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Today we are going to hit on a new levee that ties diet to exercise and throws in a bit of leptin. I am going to apologize in advance, because there is going to be some mind bending biochemistry with in it. I think after explaining it to you, it will begin to help you understand how some of my recent blog posts are all tied together and needed for optimization. It also will help show you why low volume HIIT exercise is optimal for health, and endurance exercise is not. The levee under discussion today is number 12. PPAR (peroxisome proliferator-activated receptor) gamma is regarded as the master regulator of the adipocyte and of lipid metabolism in the cell. It is under the direct control of leptin and its receptors and is heavily impacted by the lighting in your environment,  as you will see as the blog progresses.  Fat cells in humans sit right below our skin surface. In my opinion, with time, it will be proven surface chemistry of the skin and gut is the most important driver for adipocyte biochemistry for humans. This is also where omega six pathways enter into to the healthy or inflammatory cascade and determine our ultimate health.

PPAR’s form heterodimers with retinoid X receptors (RXRs), and these heterodimers regulate transcription of various genes involved with our fat cells. RXR receptors link to DHA tissue levels.  These genes are up-regulated by both carbohydrates and lipids in our diet. PPAR-gamma activates the PON1 gene, increasing synthesis and release of paraoxonase 1 from the liver, reducing atherosclerosis. It functions as a plasma antioxidant; it prevents the oxidation of LDL found in the plasma. High levels of paraoxanase are also seen with high levels of glutathione in our plasma. They tend to walk hand in hand with one another. Low levels of plasma paraoxanase is tied to the development of atherosclerosis and cardiovascular disease.  Both are linked to artificial light and low Vitamin K2 and D3 levels.  Artificial light lowers the amount of natural UV and IR light people should get on their skin.  This lowers glutathione in tissues as well.  This is why medical lasers are useless in many skin pigmentation cases caused by altered sun exposures.

Low levels of glutathione are also found when these diseases develop. Low levels of paraoxanase are also tied to Vitamin K2 depletion in arterial walls. PON1 gene transcription occurs in the hepatocyte. Its coded protein is synthesized in the liver and transported along with HDL in the plasma. Low levels of HDL are associated with vitamin K2 depletion in arterial walls. A large study of more than 4,800 subjects followed for 7-10 years in the Netherlands demonstrated that people in the highest one-third of vitamin K2 intake had a 57{a7b724a0454d92c70890dedf5ec22a026af4df067c7b55aa6009b4d34d5da3c6} reduction in risk of dying from vascular disease, compared to those with the lowest intake. Vitamin K2 absorbs UV light too.  Furthermore, their risk of having severe aortic calcification plummeted by 52{a7b724a0454d92c70890dedf5ec22a026af4df067c7b55aa6009b4d34d5da3c6}”a clear demonstration of the vitamin’s protective effects (Geleijnse, 2004). Another study by the same group showed that higher vitamin K2 intake was associated with a 20{a7b724a0454d92c70890dedf5ec22a026af4df067c7b55aa6009b4d34d5da3c6} decreased risk of coronary artery calcification (Beulens, 2009).

It appears when your plasma HDL is low, so is your level of paraoxonase. In my clinic, I have noticed that people with low HDL’s almost always live a life indoors as well.  So HDL is a type of a clinical marker for paraoxanase (and perhaps UV light exposure and Vitamin K2 levels by extrapolation). This should explain to you why I use HDL as a measure of how leaky our gut is (and why your Vitamin K2 is likely low too) to endotoxins that then are able to oxidize our LDL molecules. The absolute level of LDL is of little consequence to me in clinical evaluation. The level of oxidation of the plasma, however, is hugely important. So when one has a low HDL, high hs-CRP, and a high ferritin level you have the “trifecta of a highly inflammatory serum plasma” and one that causes all kinds of neolithic diseases. This lowers the exclusion zone in water part of blood plasma to carry energy all over the body.  It is also associated with lower hemoglobin and hematocrit levels.  Hemoglobin is loaded with porphyrins that also absorb all frequencies of UV light.  This linkage is tied to a higher HDL level in blood plasma and lower LDL in the plasma.  Most people who eat a ketogenic diet and have a high LDL  do so because they live in artificial light and not natural sunlight.  This is why your H/H is a key redox measure.  The link to HDL was explained in detail in my VAP and leaky gut posts here.

