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What ketosis does to the brain

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And why it’s relevant to failsafers!

Our objective was to study brain amino acid metabolism in response to ketosis. The underlying hypothesis is that ketosis is associated with a fundamental change of brain amino acid handling and that this alteration is a factor in the anti-epileptic effect of the ketogenic diet. Specifically, we hypothesize that brain converts ketone bodies to acetyl-CoA and that this results in increased flux through the citrate synthetase reaction. As a result, oxaloacetate is consumed and is less available to the aspartate aminotransferase reaction; therefore, less glutamate is converted to aspartate and relatively more glutamate becomes available to the glutamine synthetase and glutamate decarboxylase reactions. We found in a mouse model of ketosis that the concentration of forebrain aspartate was diminished but the concentration of acetyl-CoA was increased. Studies of the incorporation of 13C into glutamate and glutamine with either [1-(13)C]glucose or [2-(13)C]acetate as precursor showed that ketotic brain metabolized relatively less glucose and relatively more acetate. When the ketotic mice were administered both acetate and a nitrogen donor, such as alanine or leucine, they manifested an increased forebrain concentration of glutamine and GABA. These findings supported the hypothesis that in ketosis there is greater production of acetyl-CoA and a consequent alteration in the equilibrium of the aspartate aminotransferase reaction that results in diminished aspartate production and potentially enhanced synthesis of glutamine and GABA. Response of brain amino acid metabolism to ketosis

There are a number of different studies by Daikhin and Yudkoff that have confirmed the above hypothesis in different ways. They can be found in pubmed. I won’t repeat them all here.

Here is a study that found other differences:

The ketogenic diet (KD) is an established treatment for medically refractory pediatric epilepsy. Its anticonvulsant mechanism is still unclear. We examined the influence of the KD on the CSF levels of excitatory and inhibitory amino acids in 26 children (mean age 6.1 years) with refractory epilepsy. Seventeen amino acids were determined before and at a mean of 4 months after the start of the KD. Seizures were quantified. Highly significant changes were found in eight amino acids: increases in GABA, taurine, serine, and glycine and decreases in asparagine, alanine, tyrosine and phenylalanine. However, aspartate, glutamate, arginine, threonine, citrulline, leucine, isoleucine and valine/methionine remained unchanged. A significant correlation with seizure response was found for threonine (P=0.016). The GABA levels were higher in responders (>50% seizure reduction) than in nonresponders during the diet (P=0.041). In the very good responders (>90% seizure reduction), the GABA levels were significantly higher at baseline as well as during the diet. Age differences were found with significantly larger decreases in glutamate and increases in GABA in connection with the diet in younger children. Our results indicate that the KD significantly alters the levels of several CSF amino acids that may be involved in its mechanism of action and the increase in GABA is of particular interest. The ketogenic diet influences the levels of excitatory and inhibitory amino acids in the CSF in children with refractory epilepsy

Glutamate and aspartate are both ‘bad’ neurotransmitters for people with food chemical intolerance (aspartate is involved in salicylate reactions on NMDA receptors). Ketosis appears to reduce aspartate levels by moving glutamate production away from aspartate and towards GABA and glutamine. Other glutamate-opposing amino acids like taurine, serine and glycine are raised too. GABA and glutamine are both ‘good’, calming neurotransmitters for failsafers.

The ketogenic diet has been studied for many years in relation to intractable epilepsy in children. It has also been hypothesised to help bipolar disorder:

The ketogenic diet, originally introduced in the 1920s, has been undergoing a recent resurgence as an adjunctive treatment for refractory epilepsy, particularly in children. In this difficult-to-treat population, the diet exhibits remarkable efficacy with two-thirds showing significant reduction in seizure frequency and one-third becoming nearly seizure-free. There are several reasons to suspect that the ketogenic diet may also have utility as a mood stabilizer in bipolar illness. These include the observation that several anticonvulsant interventions may improve outcome in mood disorders. Furthermore, beneficial changes in brain-energy profile are noted in subjects on the ketogenic diet. This is important since global cerebral hypometabolism is a characteristic of the brains of depressed or manic individuals. Finally, the extracellular changes that occur in ketosis would be expected to decrease intracellular sodium concentrations, a common property of all effective mood stabilizers. Trials of the ketogenic diet in relapse prevention of bipolar mood episodes are warranted. The ketogenic diet may have mood-stabilizing properties

