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The Hormesis Files: Chronic Ketosis and The Case of The Missing Glutathione

In a previous series covering 17 posts with about 1,500 total comments, we explored the Inuit population vis-a-vis justification for maintaining a state of perpetual ketosis. The rub is that the Inuit were never a ketogenic society—at least not over the last 150 years when they were studied. However, just because they weren’t is not to say that a ketogenic (high fat, low carb, limited protein) diet is unhealthful, just that the Inuit are not a sound justification for the proposition.

This new series of posts is going to be about hormesis.

Hormesis (from Greek hórmēsis “rapid motion, eagerness,” from ancient Greek hormáein “to set in motion, impel, urge on”) is the term for generally favorable biological responses to low exposures to toxins and other stressors. A pollutant or toxin showing hormesis thus has the opposite effect in small doses as in large doses.

We’ll be taking a general approach, looking at a lot of different stressors. ketosis is merely one of them and we went with it first, just because. We’re going to be somewhat speculative, because that’s how quests for new understandings get started. But no matter how this shakes out, it sets the stage for a better understanding of ancestral health, and our willingness to accept our own potential for a beneficial response to intermittent stress.

This initial post has been compiled by “Duck Dodgers,” my principal collaborator in the Inuit series. There are and will be others in future posts. Moreover, Duck has his own set of collaborators. You’re welcome to speculate about who’s who and what credentials they hold, but just remember: the post is written in English.

So here we go.

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The New Conventional Wisdom on Oxidative Stress

Among other things, one of the rationales for a ketogenic diet is to avoid harm from high blood glucose and its byproducts. The theory goes—and I’m reciting from Dr. Eades here“Let those ketones do the job of blood sugar, keeping your blood sugar low. Lower sugar, lower [Advanced Glycation Endproducts] AGEs, Lower AGEs, longer life.” This quest to minimize carbohydrates is based on a fear of byproducts of glucose metabolism. It is well known that high levels of these byproducts can be particularly problematic from hyperglycemic toxicity. Mark Sisson explains the main issues with hyperglycemic toxicity:

Dear Mark: Why Hyperglycemia Is Bad and Those Stubborn Final Pounds

Reactive oxygen species (ROS) generation is a normal byproduct of glucose metabolism by the cell’s mitochondria. If the stream of glucose into the cell is unregulated, bad things begin to happen: excessive ROS, a mediator of increased oxidative stress; depletion of glutathione, the prime antioxidant in our bodies; advanced glycation endproduct (AGE) formation; and activation of protein kinase C, a family of enzymes involved in many diabetes-related complications. It’s messy stuff.

Indeed. And a key compound in this process is methylglyoxal (MG), a potent generator of ROS. Methylglyoxal is also a normal and unavoidable byproduct of metabolism and stress in both plants and animals. In fact, as Chris Masterjohn has suggested, both MG and AGEs are believed to act as regulatory molecules for metabolic processes. However, if a plant or animal generates too much of these regulatory molecules, it can lead to disease and rapid aging. But as with any toxin, the dose makes the poison and even a poison can be therapeutic in the right context.

For those who want to learn more about methylglyoxal, its role in oxidative stress and as a regulatory function, I highly recommend Chris Masterjohn’s AHS 2012 talk on Oxidative Stress. The discussion on Methylglyoxal begins at 28:20. Chris states…

AHS 2012: Chris Masterjohn: Oxidative Stress and Carbohydrate Intolerance

Methylglyoxal…reacts with amino acids to form Advanced Glycation Endproducts (AGEs). A lot of people blame Advanced Glycation Endproducts on glucose, and the misnomer glycation really, really facilitates this unfortunately. But in fact, most AGEs in the human body are not produced by glucose directly, they’re produced by methylglyoxal and a couple other similar molecules… Most people don’t talk about Advanced Glycation Endproducts as regulatory molecules, but I think Advanced Glycation Endproducts are regulatory molecules and are involved in communication. And here’s a little scenario on how that might work.

So, Methylglyoxal can primarily come from two sources. One source is from glucose, but not directly, but through the process of glycolysis. Glycolysis is…basically splitting glucose in half, and that’s the first step in burning it for energy. When we do that, we form some methylglyoxal in that process.

The other place we get methylglyoxal is from acetone. Does anyone know where acetone comes from?… Fatty acid metabolism. Acetone is produced during ketogenesis. So, we break down fatty acids for energy, and we produce some acetone. And acetone gets converted into methylglyoxal.

Now there’s two things that happen here. The first is that when we produce methylglyoxal from glycolysis, methylglyoxal inhibits glycolysis. Now, I don’t think that’s an accident—I think that’s a system of negative feedback. That helps keep glycolysis in check. If you’re breaking down too much glucose, you get more methylglyoxal—methylglyoxal comes back and stops that process. It just keeps it in check…

In a post on his blog, Masterjohn boils it down…

Where Do Most AGEs Come From? O Glycation, How Thy Name Hast Deceived Me!

Methylglyoxal, in fact, comes from carbohydrate, protein, and fat… It would be quite silly to blame AGEs on “carbohydrate,” or “protein,” or “fat,” because these dicarbonyls cause nary a whiff of harm unless they slip past our good friend glutathione.

As Chris explains in his article, producing or consuming MG may not be the problem. What likely matters is whether or not we can detoxify MG from our bodies and our cells. MG is unavoidable and normal levels are no big deal, particularly when we have glutathione (GSH) to save the day. However, as Chris later explains, elevated MG levels are implicated in a number of chronic diseases. As Mark Sisson said: it gets messy.

Perhaps a reduced ability to detoxify MG and AGEs may eventually become more impaired on chronic ketogenic diets than most low carb dieters are aware of, especially once supposedly benign physiological insulin resistance kicks in. Incidentally, Robb Wolf acknowledged this potential problem here:

Robb Wolf: paleo Solution Episode 132

The state that you see rampant methylglyoxal production and a very low level of the enzymes that undo the methylglyoxal reactivity is actually during glycolysis and when we start seeing a lot of glycolysis is when people are insulin resistant, they’re not able to access carbohydrate in a normal fashion for fuel and we actually see people heading in this more kind of acidotic glycolytic kind of direction.

I’m a fan of Robb Wolf, and I know he’s willing to evolve his thinking. But at least back then, he portrayed this as getting ketogenic diets off the hook when it actually does the opposite.

Methylglyoxal on a ketogenic Diet

I’m picking an old wound here that should be given another look. In 2005, a study came out showing that methylglyoxal significantly increases in those following a ketogenic Atkins diet. The study was titled: Ketosis leads to increased methylglyoxal production on the Atkins diet (Free Download). If you read the study, you’ll find a troubling chart where MG goes through the roof after 20 days on the Atkins diet and stayed elevated thereafter, for at least six weeks. Here’s the chart.

mgo atkins
 

This particular chart was from a preliminary study, on one individual—including through the initial “induction phase”—who reportedly benefited from the Atkins diet. When the actual study was done with volunteers (Beisswenger, et al; 2005, Free Download), the researchers found that those who were compliant with the diet had their MG levels doubled. The paper also points out…

Ketosis leads to increased methylglyoxal production on the Atkins diet

The specific aim of this study is to evaluate the potentially toxic effect of the Atkins diet through the increased production of the important glycation product, methylglyoxal. Methylglyoxal (MG) is up to 40,000 times more chemically reactive than glucose, and it has multiple cytotoxic effects. These include inhibition of cell growth, apoptosis, mutagenic effects, inhibition of enzymatic activity, production of protein cross-linking and fragmentation, and serving as an important precursor for advanced glycation end product (AGE) formation…The time people stay on the diet varies, but many stay on it for several months or more, and recent recommendations by the Atkins group suggest that the diet be used “life-long.” Since most people who use the diet return to near their original weight within a year, the justification for exposure to high levels of MG and possible accumulation of toxic AGEs should be considered when balancing the risks and benefits of very-low-carbohydrate diets. Because of the tremendous popularity of low-carbohydrate diets, more studies of methylglyoxal metabolism and ketosis-producing diets are needed. Important additional information would include studies to determine whether or not, or in what time frame, methylglyoxal levels return to baseline after the diet is stopped; how long it takes for higher levels of methylglyoxal levels in the blood to start creating irreversible AGEs; and if other diets produce weight loss without increasing methylglyoxal levels. Because of the large number of people nationwide who are on the Atkins diet and the fact that complications resulting from high levels of methylglyoxal can appear after a delayed period of time, very-low-carbohydrate diets could lead to significant health problems in the future.