Paraoxonase serum concentration is influenced directly by these inflammatory changes and the levels of serum oxidized-LDL. Proliferator-activated receptor-γ (PPAR) has a co-activator called (PGC)-1 alpha. PGC-1 alpha is a member of a family of transcription co-activators that plays a central role in the regulation of all cellular energy metabolism. PGC-1 alpha protein may be also involved in controlling blood pressure, regulating cellular cholesterol homoeostasis, and the development of obesity and T2D.   PGc-1 alpha also helps control mitochondrial number and density within a cell. Mitochondrial numbers are regulated by mitochondrial biogenesis to meet the energy demands of the cell and compensate for cell dam­age. This process is mediated by peroxisome­ proliferator–activated receptor γ coactivator 1α (PGC­1α), which is relevant to mitochondrial dynamics since it is a transcriptional coactivator of the fusion mediator mitofusin­-2.  Mitofusin-2 is what connects the endoplasmic reticulum to mitochondria and control calcium homeostasis in the cell. Mitochondria– endoplasmic reticulum connectivity is regulated by mitofusin­-2 and can create microdomains that facilitate fission.

PGC-1 alpha can interact with, and regulate the activities of, cAMP response element binding protein (CREB) and nuclear respiratory factors (NRF’s) that allows us to make new mitochondria to produce more energy. CREB interacts with UV light as well in the brain to stimulate neuron growth.  This is likely how exercise links to neocortical growth and repair in neuro-degeneration cases like Alzheimer’s disease.  PGC-1 alpha is strongly induced by cold exposure. This is why I use ice when I exercise and swim in freezing water; it also links the environmental stimulus to adaptive thermogenesis (think UPC-1 from the leptin series). If one can mix this cold exposure to AM sunlight you really are doing yourself a big help in reversing diseases.  The link to cold exposure and UV sunlight on the skin and circulatory system also involves AMPk pathways. The reason for this is how the AMP-activated protein kinase pathway (AMPk) works to these environment stimuli. The AMPk pathway is best described as a fuel sensor for lipid and glucose metabolism. Activated AMPk inhibits PPAR-{alpha} and PPAR-gamma .  Cold exposure on our skin surfaces and face increase fat release from adipocytes.  AMPk rises with cold. Ultraviolet radiation and reactive oxygen species from cytochrome 1 (ROS) impair the AMPk signaling axis.  This is how AMPk works within a circadian cycle with UV light.  Both leptin (nutrition success) and adiponectin (nutrition deprivation) activate AMPk pathways.  Cold and UV light are at opposite ends of the circadian cycles.    Metformin mimics cold exposure but it does not work ideally in a artificial lit environment.

The ROS of cytochrome 1 is also linked to light and seasons.  Recent studies show that cytochrome bc1 complex-linked ROS production is primarily promoted by a partially oxidized rather than by a fully reduced ubiquinone pool. The difference is felt in the amount of ELF-UV light released from cytochrome 1 and the singlet or triplet state of ROS released.  The resulting mechanism of ROS production has offered a straightforward explanation of how the redox state of the ubiquinone pool could play a central role in mitochondrial redox signaling.
The mitochondrial respiratory chain is not only the main source of ATP in eukaryotic cells, but it is also responsible for the production of deleterious reactive oxygen species ROS. ROS have been implicated in apoptosis, cellular injury during ischemia and reperfusion, and the aging process (low NAD+) as well as in the pathophysiology of several neurodegenerative diseases including Parkinson, Huntington, and Alzheimer diseases.

PGC-1 alpha stimulates mitochondrial biogenesis (new fat burning plants) and this promotes the remodeling of muscle tissue (muscle becomes LS and adapts to at burning fat over sugar) to a fiber-type composition that is metabolically more oxidative (fat burning furnace-LS) and less glycolytic (sugar burner-LR) in nature. PGC-1 alpha and PPAR- gamma also effect the AMPk pathways we discussed in the Intermittent fasting blog and helps further explain how we gain muscle mass and change our fiber content over time using IFing. Moreover, PPAR gamma and these co-activators participates in the direct regulation of both carbohydrate and lipid metabolism in all cells. Rub your head now…I know it hurts. Just re read this a few times and click on the links. You will begin to see how this orchestra of pathways makes beautiful music for our bodies when we are in a natural environment.  Modern humans rarely are.

It is highly likely from the multitudes of peer reviewed articles I have read, that PGC-1 alpha is intimately involved in disorders such as obesity, diabetes, and exercise induced cardiomyopathy. We also should say at this point, that PQQ is intimately tied to the activation of the PGC-1 alpha pathway. Remember, I just introduced you PQQ in my last blog. This is why many researchers and clinicians have called PQQ the “exercise pill.” I am not a fan of supplementation but food that contains PQQ.  All quinones are UV light absorbers.  Exercise directly up regulates the PPAR-gamma and PGC-1 alpha pathways. So when one is fit and exercises, we are adapted to burning fats and not sugars. This is what we want when we are leptin sensitive and UV light is present. When we are leptin resistant we cannot do this well.  In cold environments, adiponectin predominates and empties fat cells of their fatty acids.