When the researchers say that anticonvulsant interventions help bipolar disorder, one example is the prescribing of sodium valproate for people who have bipolar disorder. I have a close friend with epilepsy who is familiar with both valproate and ketosis. Valproate is an acetone mimic that produces effects on the brain that are identical to ketosis. The difference is that valproate comes with a range of side effects that a ketogenic diet doesn’t have.

If valproate is used for bipolar disorder it naturally follows that ketosis would help too.

Unfortunately no studies have yet been conducted to back up the use of a ketogenic diet for bipolar disorder. Which is a dreadful shame. It has helped (as in ‘effectively cured whilst diet is maintained’) three members of my family who have bipolar tendencies but are just short of official diagnosis – something that Prozac didn’t do for their depression.

Written by alienrobotgirl

13 May, 2008 at 6:47 pm

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Eades versus Colpo

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Michael Eades and Anthony Colpo have been involved in what can politely be described as a ‘debate’ recently. Less politely it might be described as Eades trying his best to remain calm and professional whilst Colpo lashes out with personal insults like a rabid attack-dog. I enjoy both of their outputs – as long as they both stay off the subject of politics – though I worry about Colpo sometimes, if the man is THAT angry ALL the time, there must be something very wrong.

Eades has put up a post citing science in favour of the metabolic advantage. He quotes from a recent study on mice who were put on a ketogenic diet and lost more weight than controls due to changes in gene expression that caused them to burn at a hotter rate. The results of the study didn’t break the laws of thermodynamics.

On the other hand we have Colpo saying “Calories in equal calories out, there is no metabolic advantage.” Because that’s one of the main premises of his weight loss book, I haven’t bought it, as I’ve a more complex understanding of metabolism.

I honestly don’t know what these two are fighting about. It’s apparent that a ketogenic diet (usually but not always) makes one burn more calories than a carbohydrate-based diet because it increases metabolism and heat expulsion, at the very least in the short term. This theory has been around since at least the 1950’s. This doesn’t break the calories in = calories out rule, it never has. I think there are genetic exceptions to this too. Some people fair better with more carbohydrates in their diet, or less protein or more protein. I tend to favour ‘cycling’ between low and moderate carbohydrate content and not eating too much protein in order to maintain weight loss over an extended period – and eating very low chemical and opioid free.

Anyway, I’m not posting this to get into a tired old debate about the metabolic advantage. I’m here to fill in this blank:

What if underlying levels of fatness or genetics or _____ (we’ll fill in the blank later) cause us to eat more and burn less? Eades

With something like this:

What if underlying levels of fatness or genetics or increased insulin output caused by salicylates, amines, glutamates, additives and other food chemicals cause us to eat more and burn less?

Because that’s the way it went for me. I spent several years struggling with frighteningly rapid weight gain caused by food chemicals until I found the failsafe diet. I was very successful at controlling this weight gain though. This is because I have a will of iron – I may not be Posh Spice in terms of discipline, but I’m not Kirstie Alley either! Every three months or so I had to resort to a ketogenic diet in order to lose the weight I’d gained on the Atkins maintenance diet. I really didn’t eat that much – and believe me, I calculated my calorie intake very truthfully in FitDay. In fact, eating lots of fat and calories had the perverse effect of making me lose several pounds. I was extremely sensitive to relatively small amounts of carbohydrate though.

These days I eat a lot more carbohydrate and I don’t gain any weight at all. I only gain weight when I’ve cheated on failsafe – most usually by visiting a restaurant and eating meat or fish that is too old and aminey/glutamatey. Vacuum packed meat at home does the same thing to me. Physically I may not even feel bad (in fact I often feel happy-high), but I certainly feel it on my backside after a couple of days!

Whether you are underweight or overweight, if you struggle to control your weight on a normal diet, consider lowering your food chemical intake.

