You’re Welcome To Join In: What Is RAPE, Exactly? The Bill Cosby Files.

No idea this would touch off a barrage of lots of stupid—mostly from men (I guess, writing what they surmise women want them to write).

I engender discriminating and distinguishing minds. I have little use for equivocating minds.

I've disabled this post from comments. The previous post on the Bill Cosby rape allegations is where any comments need to go.

So come take me on, if you have the spirt. Be sure to integrate a 35-year timeframe if you wish for me to take you seriously. Know that you don't get to have your cake and eat it too. You must deal with ALL the known and not fantasize about the unknown. Furthermore, you must weigh evidence, fallibly, as we all do. But, you must do your best.

So Bill Cosby is a Rapist, Now

Hell, I'm sure a niece or friend had sex with Bill in the late 70s', early 80's.

They cry RAPE! 35+ years later?

Dismissed.

What I’m Up To

Rigorously running down stuff Woo posted about what Peter posted about.

Not fucking actually. Actually, I've read none of it. Not a word (in amusement, I'm going 100% third hand so far). What I and Duck have done is of record. It's pristine, and from what I've read of that third hand, Even Peter didn't understand the studies.

Aren't they very late to the party, 17 posts and 1,500 comments later? Here's the next thing: The Hormesis Files: Chronic Ketosis and The Case of The Missing Glutathione. Hopefully, it will take fewer posts than 17 for Woo and Peter to get their shit together and stir it up.

...In important news, I got a WiFi Thermostat (Emerson Sensi) working for my backup heater here, a Wlliams gas wall furnace and I can now control the temperature in my Arnold, CA cabin from anywhere in the world via my phone. It required tying into a continuous power source (a "C" wire) to run the WiFi.

Sorry, Woo, just slightly more important.

Woo: go get laid. Please. Or, at least install a WiFi thermostat with a mobile app.

UPDATE: I have added a comment from Duck below that was posted in a separate thread.

Well, Given a Gaudy Shirt, We Sure as Must Need to Put a Woman on Mars, Now

Jannet "Judgy Bitch" Bloomfield's post: It’s not advanced math and rigorous training that keeps women out of STEM. It’s sexist shirts. Watch feminists break the stupid meter.

STEM = Science Technology Engineering Math

Anyway, some geek scientist that helped happen an unwomaned lander land on a rapidly spinning comet in space, traveling at a bazillion MPH wore a shirt that a only a true geek, autistic savant, or Aspergers would wear in public. Or, perhaps an asshole like me, whilst sporting a grin and a middle finger.

Via Amy Alkon: David Burge with the nutshell on the furor:

@Iowahawkblog
"Man Forced to Apologize for Sexist Shirt After Successfully Landing Spacecraft on Comet" has to be the ultimate headline for our age.

JB frames it exactly right for my taste.

stupid meter
 

I love what Janet and others do in the men are men space, it's just not my quotidian bag. I've never been with A Stupid as man-woman deal (avoid plagues); and as an employer, I easily filtered out such Stupid from every person hired (I discriminate). Easy to filter. Just give 'em rope. My mom—and grandmother, and great grandmother, in their living days—lafs at the impotence of feminists and their childlike entitlement angle. ...My great grandmother dumped a number of men, raised two kids by herself during the Great Depression—had her first kid of two at 15. She was 58 when I was born, died when I was 29.

Sorry children-femmes: my great grandmother taught me what a real woman of adult determination was like. She never pouted about men. Actually, I don't think she ever worried much about them, untoward like. She adored her great grandkids, though. I know, firsthand. When I was a boy, a trip to see grandnanna was just the dessert of life, then.

But with feminism, it's those High-School Bitch films all over again.

This blue comet upon which we dwell is now simply swimming in meaningless feelings. Everybody has feelings. Feelings have become as ubiquitous and as faux "important" as the latest narcissist Facebook update you saw of someone's check-in, or what they happen to "think" about something.

I don't give a fuck about anyone's feelings. Not truly. Not when its unimportant; and the world I live in now is most focussed on the unimportant and facile.

Why should you? Care, I mean. If someone has some legit beef about something, U did them wrong in some way; ...or, perhaps they care about you enough to let you know that they think you're just wrong, but with actual adult-like reasons? We don't do that on this comet, anymore. We're all rushing to be narcissist, solipsist children as fast as possible—and there's many apps for that...

