Archive for the ‘Methyl Donors’ Category
Following on from a previous post in which exposure to methylation supplements like folate during pregnancy appears to increase the risk of food chemical intolerance symptoms in children by causing DNA hypermethylation, there are also hints that DNA hypermethylation can be harmful in a different way:
ScienceDaily (Aug. 1, 2008) — Autopsies usually point to a cause of death but now a study of brain tissue collected during these procedures, may explain an underlying cause of major depression and suicide.
The international research group, led by Dr. Michael O. Poulter of Robarts Research Institute at The University of Western Ontario and Dr. Hymie Anisman of the Neuroscience Research Institute at Carleton University, is the first to show that proteins that modify DNA directly are more highly expressed in the brains of people who commit suicide.
These proteins are involved in chemically modifying DNA in a process called epigenomic regulation. The paper is published in Biological Psychiatry.
The researchers compared the brains of people who committed suicide with those of a control group who died suddenly, from heart attacks and other causes. They found that the genome in depressed people who had committed suicide was chemically modified by a process that is normally involved in regulating the essential characteristics of all cells in the body. As Poulter explains, “We have about 40,000 genes in every cell and the main reason a brain cell is a brain cell is because only a small fraction of the genes are turned on. The remaining genes that are not expressed are shut down by an epigenetic process called DNA methylation.”
The rate of methylation in the suicide brains was found to be much greater than that of the control group. Importantly, one of the genes they studied was shown to be heavily chemically modified and its expression was reduced. This particular gene plays a major role in regulating brain activity. “Interestingly, the nature of this chemical modification is long term and hard to reverse, and this fits with depression,” says Poulter.
“The whole idea that the genome is so malleable in the brain is surprising. Finding that epigenetic mechanisms continue to influence gene expression is pretty unusual,” says Poulter, who is also a professor in the Department of Physiology and Pharmacology at Western’s Schulich School of Medicine & Dentistry. “These observations open an entirely new avenue of research and potential therapeutic interventions.” The research was funded through the Canadian Institutes of Health Research. Autopsies Reveal Changes To DNA In Major Depression And Suicide
The gene in question that becomes hypermethylated is the GABA-A receptor. Here’s the associated abstract:
BACKGROUND: Epigenetic mechanisms may be involved in the reprogramming of gene expression in response to stressful stimuli. This investigation determined whether epigenetic phenomena might similarly be associated with suicide/depression.
METHODS: The expression of DNA methyltransferase (DNMT) mRNA was assessed in several brain regions of individuals who had committed suicide and had been diagnosed with major depression relative to that of individuals who had died suddenly as a result of factors other than suicide.
RESULTS: The DNMT gene transcripts’ expression was altered in several brains regions of suicides, including frontopolar cortex, amygdala, and the paraventricular nucleus of the hypothalamus. Importantly, an increase of both mRNA and protein expression was found in the frontopolar cortex. In addition, although transcript abundance of various forms of DNMT was highly correlated in normal control subjects, this coordination of DNMT isoform expression was diminished in suicide brain. Further, within the frontopolar cortex, gene-specific aberrations in DNA methylation were apparent in the gamma-aminobutyric acid (GABA)(A) receptor alpha1 subunit promoter region, the transcript of which is underexpressed in suicide/major depressive disorder (MDD) brains. Indeed, three cytosine/guanosine sites were hypermethylated relative to control subjects. Finally, we found that DNMT-3B mRNA abundance was inversely correlated to alpha1 mRNA abundance.
CONCLUSIONS: These data show that DNMT mRNA expression was altered in suicide brain, and this change in expression in the frontopolar cortex was associated with increased methylation of a gene whose mRNA expression has previously been shown to be reduced. These observations suggest that epigenetic mechanisms may be associated with altered gene expression in suicide/MDD. GABAA receptor promoter hypermethylation in suicide brain: implications for the involvement of epigenetic processes
Why is this important to failsafers?
Well, ketosis (low carbing) raises GABA levels. GABA levels are thought to be deficient in people with bipolar disorder and autism. The manic/depressive swings associated with bipolar disorder are thought to be caused by the subsequent deregulation of glutamate. During manic phases, glutamate levels are too high, and during depressive phases, glutamate levels are too low. I will write more on this subject soon.
Salicylates are thought to interfere with DNA methylation – they are thought to protect against DNA hypomethylation. Does this go as far as increasing the risk of DNA hypermethylation? It would not surprise me.
In the brain, salicylates are thought to act on excitatory NMDA receptors (a form of glutamate receptor). They are also thought to block GABA release by acting on calcium channels.
Crystal meth, or methamphetamine is the notorious drug of choice for troubled young Hollywood starlets these days.
A certain young pop singer whose career is taking a tumble down hill was rumoured to have shaved off her hair earlier this year due to a bout of crystal meth psychosis. Meth can induce crawling and itching sensations and hallucinations of bugs – one source reported that said the girl complained that lice or bugs were ‘eating her hair extensions’ and driving her crazy and making her head itch and skin crawl. There are much less radical solutions to a bout of head lice than shaving one’s head – any good hairdresser could have taken out her extensions and treated the problem properly. But crystal meth can also cause you to lose your inhibitions and do strange things – like sitting next to a swimming pool shaving your legs in public, or going to the toilet with the door open, or flashing your wares to the paparazzi, to name but a few of this poor lass’s recent antics. This is also the kind of experience someone would have if they were, say, bipolar, and were having an episode of delusional mania.