Since it was only one study with no control group, and wasn’t peer reviewed, it was dismissed by Dr. Eades, Peter of Hyperlipid, Ned Kock and others. Kock even fell back on the Inuit to make his case. However, the Inuit are no longer a valid defense and the discussion is often riddled with logical fallacies.

Despite that methylglyoxal is reportedly up to 40,000 times more chemically reactive than glucose, most of Dr. Eades’ retorts argued that a hypothetical doubling of MG in VLC dieters would still be less problematic than burning glucose. But Dr. Eades also raised a good point when he began to look at the data:

All these papers state that fasting or intermittent fasting (both of which decrease the amount of time spent in glycolysis) markedly reduces the levels of MG. And fasting and intermittent fasting produce large amounts of ketones. So how can the production of ketones cause an increase in MG if dietary strategies that increase ketosis end up reducing the levels of MG?

I suspect Dr. Eades answered his own question. The fasting strategies that reduced MG were not long term strategies—they were temporary or “intermittent” stresses that encouraged a hormetic response. After all, Beisswenger, et al., showed that it took weeks for MG to really accumulate. For all we know, MG went down, before going up, or never gets much of a chance to accumulate over the very short term when ketosis is intermittent.

Dr. Eades also presented a paper showing that over the short term (14 days), antioxidative capacity is improved on a ketogenic diet without increasing oxidative stress. And, he highlighted another paper, showing that ketogenic diets raise glutathione levels in the mitochondria of rats, over 3 weeks, which was certainly reassuring since that’s where AGEs might cause the most harm.

Low-carb diets reduce oxidative stress

Oh, and speaking of ketones and antioxidant capacity, when I was going through the medical literature looking for other papers on the subject, I came across a paper waiting to be published in the Journal of Neurochemistry showing that a ketogenic diet increases the levels of glutathione inside the mitochondria. For decades scientists have known that mitochondria throw off free radicals as they do their work of converting food energy to ATP, the energy currency of the body. And scientists have known that these free radicals damage the mitochondria. Long ago the assumption was made that taking antioxidants in the form of supplements should squelch the free radicals generated within the mitochondria and result in a prolongation of life. Problem is that it doesn’t work, apparently because antioxidants taken orally don’t penetrate into the mitochondria where the free radicals are. A zillion studies have shown that taking antioxidants doesn’t increase lifespan.

The only thing that reliably does increase lifespan is caloric restriction (CR) in lab animals, at least. CR is thought to work in great measure by decreasing the number of free radicals fired off in the mitochondria as a consequence of the mitochondria having less food that they have to process. The mitochondria make their own antioxidants — one of which is glutathione — to help protect themselves from the free radicals they generate. Anything that increases the glutathione within the mitochondria is going to help increase longevity and decrease many of the ravages of disease, many of which stem from excess mitochondrial free radical production. This study indicates that a ketogenic diet significantly increases the production of glutathione within the mitochondria, which is right where you want it, especially to protect the mitochondrial DNA…Granted, this study was a rat study, and I’m not a big fan of extrapolating rat studies to human studies. But, rat mitochondria aren’t that different from ours so it’s a little easier to make the leap of faith.

The 2008 paper that Eades found: The ketogenic diet increases mitochondrial glutathione levels, by S. Jarrett, J. Milder, L. Liang and M. Patel. Eades was perfectly right—ketogenic diets do appear to increase glutathione in the mitochondria. More importantly, he was right that most studies show that increasing one’s antioxidant intake has the opposite effect, leading to early mortality—a subject we’ll be exploring in future posts.

So far, we are all on the same page.

ketogenic Diets, Hormetic Oxidative Stress and Glutathione

What Dr. Eades couldn’t have known, back in 2008, is that the same group of researchers (sans Jarrett) published another exciting paper in 2010—again with rats—showing that a ketogenic diet appears to produce its therapeutic benefits with a hormetic dose of oxidative stress, which activates the cytoprotective nuclear factor erythroid 2-related factor 2 (Nrf2)-signaling pathway. The Nrf2 pathway activates genes that are involved in detoxification of chemicals and antioxidant defense. That kind of stress is a good thing, at the right dose. The Nrf2 pathway itself is described by some as a key hormetic pathway and has been linked to longevity. And in fact, some studies suggest that trying to avoid low levels of oxidative stress is counterproductive.

However, the researchers stumbled onto a potential troubling side effect of ketogenic diets after a few weeks…

Acute oxidative stress and systemic Nrf2 activation by the ketogenic diet

Since the liver is known to supply extrahepatic tissues with [glutathione] GSH, we examined the effects of the [Ketogenic Diet] KD on liver GSH levels. A profound depletion of liver tissue GSH, accompanied by improved mitochondrial antioxidant capacity, was observed

CoASH was significantly depleted after 3 days on a KD compared to control but was significantly increased after 3 weeks on a KD (Fig. 5B), despite the chronic depletion of tissue GSH. These data suggest that acute mitochondrial oxidative stress occurs in the liver, much like the brain, and that the mitochondrial antioxidant capacity improves above control levels by 3 weeks on a KD…

The bulk of KD research has focused on the brain, as the diet’s clinical application is primarily for the control of intractable epilepsies. This has left a void in the literature on the systemic effects of such a diet. One of the primary sources of brain GSH is export from the liver, which is consistent with our observation of depletion of liver GSH levels. This suggests that the liver may be exporting GSH to sustain GSH levels for other organs such as the brain. Even more striking was the finding that CoASH, a reduced mitochondrial thiol, was significantly increased in liver of KD-fed rats, suggesting a highly compartment-specific effect of the KD. These data suggest that mitochondria are specifically increasing their thiol pools and thereby maintaining a reduced state, despite ongoing GSH depletion in nonmitochondrial compartments, such as the cytosol. To our knowledge, the only other instance in which this has been reported is during fasting. It was found that during a 48-hour fast, hepatic GSH concentrations were depleted, while CoASH concentrations were increased (Jenniskens et al., 2002). This is particularly interesting given that the KD was initially designed to metabolically mimic the fasted state. With respect to Nrf2 activation in the liver, our results strikingly parallel those of acetaminophen toxicity studies in which liver GSH is depleted, concomitant with nuclear translocation of Nrf2 and increased transcription of Gclc and HO-1 (Goldring et al., 2004). Thus, the health effects of chronically depleting liver GSH need to be addressed in future studies of the KD… The novel data that chronic consumption of a KD depletes liver GSH make it essential for the medical community to recognize the importance of systemic and brain GSH and how they are affected by the KD.

If you didn’t catch that, what this study showed is that chronic ketogenic diets (3 weeks) appear to deplete the liver of glutathione in the same way as taking Tylenol every day!

Chris Masterjohn alluded to how this might be exacerbated in his talk, but to summarize (if I’m getting this right) in 1997 increased methylglyoxal was shown to decrease concentrations of antioxidants in the liver. In 2013, decreased glutathione was shown to increase concentrations of MG in rats. Interestingly, increased MG may also have a side effect of increasing physiological insulin resistance—something that has been reported in some VLC dieters and should contribute to further increased MG production according to Robb Wolf’s comment, above. I don’t mind being corrected if I’m wrong, but we appear to have a potential mechanism for explaining the higher concentrations of MG that Beisswenger, et al. found in Atkins dieters over the span of a few weeks.

And, it’s worth noting that Paul Jaminet did warn about glutathione depletion with VLC diets:

Jimmy Moore’s seminar on “safe starches”: My reply

It happens that the incidence of kidney stones, glutathione deficiency, and vitamin C deficiency is increased on very low carb ketogenic diets for epilepsy, and other very low carb diets.