In short—and it's getting embarrassing to post about this anymore—dealing with feminism is simply an exercise in dealing with children. And, as you know, it's always, and always: for the children. THE CHILD...REN! Yea, 100% of feminists bought that pathetic wife of a public presidential philanderer line, and: It Takes a Village.

Feminists are a CAFO OF USELESS BULLSHIT FEELING.

CAFO = Concentrated Animal Feeding Operation

...I liked this JB riff the best:

A woman made the shirt for him. There’s your first clue, Einstein. That shirt does not offend or demean 50% of the world’s population. It offends joyless, petulant, irrational, victim worshipping feminists cunts like you!

Yeah, yeah, cunt is a bit harsh, but do you know why I like using those words, especially to describe feminists? It’s a way of iterating, forcefully, that their precious feelz matter not one fucking bit to me. Women’s feelings do not matter more than men’s feelings, women do not have the right to walk through life in a state of perpetual comfort, never offended by anything at any time anywhere. It is not wrong to offend women and most women know this already!

It’s feminist bitches who seem to think the world owes them permanent obsequious and obedience. Remember this pathetic attention whore? Tweeting out her butthurt over a Dongle joke that wasn’t even addressed to her?

As I said, this stuff is just not particularly in my wheelhouse (see the meter at the top). I've had my run ins, but they fade away. I never cared a runny shit for their feelings. JB can probably get away with using THE C-WORD, since she's a woman. Oh, wait. She loves and celebrates men, and derides feminists. Nevermind.

...The thing Janet is deriding, though, is the idea that things like a geek wearing a "sexist" shirt (rather than in simple bad taste, like your great grandmother taught you) is what's keeping women from pursuing STEM carriers.

They hear comments about “bitches” while out at a bar with fellow science students, and they decide to change majors.

stripper
Futre Stripper, Not STEM

From my perspective on this comet for nearly 54 years, women make it go round one way; and men, another. Neither orbits nor rotations are pristine. It's evolutionary and animal. It ought be free.

Thank doG.

I'll close with Amy Alkon.

Clearly, feminism is no longer about demanding that women be treated as equals, but as eggshells.

Is A High Fat Ketogenic Diet For Everyone? Obviously Not

Here's Kati, in commnets:

I was eating a lower fat low glycemic south beach style diet and dropped to my very happy adult weight, then eventually found ketosis. Gained 40+ lbs in a couple years and could not figure out for the life of me why my eyes were always dry to the point of contacts not staying in, bad insomnia and why the weight was creeping on. It couldn’t be my perfect diet! Fast forward to about a year ago last winter, I thought I was going to die. I kept getting respiratory infections and real influenza hit me hard, And any cold I got turned into a secondary infection requiring antibiotics. I think I was on antibiotics 3 times in 4 months. Anyway, all that to say, I’m glad to be back with what seems most sane, with a couple fasts thrown in per week for fat loss ( eat stop eat- the fat is finally coming off again). I just love you guys here. You have helped so much with me not being afraid of carbs (Paul Jaminet has helped too), and for me starting to regain my once robust immune system back. I love all the articles on resistant starch, chronic nutritional Ketosis busting and even the occasional controversy. It gives me a lot to think about.

And here's Bret:

Kati,

Thanks for sharing your story. As you have certainly seen, a lot of chronic ketosis advocates seem to believe unconditionally that chronic ketosis is the “right” or “perfect” diet for everyone. Anecdotes like yours are important, because they provide hard proof that such a belief is wrong.

I remember getting swept up in the chronic ketosis hysteria myself. All these smart (and seemingly smart) doctors, authors, bloggers, etc were speaking with such confidence and so many technical details, it was difficult not to believe they were correct. But really, all they did was proffer another hypothesis that, while largely antithetical to the mainstream in its specific advice, was equally fallible and, as we now know, equally flawed.

I have been fooled once by the mainstream dogma. I was fooled again by the VLC dogma. I do not intend to be fooled a third time. Every piece of advice that comes my way now will be taken with a grain of salt and regarded with much skepticism and scrutiny. There is simply too much room for bullshit, no matter who is doing the advising.

But to be fair, here's Mark:

Being a Type 2 diabetic, I guess the importance I see in all this is that the Inuits did eat low carbs ( I saw 30-40 grams re the snip it of Rabinowitch scientific literature presented by Duck Dodger) which is 5-6% of the carbohydrate portion of daily calorie consumption. IF this is so, I feel confident they were indeed insulin resistant and would fail an OGTT. I don’t see where this is proving anything detrimental about low carb, it just debunks the “they ate no carbs” myth. What does anything in any of the “scientific literature” say about them having diabetes or CVD? Did they have any deficiencies due to, I assume, a very low level of resistant starch in their diet?