Methamphetamine (methylamphetamine or desoxyephedrine), popularly shortened to meth or ice, is a psychostimulant and sympathomimetic drug. The dextrorotatory isomer dextromethamphetamine can be prescribed to treat attention-deficit hyperactivity disorder, though unmethylated amphetamine is more commonly prescribed.
Methamphetamine enters the brain and triggers a cascading release of norepinephrine, dopamine and serotonin. To a lesser extent methamphetamine acts as a dopaminergic and adrenergic reuptake inhibitor and in high concentrations as a monamine oxidase inhibitor (MAOI). Since it stimulates the mesolimbic reward pathway, causing euphoria and excitement, it is prone to abuse and addiction. Users may become obsessed or perform repetitive tasks such as cleaning, hand-washing, or assembling and disassembling objects. Withdrawal is characterized by excessive sleeping, eating and depression-like symptoms, often accompanied by anxiety and drug-craving. Users of methamphetamine often take one or more benzodiazepines as a means of “coming down”.
Because of its social stigma, Desoxyn is not generally prescribed for ADHD unless other stimulants, such as methylphenidate (Ritalin®), dextroamphetamine (Dexedrine®) or mixed amphetamines (Adderall®) have failed.
Range of Effects
- Increased energy and attentiveness
- Diarrhea, nausea
- Excessive sweating
- Loss of appetite, insomnia, tremor, jaw-clenching (Bruxism)
- Agitation, compulsive fascination with repetitive tasks (Punding)
- Talkativeness, irritability, panic attacks
- Increased libido
Side effects associated with chronic use:
- Drug craving
- Weight loss
- Withdrawal-related depression and anhedonia
- Rapid tooth decay (“meth mouth”)
- Amphetamine psychosis
Side effects associated with overdose:
- Brain damage/ Meningitis caused by lead poisoning(Neurotoxicity)
- Formication (sensation of flesh crawling with bugs, with possible associated compulsive picking and infecting sores)
- Paranoia, delusions, hallucinations, which may trigger a tension headache.
- Rhabdomyolysis (Muscle breakdown) which leads to kidney failure
Death from overdose is usually due to stroke, heart failure, but can also be caused by cardiac arrest (sudden death) or hyperthermia. Methamphetamine Wiki
As well as disturbing the levels of catecholamines in the brain, crystal meth appears to be a methyl donor as it raises blood levels of SAMe. In light of both of these effects, it’s not surprising that it causes the symptoms listed above.
These symptoms overlap with some of the symptoms – albeit much milder – that I experienced during my recent methyl donor experiment. Though the experiment finished three weeks ago, I’m still paying for it with rebound depression and very slow skin healing. Caffeine and folate have the same side effects.
Physical illnesses that can underly secondary organic delusional parasitosis include: hypothyroidism, cancer, cerebrovascular disease, tuberculosis, neurological disorders, vitamin B12 deficiency, and diabetes mellitus. Any illness of medication of which formication is a symptom or side effect can become a trigger or underlying cause of delusional parasitosis.
Other physiological factors which can contribute to the condition include menopause; allergies; drug abuse, including but not limited to cocaine and methamphetamine (as in amphetamine psychosis); certain medical conditions; and poor nutrition. It appears that many of these physiological factors, as well as environmental factors such as airborne irritants, are capable of inducing the “crawling” sensation in otherwise healthy individuals, but that some people become fixated on the sensation, and this fixation may then develop into delusional parasitosis.
Details of delusional parasitosis vary among sufferers, but is most commonly described as involving perceived parasites crawling upon or burrowing into the skin, sometimes accompanied by an actual physical sensation (known as formication). Individuals suffering from this condition may injure themselves in attempts to be rid of the “parasites”, and sometimes are able to induce the condition in others through suggestion (a phenomenon dubbed folie à deux). Nearly any marking upon the skin, or small object or particle found on the person or their clothing, can be interpreted as evidence for the parasitic infestation, and sufferers commonly compulsively gather such “evidence” and then present it to medical professionals when seeking help. The condition is seen most commonly in women, and the frequency is much higher past the age of 40. Delusional parasitosis
And here we enter the weird world of ‘Morgellon’s disease’.
Persons who suffer from this unexplained condition report crawling, biting, and stinging sensations; finding fibers on or under the skin; and persistent skin lesions (e.g. rashes or sores). In addition to skin manifestations, some also report fatigue, mental confusion, short term memory loss, joint pain, and changes in vision. It is not known at present whether the condition represents a new disease entity, or whether persons who identify themselves as having Morgellons have a common cause for their symptoms, share common risk factors, or are contagious. A majority of health professionals, including most dermatologists, regard Morgellons as a manifestation of other known medical conditions, including delusional parasitosis. The Morgellons Research Foundation, a non-profit advocacy organization, believes that it is a new infectious disease that will be confirmed by future research. Morgellons
“I am an ex-methamphetamine addict. I am also an ex-morgie.” Writes a man who goes by the pseudonym Tall Cotton.
My nightmare began when a hole developed in my right lower jawline, beneath my ear. A sticky, oil-like material oozed from the hole. I’m not certain that the two events were directly related, but in retrospect I came to believe that that was about the same time that I had begun using methamphetamines. As I sat, peeling away a skin-like layer of material that had dried around that weeping hole, I realized there was no material lying where I had dropped it, not a single strip of this skin-like material. I thought that seemed very strange, because I knew I had dropped it, so I went to a mirror in the bathroom, and in the bright light projected by the bulbs that bordered the mirror, I peel away another strip of material as one might peel away sunburned skin. But the instant that material broke free from the skin on my face, it shot into the tip of my finger and disappeared from sight. I thought to myself, “Whatever it is, it doesn’t want to leave!” I came to a quick, but false hypothesis, the first of many false conclusions, that the material had a mind of its own.