It makes sense that increasing mitochondrial and brain glutathione might be a good idea for some people with specific health conditions—such as epilepsy. But what about the depletion of liver glutathione? Could it be that the depletion of liver glutathione and subsequent increase in MG may also offer some therapies when the mitochondria and brain are protected by increased glutathione, exported from the liver?

A recent study, that was in part inspired by the Atkins methylglyoxal study, above—which perhaps shows that at least some researchers took Beisswenger seriously—showed that elevated methylglyoxal helped reduce seizures in mice. Could this be why a ketogenic diet helps epileptic children? It was originally thought that acetone was the main anticonvulsant factor, but as it turns out, the metabolism to MG is one of the leading hypotheses in the medical literature right now.

Possible mechanism for the effect of ketogenic diet in cases of uncontrolled seizures: The reconsideration of acetone theory, by Miklós Péter Kalapos (2007)

Here it is proposed that not acetone itself, but rather its metabolism to methylglyoxal and S-d-lactoylglutathione is the factor having an influence upon the control over seizures by the modulation of ion channels. With other words, the breakdown of acetone is a prerequisite to any seizure controlling effect…The seizure suppressing effect of acetone would be attributed to the counteraction between two intermediates of its breakdown. On its own acetone is ineffective in controlling seizures, while methylglyoxal and S-D-lactoylglutathione are suggested to be involved in this crucial interplay.

And here’s where it starts to get really interesting. There’s evidence that methylglyoxal can even act as an antimicrobial, a biofilm disruptor, and an antiviral. Additionally, I remember Paul Jaminet had mentioned bacteria and viruses can’t metabolize ketones, and may explain why chronic ketosis might be therapeutic for some people with difficult health issues. We all have different kinds of pathogens and many can be located in various parts of the body, including the brain, organs and tissues. Different strokes for different folks.

The Beneficial Effects of Methylglyoxal

Manuka honey, which naturally contains a precursor to methylglyoxal, will increase its MG content as it sits on the shelf. We know that Manuka honey can be very therapeutic, but it turns out the therapeutic properties of Manuka honey are attributed to methylglyoxal. If that’s indeed true, then the benefits some people get from being on a chronic ketogenic diet may have something to do with increased MG in their blood (from decreased liver glutathione), while the mitochondria and brain are infused with glutathione to protect them. It gets even more interesting (and complicated) when we consider that methylglyoxal appears to play a role in signals that are communicated to and within the microbiome, and some species appear to be able to metabolize and detoxify MG.

And, if Midler, et al. are correct in their hypothesis that the liver may be effectively exporting glutathione to the mitochondria and brain—perhaps to protect them—this might allow MG to rise and provide its therapeutic effects to those who need it, while protecting cells and DNA.

Critical evaluation of toxic versus beneficial effects of methylglyoxal, by D. Talukdar et al. (2009)

Several in vitro and in vivo studies showed that methylglyoxal acts specifically against different types of malignant cells. These studies culminated in a recent investigation to evaluate a methylglyoxal-based formulation in treating a small group of cancer patients, and the results were promising. Methylglyoxal acts against a number of pathogenic microorganisms. However, recent literature abounds with the toxic effects of methylglyoxal, which are supposed to be mediated through methylglyoxal-derived advanced glycation end products (AGE). Many diseases such as diabetes, cataract formation, hypertension, and uremia are proposed to be intimately linked with methylglyoxal-derived AGE. However methylglyoxal-derived AGE formation and subsequent pathogenesis might be a very minor event because AGE are nonspecific reaction products that are derived through the reactions of carbonyl groups of reducing sugars with amino groups present in the side chains of lysine and arginine and in terminal amino groups of proteins. Moreover, the results of some in vitro experiments with methylglyoxal under non-physiological conditions were extrapolated to the in vivo situation. Some experiments even showed contradictory results and were differently interpreted. For this reason conclusions about the potential beneficial effects of methylglyoxal have often been neglected, thus hindering the advancement of medical science and causing some confusion in fundamental understanding. Overall, the potential beneficial effects of methylglyoxal far outweigh its possible toxic role in vivo, and it should be utilized for the benefit of suffering humanity.

If you’re someone who needs extra methylglyoxal running through your blood—either to keep infections of bacteria or viruses at bay, or mediate cancer—ketosis might be worth considering to help manage the symptoms. But perhaps…temporarily…in doses?

We don’t have enough data to really know for sure. For all we know, the therapeutic signals diminish over time. If you’re someone with a yeast or fungal infection, perhaps chronic ketosis might be counterproductive, since there’s evidence that yeasts can metabolize MG and rapidly metabolize ketones too. Perhaps this is why some people feel better with chronic ketosis and others feel worse? Different therapies for different conditions. Either way, it will require further research as there are likely many confounding issues at play and such a therapy does not necessarily treat the underlying condition, nor does it promise a cure. It’s a bit like a pharmaceutical, with side effects, and not enough long term data.

As interesting as that is, it seems unlikely that the potential for liver glutathione depletion over the long term, in conjunction with increased MG, would be an ideal tradeoff for everyone all the time—along with rainbow farting, flying unicorns. And what we don’t know is how long someone can really be on such a therapy since the Inuit are no longer an acceptable proof of a LCHF diet’s long term safety.

Hormesis

Nevertheless, the discovery that a ketogenic diet activates the hormetic Nrf2 pathway is very exciting news. In fact, in 2011, Midler and Patel got back together to write a review of the literature: reporting that some of the benefits of the ketogenic diet may come from this hormetic dose of oxidative stress through the Nrf2 pathway.

Of course, this raises all sorts of new questions. For instance, if the reduced oxidative stress observed in short term ketosis is due to a hormetic dose of oxidative stress, surely there are other ways to activate the Nrf2 pathway without chronic ketosis and its documented and anecdotal side effects in many? Does everyone need the kinds of pharmaceutical-like therapies that chronic ketosis is known to provide for some? Moreover, if there are hormetic benefits to intermittent ketosis, that’s easy for anyone to achieve on any diet, by simply going 24-30 hours, once or twice per week, in a fasted state.

Incidentally, Stephen Guyenet wrote about Nrf2 a few years ago, pointing out that contrary to popular belief, polyphenols appear to be mildly harmful stressors that activate this hormetic pathway. Everything from orange juice to chocolate, wine, tea and blueberries appear to harness this pathway with mildly harmful xenobiotic compounds.

Polyphenols, Hormesis and Disease: Part II

Nrf2 is one of the main pathways by which polyphenols increase stress resistance and antioxidant defenses, including the key cellular antioxidant glutathione (14). Nrf2 activity is correlated with longevity across species (15). Inducing Nrf2 activity via polyphenols or by other means substantially reduces the risk of common lifestyle disorders in animal models, including cardiovascular disease, diabetes and cancer (16, 17, 18), although Nrf2 isn’t necessarily the only mechanism. The human evidence is broadly consistent with the studies in animals, although not as well developed.

One of the most interesting effects of hormesis is that exposure to one stressor can increase resistance to other stressors. For example, long-term consumption of high-polyphenol chocolate increases sunburn resistance in humans, implying that it induces a hormetic response in skin (19). Polyphenol-rich foods such as green tea reduce sunburn and skin cancer development in animals (20, 21).

In the world of hormesis, up is down and down is up. What we perceive to be beneficial to us may actually be harmful and what we fear may be the very antidote our bodies require. This ties into why many naturally occurring toxins and poisons can be extremely therapeutic in low doses. The phenomenon was further explored in a recent article:

Fruits and Vegetables Are Trying to Kill You, by Moises Velasquez-Manoff

Consider fresh broccoli sprouts. Like other cruciferous vegetables, they contain an antifeedant called sulforaphane. Because sulforaphane is a mild oxidant, we should, according to old ideas about the dangers of oxidants, avoid its consumption. Yet studies have shown that eating vegetables with sulforaphane reduces oxidative stress… When sulforaphane enters your blood stream, it triggers release in your cells of a protein called Nrf2. This protein, called by some the “master regulator” of aging, then activates over 200 genes. They include genes that produce antioxidants, enzymes to metabolize toxins, proteins to flush out heavy metals, and factors that enhance tumor suppression, among other important health-promoting functions… Harvard scientist David Sinclair and his colleague Konrad Howitz call this xenohormesis: benefitting from the stress of others. Many phytonutrients trigger the same few cellular responses linked to longevity in eukaryotic organisms, from yeasts to humans. Years of research on Nrf2 in rodents suggest that activating this protein increases expression of hundreds of health-promoting genes, including those involved in detoxification, antioxidant production, control of inflammation, and tumor suppression.