It has also been shown recently that exercise has been shown to help those with severe neurodegenerative disease like Alzheimer’s disease.  The same is true with cold exposure.  This has shocked many researchers and people until they begin to understand this complex biochemistry. The 2011 publication “The neuroprotective action of pyrroloquinoline quinone against glutamate-induced apoptosis in hippocampal neurons is mediated through the activation of PI3K/Akt pathway” was a seminal paper in this area. It clearly gave us a biochemical link of how PQQ reversed excitotoxic damage at the memory center (hippocampus) of the brain. PQQ is induced by exercise so it stands to reason that memory and cognition can also be improved and expanded by using PQQ as well. We know PQQ is a UV light absorber and it is also a direct agonist of the PGC-1 alpha pathway, so it appears to simulate the exact response we get from exercise. All cells are known to release ELF-UV light.  I think using high dose PQQ is something that should be studied in all neurodegenerative diseases for this reason.  Going out in the AM sun before one does this might also be most wise.  This quinone link also should make us realize that artificial light exposure alone may alter singlet and triplet ROS signaling to set the stage for neurodegeneration after diabetes is firmly entrenched.

Moreover, I use PQQ with an exercise to enhance the HIIT routines I recommend with after a successful leptin reset. This is why it is on my top ten paleo supplement list. When you understand this biochemistry, you will understand why I do not recommend cardio much at all. If you happen to be leptin resistant, doing any endurance exercise may cause you to “kill” your mitochondrial biogenesis signals by raising ROS signaling in your sugar burning mitochondria. If you continue to do this exercise while leptin resistant, you are inducing an apoptotic signal in your own mitochondria to force them into apoptosis. This in turn, makes you even more energy inefficient and you feel really bad. In other words, you are killing your own fat burning furnaces! This maneuver, in turn, depletes your stem cell supply. A stem cell supply is your eventual replacement cells. This is why we must make sure our exercise routines are hormetic and not apoptotic! People who over-train often talk about adrenal resistance issues that may develop. The real issue that plagues them is the loss of mitochondria and stem cells. They are killing their mitochondria off instead of stimulating new ones to form and this depletes their adrenal gland and kills their stem cells. I don’t believe many people have made this connection. I know Art DeVany has often made this link and I applaud him for doing so.

A key clinical sign of this occurring is when you have excessive pain with exercise and it persists into the next few days. Other signs to pay attention for are having no weight loss response to exercise at all. Many overweight people face this and few people can tell them why. This biochemistry is precisely why it happens. If you are killing off fat burning mitochondria, you can’t lose weight! If you feel terrible after exercise, this is another sign that you may need to back off. Most fit people do not understand this feeling because they get the exact opposite feeling of euphoria or a general sense of well being from most exercise. This is due to the endogenous opioid release that exercise usually causes in people who are leptin sensitive. When this occurs we generally call exercise a hormetic adaptation. This signal is not present in those who are leptin resistant.

These adaptations may not be of consequence to you currently when you are younger, but the lifetime effects of this, will shorten your lifespan at the back end of your life when your closer to death or your cells Hayslip number is up! When you reach your Hayslip number for a particular cell line the end result is cellular senescence because there are no more left cells to divide. Why? Because your telomeres have become critically shortened. This is why short telomere lengths are associated with aging and degeneration and cancer regardless of chronological age. I have actually tested my own telomere lengths before I started my optimized life program. I have retested it about 6 months ago to see the difference. I went from a biologic age of 55 years 5 years ago to 29 years old today! So we can change change our biology if we know how! Do not give up!

When telomere shortening occurs, you get end stage degenerative conditions. This is why we see so many joint replacements and spine surgery in this country. This is precisely why we see much evidence in the literature of endurance athletes getting sick and dying early from neolithic diseases we would not normally expect. It is because they have exhausted their stem cells supplies. There are no cells left to replace the dying ones. This is why long time marathoners have signs of cardiac fibrosis in their hearts. It is also why we see many acute changes in runners heart after a marathon. We are placing huge metabolic stresses on our mitochondria in too short a time for proper excerise hormesis. A better way to approach exercise is to use it to hormetically stimulate your cells to make new mitochondria instead of killing them off. Low volume HIIT in sunlight is essentially hormetic and stimulates your cells to make new mitochondria. PQQ is a big time adjuvant to doing just this. This is why it was included in my top ten paleo supplement list. The early data is quite compelling that using supplemental PQQ can often times give the same metabolic stimulus to the PPAR gamma and PGC-1 alpha pathways as real HIIT exercise does! This is why many think PQQ is the exercise helping pill! I think exercising indoors in a gym and not out in nature is abd idea because of how AM sunlight and PQQ act in unison to increase cell signaling.  Exercise-induced expression of PGC 1 alpha appears to enhance insulin sensitivity too. So does sun exposure because sunlight is natural calcium channel blocker.  This makes sense because many reports link exercise to improvements in insulin sensitivity as well. Thus, it is likely that maintenance of up-regulated levels of PGC-1 alpha and PPAR- gamma are protective against diabetes and neurodegenerative disorders. Right now, I see no reason not to consider it as an adjuvant of a healthy lifestyle and low volume HIIT. I use it myself and have several patients in my Optimized Life practice also using it.