More on this debate here. The comments section gets quite nasty!

Written by alienrobotgirl

28 September, 2007 at 7:39 pm

Inflammation and intermittent fasting

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Eades annoyed me a few months ago with an ill-educated “MSG is harmless” post. I still have his blog on my RSS feed though, and he has posted an interesting article on inflammation and intermittent fasting recently.

The long and the short of it is that intermittent fasting spontaneously reduced homocysteine levels and increased B12 and folate levels, despite the diet not containing any additional B12 or folate. Somehow it becomes more bioavailable. So theoretically intermittent fasting should be good for people with food chemical intolerance and autism spectrum syndromes.

This matches my experience. I always feel very good when I forget to eat or I am dieting. It might help explain the honeymoon period of good health I went through when I first did the Atkins diet.

Written by alienrobotgirl

17 August, 2007 at 6:24 pm

The superfood that feeds both your muscles and your brain

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There are three main food groups: proteins, carbohydrates and fat. Now the US Defense Advanced Research Projects Agency (DARPA) is trying to create a fourth group. In doing so it hopes to provide soldiers, mountaineers and athletes with an extra source of energy and a means of maintaining their peak physical performance for longer.

During exercise, your muscles get most of their energy by burning a mixture of carbohydrates and fat. But if you are starving, the body begins to get extra energy from ketone bodies, acidic chemicals produced when the liver breaks down fatty acids. These are particularly important for the brain, as they can cross the blood-brain barrier and keep it supplied with energy.

Ketone bodies are not usually produced in large amounts, and they are not easy to get from food. But they are a more efficient source of fuel than fatty acids.

“The question we asked ourselves was ‘can we fundamentally modify a person’s diet to maintain their peak performance for longer?'” says Brett Giroir, manager of DARPA’s Peak Soldier Performance programme. For the past few years, Kieran Clarke and her colleagues at the University of Oxford have been collaborating with DARPA to find forms of ketone bodies that could be taken up by the gut and used as a fuel.

“You can’t give pure ketones, because they are too acid, and they would get used up very quickly,” says Clarke. Instead, her team has created “ketone polymers” – chains of ketone bodies that can be broken down over time to create a sustained release of ketones.

Rats fed with ketone polymers ran 30 per cent faster and 30 per cent further on a treadmill on five consecutive days than those fed carbohydrates or fat. They also showed enhanced cognitive abilities. Human trials of the polymers are expected to start this year. New Scientist, Superfood that feeds both your muscles and your brain (subscription only).

How amusing is this?! It’s a sidebar in an article about athletic performance and differences in genes in different sports people that affect the way they burn energy and grow different types of muscle fibres, and even how muscles can be trained to use different types of fuel for energy. A significant part of the article is taken up in speculation about Lance Armstrong’s special endurance abilities during the Tour de France – he was born with a larger heart and lungs than most people, and he appears to be much better at burning fat – triglycerides – and therefore conserves his glycogen supplies for longer.

The question it begs is: if ketones are so great for both energy and endurance, and the body has it’s own slow-release ketone-creation mechanism built in, why doesn’t DARPA spend more time studying the usefulness of a ketogenic diet for energy and endurance?

I’ve been fiddling with my diet and have just gone into ketosis today. I’d forgotten how energetic it made me feel.

Written by alienrobotgirl

6 August, 2007 at 4:01 pm

Those rats who live long lives again

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Remember the caloric restriction rats that live much longer lives than ordinary rats? They think they have figured out why that is the case:

The July 20, 2007 issue of Science published the results of research conducted at Children’s Hospital in Boston which provides one explanation for the benefits of improved eating habits and exercise on life span.