AGEs Revisited

But, just to complicate things, there are exceptions to the rule. For instance, AGEs can be scavenged by certain food compounds and those polyphenols really can help reduce harmful oxidation in the gastrointestinal tract. And it turns out that cancer cells up-regulate endogenous antioxidants via the Nrf2 pathway when they are exposed to chemotherapy and radiation therapy. This is further complicated by the fact that nobody wants to claim that their supplement, food or diet is therapeutic because it’s technically harmful. No wonder health sciences is such a mess!

So, the question now isn’t whether ketosis or other mild hormetic stressors are beneficial. Indeed, they appear to be. The question is whether or not the side effects of a chronic stress—such as depleted liver glycogen as just one example—are worth it for most people. Keep in mind that most hormetic stressors tend to be dosed intermittently, or for a set period of time. For instance, hormetic cold/heat shock treatments aren’t done constantly. Nor do people lift weights every waking moment of their lives. There would likely be a price to pay for such chronic endeavors.

I would imagine that the answer probably depends on the individual. If someone with a neurological disorder, certain kinds of cancer, or a bacterial or viral infection, is able to stave off their symptoms with a chronic ketogenic diet, the reduction in liver glutathione may be a tolerable side effect for them. But does that mean that everyone should tolerate an acetaminophen-like side effect from a ketogenic diet? Probably not. Nor does it necessarily indicate that a ketogenic diet is treating the underlying cause of the issue either—it may very well just be managing it. And we won’t even know how well it does that, or for how long, without further research.

What about a cyclical ketogenic diet? Perhaps when someone’s gut is too fragile to tolerate hormetic doses of plant toxins that would ordinarily activate the Nrf2 pathway, maybe it makes sense for them to get their hormetic stress from ketosis while obtaining some carbs cyclically—particularly if they have a bacterial or viral infection. They may even choose to rely on supplements to replenish their depleted liver glutathione—although, that could be counterproductive to keeping therapeutic MG elevated. Unfortunately, since it only takes 3 days of LCHF to lose carb tolerance, someone on a cyclical ketogenic diet may never become accustomed to carbohydrates. Different strokes for different folks, I suppose.

Blood Glucose Concerns

At least up until now, the issues with methylglyoxal have all been dismissed by the VLC crowd, much like their assurances that physiological insulin resistance is benign. The most adamant VLCers might try to convince us that physiological insulin resistance and methylglyoxal are not a problem if you avoid all carbs that spike your blood glucose above a certain level. They often claim that the rising fasting blood glucose of VLCers should level off at a reasonable level, which they tend to hypocritically set at a level for low carb dieters that’s above what they discuss as safe when it comes to high carb dieters. In other words, a 115-120 mg/dl fasting blood glucose is fine for VLCers but a sign of damaging pre-diabetes and Alzheimer’s developing in people eating higher levels of carbohydrates. This effect hasn’t been well studied, so I would imagine further research is needed.

Conclusion and Lingering Questions

And with that, we leave the subject of ketosis for those who are interested to sort out. As Mildred et al. suggested, further research will likely be required. I don’t expect this to turn into a heated debate—particularly since there is so much to learn here and any discussion on the topic will be fascinating. So, I look forward to learning more about the subject from those actually interested in discussion. I’m sure I made a few mistakes above—and I don’t claim to be an expert in any of the subjects mentioned. So feel free to comment and help refine all this data in the comments, below.