The level of activation of PPAR-gamma affects the amount of leptin released per unit fat mass. So PPAR-gamma is clearly linked to diet and fat mass. It is also linked to AM sunlight.  PPAR-gamma deficiency leads to hyper secretion of leptin from adipocytes; humans become very slender and adipocytes very small because the brain thinks the body is fat. The leptin released from the fat cells is easily signaled to the hypothalamus and the brain is told not stimulate feeding. Hunger is kept at bay in this scenario. So naturally lean folks tend not to have a lot of PPAR-gamma activation by leptin. They tend to be quite sensitive to leptin as a result. Obese people tend to have a lot of PPAR-gamma activation because their fat cells are loaded with leptin from excessive carbohydrates and lipids in the diet. I find it very interesting that PPAR-gamma activation is not really affected by protein intake.

This is also why I use high protein levels in my leptin reset protocols. PPAR-gamma is not really activated by protein and neither are the neuropeptides that control hunger or satiety in the hypothalamus. I think this is why protein levels are critical to reengineering a human and reseting their hypothalamic thermostat. It is also why high protein meals abolish hunger quickly, in artificial lit environments that we live in today.  Fats can do this too,  but protein loads tend to demolish hunger and keep us satiated for much longer times. When someone begins to use sunlight more I like them migrating to a higher fat version of the Leptin Rx.  Fats contain carotenoids that help us absorb more energy from AM sunlight to quicken a reversal using our skin as a solar panel booster.

Any person who has tried my Leptin Rx will attest to the loss of hunger and to carbohydrate cravings. This is why it occurs! We are effectively resetting their PPAR activation when we use the Leptin Rx protocol. Natural sunlight and cool temperatures can really augment the results.  I learned these things from the Amgen trials on synthetic leptin and from the work done by protein researchers over the last 50 years. PPAR-gamma is heavily influenced by diet and its macronutrients. PPAR-gamma agonists have been used in the treatment of dyslipidemia and hyperglycemia seen in humans as well. Interestingly enough, these trials by big pharma have been epic failures. It appears this system is so vital that tinkering with it can cause death. The best way to activate PPAR gamma is not the newer CETP drugs….it is from exercise, inducing PQQ via exercise, supplementing PQQ, and remaining leptin sensitive your entire life. Peter from Hyperlipid has done some great blogs on the risks of CETP drugs for humans. I fear that once Big Pharma “cooks” the upcoming data on CETP drugs, they will use them to replace statins and people will die in large numbers. I have overheard some cardiologists on Sirius Doctor Radio talking about sub group populations who likely would do quite well on CETP drugs! This is appalling to me and shows me the really don’t understand rudimentary lipid biochemistry. Medicine applies technical solutions to adaptive challenges today and this is why it is failing. 

It also shows that they do not critically read their own literature. Please read Peter’s blogs if your doctor ever pushes these drugs on you in the future. These drugs are some of the most deadly ever tested so far. Evolution and/or God don’t take too kindly to messing with PPAR-gamma. The moral here is always make exercise a part of your wellness platform but make sure it is the correct exercise Rx for our evolutionary biology and the current environment you inhabit!

Brendel C, Gelman L, Auwerx J (June 2002). “Multiprotein bridging factor-1 (MBF-1) is a cofactor for nuclear receptors that regulate lipid metabolism”. Mol. Endocrinol. 16 (6): 1367-77. doi:10.1210/me.16.6.1367. PMID 12040021.
Hamblin M, Chang L, Fan Y, Zhang J, Chen YE (June 2009). “PPARs and the cardiovascular system”. Antioxid. Redox Signal. 11 (6): 1415-52. doi:10.1089/ARS.2008.2280. PMC 2737093. PMID 19061437. (acute cardiac manifestations in marathoners)
J Appl Physiol (February 17, 2011). doi:10.1152/japplphysiol.01280.2010 (marathoners and cardiac fibrosis)

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  1. Jim October 1, 2011 at 4:10 pm - Reply

    Another great post. Thanks Jack. It wasn't as difficult a read as your "mind-bending biochemistry" warning made me expect.

    I was on the fence about PQQ after your supplement post, but this one has really made it obvious how important it is.

    When do you recommend taking the PQQ? Just normally with a meal or pre-exercise?