On several occasions, after flicking the material off of my fingertips, it would take the shape of a tiny clam. I’ve chased these across my floors on many occasions. I quickly learned that these objects could turn on the heat. It would come suddenly, and it would be extremely intense. It burned into my flesh and into any object it seemingly “chose” to. I learned to run them down and snag them with my locking tweezers. Two of these objects exploded in a small cardboard box where I housed them. The explosions yielded a multitude of multi-colored rocks, a half dozen white hairs, a half dozen black hairs, and one green hair. These hairs were about 2 inches in length. But there was one large, jet black hair, about 3 inches in length, and obviously motile. There was also half a portion of one of the clam shells. Inside it had compartments, and stored inside there were coils of cottony white fiber.
On another occasion, I found a wax-like drop of goo, inside the lid of my dishwasher. As I stared at the droplet it exploded with a pop. My forearms were instantly penetrated with sharp shrapnel. These pieces of material were burning my skin and working their way deeper. I grabbed my tweezers and I pulled long, needles of material out of my skin. I also pull out a portion of white fiber, but it seemed to be holding on with a million tiny tentacles, and it was impossible for me to retrieve it all. When two of friends came into my kitchen and saw what I was doing, they thought I had gone crazy. There were splats of blood, all down my countertop, where I had slapped the needle-like spines out of my tweezers and quickly returned to my flesh for more. The craziest thing was this. When I tried to show them the needles, just as I began clamping onto them with my tweezers, they melted before my eyes. The Lie of Morgellons
Methylation disorders and catecholamine imbalances are connected not only to ADHD, autism and fibromyalgia, but also to bipolar delusional mania and schizophrenia. Hallucinating bugs and things coming out of or going into the body is very common in schizophrenia. One of my friends at university was a schizophrenic who had bug hallucinations. She also had many symptoms of B12 deficiency including goiter – her first ‘episode’ began, unusually, after menopause, only two years after she became a vegetarian. I suspect she has a number of genes that left her very vulnerable after her change in diet. These are the consequences of screwing around with methylation vitamins like B12, zinc, B6, folate, SAMe, choline and betaine/TMG. Be careful.
Coming down off methyl donors is hell.
When I used to drink caffeine I felt the same way. Sometimes caffeine hits me like speed. Withdrawal gives me the shakes, brain fog, headaches and back pain. I feel like my head is full of wool. Memory completely shot. Misspellings. Malapropisms. Inability to speak sentences, get words out. This is what it feels like to be a nonverbal autistic. Like my brain is one big stutter.
Once in the brain, the principal mode of action of caffeine is as an antagonist of adenosine receptors found in the brain. The caffeine molecule is structurally similar to adenosine, and binds to adenosine receptors on the surface of cells without activating them (an “antagonist” mechanism of action). Therefore, caffeine acts as a competitive inhibitor. The reduction in adenosine activity results in increased activity of the neurotransmitter dopamine, largely accounting for the stimulatory effects of caffeine. Caffeine can also increase levels of epinephrine/adrenaline, possibly via a different mechanism. Acute usage of caffeine also increases levels of serotonin, causing positive changes in mood. Caffeine Mechanisms of Action
On top of inhibiting adenosine, caffeine – trimethylxanthine – is a methyl donor. The liver detoxifies caffeine by stripping off the methyl groups and using them for other tasks. During the first pass through the liver, one methyl group is stripped away, and this has the effect of changing the shape of the caffeine into dimethylxanthine so it becomes physiologically more active. This is why caffeine usually hits you about an hour or two after you’ve drunk it.
The half-life of caffeine—the time required for the body to eliminate one-half of the total amount of caffeine consumed at a given time—varies widely among individuals according to such factors as age, liver function, pregnancy, some concurrent medications, and the level of enzymes in the liver needed for caffeine metabolism. In healthy adults, caffeine’s half-life is approximately 3–4 hours. In women taking oral contraceptives this is increased to 5–10 hours, and in pregnant women the half-life is roughly 9–11 hours. Caffeine can accumulate in individuals with severe liver disease when its half-life can increase to 96 hours. Caffeine Metabolism
I wonder what the half-life of salicylate is in my body?
Funny story. I went to the supermarket earlier and I decided to buy some pesticide. Much as I would love to be totally organic, I have a small yucca that is infested with black fly and I can’t seem to shift them just by physical removal.
I am coming down off methyl donors and inevitably I have brain fog today.
I sprayed the pesticide on my yucca. I held my breath, but I got a good whiff of the stuff anyway. It smelled like moth balls. Within seconds of smelling this stuff my brain fog cleared. I looked to see what the active ingredient was: bifenthrin. What’s in it?
Shame the effect only lasted ten minutes.
For want of cash, medical resources and obscure genetic knowledge, I’ve been doing methylation experiments on myself for a couple of years now. I spent my house renovation time continuing that. The events described below are a dramatic portrayal not an actual diary, and are based on multiple, repeated experiments.
The quantities described below are all roughly EU RDA amounts – around 200mcg for folate (any more just doubles the symptoms).
Day 1: This seems to have helped a lot with my brain fog.
Day 2: This stuff is pretty good. I feel on top of the world! Maybe I’m cured!
Day 3: Hmm, I feel pretty awful if I don’t take this stuff.
Day 4: What is with these rashes, insomnia and nightmares? Why do I have brain fog? I took my folic acid! Maybe I need a higher dose today… Yes, I feel a bit better for that.