The good news, for those of us not interested in pursuing a ketogenic diet, is that there are many other ways to activate the Nrf2 pathway and there are other lesser-known hormetic pathways that can be activated. Richard will likely be exploring those various pathways in future posts, and in Part II, we’ll attempt to explore the role of the microbiome and prebiotics in managing our oxidative stress and how it fits into hormesis and boosting glutathione in our tissues. We’ll also discuss how this all fits into the coddled and toxin-fearing and glucose-fearing lifestyle that was somehow advocated and encouraged by the modern paleo Diet™. Hopefully this new perspective on hormesis will help us solve a few puzzles of why indigenous cultures seem to thrive while consuming starches and toxic plants, all while harboring pathogenic bacteria, and living in less sanitary and far less comfortable conditions. Stay tuned…

~~~

Duck and his collaborators put lots of effort into this over some weeks. I must have seen a dozen different drafts.

Please, do him the courtesy of dropping a comment, and sharing it on your social media channels.

Richard Nikoley

I'm Richard Nikoley. Free The Animal began in 2003 and as of 2021, contains 5,000 posts. I blog what I wish...from health, diet, and food to travel and lifestyle; to politics, social antagonism, expat-living location and time independent—while you sleep—income. I celebrate the audacity and hubris to live by your own exclusive authority and take your own chances. Read More

81 Comments

  1. Dwayne Lunsford on November 14, 2014 at 10:17

    “…for everyone all the time—along with rainbow farting, flying unicorns.” Richard, pure poetry. We have got to sit down and have a few beers sometime.

    • Richard Nikoley on November 14, 2014 at 10:33

      Dwayne.

      That was the single bit or artistic license I took with Duck’s writing, editing wise.

  2. Austin on November 14, 2014 at 10:41

    It is posts like these that make this one of only three blogs that I read regularly. If it weren’t for the posts on the Inuit and their lack of ketosis, I would still be eating a low carb ketogenic diet. Thankfully, I’m not, and I not only feel better, but feel freer and enjoy my diet much more. Keep up the great work!

  3. Austin on November 14, 2014 at 11:00

    Richard, I have to ask: has your research into plant toxins, hormesis, and the microbiome changed your stance at all on gluten-containing grains? I know that it is vilified in many Paleo circles, but I can’t help but wonder if it is as bad as they make it out to be. After all, the same circles avoid white potatoes, rice, and beans (among other foods), but you’ve come to embrace them in the past year or so.

    I haven’t eaten gluten-containing grains for the past two years, and my mom is a Celiac, but I feel more and more that I’m restricting myself unnecessarily.

    Thanks for your thoughts!

  4. Marc on November 14, 2014 at 11:37

    wow! And perhaps another reason Art D. has been soo serious about his glutathione supps.

    • Richard Nikoley on November 14, 2014 at 12:18

      Glutathione sups are absolutely not bioavailable.

      Art is living in rainbow farting, flying unicorn land about that.

    • Douglas on November 15, 2014 at 12:21

      The supplementing (if one choses) needs to be done N-acetyl cysteine.

    • Sky on November 15, 2014 at 22:07

      You’re better off supplementing with methylsulfonylmethane (MSM). MSM is 34% sulfur by weight and without sulfur, glutathione simply cannot work!

      Good food sources containing sulfur are the cruciferous veggies, such as onions, garlic, broccoli, cauliflower, cabbage, etc. Eggs are another great source of sulfur as are animal foods and seafood.

    • Sky on November 15, 2014 at 22:38

      I assume they don’t have something like
      Liposomal Glutathione in Flying Unicorn Land!

    • Richard Nikoley on November 16, 2014 at 00:50

      Perhaps not. But how about the farting rainbows? And…Hope?

  5. Marc on November 14, 2014 at 13:53

    Correct…On bioavailable and flying unicorn land.

  6. Steve Cooksey on November 14, 2014 at 14:07

    Excellent information, clearly presented.

    Thanks!

  7. McSack on November 14, 2014 at 14:36

    Great article Duck! I have few newbie questions though.

    First, are oxidative compounds like MG created deliberately by our cells to essentially harvest energy from food sources, and then antioxidants are produced as protectants to keep them in check?

    Also is MG one of the primary components in autophagy? Could the increase in MG be related to the body harvesting any available energy source including breaking down its own cells during ketosis and/or starvation? Is that maybe why it works as an antimicrobial?

    • Gemma on November 15, 2014 at 05:28

      Do not forget the microbiota, they are made of cells too. Methylglyoxal is produced by human AND bacterial cells when exposed to disturbed glucose metabolism, when the nutrients are scarce. It is a high risk strategy though, because methylglyoxal serves both as an antimicrobial defence and a signalling compound too, and the other microbes are listening. The dose and timing matters.

  8. Dave on November 14, 2014 at 16:19

    How about the bio-availability of sulforaphane supplements? I also thought about buying broccoli seeds and sprouting them.

  9. Bob on November 14, 2014 at 19:40

    “The protective effects of sugar, and the harmful effects of excessive fat metabolism, are now being widely recognized, in every field of physiology. The unsaturated vegetable fats, linoleic and linolenic acid and their derivatives, such as arachidonic acid and the long chain fish oils, have excitatory, stress promoting effects, that shift metabolism away from the oxidation of glucose, and finally destroy the respiratory metabolism altogether. Since cell injury and death generally involve an imbalance between excitation and the ability to produce energy, it is significant that the oxidation of unsaturated fatty acids seems to consume energy, lowering cellular ATP (Clejan, et al, 1986).

    The bulk of the age-related tissue damage classified as “glycation end-products” (or “advanced glycation end-products,” AGE) is produced by decomposition of the polyunsaturated fats, rather than by sugars, and this would be minimized by the protective oxidation of glucose to carbon dioxide.” – Ray Peat

  10. Jane Karlsson on November 15, 2014 at 04:55

    Another brilliant piece of work by Duck. Here’s something else that might interest him.

    1. Nrf2 induces MnSOD
    ‘…The transcription factor NF-E2-related factor 2 (Nrf2) is a critical regulator of MnSOD …”
    http://www.ncbi.nlm.nih.gov/pubmed/21787690

    2. Beta hydroxybutyrate also induces MnSOD (BOHB -> HDAC inhibition -> FOXO3A -> MnSOD).
    http://www.ncbi.nlm.nih.gov/pubmed/23223453

    3. In ancient England, epilepsy was treated with lupine, which is ‘exceptionally high in manganese’.

    “The most frequently prescribed herb for “devil-sickness” in the vernacular medical books from Anglo-Saxon England, the lupine, is exceptionally high in manganese. Since manganese depletion has been linked with recurring seizures in both clinical and experimental studies, it is possible that lupine administration responded to the particular pathophysiology of epilepsy. …”
    http://www.ncbi.nlm.nih.gov/pubmed/23223453

    • Duck Dodgers on November 15, 2014 at 07:04

      Thanks, Jane! That is interesting.

      I meant to ask you about wheat last time. What kind of wheat do you prefer (Einkhorn, Emmer, etc.) and what are your thoughts on gluten for people who tolerate it? I’m starting to have a more open mind on these things and I suspect the biome plays a role.

    • Duck Dodgers on November 15, 2014 at 07:35

      And if I wasn’t clear. I’m starting to wonder if some of the negatives of wheat are offset by hormetic effects (at least in some people).

  11. Nürnberg on November 16, 2014 at 01:30

    Awesome work as usual Duck et al.. Hope yall get nice christmas presents. Too bad the newbies considering going VLC won’t find this kind of information upon googling but likely will stumble upon some fucktarded dietician telling them easily dismissed things like sat fat will kill them, and then Protein Power etc.

  12. Jane Karlsson on November 16, 2014 at 04:49

    Hi Duck
    Yes I think you’re right. There shouldn’t be any problem with wheat, even modern wheat, as long as gut bacteria and detoxification systems are working well. Detox systems depend on gene activation by MnSOD as I expect you remember. Here is the paper.
    http://www.ncbi.nlm.nih.gov/pubmed/18067683

    Some of the genes activated by MnSOD are autophagy genes. I know Richard is very interested in autophagy. It depends on proper functioning of lysosomes, and I suspect lysosome malfunction lies behind many of the problems with wheat. For instance, lectins normally get taken into enterocytes and (probably) degraded in lysosomes. And protease inhibitors have S-S bonds which can only be broken in lysosomes. The very tricky 33-mer peptide of gluten probably gets its Pro-Pro bonds broken in there too.

    Gluten is notorious for opening tight junctions in the gut, but actually opening tight junctions is necessary for induction of oral tolerance. The protein has to get inside the gut wall to access the immune system. Loss of oral tolerance seems to be due in large part to malfunctioning gut bacteria, which you probably know more about than I do.

    BTW I’ve never tried either Emmer or Einkorn. I eat a lot of bread but it’s modern wheat. Organic stone ground wholemeal of course.

    • FrenchFry on November 16, 2014 at 10:12

      Then you should try spelt! Better than einkorn for bread, very little shit in it, unlike modern wheat. You won’t make croissants with spelt but nothing is perfect 🙂

    • FrenchFry on November 16, 2014 at 10:13

      … because its gluten is very brittle and degrades easily at warm temperatures. People tolerate spelt much better than wheat usually.

    • Jane Karlsson on November 17, 2014 at 02:32

      Hi FrenchFry
      Yes I did try my baker’s spelt once. He makes absolutely wonderful wholemeal wheat with seeds in it and a little sourdough added to give it just a hint of sourness. It tastes like heaven. I eat it instead of meat, and I really don’t want meat if I can have bread like that.

