control all hell can break loose from a control stand point. It also stands to follow that the lowered levels of these hormones are predictive of this process to the inquiring physician by lab testing. What I look for in these actue cases like this is a raised cortisol level with a decreased hormone panel early on the disease process.  As this process become chronic cortisol and the hormone panel become flat lined.   The steroid cascade from cholesterol’s conversion is disrupted because of a lack of either T3 and/or Vitamin A are required for steroid conversion.   After cholesterol is converted by this process it becomes pregnenolone , DHEA, and progesterone and the remained of the sex steroid hormones.  Those bio-chemicals are very proximal to the cholesterol conversion defect.  T3 is a measure of a lack of sunlight and Vitmin A abnormalities are a proxy for a badly lit environment of the patient by fake light or a lack of sunlight during daytime.  If they are lowered then we know we really have got a problem brewing. So this is why I use those hormone assays as clues to what is going on in the cell during stress. For example, in ICU patients who are sick and cant sleep well they suffer from very low levels of DHEA. Low DHEA levels correlate with very high IL-6 levels and poor sleep. If this is allowed to go on long enough patients may get an acute ICU psychosis called delirium. In brain trauma patients we see very low levels of progesterone and this correlates with poor neurologic outcome because progesterone is a co factor in brain derived growth factor to make new neurons.

This means that all the steroids formed from cholesterol will also be lower if this chronically goes one. That means the sex steroid hormones also fall, and so does Vitamin D3 levels. This is why low estrogen, testosterone, progesterone and vitamin D levels are all associated with heart disease, many cancers, autoimmune diseases and a chronic leaky gut and lower HDL level! Its all simple cellular biochemistry that many of us have forgotten.

Now that we have covered an acute cellular stress response lets talk about a chronic one we all will become familiar with…..aging. In aging, our metabolic rates drop we tend to sleep less. This means that we will have a lower T3 level as we age as heteroplasmy rates in mitochondria rise. This is, in fact, what we see in aging. We just reviewed above what a low T3 can do in acute cellular stress. What do you think happens with aging? You’re catching on now. It does the same thing but the onset is more insidious. And as this happens slowly over time what occurs? Our hormone levels all decline slowly as mitochondria become pseudohypoxic and have lowered voltage and a low NAD+ level.  For some this decline happens to certain hormones quicker than others. But with testing we can predict what this means means to the aging person’s cellular stress.

In the acute cellular example I gave you I told you about needing more cholesterol for stabilizing the inner mitochondrial membrane to make more ATP (energy). In aging, we need to raise cholesterol for another more dire reason. As we age our cell divides multiple times over the decades. As it does this over and over again it shortens a part of chromosomes called a telomere. This is actually a biomarker for really how old our cell is. But here is the important part. As a cell divides it needs cholesterol to make a new cell and new chromosomes. Cholesterol is found in the nucleus in our chromosomes. It is even bound to our DNA and to the nuclear terroir surrounding our chromosomes. This cholesterol helps to control how a cell’s chromosomes divide. This is called a mitotic spindle. Cholesterol also is needed to activate our genes and their epigenetic switches that turn them on and off. If that cholesterol is not present, chromosomes don’t divide properly and genes get turned on and off at the wrong times. This results in bad signals and sometimes the wrong number of chromosomes. This is called cellular aneuploidy. When this happens we generally see can cancer form in the the cell. This is why we see cancer develop  in older people.  This is also much more common when the LDL cholesterol is low.  This is also why people with lower levels of LDL cholesterol have higher rates of cancer in multiple studies! Even the highly touted Framingham Heart study showed this realtionship  between cancer and low LDL to be true. Ironically, however we still think in medicine a lower cholesterol is somehow better? So as we age the cell’s normal response is to make more cholesterol to make cell division perfectly safe and carefree.  It also help the inner mitochondrial membrane make CO2 and ATP properly.