Collin, I’m with ya on low carb, but I crush 1250 LCHF calories in just my 2 cups of BP coffee every morning then add 3egg&cheese omelet and bacon for breakfast on top of that.

Not saying LCHF is for everybody, obviously it is not. I know the ADA recommended diet is not for me. I do know that I tolerate retrograded starch in Anasazi beans and resistant starch in BRM’s unmodified potato starch and wanting to know more about it.

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.

~~~

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.

I Picked The Only White Guy Doctor. Here’s Why.

I blogged already about my recent health issue. What In The Hell I’m Up To: I’m Telling Myself to Fuck Off Regularly.

That was midway through what turned out to be a 17-day stay at the cabin, mostly in solitude.

aae66c14 6e9f 419c b260 8abbaba21dd9 1 10
 

The upside was the diversion over that time. All four seasons of Game of Thrones: in the can. Had heard about it endlessly, had never seen a single episode. Quite cool on levels. Love it. Can't wait for the next season.

Here was my self-designed therapy:

  1. Solitude. That way, I had to do everything I really wanted to do for myself. Moreover, didn't need anyone telling me what a poor little bunny I am. That, I save for when I have a Man Cold.
  2. Lafed at myself when it hurt too much to do normal stuff. Did it facing myself in the mirror when necessary. Called myself a pussy and a cunt as much as possible. (This is the Dr. Sarno angle. While the pain is physically real, there's a psych element promoting it. Understanding this is very helpful.)
  3. Spent $30 on a ridiculous device that actually works: Sunbeam 730-811 Heating Pad plus Massage.

In terms of #3, I can see myself lafing uproariously at my wife and others who like this kinda silly shit. But it fucking worked: and well and quickly. Back when I had my cervical herniation, I used a straight heating pad on my arm to mediate the ache. But, a lumbar herniation comes with back pain, knife in the hip, an aching hamstring and quadricep, aching calf, and numb and tingling toes.

Initially, I used that silly device on just my lower back and left butt (for the hip). What it did was tremendously reduce the sharpness of pain...the knife angle, if you will.

...And I had a phone consultation with a longtime reader who also happens to be a long practicing chiropractor. Rick told me that my Sarno approach was valid, but that there still may be a physical aspect that needs addressing. Probably true. After all, in the last 5 years, my dad and two younger brothers all had lumbar herniations, all got surgery, all swear by it.

Some days later, I had a very bad day. My left hamstring and quadricep ached so much I wanted to tear them off and feed them to dogs. I'd gone to bed at 10, Woke up at 12, and ached so much I never slept another wink (if I can't sleep, I lay and try to relax instead). Got up at 6, still dark—prior to the fucktarded exercise in changing the clocks that we do.

I had an idea. What if I put that silly, vibrating heating pad under my leg, my left hamstring, as I just sit there? And, breakthrough! In 2 hours. It changed everything. I could feel my toes, and my hip didn't hurt so bad. I got very tired. At 8 or 9 AM, went to bed and next thing I know, it's 3 PM.

Going on nearly 2 weeks were such miracles happen. Thank doG.

However, I still have chronic pain. It's 60-80% better on average, 95% better some days, some hours. I don't know how long it will last, but I'm getting very, very tired of it. The other day, I was so tired of the management that I went to bed at 8 pm, did a potty break at 3, then woke up at 6:30. It can get very fatiguing. Surprisingly so—where you're not aware until you are. The pain mitigation has at least allowed me to sleep, and there has been massive catchup. I could probably sleep for 6 hours right now, even though I woke up 4 hours ago from a decent 8 hour soak.

...So, yesterday, decided to go see a doc, see if I can scrounge and MRI so I can know if this is short, or probably long term and recurring. I have Kaiser. My previous doc, Shranz, retired. Hadn't been to see him in 2-3 years. Had to pick a new one. There's 4 web pages of docs taking new patients. Dozens of docs.

One single white guy.

Why? It's not racist whatsoever. I've had a female Indian doc stick her lubricated and latexted finger up my ass and feel around—after she fondled my front side and I had to cough. But, she didn't get my jokes about it. I need someone to get my jokes and especially, commiserate with my self-deprecating delve into various forms of irony and innuendo.

Most likely to be a white guy. For me.