      I’m actually doing a long term n=1 experiment continuing Sir Robert McCarrison’s work on the wheat-eating Hunza. I wanted to know whether their diet would produce good health using modern ingredients. So far, so good. I haven’t seen a doctor for 25 years except for a thorn in my thumb, and the mild skeletal deformities I had are now largely corrected.

    • GTR on November 22, 2014 at 11:45

      @Jane – an evolutionary path leading to a particular person might include not eating wheat at all. Even during “grain times”, by eating different grains then. Rice eating Asians being an obvious example. Many Europeans don’t realize that they may have similar history, coming from lineages that grew millet, buckwheat, peas, barley, rye or just were fishermen. For such people eating wheat is a modern self-experiment; a risky one since wheat has known issues.

  13. Tim Maitski on November 16, 2014 at 05:18

    Just want to say thank you for taking all the time to put this together.

    For me, this is helpful for thinking about how best to detoxify from mercury fillings. From what I’ve read, glutathione seems to be the key for the liver eliminating mercury. Therefore, I would think that a ketogenic diet probably wouldn’t be very helpful for mercury detoxification. I remember Jimmy Moore saying that he was going to have all of his mercury fillings removed. I never saw any mention of his results of that. I would think that his chronic ketogenic diet would hinder him getting the mercury out of his system.

    • Craig on November 17, 2014 at 03:31

      Tim Maitski, you had mercury fillings? Or amalgam fillings that contain mercury?

    • Tim+Maitski on November 18, 2014 at 04:03

      I guess some people call them amalgam fillings but from what i read dental amalgam is 50% mercury. I used to call them silver fillings but they have little silver. So when it comes to talking about toxicity, i prefer to refer to them as mercury fillings so one understands the toxicity that i am concerned about.

      A silver dollar is 90% silver. I don’t call it an amalgam dollar.

      But thanks for clarifying what i’m talking about.

  14. K. on November 16, 2014 at 08:12

    This was great, thanks for all your work. I look forward to the Paleo follow up.

    I remember once I had actually began researching things for myself , I could never understand the over the top fear of plant “toxins” the paleo authors have.

    How would they ever have survived eating wild plants if modern day domesticated bred down plants are so poisonous?

  15. colin nelson henley on November 16, 2014 at 15:18

    hi- interesting stuff as always. I’ve experienced noticeable health benefits by incorporating home-fermented sauerkraut and garlic, and this series of articles dethroning ketogenic diets as some sort of ideal has been interesting to say the least. my one negative observation would be that having a quarter of my screen taken up by a banner screaming ‘click me!!!’ regarding an article I’ve already read is a major PITA. thanks for your work sir.

  16. Anand+Srivastava on November 16, 2014 at 22:42

    This post was amazing. Thanks Duck and Richard.

  17. Resurgent on November 17, 2014 at 00:53

    A Great write-up.. Looking forward to part 2

  18. FrenchFry on November 17, 2014 at 02:10

    Just passing by to say it was a very interesting read. Keep them coming.

  19. Michael44 on November 17, 2014 at 17:28

    Thanks Duck and Richard.

  20. Sky on November 18, 2014 at 16:57

    Just wanted to say, Thanks to Richard and Du… oh, wait a minute! Here’s a Special News Bulletin just in from the Land of Farting Flying Unicorns:

    http://itsthewooo.blogspot.com/2014/11/an-intellectual-giant-amongst-mental.html

    I wonder what the fallout will be from this nuking fuking story from the Land of Farting Flying Unicorns?

    • Duck Dodgers on November 18, 2014 at 20:48

      Nice try. Woo is too dumb to realize that Peter’s discovery just confirms the research that I quoted in my articles. High serum FFAs in the Inuit were shown as early as 1936, in the very same studies that concluded no ketosis in the Inuit.

      Rabinowitch and Corcoran 1936 concluded no ketosis but showed high FFAs.

      Bang & Dyerberg 1975 said: “One of the most remarkable differences is the high amount of certain long-chained fatty acids in the Greenland Eskimos, not occurring to that extent in other groups. This is valid especially for timnodonic acid (20:5), which represented in the Eskimo maritime food and in their plasma lipids.”

      Ho 1972 said: “Each Eskimo’s serum was tested for the presence of ketone bodies….and all serums were negative…. The fact that the Eskimos had high serum FFA and low glucose levels…indicated that free fatty acids played a major role in body energy production.

      I never claimed that the Inuit were high carb. They were low carb, high FFAs, but not in ketosis (they ate too much protein).

      The problem with you keto-tards is that you don’t bother to read any of the scientific literature. You just mouth off with knee-jerk reactions—proving that you don’t really take the time to actually investigate anything in-depth. If you bothered to turn a page, or open a document, you would see that no ketosis and high FFAs was commonly observed in the Inuit scientific literature, for well over the past 75 years.

      Personally, I found the high FFAs discovery by Peter to be extremely interesting. Stefansson had observed that the Inuit were known to age more rapidly than other cultures. Perhaps the elevated FFAs and low insulin (a recipe for damage from highly reactive dicarbonyls) ties into that observation.

    • GTR on November 19, 2014 at 05:55

      So if Inuit have special genes, that only they have special gene that almost only they have it means they are NOT close to our ancestral population, so they shouldn’t be considered as an example when talking about our ancestral diets.

    • GTR on November 19, 2014 at 06:11

      From hyperlipid blog: “The mutation is linked, not surprisingly, to failure to generate ketones in infancy […]
      Three of the seven patients and two cousins had hypoketotic hypoglycemia attributable to CPT-Ia deficiency
      […]
      if you can’t transport LCFAs in to your mitochondria, you should run your metabolism on glucose/pyruvate […]
      This means raw corn starch “

    • Richard Nikoley on November 19, 2014 at 10:37

      Sky:

      I’ve had a substantial history with Woo. At one point, she had put up over 800 comments here (now all deleted). It’s long and boring.

      I simply don’t care what Woo thinks or writes. Last time I saw, she was calling me a pedophile or something.

      There’s no point in suing someone who can’t even keep an apartment.

    • Sky on November 19, 2014 at 18:29

      Richard:

      I’m well aware of the battles between you and her. I was one of the members of the silent majority watching the both of you go at it. Actually, I did make one comment under a different alias that you couldn’t call her a cunt, since she appeared to be lacking in both depth and warmth, if you remember.

      I apologize for bringing her into this discussion. I was directed to her post by one of Bill Lagakos’ tweets, but later realized it was Peter from Hyperlipid who posted the original discussion concerning the Inuits and ketones.

      I like to play Devil’s Advocate at times in hopes of starting a discussion pertaining to some tweet/post I may have come across or some research article that perhaps challenges what is being discussed here. I’m still on the fence concerning a lot of this “stuff” and still trying to fit all the pieces together so I can make some sense of what the big puzzle concerning healthy eating will finally look like!

      BTW….It’s a little disconcerting to see you and your old friend, Dr. Mike, going at it of late. Hopefully the both of you can agree to disagree and remain good friends! I also don’t always agree with what Dr. Mike has tweeted or posted on his blog, especially about some carbs such as berries not being important in a diet, or that there’s no difference in eating meat from grain-fed cows vs. grass-fed, unless he’s changed his mind of late. While I don’t believe in a Keto-diet or even a Paleo diet, I do follow a relatively low-carb diet by only eating organic berries for fruit and organic veggies as my carb sources. Nothing processed for me and my family, including all grains.

      I should also mention that I did try the potato starch for a few months, but was forced to stop due to joint pains, which ceased once I stopped taking the potato starch. That may be because I’m sensitive to night-shade plants. I now supplement instead with inulin, whole husk psyllium, and Larch Tree Arabinogalactan. I’m also thinking of adding Prebiotin Prebiotic Fiber for insurance.

      Has anyone here tried the Prebiotin Prebiotic Fiber?

  21. Bret on November 19, 2014 at 17:48

    …since the Inuit are no longer an acceptable proof of a LCHF diet’s long term safety.

    And never have been. It has always been erroneous to point to the Inuit as an example of LCHF and/or chronic ketosis.

    Nice piece, Duck. I am sure it is not exactly pleasant to be taking on the VLC mini industry establishment with this inconvenient (to them) information, but I am glad you are doing it. Keep up the good work.

  22. GTR on November 20, 2014 at 16:36

    This ketosis thing almost sounds like a weird version of The Selfish Brain Theory. You have a state where your brain gets:
    – lots of ketones for energy,
    – good dose of glucose via increasing the fasting glucose to high levels, but still below the dangerous level of 140mg/dl that damages nerves,
    – glutatione stolen from the liver,
    – methylhlyoxal for antimicrobial activity.
    So the brain feels good, wants to keep this state, while not caring about the well-being of other organs (“selfish brain”)?

    • GTR on November 21, 2014 at 02:05

      A related info from Paul Jaminet interview that someone found in the past and linked at this site some time ago previously (I’m repeating this).

      http://liveto110.com/68-perfect-health-diet-weight-loss-dr-paul-jaminet/