Working with mice, Akiko Tachi, PhD, Lynn Wartschow, and Morris White of Harvard demonstrate that reducing insulin receptor substrate-2 (Irs-2) signaling increases life span as well as brain levels of superoxide dismutase, a protective antioxidant enzyme. Acting on the basis of previous research in roundworms and fruit files which found an increase in life span associated with a reduction in insulin signaling, the trio engineered mice to reduce the amount of Irs-2, a protein that carries the insulin signal inside the cell, by half. Because reducing insulin signaling can cause diabetes, the researchers tested their hypothesis that reducing insulin signaling just in the brain, but not the rest of the body, would result in an increase in life span. They engineered two groups of animals to experience a reduction in Irs-2 in their brains alone, while one group of animals was engineered to have lower Irs-2 in all cells, and another group served as controls.

“To our surprise, all of the engineered mice lived longer,” Dr Taguchi remarked. Despite being overweight and having higher insulin levels, animals with diminished brain insulin signaling experienced an 18 percent increase in lifespan compared to the normal controls. The mice were also more active and retained greater levels of superoxide dismutase in old age.

“The idea that insulin reduces lifespan is difficult to reconcile with decades of clinical practice and scientific investigation to treat diabetes,” Dr White noted. “The engineered mice live longer because the diseases that kill them – cancer, cardiovascular disease and others – are being postponed by reducing insulin-like signaling in the brain regardless of how much insulin there is in the rest of the body. The easiest way to keep insulin levels low in the brain is old-fashioned diet and exercise.”

“Our findings put a mechanism behind what your mother told when you were growing up—eat a good diet and exercise, and it will keep you healthy,” White observed. “Diet, exercise and lower weight keep your peripheral tissues sensitive to insulin. That reduces the amount and duration of insulin secretion needed to keep your glucose under control when you eat. Therefore, the brain is exposed to less insulin. Since insulin turns on Irs2 in the brain, that means lower Irs2 activity, which we’ve linked to longer lifespan in the mouse.”

“We are beginning to appreciate that obesity, insulin resistance, and high blood insulin levels are connected to Alzheimer’s disease, Huntington’s disease, and dementias in general,” he added. “It might be that, in people who are genetically predisposed to these diseases, too much insulin overactivates Irs2 in the brain and accelerates disease progression. Thus, insulin resistance and higher insulin levels might be the environmental influences that promote these diseases.” LEF Magazine

I think my first responses have to be “DUH!”, and “I told you so!”

Imagine what would have happened if those caloric-restriction scientists had fed the rats an Atkins diet. They would have got the same positive results on lifespan. Except those results would have been ignored and buried because they didn’t fit the warped dominant nutritional paradigm. Instead they have been harping on about how longevity is all about caloric restriction, because it fits that paradigm.

The most ironic quote:

“The idea that insulin reduces lifespan is difficult to reconcile with decades of clinical practice and scientific investigation to treat diabetes.”

Doctors Atkins and Bernstein wouldn’t agree with that comment. Atkins and Bernstein have both been saying for at least 35 years that insulin ages you and kills you young from cardiovascular disease and cancer. Dr Bernstein, who eats a very low carbohydrate diet, is the oldest living T1 diabetic on the planet. There are no coincidences. Bernstein was an engineer. He was around two years from death when he took matters into his own hands and decided to learn how to control his own blood sugar, and turned his life around. When he realised no one in the medical profession was listening to him he became a doctor. It took an engineer’s mind, rather than a medical mind, to figure out what he had to do to save his life.

Carbohydrates increase insulin output in proportion to the quantity that you eat. If you ask an expert on insulin like Dr Bernstein on how low GI diets affect insulin output, he will point out to you that they just cause the same amount of insulin to be released more slowly with less spikes.

Salicylates also increase insulin levels, by the way. Another reason fruits and vegetables aren’t so good for you after all. Free glutamates, like the ones you find in meat that is too old, also raise your insulin levels.

Written by alienrobotgirl

2 August, 2007 at 6:55 pm

Cancer, ketones, dichloroacetate

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I wrote a very long essay on cancer last year but took it down, and I really need to get it back online. In it I mentioned how a ketogenic diet has shown a lot of promise in treating cancer. Eades posted a couple of items on it last September.

The theory behind it is that cancer cells have defective mitochondria that make them 1) unable to burn fat and 2) forced to burn glucose through anaerobic fermentation, producing lactic acid as an end product.