Day 5: I am totally dependent on this stuff and it’s making me feel rotten. I have had brain fog all day in spite of taking folic acid. I can’t take a higher and higher dose every day to clear my brain fog!
Folinic Acid (5-formyltetrahydrofolate) – unfortunately this supplement also contains an RDA quantity of methylcobalamin, which obscures results somewhat
Day 1: This seems to have helped A LOT with my brain fog!
Day 2: Damn this stuff is amazing! I am going to use this all the time! I feel great! Wheeee!
Day 3: Why have I got the shakes and brain fog? Never mind, I’ll feel better when I’ve taken some folinic acid! Hmm, that didn’t work as well as I’d hoped.
Day 4: I feel like death warmed up. I am walking around like a zombie. I have to stop taking this stuff before it kills me.
Food Folate (5-methyltetrahydrofolate, 5-MTHF) from failsafe food (mixed beans/pulses)
Day 1: I am having minor issues with bean chemicals, but I feel pretty good and clear.
Day 2: More issues, but I feel pretty good and clear. This tinnitus is a pain.
Day 3: Issues are outweighing the good feeling; I may need to take a break soon. I seem to be gaining some weight. I have tinnitus and insomnia now.
Day 4: I still feel good/clear, but the symptoms are becoming a problem.
Day 5: I feel a bit foggy and my skin is not great, I really need a break.
Food Folate (5-methyltetrahydrofolate, 5-MTHF), Betaine and a bit of MeB12 from failsafe food (wheatgerm with milk)
Day 1: I am having minor bloating issues, but I feel pretty good and clear.
Day 2: More bloating issues, but I feel pretty good and clear. I want some more wheatgerm.
Day 3: I may need to take a break soon. I seem to be gaining some weight. I seem to be craving wheatgerm. Gosh it’s making me sleepy.
Day 4: I still feel good/clear, I seem to be gaining some weight. I feel pretty bloated. I can’t be bothered to do anything.
Day 5: I need to take a break before I get fat and lazy.
Food Folate (5-methyltetrahydrofolate, 5-MTHF), B12 and SAMe from NON failsafe food (liver)
Day 1: I am having some issues with chemicals, but I feel pretty good and clear.
Day 2: I seem to be feeling okay today. I am itching though and have some dermatitis.
Day 3: I seem to have a headache and be itchy and my skin looks awful. I don’t feel as clear today.
Day 4: I feel pretty foggy and awful today with the same symptoms as yesterday. Wish I could get rid of this horrendous back pain. This really can’t go on.
Low food folate failsafe diet
Day 1: I feel fine and I’m glad to be off the wheatgerm/beans.
Day 2: I feel much better but I have some wheatgerm cravings.
Day 3: I feel fine.
Day 4: I feel fine.
Day 5: I seem to be a little bit more sensitive than usual.
Day 6: I do seem to be a bit more sensitive than usual.
Day 7: I think I felt marginally better when I was eating wheatgerm.
Methylcobalamin (Methyl-B12, MeB12)
Day 1: This seems to have helped A LOT with my brain fog! Wish I could get to sleep though.
Day 2: Damn this stuff is amazing! I am going to use this all the time! I feel great! Wheeee! I can’t sleep but what the heck! My skin looks better! God I’m happy!
Day 3: Why have I got the shakes and brain fog? Never mind, I’ll feel better when I’ve taken some MeB12! Hmm, that didn’t work as well as I’d hoped. But my skin is still looking great and I feel really positive!
Day 4: I feel better again today. Hurrah. I really need this MeB12 though! Wish I could sort my sleep pattern out. I seem to have insomnia, yet I’m waking up early! I really need some more sleep! It seems to be making me twitchy too. I feel a bit aminey or glutamatey and I have tinnitus!
Day 5: I still feel pretty good but I really need this MeB12, I have shakes and brain fog without it! I have had some strange tingling sensations in my fingers and toes though. Also I still have that insomnia problem and I keep having hypnic jerks! Not sure I like all the weird dreams I’ve been having. Also, why do I keep getting this strange unpleasant trapped nerve sensation in my neck all the time? I hope I’m not wrecking my myelin with this stuff. But I feel really happy-high and I like the way I have stopped putting on weight when I eat bread!
Day 6: Oops I got overconfident with food chemicals because I thought I was cured. Guess strawberries and old meat were a really bad idea. I feel absolutely horrendous.
Day 7: I feel much better again today. Hurrah. I’m cured, I knew I was! I seem to have lost the ability to spell things though!
Day 7-21: Repeat above ad infinitum.
Day 22: Why have I come down with a cold? I never get colds anymore. Hang on, wait a minute, I came down with colds the last two times I supplemented with MeB12 for a while. Maybe I should stop taking it!
Betaine (Trimethylglycine, TMG)
Day 1: I feel pretty good! This stuff is giving me a bit of insomnia though!
Day 2: I still feel good! More insomnia and hypnic jerks though!
Day 3: I don’t feel as great as I do on MeB12.
Day 4: Yep, I’m fine. This stuff seems to contribute to hypnic jerking when I take it with MeB12.
[More experiments are needed to clarify this one as I rarely take it in isolation.]
S-adenosyl-L-methionine (SAMe) and Folapro (supplement form 5MTHF)
I haven’t tested these yet because I can’t afford the $$$ US shipping expenses.
I suspect as I do well on 5MTHF from food sources that I have a MTHFR polymorphism and can’t use synthetic folic/folinic acids in the same way as food source folate.