    I currently lift weights 3 times per week and do HIIT once or twice per week. I also walk my dogs 3 or 4 miles every morning. I eat relatively low-carb paleo but have recently added more carbs (read white rice and sweet potatoes) on lifting days.

    I supplement with basically everything on your top 10 supplement list except added B and C over and above the multivitamin I take.

    I am stronger and healthier at 44 than I can ever remember being.

    • Jack October 1, 2011 at 9:45 pm - Reply

      @Jim Thanks for the kind words. Maybe you're just getting used to my biochemistry talk? LOL I am trying to tone down the geekiness but every so often I have to explain the science behind how our Ferrari works. I think it is critical to teach patients how to gain control over their health by imparting some of this information so they can partner with their own doctor to get the healthcare they want to be optimal for them.

  2. Tim October 1, 2011 at 4:17 pm - Reply

    LEF sells PQQ in 10mg capsules. Is one a day of these about right?

    • Jack October 1, 2011 at 9:41 pm - Reply

      @Tim I think that level is fine if youre eating a ton of foods with PQQ in it. For me personally, I use more because I had to change a 351 lbs body into a 200 lbs hard body. I needed all the PQQ i could must to leverage my exercise.

  3. terrence October 1, 2011 at 6:44 pm - Reply

    Dr K – what do you think about Dr Doug McGuff's "Body by Science" approach to exercise?

    He suggests one workout every seven days (or so) for fit males. It consists of slowly working the five main muscle groups to exhaustion. You use weights so heavy that you cannot quite finish the third repetition in a set. Each set takes about 90 seconds; all five sets will take 10 to 15 minutes.

    I tried it several months ago for a number of months. I got stronger over time and looked forward to each workout. But, then I traveled a lot, got away from it, and have not done it for awhile.

    • Jack October 1, 2011 at 9:40 pm - Reply

      @Terrence I think what he is advocating is perfectly fine. My ideas are a bit different because I am trying to make people understand how our body essentially works. When you understand how the Ferrari works you can reengineer your body when your obese, fit, or somewhere in between. Having been morbidly obese I fully understand what it takes to re create one's physical, emotional, and mental self. I support any person who is trying to help someone else improve their former selves.

  4. akman October 1, 2011 at 9:09 pm - Reply

    Tim – Check the last blog, Dr. K says 20mg is the best dose.

    Dr. K. – I see there is PQQ in vegetables like celery and parsley (and natto, yuck). Is it possible to get enough PQQ from food sources?

    • Jack October 1, 2011 at 9:32 pm - Reply

      @Akman Is it possible? yes to become OK. This post is about becoming optimal. I view PQQ as a life extending technique. I think the earlier you begin a program on it the better. I don't care how you get it. Just get it and make it additive to your exercise routine. I personally take 20 mgs a day and have for six yrs.

  5. Jack October 2, 2011 at 2:26 am - Reply

    @Jane Hereditary disorders of all PPARs have been described, generally leading to a loss in function and concomitant lipodystrophy, insulin resistance, and/or acanthosis nigricans.

  6. Dan H October 2, 2011 at 2:29 am - Reply

    Sick, sick article. great job Doc, you've convinced me to supplement PQQ despite my being a poor med student. So how often do you lift/perform low volume HIIT a week, and how much per workout?

    I'm cutting aerobic exercise out but I tend to overtrain based on my history of having done amateur boxing. I mainly lift, sprint and hit the heavy bag HARD but i do this almost everyday. Thanks again and for responding to my question about cancer!


  7. Glamorama October 2, 2011 at 2:55 am - Reply

    Great post, I actually got it after just one read, not bad for a designer! It's actually interesting to see that since doing your Leptin-Rx, I have been getting stronger and faster on very little weekly exercise. Nor does it make me rave carbs like in the past when I did cardio and ate low-cal CW. I've been amazed at how active I can be, yet not crave anything nor fight hunger. This post explained why this is so.

  8. Jack October 2, 2011 at 3:18 am - Reply

    @Dan PQQ is something I wish I had taken when I was in residency……I could have used it. I lift 3 times a week 15-20 minutes a time with very heavy weight and low reps. I run 40 yd sprints twice a week. I meditate 7 days a week. And I drink things twice a week to alter my PGC-1 alpha pathway too.

  9. Jack October 2, 2011 at 3:20 am - Reply

    @Glamorama Your getting it faster because you understand leptin fully now. That is why. My goal is for you to understand every post one time through because they are all linked together at some point. My job is to show you how they are and show you how to use it to benefit your longevity.