      “Well, the biggest problem is – what your body does is it ramps up energy production in mitochondria. They try to get rid of the oil and the fat. And in that situation with an excess of energy and an excess of oil around – the mitochondria, it’s sort of a 2-way process. You’re going to put fats in on one end and you get ATP out through the other.

      But once you’ve burned a lot of fats and you filled yourselves up with ATP more than they need, then it creates a kind of back pressure in the mitochondria and it leads the mitochondria to produce reactive oxygen species. That’s kind of a signal, “Don’t give us any more energy.”

      But if you’re eating an excess of fat, then your body is also driving things from the other end saying, “Mitochondria, destroy more energy for us. We’ve got extra fat that we need hanging around.”

      And so what ends up happening is that the muscle tissue, which is the main place you dispose of excess energy is producing a lot of reactive oxygen species. That can lead to health problems especially if you’re deficient in antioxidants.

      The place it will show up first is the heart often because the heart is a muscle, a muscle is full of mitochondria and so it’s generating lots of reactive oxygen species. The heart can really get damaged.

      I rather suspect that maybe what happens when you have too few antioxidants and too much reactive oxygen species, you injure the neighboring cells. And in the heart, you get cardiomegaly, you get injured heart tissue, the heart overgrows in order to make up for the lost function. And then, you’re likely to have a heart attack.

      That’s actually what Seth Roberts recently died of. I think part of it was he was eating this very high fat diet. He’d supplement with flax seed oil and butter. So he was eating a large amount of supplemental fat per day because he found it improves our biomarkers he was looking at, which were related to brain and neurological function. And the brain and the nerves, they’re very fat-rich. So if you had a fat-rich diet, you can see improvements in your brain and neurological problems, but you can also see problems because of the reactive oxygen species being produced in muscles.”

    • Sky on November 21, 2014 at 17:08

      “That’s actually what Seth Roberts recently died of. I think part of it was he was eating this very high fat diet. He’d supplement with flax seed oil and butter. ”

      Actually, he died from complications involving mercury toxicity which was “found to correlate with a 9% increase in AMI [acute myocardial infarction].

      According to his mother, one of the lab tests “showed that butter was beneficial for him, and his heavy ingestion of it, showed an improvement in his score: ‘Most people get about 25% worse each year. My second scan showed regression (= improvement). It was 40% better (less) than expected (a 25% increase).”

      You can read his mother’s post here commenting on the cause of his death:

      So much for your hypothesis!

    • GTR on November 21, 2014 at 02:16

      To be fair: some LC advocates also advocate taking lots of supplements, that include Glutathione (eg. that Asprey guy), or CoQ10,Ubiquinol, PQQ for mitochondria.
      So it’s like in Richard’s analgoy that this LC thing is like veganism, where the practitioners need to take supplements of B12, and essential amino acids powders or something similar.

    • GTR on November 21, 2014 at 02:30

      One hole in “LC for selfish brain vs. other organs” hypothesis is that self-control runs better with availability of glucose. Or maybe high fasting glucose of VLCs is exactly for that?

      http://www.newyorker.com/tech/elements/sugar-on-the-brain

    • Bret on November 21, 2014 at 13:23

      Careful, GTR. With all this talk about fat causing heart disease, the VLC/ZC/KG people are bound to chase you down with pitchforks.

    • Bret on November 21, 2014 at 17:25

      All of what Justine wrote on Seth’s blog concerning cause of death and factors of cardio analyses was correlation substituted for causation.

      Roberts’ greater ingestion of butter correlated with his improved score. His mercury levels correlated with his death. Correlation is not causation. Do you understand basic science?

      Paul was at least honest enough to call his speculative hypothesis what it was: a speculative hypothesis. You, on the other hand, call your speculation (well, others’ speculation) proven science.

      You are one intellectually repugnant creature, Sky. Go eat a shiny brown turd.

    • GTR on November 22, 2014 at 11:25

      @Bret – many facts about fat shows that that it has a substance that you should be careful about.

      Even simple calories – at 9000 kcal/kg a simple mistake in measuring a portion size gives you a big portion additional calories. One orange has like 62 kcal – you feel it if you eat too much.

      Lack of measurment of fat intake that some diet proponents promote really looks like a very wrong advice. For protein humans have a security mechanism protecting from overeating – this stop signal, when after eating a certain amount the feelings about eating more protein prevent you from eating more. For carbs mechanisms are there, though much weaker. Eating fat alone doesn’t result in a “stop” signal, a person can eat, and eat, and eat… In natural food like meat protein could stop overeating, with milk the water volume alone gives a stop signal etc. For butter or other extracted fats the natural intake control barriers is not strong.

      Eg.

      “Generally speaking, foods that rank high in the satiety index (SI) and satisfy your hunger for a longer period of time, are foods with high protein, water and/or fibre content. […] The highest SI score was produced by boiled potatoes […] Fatty foods do not come up high on the satiety index list”

      http://healthland.time.com/2013/02/26/salt-sugar-fat-qa-with-author-michael-moss/
      (about junk food)
      “Take sugar for example. The optimum amount of sugar in a product became known as the “bliss point. […] There is almost no limit to the bliss point in fat. If there is one, it’s up in heavy cream some place. So the companies discovered they could add as much fat as they wanted to products, and unless people looked closely at the nutrition facts, they are going to totally love it more than they would without the fat.”

      And jumans can absorb like 100% absorption of that fat eaten.
      (at around 29 mins.)
      http://body.io/body-io-fm-32-dr-bill-lagakos/

      “The stuff I learned was that we’re extremaly good at absorbing fat. I mean you could probably eat a pound of butter and absorb every last gram of it […] The body will not waste any fat. […] There was one study from like 70 years ago and they just were giving a guy 500 g per day, and they were recovering none of it in the feces. ”

      So due to the lack of natural protection fat consumed in extracted for should thus be limited consciously, artificially by weighting and counting. And current high fat diets discourage it. Looks like a big mistake.

      It’s not about surrendering to the vegan propaganda that every drop of fat is evil. Though the negative effects of fat are real, it looks like they show with excess consumption. The issue in Paul Jaminet’s post was about quantity, the blood coagulation issue mentioned by vegans is also depenand on quality. And it’s exactly the excess consumption of fat is what we are not naturally protected from by our bodies, while being encouraged to it by modern LC proponents.A substance one needs to be careful with basically, but safe at appropriate doses.

    • Sky on November 22, 2014 at 04:08

      I’m so happy that someone KNOWS FOR SURE what it was that caused his death! That it would be you, or course! LMAO!

      Obviously, you’ve revealed yourself to be a very sensitive little girl whose widdle fweelings get hurt whenever her ideas are challenged and intellectual inferiority is exposed.

      If you can’t stand the heat here, I suggest you leave and go post on some knitting site that’s more suitable to your disposition.

      Toodle-loo, dear!

    • Bret on November 22, 2014 at 05:27

      Did you even read my comment, moron? Where exactly did I say or imply that I was certain of his cause of death? The point is that no one knows, but that doesn’t stop fucktard apes like you from claiming otherwise.

      Seriously, Sky, take a bit wet bite out of a used tampon. I am pretty sure you are an abortion that lived. Go pop some of your pimples (the really ugly ones) and then get your homework done before bed.

    • Bret on November 22, 2014 at 16:00

      Thanks for the info, GTR, but my comment was completely in jest (which I thought was obvious).

      I am on board with the idea that we should not eat and drink gallons of animal fat per day. My point was that the zealous VLC enthusiasts have chosen, consciously or not, to ignore evidence such as what you presented above.

    • Richard Nikoley on November 22, 2014 at 16:58

      +1 GTR

      On board 100%. Recently, I’ve been much more sparing in dressing salads, for instance and you know what, they taste better, more varied to me. Also, if I do eat out and get a salad, I always get dressing on the side. And cooking, I use way less and don’t do other added fats, anymore.

    • Sky on November 24, 2014 at 02:40

      Brettany…

      Are you ALWAYS this retarded or are you ALWAYS this retarded? You’re ALWAYS this retarded, arent’ you?!

      Rumor has it you were a test tube baby conceived by some mad scientist in an old abandoned Twinkie factory using sheep eggs and sperm from some escaped mental patient from Bellevue Hospital. The result was you, a monstrosity of a mistake the scientist was about to flush down the toilet but your daddy unfortunately stopped him exclaiming, “Look…..at least it has eyes!”

      It’s Monday morning, Brettany! Time to get your retrofitted football helmet on and get ready for the short yellow school bus that should be along soon.

      Have a nice day, dear!

    • Bret on November 24, 2014 at 03:42

      Sky:

      Eat four pounds of liver, take a shit into your hand, eat it, throw it up, eat it again, catch the vomit in your mouth this time, swallow it back down, blow it out of your sphincter, catch the discharge in a bucket, inject it intravenously, fuck your asshole with a cheese grater, tell your mother how many times you’ve swallowed semen for crystal meth, and go play on a busy freeway.

    • Sky on November 24, 2014 at 04:25

      Richard…

      As you know, most salad dressings one finds in restaurants and supermarkets today are made from polyunsaturated vegetable oils. But adding good fats/oils with your salads is very beneficial since most of the fat soluble vitamins need the fats in order to be assimilated properly.

      I make my own using olive oil.

    • Sky on November 24, 2014 at 04:41

      Must be that time of the month, huh Brettany? LMAO…!!! :0D

      You’re about as funny and entertaining as watching an orphanage full of kids burn down!

      Why don’t you stop bitching like a snarling Eunuch rubbing Rogaine on your swollen manboobs in hopes of growing some chest hair, and then get away from your cellar window that you’re wiggling your ass out of in hopes that some passing stranger will grab it for your very 1st sexual experience, you smelly little cunt!

      Then you can go and drink the breakfast mommy made for you consisting of Alpo dog food, Monsanto’s pesticide, and frog’s piss!

    • Bret on November 24, 2014 at 05:49

      Open your mouth and look up, Sky. I’ve got a turtle head poking out with your name all over it.

    • Richard Nikoley on November 24, 2014 at 07:49

      I understand this. I use raw greek EVOO on my salads at home.

      But I’m no purist. If from time to time I go to a resto and have a salad, I dress it with what they have (creamy blue cheese, typically—and I like it on crunchy iceberg, too). Not going to kill me and in fact, in small doses, it’s probably hormetic, like other poisons.

    • Sky on November 24, 2014 at 10:18

      Brettany…

      Seriously, how old are you anyways? My nephew, who’s in the 5th grade, is more creative and witty crafting grammar school toilet humor than what you’ve shown me!

      I understand you recently lost your job down at the local Sperm Bank for drinking on the job so while your mommy’s at work you’re using her computer to abuse the nice people who are posting here.

      Why not be a good little girl, stop playing with your mommy’s computer, and instead go and abuse your life-size blow-up doll of Pee-Wee Herman..?!

    • Bret on November 24, 2014 at 13:02

      Sky:

      Eat a dick and choke on the foreskin.

      (By the way, numbnuts, I am not reading your long comments. Hope you’re enjoying writing them, you stupid fuck.)

    • Sky on November 24, 2014 at 16:41

      [I am not reading your long comments.]

      Translation: You’re crying like a little girl because your widdle ego can’t stand being shit on any further! LMAO @ YOU, my little bitch!

      [Hope you’re enjoying writing them]

      That I do! I love having fun at your expense and making fools out of bitchy temperamental mental midgets like yourself. The next time someone disagrees with whatever nonsensical verbiage you tend to spew here, learn to shut your ugly face and to take it like a man!

      Get my drift, my little bitch?

    • Richard Nikoley on November 24, 2014 at 16:50

      Knock it off both of you (Bret and Sky).

      Even I have zero clue what the dispute is about, and I always read every comment.

      Insults too, are contextual. In a total vacuum, with nothing new added, they are meaningless and have gone far beyond any sense of propriety—now straight up blog comment pollution.

  23. michael goroncy on November 21, 2014 at 19:16

    2 Novel ideas….either ignoramus or ingenious.
    Much is talked about the Masai and Eskimos and used as a paradigm for ‘Good Health’ and ‘Longevity’. And! Basically/totally ‘Diet/Nutrition’ related.

    However! What if? …..’Lifestyle’ is the major factor.

    (1) The Masai….Have you noticed how they ‘jump up and down’ (kinda of ‘African River-dance” at every opportunity? Their ‘Lymphatic system’ would run like a ‘Rolls Royce’ engine. Also they are regularly ‘smiling and singing’. I don’t think ‘Cortisol’ is in their vocabulary.
    (2) The Eskimo….Anyone for ‘Cold Thermogenisis’?

    • Duck Dodgers on November 21, 2014 at 20:34

      Well, what can I say, Michael. Look at the data when childhood mortality is removed from the equation. Most HG societies have an average life expectancy of 64 years of age for those individuals who are lucky enough to reach the age of 45.[1]

      Indigenous cultures are usually recognized for a lack of chronic disease—which the Inuit are not immune to. But, I’m not aware of any indigenous cultures being touted for lots of centenarians, are you?

    • Duck Dodgers on November 21, 2014 at 19:41

      Good points. Though, recent studies have shown that the Inuit were abnormally prone to excessive cerebral hemorrhages and had just as much CVD as Westerners. Bang & Dyerberg were the ones who claimed that the Inuit were free from CVD, but they were debunked by a recent review of the literature, earlier this year.

      As for the Masai, they ate lots of honey, traded their meats for carbs with neighboring tribes, and consumed lots of acacia bark extractions with every meal. So, lots of confounding variables that few people are aware of. And, I’m sure the dancing helps too 🙂

      Though, it’s worth pointing out that neither culture is really known for longevity.

    • Bret on November 21, 2014 at 19:43

      I absolutely love the way you think, michael.

    • michael goroncy on November 21, 2014 at 20:07

      Yo! Quack…..I mean Duck.
      You are doing an excellent effort to cloud the waters…..well done. Your work may swim us into clear water eventually. My brain does not have the stamina to exhaustively research data.
      Have you noticed how the health blogs mimic each other regarding ‘sleep’ ..water,food etc. Not to mention Tim Steels/Resistant Starch…..”as though it has always been”

      “Though, it’s worth pointing out that neither culture is really known for longevity. “ the opposite of what I have read.

      “So, lots of confounding variables “…..say it again!

    • GTR on November 22, 2014 at 10:14

      @Duck – the group leader in the video about robbing lions of their meat is 65. “At 65 he’s a veteran hunter who takest hunter who takes the lead”

      https://www.youtube.com/watch?v=TBpu4DAvwI8

    • Sky on November 24, 2014 at 03:31

      [However! What if? …..’Lifestyle’ is the major factor.]

      Michael…

      Variations of gut microbes has already been explained by differences in diet, the environment, lifestyle, and the health of the host. Now scientists/researchers are realizing that genetics also plays a role: https://www.genomeweb.com/clinical-genomics/study-twins-finds-host-genetics-influence-gut-microbes-though-both-affect-body-w

      And as Peter from Hyperlipid has so eloquently pointed out, the Inuits have a genetic mutation that sets them apart from the general population in terms of how they metabolize macronutrients, esp. FFAs and carbs. Would you suggest to an Inuit that they eat a diet that the Masai are accustomed to eating? Would you suggest the Inuit start eating PS?

      Taking ALL that into consideration…. why is anyone using the Inuits and/or the Masai as examples in trying to come up with a diet (way of eating) that would benefit EVERYONE…?!

    • Sky on November 24, 2014 at 03:41

      [Though, recent studies have shown that the Inuit were abnormally prone to excessive cerebral hemorrhages and had just as much CVD as Westerners.]

      Well, couldn’t that be attributed to the fact that they have been migrating to cities in recent years and have been eating a Western diet of late?

      The same thing happened and has been noted with other indigenous cultures, such as the Aborigines of Australia and the Maori of NZ. Once they went back to eating the way of their ancestors their health was restored.

    • DrJE on January 15, 2015 at 21:59

      Holy Shit do even read the papers you post? It says familial aggregation right in the title. and the conclusion of the authors is it’s likely genetic. What that has to do with a HFLC diet is anyone’s guess.

    • Duck Dodgers on January 16, 2015 at 08:31

      Easy buddy. Read it again.

      The Inuits had a much higher prevalence of aneurysms than their Dane counterparts who also had a family history. So, diet may explain the difference between the two populations, since it wasn’t controlled for (or it may be genetic, but we don’t know).

      The question was posed as to whether the Inuits were a model of good health and longevity. They are not.

  24. michael goroncy on November 21, 2014 at 20:26

    Yo! Bret
    You must be mental….I haven’t had a compliment since 1972

    • Sky on November 24, 2014 at 02:26

      [Yo! Bret. You must be mental.]

      That’s an overstatement. She’s not exactly the brightest crayon in the box, is she?! LMAO! ;0)

  25. michael goroncy on November 21, 2014 at 21:44

    Well! Duck
    I won’t ‘google’ and just pluck these out of my arse. I will try harder if there is a prize.
    “ I’m not aware of any indigenous cultures being touted for lots of centenarians, are you?

    A= Hunza?

    “ Most HG societies have an average life expectancy of 64 years of age for those individuals who are lucky enough to reach the age of 45.”

    A= I know(I think) Marathon runners and certain sports groups….won’t reach octogenarians status.

  26. Bret on November 23, 2014 at 19:20

    Semi off topic.

    A friend shared this article on Facebook sorry, Richard Voldemort tonight, and I was ecstatic.

    I am used to seeing good information on blogs such as FTA and Fat Head, but every time a friend outside that orbit posts an article, I usually see some shit about whole grains.

    So, this is progress from my point of view.

  27. Richard Nikoley on January 5, 2015 at 11:34

    Part 2 is posted:

    The Hormesis Files: Who’s Afraid of Unrefined Sugar?

    https://freetheanimal.com/2015/01/hormesis-afraid-unrefined.html

  28. Just wondering on August 17, 2017 at 11:11

    http://www.cell.com/cell-chemical-biology/fulltext/S2451-9456(17)30270-2

    Wonders if this means that ketones do not lead to elevated MG

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