I do even better on MeB12, which makes sense as it is a form of B12 that has already been methylated by 5MTHF. Unfortunately the side effects from taking MeB12 aren’t very nice, and taking MeB12, whilst it seems to raise my reaction level, still does not protect me. The MeB12 also has some awful negative effects. It seems to make me manic and is probably raising my amine levels, yet also somehow allowing me to deactivate some of those amines – just not as well as I should be able to. Perhaps this is where an MAO-A or a COMT mutation comes in to play. MeB12 can interfere with melatonin levels, and I suspect this is why it gives me insomnia and makes me come down with infections, since melatonin is important for the immune system.
On top of this, it’s as though the other forms of folic acid are being used in other metabolic processes that are making me feel worse. What I don’t understand is why they make me feel ‘amined’, which seems contradictory *if* I have a MTHFR mutation – unless there is something I am missing. Folate also interacts with the glutamatergic system but I am not clear on what it does at what point in the folate cycle. Am I putting pressure on another polymorphism like MTR (methionine synthase) or MTTR (methionine synthase reductase)? Or am I putting pressure on my detox system in some way? PABA, a folic acid precursor is not failsafe and reactive in its own right. Perhaps regular folic acid is simply being degraded and becoming reactive in some way? Or am I using artificial folic acid to make purines? I must admit to feeling ‘gouty’ on rare occasions – aching toe joints and such, but never anything serious.
As you can see I have yet to make a big impact on my food chemical intolerances, and even if I did I wouldn’t be able to ‘cure’ myself, as my methylation enzymes will always be functioning at a slower rate. I have taken very high amounts of MeB12 (1000mcg) in the past and the result has been a very extreme version of the above portrayal. Sure, I felt great for a while but I had severe hypnic jerks and almost gave myself a seizure. I actually felt better when I stopped the supplements.
Update: I’ve now done a food folate trial with a 5-MTHF supplement (FolaPro). It does the same thing to me as folic acid and folinic acid, only it’s less ‘harsh’ than folic acid, and much less ‘harsh’ than folinic acid.
A Pregnant Mother’s Diet May Turn the Genes Around
With the help of some fat yellow mice, scientists have discovered exactly how a mother’s diet can permanently alter the functioning of genes in her offspring without changing the genes themselves.
The unusual strain of mouse carries a kind of trigger near the gene that determines not only the color of its coat but also its predisposition to obesity, diabetes and cancer. When pregnant mice were fed extra vitamins and supplements, the supplements interacted with the trigger in the fetal mice and shut down the gene. As a result, obese yellow mothers gave birth to standard brown baby mice that grew up lean and healthy.
Scientists have long known that what pregnant mothers eat — whether they are mice, fruit flies or humans — can profoundly affect the susceptibility of their offspring to disease. But until now they have not understood why, said Dr. Randy Jirtle, a professor of radiation oncology at Duke and senior investigator of the study, which was reported in the Aug. 1 issue of Molecular and Cellular Biology.
The research is a milestone in the relatively new science of epigenetics, the study of how environmental factors like diet, stress and maternal nutrition can change gene function without altering the DNA sequence in any way.
Such factors have been shown to play a role in cancer, stroke, diabetes, schizophrenia, manic depression and other diseases as well as in shaping behavioral traits in offspring.
Most geneticists are focusing on sequences of genes in trying to understand which gene goes with which illness or behavior, said Dr. Thomas Insel, director of the National Institute of Mental Health. ”But these epigenetic effects could turn out to be much more important. The field is revolutionary,” he said, ”and humbling.”
Epigenetics may indeed hold answers to many mysteries that classical genetic approaches have been unable to solve, said Dr. Arturas Petronis, an associate professor of psychiatry at the Center for Addiction and Mental Health at the University of Toronto.
For example, why does one identical twin develop schizophrenia and not the other? Why do certain disease genes seem to affect or ”penetrate” some people more than others? Why do complex diseases like autism turn up in more boys than girls?
For answers, epigeneticists are looking at biological mechanisms other than mutation that affect how genes function. One, called methylation, acts like a gas pedal or brake. It can turn gene expression up or down, on or off, depending on how much of it is around and what part of the genetic machinery it affects.
During methylation, a quartet of atoms called a methyl group attaches to a gene at a specific point and induces changes in the way the gene is expressed.
The process often inactivates genes not needed by a cell. The genes on one of the two X chromosomes in each female cell are silenced by methylation.
Methyl groups and other small molecules may sometimes attach to certain spots on chromosomes, helping to relax tightly coiled strands of DNA so that genes can be expressed.
Sometimes the coils are made tighter so that active genes are inactivated.
Methyl groups also inactivate remnants of past viral infections, called transposons. Forty percent of the human genome is made up of parasitic transposons.
Finally, methyl groups play a critical role in controlling genes involved in prenatal and postnatal development, including some 80 genes inherited from only one parent. Because these so-called imprinted genes must be methylated to function, they are vulnerable to diet and other environmental factors.
When a sperm and egg meet to form an embryo, each has a different pattern of methylated genes. The patterns are not passed on as genes are, but in a chemical battle of the sexes some of the egg and sperm patterns do seem to be inherited. In general, the egg seems to have the upper hand.
”We’re compounds, mosaics of epigenetic patterns and gene sequences,” said Dr. Arthur Beaudet, chairman of the molecular and human genetics department at Baylor College of Medicine in Houston. While DNA sequences are commonly compared to a text of written letters, he said, epigenetics is like the formatting in a word processing program.
Though the primary letters do not vary, the font can be large or small, Times Roman or Arial, italicized, bold, upper case, lower case, underlined or shadowed. They can be any color of the rainbow.
Methylation is nature’s way of allowing environmental factors to tweak gene expression without making permanent mutations, Dr. Jirtle said.