...On the other hand, my dad had to have a urinary roto-rooter job performed a couple of years back, and the surgeon who did it was a young, female, Dr. Wang—and she ate up the jokes.

On that note, here's the very adorable Doctor Leana Wen. She's trying to change shit by pointing out what she dubs The White Coat Disease of Fear, juxtaposed with the typical patient's fear of disease.

She got 'innuendo death threats' from other doctors over this, so makes her heroic in my book.

Wouldn’t you want to know if your doctor was a paid spokesman for a drug company? Or held personal beliefs incompatible with the treatment you want? Right now, in the US at least, your doctor simply doesn’t have to tell you about that. And when physician Leana Wen asked her fellow doctors to open up, the reaction she got was … unsettling.

The times? Changin'.

Come gather ’round people
Wherever you roam
And admit that the waters
Around you have grown
And accept it that soon
You’ll be drenched to the bone
If your time to you is worth savin’
Then you better start swimmin’ or you’ll sink like a stone
For the times they are a-changin’

Come writers and critics
Who prophesize with your pen
And keep your eyes wide
The chance won’t come again
And don’t speak too soon
For the wheel’s still in spin
And there’s no tellin’ who that it’s namin’
For the loser now will be later to win
For the times they are a-changin’

Come senators, congressmen
Please heed the call
Don’t stand in the doorway
Don’t block up the hall
For he that gets hurt
Will be he who has stalled
There’s a battle outside and it is ragin’
It’ll soon shake your windows and rattle your walls
For the times they are a-changin’

Come mothers and fathers
Throughout the land
And don’t criticize
What you can’t understand
Your sons and your daughters
Are beyond your command
Your old road is rapidly agin’
Please get out of the new one if you can’t lend your hand
For the times they are a-changin’

The line it is drawn
The curse it is cast
The slow one now
Will later be fast
As the present now
Will later be past
The order is rapidly fadin’
And the first one now will later be last
For the times they are a-changin’

Go ahead, Bob. Put a tune and harp to it.

Drug Policy In America: It Is To Laf

I try not to ever seriously admonish anyone to WATCH THIS VIDEO!

But, WATCH THIS VIDEO! Every. Body. Just watch it.

Ethan Nadelmann: Why we need to end the War on Drugs

It's so very impassioned. This is his life. He gets everything exactly right in terms of the insanity of drug prohibition. Here's the transcript, should you prefer to read.

I'm not interested in regulating anything ever in a top-down, initiation of force manner; and every cent ever collected in "taxes" is a giant euphemism for theft and robbery. But I try not to quibble too loudly when a better direction is being taken concomitant with less harm to good people and those they love.

Funny, prescient quote at about 6 minutes in:

Put it this way, and I exaggerate only slightly: If the principal smokers of cocaine were affluent older white men and the principal consumers of Viagra were poor young black men, then smokable cocaine would be easy to get with a prescription from your doctor and selling Viagra would get you five to 10 years behind bars.

Go take a watch.

Leaving The Inuit Behind: Hormesis For The Rest Of Us

As most readers know, some months back, a collaborator came to me with some interesting findings in terms of research he'd discovered concerning what's commonly called "animal fiber" (bits of animals that can feed the microbiome). This led to more digging and the understanding that when animals are eaten fresh, raw or frozen, many contain non-degraded glycogen, particularly in organs like the liver.

This then led to even more digging, particularly in terms of the Inuit, and the realization that for decades now, they've been touted as confirmation that a chronically very low carbohydrate or ketogenic "lifestyle" is just hunky dory.

We soundly dispute that notion and have posted about research going back over 100 years to demonstrate that apart from the question of whether the new brand of ketogenic "lifestyle" (ironically dubbed 'nutritional' ketosis) is particularly healthy, the Inuit were never a ketogenic society in spite of a low carbohydrate intake. Clue: far too much protein intake. Their diet is principally a high-protein, not a high fat diet.

Here's the list of posts with comment counts (as of today, 12-Nov-2014).

  1. Disrupting Paleo: Inuit and Masai Ate Carbs and Prebiotics, Part 1 (110 Comments)
  2. Disrupting Paleo: Inuit and Masai Ate Carbs and Prebiotics, Part 2 (193 Comments)
  3. To Reiterate, Just In Case You Missed It: No Elevated Ketone Levels in the Inuit (150 Comments)