  10. Jack October 2, 2011 at 3:20 am - Reply

    @ Hubert Great email! Here is my response. PGC-1a was originally cloned as a cold-inducible coactivator of PPAR-g in brown adipose tissue, but it has emerged as a potent coactivator of a plethora of transcription factors impacting on whole-body energy expenditure and not just the pathways I spoke about here. More on that later.

  11. moreporkplease October 2, 2011 at 5:11 am - Reply

    Please tell us how to lengthen our telomeres without taking the expensive TA-65.

  12. Jim October 2, 2011 at 12:57 pm - Reply


    I agree with your comment to Glamorama. Up until finding your website I thought that leptin was just one of a bunch of chemicals that regulate appetite and satiety with insulin being the driver. The recent debates between Stephan Guyunet and Gary Taubes got me thinking about how everything works and I followed a link here. Best link I've clicked in a long time.

    Initially I struggled with all the biochemistry and pathways and acronyms. But the more of your stuff I read, the better I get that and the more I understand your way of thinking.

    A friend commented on the number of supplements I'm taking now. "I thought you were all about getting everything from real food", she said. I think you can be very healthy from eating whole, real foods. If you want optimum performance and longevity, maybe you need a little help.

    It took me a while to find PQQ yesterday. The first place I went had never heard of it. The second place they had to get the manager who happened to have sold a bottle last week. Maybe another follower of your blog? 🙂

    • Jack October 2, 2011 at 3:15 pm - Reply

      @Jim I am staying out of that mess with SG and GT. I still think the argument is misplaced. The whole obesity story is a brain story at the hypocretin neurons. Read my three part Central leptin series and you will see my thoughts. Reward theory is out there and studied well but it is not the major cause of obesity because it is an outflow track. I posted a few comments over at SG site but he wont publish them . I have a couple of theories why. I think the dispute between him and GT is now personal and since GT tried to go after SG at the AHS they want to get a pound of flesh from one another. To me…….a total waste of testosterone.

  13. Dean October 2, 2011 at 2:12 pm - Reply

    I'm starting to love what you're doing on this blog. I might need you to hack me too at some point.

    You mention low HDL indicating leaky gut. I think I have leaky gut due to dysbiosis, but my HDL was 90, LDL was 293, Triglycerides 54, TC 400 though it doesn't add up. Fasted blood glucose was 54 and CRP 0.2 despite having inflammation symptoms like TMJ and mild proctitis (that's what it started with and it's definitely exacerbated with starch and FODMAPs).

    Other symptoms: muscle twitching and paresthesia, brain fog, ongoing proteinuria, occasional bone and muscle pain, occasional acne. What's your take on this? Leaky gut?

    An almost zero carb diet with natural antimicrobials and supplements like iodine seems to have helped best so far, since my doctors haven't been very helpful. I think I had SIBO but my latest breath test of 2.5 hours was negative. I also felt better recently but the lactulose might have made me feel worse again for a few days. Something else I suspected is Lactic Acidosis because I got better after stopping L. Acidophilus.

    • Jack October 2, 2011 at 3:11 pm - Reply

      @Dean Why dont you just go get a full GI workup with Genova or Metametrix and then take it to a local doc? I do think you are correct that it could be dybiosis but another thing I would recommend you get is a homocystein level with your labs. When I see a good HDL with other lipid numbers out of whack a bit I start to think you have a methyl transfer issue. You actually maybe a hypo-methylator. Getting your HC level and a look see at your B12 levels maybe a smart thing to do.

  14. Dean October 2, 2011 at 5:13 pm - Reply

    Thanks, Jack. I'm in Europe so I'd have to look for another lab and find out what to test for. My lab values were different when I wasn't fully LCHF paleo but already had these issues. B12 was 906 in February. Cholesterol in April: TC 236, HDL 76,5, LDL 152, Trigs 28. The ones I posted before are from July after I had started eating more dairy fat. I have mostly replaced it with coconut oil, currently ~150ml daily. So it's probably the dietary cause often observed after going paleo and not a methyl transfer issue, yes? If I should still get it tested, I will.

    • Jack October 2, 2011 at 11:33 pm - Reply

      @Dean I am a huge believer in serial testing. I do it on myself no matter how good or bad things are going.

  15. Cú Chul October 2, 2011 at 8:26 pm - Reply

    your comment about low HDL reflecting leaky gut makes a lot of sense to me, despite a couple years at paleo my HDL is still only 54–do you have any other suggestions for healing leaky gut besides avoiding grains & using coconut milk & oil?

    • Jack October 2, 2011 at 11:29 pm - Reply

      @Cu Chulainn I would suggest you read my two blogs on the leaky gut and the VAP blog. The best way to hack a leaky gut is to first go after the easy stuff. Make sure you T3 level is optimal and Vitamin A is good. These increase endotoxin clearance in the portal circulation. You also need to have your sex steroids optimized for the same reason. A glass of red wine a day also does this. I am also a big believer in getting GI testing done in tougher cases with Genova or Metametrix. And you must eat a ton of coconut oil…….critical. Probiotics and home made bone broths from grass fed meats are critical too.