This is copied directly from the marvellous New Scientist magazine:

It sounds almost too good to be true: a cheap and simple drug that kills almost all cancers by switching off their “immortality”. The drug, dichloroacetate (DCA), has already been used for years to treat rare metabolic disorders and so is known to be relatively safe.

It also has no patent, meaning it could be manufactured for a fraction of the cost of newly developed drugs.

Evangelos Michelakis of the University of Alberta in Edmonton, Canada, and his colleagues tested DCA on human cells cultured outside the body and found that it killed lung, breast and brain cancer cells, but not healthy cells. Tumours in rats deliberately infected with human cancer also shrank drastically when they were fed DCA-laced water for several weeks.

DCA attacks a unique feature of cancer cells: the fact that they make their energy throughout the main body of the cell, rather than in distinct organelles called mitochondria. This process, called glycolysis, is inefficient and uses up vast amounts of sugar.

Until now it had been assumed that cancer cells used glycolysis because their mitochondria were irreparably damaged. However, Michelakis’s experiments prove this is not the case, because DCA reawakened the mitochondria in cancer cells. The cells then withered and died (Cancer Cell, DOI: 10.1016/j.ccr.2006.10.020).

Michelakis suggests that the switch to glycolysis as an energy source occurs when cells in the middle of an abnormal but benign lump don’t get enough oxygen for their mitochondria to work properly (see diagram). In order to survive, they switch off their mitochondria and start producing energy through glycolysis.

Crucially, though, mitochondria do another job in cells: they activate apoptosis, the process by which abnormal cells self-destruct. When cells switch mitochondria off, they become “immortal”, outliving other cells in the tumour and so becoming dominant. Once reawakened by DCA, mitochondria reactivate apoptosis and order the abnormal cells to die.

“The results are intriguing because they point to a critical role that mitochondria play:

they impart a unique trait to cancer cells that can be exploited for cancer therapy,” says Dario Altieri, director of the University of Massachusetts Cancer Center in Worcester.

The phenomenon might also explain how secondary cancers form. Glycolysis generates lactic acid, which can break down the collagen matrix holding cells together. This means abnormal cells can be released and float to other parts of the body, where they seed new tumours.

DCA can cause pain, numbness and gait disturbances in some patients, but this may be a price worth paying if it turns out to be effective against all cancers. The next step is to run clinical trials of DCA in people with cancer. These may have to be funded by charities, universities and governments: pharmaceutical companies are unlikely to pay because they can’t make money on unpatented medicines. The pay-off is that if DCA does work, it will be easy to manufacture and dirt cheap.

Paul Clarke, a cancer cell biologist at the University of Dundee in the UK, says the findings challenge the current assumption that mutations, not metabolism, spark off cancers. “The question is: which comes first?” he says. Cheap, safe drug kills most cancers

Acetic acid is basically vinegar, and one of the major ketones produced during low carbing, fasting, or weight loss. Wiki’s entry on Dichloroacetic acid:

Dichloroacetic acid (systematic name dichloroethanoic acid) is an analogue of acetic acid in which two of the three hydrogen atoms of the methyl group have been replaced by chlorine atoms. It is prepared by the reduction of trichloroacetic acid.

The chemistry of dichloroacetic acid is closely related to halogenated organic acids. It is a member of the chloroacetic acids family.

Dichloroacetate stimulates the activity of the enzyme pyruvate dehydrogenase by inhibiting the enzyme pyruvate dehydrogenase kinase (Stacpoole PW. 1989; PMID 2554095). As such it decreases lactate production by shifting the metabolism of pyruvate from glycolysis towards oxidation in the mitochondria. This property has been used to treat lactic acidosis in humans (Stacpoole et al, 1988; PMID 3337517).