  4. One Thousand Nails in the Coffin of Arctic Explorer Vilhjálmur Stefansson, and His Spawn (150 Comments)
  5. When Confirmation Bias is the Landscape, Dialectics is Your Path to Better Truth (109 Comments)
  6. What Did Indigenous People Inhabiting the Coldest Places on Earth Really Eat? (69 Comments)
  7. Sweden Update: Resistant Starch On The Rise, LCHF Stefansson Myths On The Ropes (14 Comments)
  8. More Uncovering of the Inuit Myth: Stefansson and Anderson Belleview Experiement; Compromised Glucose Tolerance (72 Comments)
  9. Logic 101: Why The Resistant Starch And Gut Biome Revolution Means Doom For VLC/Keto (179 Comments)
  10. Hunters Of Wild Game Can’t Remain In Ketosis (14 Comments)
  11. The New Nutritional Starvation Diet (32 Comments)
  12. The War On Tastebuds (78 Comments)
  13. 7 Bigger-Than-Ever Challenges Everyone Should Know About Low-Carb Ketogenic Diets (65 Comments)
  14. Physiological Insulin Resistance = Low Carbohydrate Diet Induced Insulin Resistance (25 Comments)
  15. The Swedes Look Beyond Vilhjalmur Stefansson’s NYT Obituary, to The Science He Ignored (9 Comments)
  16. Lies, Damned Lies, and The Inuit Diet (15 Comments)
  17. The Comment Dr. Michael Eades Doesn’t Want You To See (163 Comments)

In the past the logical standard for determining the safety of chronic ketosis was to point to the Inuit as a long term experiment in ketosis. While that kind of logic was often accepted, it can no longer be considered acceptable given what the literature actually says of the Inuit. In reality, the Inuit are an obscure culture that is poorly understood by Westerners, and their dietary habits should never have substituted for proper due diligence. The Inuit were nothing more than a giant distraction with no real relevance to the discussions at hand. What a colossal waste of time! With that, I hope we can leave the Inuit be, and focus on more new and exciting data!

And with that, we move on. Here's what's coming.

Collaborator(s) and I will be writing a series of posts on the subject of hormesis—how our diets and our microbiomes respond to stress. In Part I, we'll explore the therapeutic benefits of ketosis, intermittent ketosis, and consider some lingering questions concerning methylglyoxal accumulation—its potential therapeutic effects and potential side effects—with regard to new data that's come out. In Part II, we'll investigate how our microbiomes, with the help of prebiotics, can help us manage the stresses in our environment and food supply.

And yes, we'll explore whether the orthorexic fear of glycolysis and "toxins" in our foods that The Paleo Diet™ has encouraged may be causing us more harm than good.

Coming soon.

“Keto” Diet Adds Fat and Wastes Lean In Athletes

The money quote:

The commonly heard claim that ketogenic dieting would lead to significantly more beneficial improvements in body composition in dieting athletes, on the other hand, is clearly falsified by the results of the study at hand. If anything, the loss of muscle mass is more and the loss of fat mass less pronounced than it would be with a balanced medium-to-high carbohydrate diet.

That's Adel Moussa, Suppversity Blog: "Keto" Diet in Taekwando Athletes: Good for Performance, Less Beneficial for Body Composition - Non-Sign. Higher Muscle & Lower Fat Loss in 25% Deficit vs. Balanced Diet.

But here's the big rub, as Duck and I pointed out in our recent series on the noon-ketogenic state of the Inuit. The diet tested here is not even ketogenic (probably way better).

If you want to do a keto diet, say goodbuy to tons of protein: What may not be obvious to all of you is the fact that the diet at hand is low in carbs, but not high enough in fat to be truly ketogenic. With 40% protein you are not going to go into ketosis. That's simply too much protein to be converted to glucose in the liver - specifically if you get some of the protein from fast digesting protein sources like whey, which will spike the blood amino acid levels and kickstart hepatic gluconeogenesis. Unfortunately, the study does not list the absolute protein intake, but if we assume a baseline intake of 2800kcal per day for the subjects, they would have consumed 210g of protein per day - that's 3.2g/kg for these lean guys - and still lost muscle.

See, same as for the Inuit, except their average protein intake was 270 g/d.

So let's get this straight. There's a diet out there being touted as the epitome when even at 40% protein, subjects lose lean muscle and have higher fat levels. I shudder to think what happens when you take the protein down to 15% so that your blood ketone meter makes happy noises.

Fucking dumb in every way imaginable.