Fleeting exposure to anything that influences methylation patterns during development can change the animal or person for a lifetime. Methyl groups are entirely derived from the foods people eat. And the effect may be good or bad. Maternal diet during pregnancy is consequently very important, but in ways that are not yet fully understood.
For his experiment, Dr. Jirtle chose a mouse that happens to have a transposon right next to the gene that codes for coat color. The transposon induces the gene to overproduce a protein that turns the mice pure yellow or mottled yellow and brown. The protein also blocks a feeding control center in the brain. Yellow mice therefore overeat and tend to develop diabetes and cancer.
To see if extra methylation would affect the mice, the researchers fed the animals a rich supply of methyl groups in supplements of vitamin B12, folic acid, choline and betaine from sugar beets just before they got pregnant and through the time of weaning their pups. The methyl groups silenced the transposon, Dr. Jirtle said, which in turn affected the adjacent coat color gene. The babies, born a normal brownish color, had an inherited predisposition to obesity, diabetes and cancer negated by maternal diet.
Unfortunately the scientists do not know which nutrient or combination of nutrients silence the genes, but noted that it did not take much. The animals were fed only three times as much of the supplements as found in a normal diet.
”If you looked at the mouse as a black box, you could say that adding these methyl-rich supplements to our diets might reduce our risk of obesity and cancer,” Dr. Jirtle said. But, he added, there is strong reason for caution.
The positions of transposons in the human genome are completely different from the mouse pattern. Good maps of transposons in the human genome need to be made, he said. For that reason, it may be time to reassess the way the American diet is fortified with supplements, said Dr. Rob Waterland, a research fellow in Dr. Jirtle’s lab and an expert on nutrition and epigenetics.
More than a decade ago, for example, epidemiological studies showed that some women who ate diets low in folic acid ran a higher risk of having babies with abnormalities in the spinal cord and brain, called neural tube defects.
To reduce this risk, folic acid was added to grains eaten by all Americans, and the incidence of neural tube defects fell substantially. But while there is no evidence that extra folic acid is harmful to the millions of people who eat fortified grains regularly, Dr. Waterland said, there is also no evidence that it is innocuous.
The worry is that excess folic acid may play a role in disorders like obesity or autism, which are on the rise, he said. Researchers are just beginning to study the question.
Epidemiological evidence shows that undernutrition and overnutrition in critical stages of development can lead to health problems in second and third generations, Dr. Waterland said.
A Dutch famine near the end of World War II led to an increased incidence of schizophrenia in adults who had been food-deprived during the first trimester of their mothers’ pregnancy. Malnourishment among pregnant women in the South during the Civil War and the Depression has been proposed as an explanation for the high incidence of stroke among subsequent generations.
And the modern American diet, so full of fats and sugars, could be exerting epigenetic effects on future generations, positive or negative. Abnormal methylation patterns are a hallmark of most cancers, including colon, lung, prostate and breast cancer, said Dr. Peter Laird, an associate professor of biochemistry and molecular biology at the University of Southern California School of Medicine.
The anticancer properties attributed to many foods can be linked to nutrients, he said, as well as to the distinct methylation patterns of people who eat those foods. A number of drugs that inhibit methylation are now being tested as cancer treatments. Psychiatrists are also getting interested in the role of epigenetic factors in diseases like schizophrenia, Dr. Petronis said.
Methylation that occurs after birth may also shape such behavioral traits as fearfulness and confidence, said Dr. Michael Meaney, a professor of medicine and the director of the program for the study of behavior, genes and environment at McGill University in Montreal.
For reasons that are not well understood, methylation patterns are absent from very specific regions of the rat genome before birth. Twelve hours after rats are born, a new methylation pattern is formed. The mother rat then starts licking her pups. The first week is a critical period, Dr. Meaney said. Pups that are licked show decreased methylation patterns in an area of the brain that helps them handle stress. Faced with challenges later in life, they tend to be more confident and less fearful.
“We think licking affects a methylation enzyme that is ready and waiting for mother to start licking,” Dr. Meaney said. In perilous times, mothers may be able to set the stress reactivity of their offspring by licking less. When there are fewer dangers around, the mothers may lick more. A Pregnant Mother’s Diet May Turn the Genes Around
This subject has a possible relationship to autism. However, it isn’t quite the relationship that a typical Weston A. Price Foundation member thinks (“we just need to eat a really nutritious diet when we are pregnant and then our children will all grow up healthy!” which is very much a happy-sunshine-pretty-birds-and-flowers view of the world).
You can max-out the DNA methylation capacity of most mice with a few times the amount of nutrients found in the average mouse diet (I wonder what they were being fed incidentally?), and you can conceivably do the same thing with most humans – hence US guidelines to take about 600mcg of folic acid whilst pregnant. However, most is not all.
Some people are genetically predisposed to poor DNA methylation. These are people with naturally existing polymorphisms in methylation cycle. Several types of polymorphisms mean that some people do not process the folate from foods and folic acid from supplements in the same way as the average person. Their bodies find it hard to use folic acid to methylate vitamin B12. Polymorphisms exist throughout the methylation cycle, and in theory, the more you have, at the wrong combination of points, the harder it will be for you to methylate your DNA and the more vulnerable you will be to the expression of transposons. This isn’t all bad, because people with a lower turnover of DNA tend to live longer, however, you may be more prone to metabolic distortions such as some types of obesity, or certain inherited illnesses.