In recent experiments at the University of Alberta, dichloroacetate has also been shown to regulate and restore normal metabolic functions in damaged mitochondria. This has proved particularly interesting in cancer cells, which do not self-terminate upon detecting abnormalities due to damaged metabolic functions. Tiny doses of dichloroacetate shrunk breast, brain, and lung cancers in both human and rat specimens.[1] Dichloroacetic acid

Written by alienrobotgirl

19 January, 2007 at 10:58 am

Fat saves lives

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I’m just coming out of the worst reaction I’ve had since I started this diet and this blog. It beats the coffee reaction I had a couple of months ago. I should have been thinking and took some pictures of my face, but I wasn’t, which is normally how things go when a reaction occurs. Propionate reactions are very sneaky because they take days to build up. At least with salicylates and amines, I know fairly immediately when I’ve done wrong.

I’m normally either on bread or off bread. Usually I’m off bread. Last week I was on bread. I tend to crave carbs when my period is due, more so when I’m not 100% free of food chemicals (I haven’t been), so I started eating bread last Monday. The bread was fresh “bakery” bread bought in a store. I made the fatal assumption that a little bit wouldn’t hurt, and it wouldn’t necessarily have calcium propionate in it because it was fresh baked. Wednesday I felt blurry but I knew my period was due. Thursday I felt pretty tired. Friday the dreaded reaction-related back pain/migraine/fatigue syndrome erupted full-force and I could barely move let alone think. Normally I have a vague hint that my period is due the day before I get it. This was not PMS. This was PMS on steroids. I felt like my head, neck and shoulders were in a vice. My muscles were bone-breaking tense. It occurs to me that I used to spend half of my life in this state and I have no idea how I coped. How quickly we forget when we start to feel well.

Again, just like the coffee reaction, I went from having clear skin to having two small patches of dermatitis on my face, and I started to see flushing in my cheeks (and strangely also my forehead, I kinda looked lupus-like for a while). It occurred to me that I could be having a propionate reaction, so the bread was dumped. We had chicken on Friday night and stupidly left the leftovers in the fridge and made stock from it on Saturday, so I got a dose of amines to go with my period starting. The amine dose was small, but large enough to plunge me into a depression that lasted all Sunday.

I was in agony with my back from Friday through until Sunday night. I had to resort to paracetamol which would have removed all the sulphate from my liver in about 30 seconds flat. I probably poisoned myself with bicarb, epsom salts, glucuronic acid and milk thistle in an effort to get the reaction under control. I found myself frantically searching the house for my hot water bottle because I was in so much pain I could barely sit down. I’m still in pain today, but it is bearable. It’s very difficult to express how much pain you are in to other people, unless you start whimpering. Really, I was very close to whimpering.

I spent most of my life trying to appear to be normal on the outside, whilst on the inside I was in constant pain and distress. People with fibromyalgia do not get much sympathy, not that I need anyone’s pity. I probably came across to other people as being physically fine, if easily fatigued and reluctant (“lazy”), somewhat short-tempered and cranky (“hormonal”), and when pushed ready with an ailment as an excuse (“whiny”).

Last year, before I figured out what was wrong with me, my symptoms were screaming at me: “You have an autoimmune disease! There is something REALLY wrong with you! You have to figure this out because you can’t think, you’re in constant pain, and at this rate you’re going to die young!”

I spent thousands of pounds and tried hundreds of different diet/nutrition/vitamin experiments. People just thought I was obsessed with diet and health. Yes, duh! You would be if you were me! I even tried a cancer regime involving juice fasts and apricot kernels (of course all that benzaldehyde did not make me better). Very little worked, apart from one thing: custard. Custard has been my life-saver this weekend. It actually woke up my brain and took off the worst of my back pain for about three hours after I’d eaten it on all three days I ate it.

This is why I still totally believe in Kwasniewski’s Optimal Diet. This is why I know all the high-fat experiments I did last year REALLY worked. This is why I know there is something specifically GOOD for you and curative about animal fat. I have the evidence of my own body as proof. It isn’t the nutrients the fat contains, or even the choline in the eggs (I get enough of them every day). But specifically long-chain saturated and monounsaturated chemical-free animal fats. Maybe it even works by raising triglycerides and cholesterol. Maybe I just need fat calories. Woohoo! Give me woolly mammoth for supper! Give me cholesterol! Whatever it does it is wonderful. Fat saves lives!

Written by alienrobotgirl

13 November, 2006 at 12:52 pm