So the moral of this story that when you see something in the cell that is depleted or unregulated normally in response to an acute or chronic stressor you would be wise to pay attention to the cellular biochemistry to dictate what you should consider doing. Cellular signaling and depletions can lead to neolithic diseases. With depletion of magnesium due to high insulin levels we saw how diabetes becomes a problem. With cholesterol depletion acutely and chronically we see how it can lead to heart disease, acute delirium, poor sleep, complete hormonal disruption and if allowed to go on chronically you may eventually get cancer. If you are thinking that incidences of all these diseases has gone up in the last 150 years you are correct. They all go up as we age. So if you choose to do things differently than how most people handle acute and chronic cellular stressors you may exert control over your cellular fates (Levee One). If you pay attention to the cellular levees and protect against them you may never face any of these neolithic diseases. Ponder those thoughts for a while, it could save your life and likely change your DNA too.

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  1. […] This should help you guys understand it all a bit more………. CELLULAR DEPLETIONS….WHY SHOULD YOU CARE? | Jack Kruse Reply With Quote   + Reply to […]

  2. Cameron House August 20, 2011 at 7:17 pm - Reply


    I just read this and reread the VAP post and was curious if Paleo diet will reverse atherosclerosis or just prevent it's worsening? If so how?

    Also thanks again for a GREAT BLOG!

    • Jack August 20, 2011 at 7:20 pm - Reply

      It can reverse it if it contains all the correct micro nutrients and avoids dietary overproduction of sdLDL which it often does.

      • Antonis Kyriakou August 27, 2017 at 1:26 am - Reply

        What does dietary overproduction of sdLDL mean sir?

        • Jack Kruse August 28, 2017 at 7:52 am - Reply

          It means your liver is making too many when you enevironment is stealing energy from your cells.

          • Antonis Kyriakou November 26, 2017 at 3:18 am

            Thank you sir!

  3. Kaleein August 20, 2011 at 8:04 pm - Reply

    This is putting so much together for me! Even though there are many things in your blogs I don't quite understand since I was not schooled in biochemistry of the body, as you explain it all I'm amazed at how "simple" it all really is and how the medical community that spent so many years studying science could NOT KNOW this stuff!!??!!?? Too much time studying MEDICINE (big pharma) and not so much time on the science of the body, I guess.

    One of my last doctor visits where my labs were presented to me, I was telling her I needed to fix my hypothyroidism and she was telling me, "No, maybe we need to increase your Prozac because the TSH was 'normal' (4 on scale of 1-4)." Also on those labs was a lowered LDL, for which I was praised, but also lowering HDL. It wasn't totally in a danger zone yet, but the doc was "concerned" … DUH? I WAS HYPOTHYROID!!! I see now, those two are connected and I'm just astonished my doc poo-pooed my insistence that my thyroid needed help!!! Makes me really angry when doctors don't pay enough attention to patients and now I can see more of the details that supported my claim … more than the low basal body temp, the sluggishness, fatigue, etc, etc, ad nauseum. It was signalled in those labs! (TSH range SHOULD BE more like 1-3) I'm really NOT wanting to EVER go back … but I might, with this article and the rest of the blogs in hand once I'm recovered. (I am also on Armour Thyroid now, and working on balancing the thyroid along with the Leptin reset. So it should be an interesting visit with that doctor in about another six months or so.)

    Thanks so much for all you're doing, Dr Kruse!

    • Jack August 20, 2011 at 8:35 pm - Reply

      @Kaleein This is why I lean heavy on biochemistry. It may make your head hurt for many of my blogs but sooner or later you will see why I do it. It allows us to see clearly why an evolutionary approach is best for optimization. I will continue to integrate this info instead of trying to deconstruct theories and opinions. To me that is how we got in trouble in medicine. When someone argues with me now I just open a biochemistry book or an endocrine book and show them what it says. My patients really like the way I go about things because they know why they have the problem they do and I seek to fix it not only in surgery but in the grocery store and in their kitchens. Thanks for the kind words.

  4. cancerclasses August 20, 2011 at 9:40 pm - Reply

    @Cameron House: Proper diet, including paleo diets, both prevent and can reverse atherosclerosis over time.

    Check this video from the Ancestral Health Symposium, "Paleo Diet and Atheroma: A Cardiovascular Surgeon's Perspective" by Dr. Guy-Andre Pelouze http://goo.gl/0ORd3

    Among other things he explains that: native (reduced) LDL cholesterols in paleo diet meats are NOT atherogenic, only oxidized LDL causes atheroma, and without oxidized LDL it is very difficult to have plaque formation.