Some time after Pottenger did his cat experiments which produced epigenetic distortions that lasted through several generations, scientists discovered that cats are unable to synthesise taurine in their bodies. Taurine is a protein that is damaged by cooking food. Taurine is required for correct DNA methylation. It prevents DNA hypermethylation under some circumstances. In fact DNA hypermethylation can be just as harmful as DNA hypomethylation. By inactivating genes that ought to be activated, the body can become prone to cancer and other metabolic problems. It seems, like Goldilocks, the best state for DNA is not too hot, not too cold, but ‘just right’.
For more information about DNA methylation visit the DNA methylation page on Wikipedia.
Endogenous retroviral DNA consists of roughly 4-8% of the total human genome.
My eczema has been worsening ever since I started the supplements a couple of weeks ago. When I started them, my skin was completely clear. Now it is the worst mess it’s been in a long time. Why? Admittedly, I’ve had the occasional off-diet food, but a couple of weeks is long enough to determine that it’s actually the vitamins I’m taking that are causing the problem.
Folate seems to have some sort of excitatory amine-like effect on me. My face is red. Even 200-400mcg – the RDA – seems to be too high. I’ve experimented further by increasing folate intake, and yes, it makes my face more inflamed.
This makes things difficult. Folate is important for methylation. Folate methylates vitamin B12. Methylcobalamin makes me feel very good.
Will TMG work instead by bypassing the whole system? Might methylcobalamin work by itself? Folate is required to methylate B12. So methylcobalamin does not require folate. More facts:
- If B12 is deficient methylation is impaired and folate is partially trapped (methyl-folate trap) causing megaloblastic anaemia.
- B12 deficiency with high folate intake causes nervous system damage rather than anaemia, because the effects of the deficiency are “masked” or altered by the presence of folate.
I think one of the reasons that the formula worked better before but is making me worse now is that I’ve deliberately excluded vitamin C. It seems almost as though the vitamin C was “masking” some of the adverse effects of the folate.
So I’m now going to do some experiments in excluding folate and taking methylcobalamin to see what happens. I don’t know whether this will work or not. I fear not.
I fear I may be stuck in a trap of needing methylators to get over post-food chemical brain-fog reactions, then the same methylators then giving me amine/glutamate-like reactions when I keep taking them.
The Wiki entries on nitric oxide and asymmetric dimethylarginine offer a lot of insight.
In the body, nitric oxide serves several roles, mainly involving small blood vessels. Nitric oxide is synthesized from L-arginine and oxygen by various nitric oxide synthase (NOS) enzymes. The endothelium (inner lining) of blood vessels uses nitric oxide to signal the surrounding smooth muscle to relax, thus dilating the artery and increasing blood flow. This phenomenon is thought to be central to endothelial health. A large percentage of humans are deficient in their manufacture of nitric oxide, placing them at increased risk of cardiovascular disease. This underlies the action of nitroglycerin, amyl nitrate and other nitrate derivatives in the treatment of heart disease: The compounds are converted to nitric oxide (by a process that is not completely understood), which in turn dilates the coronary artery (blood vessels around the heart), thereby increasing its blood supply. A chemical known as asymmetric dimethylarginine can interfere with the production of nitric oxide and is considered a marker of cardiovascular disease.
Macrophages, cells of the immune system, produce nitric oxide in order to kill invading bacteria. Under certain conditions, this can backfire: Fulminant infection (sepsis) causes excess production of nitric oxide by macrophages, leading to vasodilatation (widening of blood vessels), probably one of the main causes of hypotension (low blood pressure) in sepsis.
Nitric oxide also serves as a neurotransmitter between nerve cells. Unlike most other neurotransmitters that only transmit information from a presynaptic to a postsynaptic neuron, the small nitric oxide molecule can diffuse all over and can thereby act on several nearby neurons, even on those not connected by a synapse. It is conjectured that this process may be involved in memory through the maintenance of long-term potentiation. Nitric oxide is an important non-adrenergic, non-cholinergic (NANC) neurotransmitter in various parts of the gastrointestinal tract. It causes relaxation of the gastrointestinal smooth muscle. In the stomach it increases the capacity of the fundus to store food/fluids. Nitric Oxide
Asymmetric dimethylarginine (ADMA) is a naturally occurring chemical found in blood plasma. It is a metabolic by-product of continual protein modification processes in the cytoplasm of all human cells. It is closely related to L-arginine, a conditionally-essential amino acid. ADMA interferes with L-arginine in the production of nitric oxide, a key chemical to endothelial and hence cardiovascular health. [...]
Asymmetric dimethylarginine is created in protein methylation, a common mechanism of post-translational protein modification. This reaction is catalyzed by an enzyme set called S-adenosylmethionine protein N-methyltransferases (protein methylases I and II). The methyl groups transferred to create ADMA are derived from the methyl group donor S-adenosylmethionine, an intermediate in the metabolism of homocysteine. (Homocysteine is an important blood chemical, because it is also a marker of cardiovascular disease). After synthesis, ADMA migrates into the extracellular space and thence into blood plasma. [..]
ADMA concentrations are substantially elevated by native or oxidized LDL cholesterol. Thus a spiralling effect occurs with high endothelial LDL levels causing greater ADMA values, which in turn inhibit NO production needed to promote vasodilation. The elimination of ADMA occurs through urine excretion and metabolism by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). The role of homocysteine as a risk factor for cardiovascular disease is suggested to be mediated by homocysteine down-regulating production of DDAH in the body. Asymmetric Dimethylarginine
The “cardiovascular” effect of NO is basically vasodilation. Asymmetric dimethylarginine is being painted as a bad guy for reducing vasodilation in people with heart disease, however, too little is as bad as too much.