  16. Jim October 3, 2011 at 2:13 am - Reply


    That's the way to do it. Just keep cranking out the good stuff and let them fight. They're both … if not wrong, exactly, they're so focused on what they think is important that they're missing the bigger picture.

    Yes, food is rewarding in varying degrees and stuff that is more rewarding makes you want to eat more. Yes, insulin can drive down blood sugar and make you want to eat more. And if your insulin is always high there are a lot of things that don't work right.

    They both seem like effects, not causes, to me.

    • Jack October 3, 2011 at 3:26 am - Reply

      @Jim…..that is the plan.

  17. Spingirl October 3, 2011 at 9:52 am - Reply

    Hi Jack

    Re your comment above " I drink things twice a week to alter my PGC-1 alpha pathway"

    Can I ask what it is you drink for this purpose?

  18. Claudia October 3, 2011 at 1:10 pm - Reply

    Dr. Kruse,

    you measured telomere length? WOW! Last time I checked this test was not available for the ordinary person, only used in scientific research . A member of Elizabeth Blackburns team said this in a video. Has this changed? I really want to test my telomeres. Where can I do that and what are the costs for testing?

  19. Jack kruse October 3, 2011 at 2:39 pm - Reply

    @springirl. Youre asking about future blogs! Lets just say PQQ is not the only substance that increases PGC1 alpha pathway signaling……..there are several drinks that do……green tea and certain red wines are the base answers. Details will come.

  20. Jack kruse October 3, 2011 at 2:43 pm - Reply

    @clauda. Testing telomere lengths is the ultimate measure of biologic success or failure of your paleo template. Spectracell Laboratories is an amazing resource.

  21. Claudia October 3, 2011 at 4:27 pm - Reply

    I googleded a bit in German "Telomer -Mesung" and found only two labs mentioned in the German press: Telome Health (California, Elizabeth Blackburn) and Life Length (Madrid, Maria Blasco). California is far cheaper, Madrid costs 500 Euros. But I live in Germany so Madrid is the only option for me. My PCP can order the test. So I will try to get the 500 € and see how old I am and what life stress has done to me or not. )

  22. andrea October 3, 2011 at 5:50 pm - Reply

    From reading this post, it would sound like PQQ isn't a beneficial supplement for those that are LR because we're resistant to leptin signalling anyway.

    Am I reading that incorrectly, is it beneficial for the leptin reset?

  23. Gene K October 4, 2011 at 3:46 am - Reply

    Dr Kruse,

    Physical activity where heart rate reaches (220-age)X.75 is believed to deliver numerous brain-related benefits, including increased learning ability, mood regulation, improvement of addiction problems, etc. Do you agree with this judgement? Call it cardiovascular exercise or not, should this type of activity be part a healthy (LS) person's lifestyle? When I do my slow-burn strength resistance exercises, my heart rate is never this high.

    Thank you!

    • Jack October 5, 2011 at 2:59 pm - Reply

      @GeneK you bring some heat here but let me redirect your heat. You must give me context to that heat. What I mean is this. SOme people I treat need much higher MAP to just live and function. This people all have PAD, Carotid or vertebral stenosis and AD. A healthy person would not do well with the same parameters. So to really answer this question you need to qualify precisely what you mean. I think I know your intent but remember there are a lot of people reading this who don't understand what biologic context means and the implications it carries.

  24. Cú Chul October 4, 2011 at 1:17 pm - Reply

    as an academic in the humanities, it is very unusual to find scholars who are good on the details & nuts & bolts of scholarship, who at the same time keep the big picture in mind in a comprehensive way–combining powers of analysis and synthesis, what Pascal called l'ésprit de géometrie and l'ésprit de finesse–Dr. Kruse looks to me like one of those rare figures, we can expect great things from him

    • Jack October 5, 2011 at 1:55 am - Reply

      @Cu Chulainn Thanks for the kind words. I think to lead people to light one needs to have a map and a good light. If you have one without the other each other is fairly useless to get to optimal

  25. MamaGrok October 4, 2011 at 9:28 pm - Reply

    What if you're constantly very bloated but HDL is 80?

    I have a hard time supplementing something as specific and isolated as PQQ for precisely the reason you give toward the end – we don't understand this stuff well enough to know the repercussions of isolating one nutrient from all the rest. I really struggle intellectually with this. For instance, we know that Ca without D, A, K2, & Mg is dangerous. What about isolated PQQ or DHEA or …?

    I'm still hanging in there and WILL have a success story for your Leptin Rx blog some day.