    Oxidized LDL cholesterols are comprised of straight molecules that pack together tightly like a bundle of straws and form dense plaque deposits that because of their molecular properties become polymer like and are difficult to emulsify with blood & plasma fluids. The reduced cholesterols in organic meats on the other hand have a different structure and do not & cannot pack together to form plaque deposits.

    From Wikipedia, Unsaturated fat: "Trans unsaturated fats are particularly risky because the double bond stereochemistry allows the fat molecules to assume a linear conformation, which leads to efficient packing (i.e., plaque formation).

    (Contrary to Trans fats,)The geometry of the CIS double bond introduces a bend in the molecule, thereby precluding (preventing) stable formations (see specific fatty acid links above for drawings that illustrate this). Natural sources of fatty acids (see above) are rich in the cis isomer." http://goo.gl/PhNnn

    From Wikipedia, Trans fat: "Trans fat is the common name for unsaturated fat with trans-isomer (E-isomer) fatty acid(s). Because the term refers to the configuration of a double carbon-carbon bond, trans fats may be monounsaturated or polyunsaturated **but never saturated**." This is why natural saturated fats and cholesterols made from them are superior to artificial fats. http://goo.gl/JrCI6

    Also, high spectrum chromatography studies of arterial plaques found over 10 different compounds but NO saturated fats. Again, this is due to the different molecular forms between oxidized fats & cholesterols as opposed to good natural saturated fats and cholesterols. http://goo.gl/wzegi

  5. Resurgent August 20, 2011 at 10:44 pm - Reply

    Once again a great post, Jack.. Thanx.!

    What is evolving is that, a normal person, regardless of his lifestyle and eating habits, regardless of his age and medical history, should regularly test for some bio-markers to know the real state of his cell health. What we need from you is a clear self help procedure, what should one test for and how often. This information, I think, should also become a very important part of the Insurance regime you proposed earlier.

    • Jack August 21, 2011 at 10:37 am - Reply

      @ Resurg Many people want this…..but it is useless unless you have someone who can decipher it. Just look at Patrik right now over at PH asking about his 23andme data? He bought it and has no clue how to make an actionable sense of it. So you must ask yourself was it any good or worthwhile?

  6. pam August 21, 2011 at 6:06 am - Reply

    "Any type of cellular stress lowers our stores of ATP and of Magnesium (Mg) … This causes a simultaneous drop in CO2."

    That's interesting to know because then CO2 would be a pretty accurate indicator for current magnesium status, wherever a RBC magnesium test isn't available. Unless there would be too many other possible causes for low CO2. What do you think?

    • Jack August 21, 2011 at 10:33 am - Reply

      Not true Pam all the time. Context of the testing and the person has to be done clinically. This is what makes medicine an art and a science. A low CO2 does not always mean a low Magnesium. You can get a real low CO2 from an acute head injury in a normal person who has good intracellular Mg for example. Remember context!! This one of the largest errors I see in many blogs that argue about macronutrients and diet. They never put things in context because few scientific papers do this as well. That is why their conclusions are usually faulty and it requires really dissecting the paper.

  7. Tim August 21, 2011 at 10:33 am - Reply

    "This means that all the steroids formed from cholesterol will also be lower if this chronically goes one. That means the sex steroid hormones also fall, and so does Vitamin D levels."

    Does supplementing with Vit D help correct this or merely shift the problem?

  8. Jack August 21, 2011 at 11:22 am - Reply

    @Tim. Just correcting Vitamin D alone helps this area but it does nothing for the hormones that are made earlier in the chain. HAving an optimal Vitamin D and a real low DHEA level may mean that with a persistent poor diet you may not get autoimmune disease of cancer but you may wind up with terrible sleep from your cratering DHEA levels and you will also notice libido, ED, osteoporosis, and energy changes from the simultaneously decrease in sex steroids. It also may be why you cant get pregnant. It may also be by your cognistion is lower now and you cant learn as well because your progesterone is too low. These are all things I see daily……all caused by a bad diet and often go undiagnosed because no testing is done to uncover these biochemical secrets of optimal health.