    • Jack October 5, 2011 at 1:53 am - Reply

      @ Mama Grok I think you might have some unusual gut issue that will require a good GI hack. You should consider Metametrix or Genova testing

  26. Cú Chul October 5, 2011 at 2:09 am - Reply

    like you I damaged my meniscus (+tore my ACL) some years ago when I was obese and inflamed–now I am in better shape but difficulties with my meniscus persist–can you recommend anything for increased stability in the knees? thanks

    • Jack October 5, 2011 at 2:54 am - Reply

      @ Cu Chulainn Read Tomorrow's blog. I think you might find what your looking for.

    • Jack October 5, 2011 at 2:44 pm - Reply

      @Cu Chulainn I focused on really strengthening my quads and my hammy on the affected leg. My knee still does not feel correct…..but It continues to feel better every month I eat Large amount of protein and lift weights.

  27. […] How To Find Your Inner Masterpiece Heavy in biochemistry but great info from Dr. Jack Kruse. […]

  28. Gene K October 7, 2011 at 6:04 pm - Reply

    @Dr K, I am sorry, I did not mean to bring any heat here. I am a lay person and trying to get useful practical information from your very in-depth explanation. Due to my high risk for CAD and relatively high calcium score, I have been following Dr William Davis's Track Your Plaque program, and have reached a healthy lipoprofile and actually reduced my calcium score. After staying on mid-high-protein low-carb diet, I conclude based on your criteria that I am LS. I would like to optimize my exercise program. I follow Fred Hahn's slow-burn routine, and I also do some cardiovascular exercise like 30 min on a step machine or an elliptical. I had an impression that you did not recommend cardiovascular exercise here, and my question was about just that. As a healthy LS person, will I benefit from a cardiovascular exercise or not? I gather that it won't necessarily contribute to my heart health or muscle building, but will it still have other benefits, like brain related as discussed in John Ratey's book (
    I hope I have provided enough context this time, and I truly appreciate the time you spend reading and answering our questions!

  29. Jack October 8, 2011 at 3:28 am - Reply

    @GeneK I'd tell you to look at this blog written today (Pal Jabekk) that addresses my feelings completely about cardio. Remember if you are not LS and you are doing tons of cardio you are just creating tons of ROS in every tissue you are LR in and this just exhausts your stem cells. This is why cardio kills in LR states. In LS states we only want to do hormetic exercise. Cardio is never hormetic. It tends to be quite damaging. I would also tell you to the read the link in the comment section on cardiac fibrosis from Feb 2011. Total eye opener and it is why I cant stand any cardio period. I do like HIIT using small reps and real heavy weights and sprinting as the only forum of running. Art DeVany also is a great resource for this too but he is a pay only site now. Here is the link.

  30. Jack October 8, 2011 at 3:37 am - Reply

    @PJ Great email about leptin. But here is the rub……the fitness of our fat as defined by those authors you site is not how I understand the biology of the adipocyte. It is not about their leptin amount or the receptor status. It is about leptin's polar opposite twin…..the fat hormone adiponectin. The optimization of your "White fat" endocrine organ is via higher adiponectin production by adipocytes as leptin falls. This is precisely what we see in a person shredding weight and what I see in my leptin reset patients on the protein or fat reset protocols I use. Low adiponectin means you have a healthier "fat store" that is not inflammatory and allows your fat to store more fat if needed. High levels of adiponectin are also clinically signaled in my protocols by seeing thermogenesis. . Better fat storing ability in our white adipose tissues predisposes us to protect against the development of insulin resistance as well. These people also have very optimal intracellular Magnesium levels on their RBC testing. Lowered intracellular magnesium is the first sign of the development of Insulin resistance and type 2 diabetes.

  31. Jack October 8, 2011 at 3:40 am - Reply

    @PJ…’re correct in your assumption. Adiponectin and leptin plays major roles in how the HCG diet mechanism works on the opioid mu receptor.

  32. alex March 4, 2012 at 6:10 pm - Reply

    Have you heard about salvestrols? They are produced by fruits and vegetables as an fungicide; they are supposed to promote good health, but modern agriculture results in very low levels, in the same way that modern wines have a fraction of the resveratrol as before anti-fungal spraying.

    • Jack March 4, 2012 at 6:46 pm - Reply

      @Alex I have David Sinclair is working with them because of the sirtuin pathway……which is tied to the ancient pathway I will describe in CT 6

  33. alex March 4, 2012 at 6:39 pm - Reply

    "Salvestrols work beyond antioxidants by eliminating the damaged cells, and only the damaged cells. Since we all have damaged cells in our bodies, taking Salvestrols helps us heal ourselves before a sufficient accumulation can make us sick."

    also, more information at this site:

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