  9. cancerclasses August 21, 2011 at 1:15 pm - Reply

    @Cameron House and everybody: For a REALLY sobering view of what TRANS fats do to your arteries take a look at the Wiki page about atherosclerosis, and the chart & pictures. http://goo.gl/QKIEA

    Might also want to look at the Wiki on atheroma, another pic and more good info there. http://goo.gl/1X5m3

    At the risk of sounding repetitive I cannot stress enough that the time to stop intake of ALL TRANS fats in processed "foods" & liquid vegetable oils is NOW, and ideally 10 or 20 years ago. But since most of us are just learning about these things we'll just have to be extra diligent with our diets from now on.

  10. pam August 21, 2011 at 2:27 pm - Reply

    "A low CO2 does not always mean a low Magnesium. You can get a real low CO2 from an acute head injury in a normal person who has good intracellular Mg for example."

    Thought so already. For example had my lowest LDL after a ferocious infection. But guess the real problem would much more subtler determinators than acute injuries or infections..

    • Jack August 21, 2011 at 3:19 pm - Reply

      If your LDL was low with infection that tells me something is not right biochemically…….so you need to monitor that. With acute infection your LDL should rise normally.

  11. pam August 21, 2011 at 4:04 pm - Reply

    Thanks for the comments. Think it might be related to testing 2 weeks later only. The infection itself occurred on vacation in India in Jan. 2010, the coldest winter there for a long time.

    However, that I had the most carbohydrates during that month for a long time (except for the week with infection, when I just fasted): chapatis made of wheat, sugar in Chai, and rice – leading to such a low LDL was for me the most wired of it all.

    From 180 mg/dl in Oct. 2009 down to 91 in Feb. and up to 142 again in April 2010. Guess the strong infection just depleted all my cholesterol stores.

    • Jack August 21, 2011 at 4:20 pm - Reply

      Or your liver was not working well…..I bet your HDL was real low too then.

  12. pam August 21, 2011 at 4:57 pm - Reply

    Don't know if it means much, but liver enzymes were actually at their best at that time: GOT 22, GPT 23 and 32 GGT. Though still low, but HDL was actually on an upward trend not interrupted by the infection. And Triglycerides made a similar move as LDL, just not as pronounced.

    However, HbA1c, EST and non-sensitive CRP have been the highest I've seen since I test regularly for almost 3 years, but still not that bad at 5.1%, 47 and 0.6.

  13. sage_ August 22, 2011 at 12:54 pm - Reply

    hi Dr. K,

    your answer to Resurgent sounds like something my doctor would say and that makes me sad. its like saying only people who can read should have access to books. why isn't it useful to have a medical history documented by specific tests even if you won't know what numbers mean? couldn't the results be used for comparison in the future as our understanding improves??

  14. Perry August 22, 2011 at 2:11 pm - Reply

    Hi Jack,

    What do you think of this? This seems huge and dove tales nicely with your Quilt layering does it not?


    • Jack August 22, 2011 at 3:05 pm - Reply

      Fits quite well…….also jives with my Alzheimer's theories as well.

  15. Perry August 22, 2011 at 2:14 pm - Reply

    This link explains more about the proteins involved.


    • Jack August 22, 2011 at 4:14 pm - Reply

      nice find!

  16. Perry August 22, 2011 at 4:44 pm - Reply

    The authors wrote that "All types of ALS are, indeed, tributaries, pouring into a common river of cellular incompetence."

    "Cellular incompetence", sounds like you wrote it for this post on depleted cells…

  17. Jack October 6, 2011 at 12:47 am - Reply


    the reason I dont like serum Mg testing

  18. Kim October 31, 2011 at 8:02 pm - Reply

    So how can I raise my cholesterol? I have been following a vlc paleo diet since May of this year. I have T2 diabetes almost under control and also am being treated for low thyroid with a natural thyroid by a naturpath. My cholesterol on SAD is around 150. It is now 114. My HDL is 32 (up from 29). My trigs are 58 and my LDL is 70 and VLDL is 12.

  19. […] This quote by experienced neurosurgeon, Dr. Jack Kruse, sums up that particular role of LDL cholesterol, in this article: […]

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