I wonder if too much nitric oxide is a problem, particularly as an inhibitor of the enzyme that converts homocysteine to methionine, as per my last post. The fact that ADMA is produced in the presence of SAM (derived from methionine) when methylation is increased, is part of an interesting feedback loop that could be out of sorts.
If levels of nitric oxide are a problem, I wonder if this would explain why nitrate and nitrite additives cause reactions in the food chemical intolerant, by further supplying fuel to the NO fire? Or are nitrates interfering with the production of NO and the opposite is true? This is of course pure speculation. Nitric oxide may just be a symptom of something else. It would also contradict the asthma issue, for which nitric oxide is extremely important in relaxing the bronchi.
Unfortunately for those of us relying on potatoes, one of the highest sources of natural nitrates and nitrites (even higher than the average additive-containing slice of bacon) is potatoes grown in artificially fertilised soil.
Folks with food chemical intolerance tend to have too much vasoconstriction: histamine, serotonin, dopamine, and tyramine all have vasoactive effects and lead to some of the unpleasant effects we experience, from skin flushing and inflammation, to varicose veins and headaches. Tyramine is a vasoconstrictor. Histamine is supposed to have mediatory effects. Perhaps nitric oxide levels are high for the same reason? And this then inhibits methylation?
Serotonin has a perverse effect, it can produce both vasoconstriction and vasodilation, depending on the receptors present. Serotonin migraines seem to be produced firstly by constriction, then the pain occurs on dilation.
Here’s a list of methyl donors. There may be more I haven’t found yet.
- Methionine (amino acid)
- Taurine (amino acid containing methionine and cysteine)
- SAM or SAMe (s-adenosyl-l-methionine)
- TMG and DMG (trimethylglycine & dimethylglycine or betaine/choline) a methylated amino acid
- Methylcobalamin (Methyl-B12) a methylated form of vitamin B12
- Acetic acid (vinegar)
- MSM (methyl sulfonyl methane)*
*Some say this “may” be a methyl donor. Looking at some of the stories of autism cases that have seen results, I’d say it absolutely is.
There are at least two separate pathways to methylation:
- B12/folic acid pathway
- TMG to choline pathway
How the other methyl donors work or affect these pathways is unknown to me as yet. If methylation helps, it seems wise to tackle from both pathways at once in case one is deficient. Tests to see which pathway is most effective should also be carried out.
I was interested to note that vitamin C eases reactions to propionates, those nasty bread additives.
Propionic acid is produced biologically from the metabolic breakdown of fatty acids containing odd numbers of carbon atoms, and also the breakdown of some amino acids. Bacteria of the genus Propionibacterium produce propionic acid as the end product of their anaerobic metabolism. These bacteria are commonly found in the stomachs of ruminants, and their activity is partially responsible for the odor of both Swiss cheese and sweat. Propionic acid
Odd chain fatty acids have also been associated with multiple sclerosis. Odd chain fatty acids are unusual in nature, but are present in larger than average amounts in the bodies of MS sufferers. They attack the myelin sheath that protects nerves and neurotransmitters from damage.
I wonder if propionibacteria can live in the human intestines? They can and do live on the skin: propionibacteria are the cause of acne.
There are multiple sclerosis failsafers who appear to be doing well.
Multiple sclerosis has also been associated with deficiencies in folic acid, B12, and B6. This is usually regarded as being because of their importance in the formation of myelin. They are also important to the methylation cycle.
Groves noted some time ago that MS might have a bread connection, but blamed it on the bread not being fermented. He’s not the first to make these connections with bread.
Propionic acid: CH3CH2COOH
A CH3 group is a methyl group.
Propionate is obviously affecting the methylation cycle, but in this case in a negative way. Is there such thing as a methyl-stealer?
What does propionate do when it meets a methyl donor?
Methyl propionate: CH3(C2H5COO)
Is it stealing methyl groups?
This is a fascinating article about the connections between undermethylation, homocysteine, and food chemical intolerance.
“Getting methyl groups “turns on” detox reactions that detox the body of chemicals, including phenols. So if you are phenol sensitive, and you increase your methylation, then theoretically your body can process more phenols. [...] Getting methyl groups “turns on” serotonin, and thus melatonin, production. Therefore, if you are a under-methylator, you can increase your methylation and have higher more appropriate levels of serotonin and melatonin. This means you may not have to take SSRIs, or may have improved sleep.” Enzyme Stuff
This gives us a potential connection between elevated homocysteine levels and food chemicals. This should be able to be tested for.
Epilepsy can be connected to low methylation levels. Poor sleep, perhaps poor melatonin levels, can cause nocturnal epilepsy. Elevated homocysteine levels are regularly found in epileptics undergoing traditional medication. I wonder if anyone has studied the homocysteine levels of epileptics who don’t medicate?
This methylation connection to food chemical detoxification also explains why my vitamin formula temporarily cleared up my skin problems!
- Vitamin A 10,000i.u.
- Vitamin D 800i.u.
- Vitamin E (mixed tocopherols) 400i.u.
- Vitamin B12 (methylcobalamin*) 1000mcg
- Vitamin B6 50mg
- Folic Acid 400mcg
- Molybdenum 150mcg*
*Methylcobalamin, or methyl-B12 is a special form of B12 that acts as a methyl donor. Methyl donors are an essential part of this formula!
** I didn’t consider the molybdenum an essential part of the refined formula I was taking, though I was taking it for most of the time I had success in keeping my skin problems under control due to my concerns about sulfites that eventually led me to failsafe.
I originally started taking this whole formula for protection against sulphites, to which I am sensitive. I was astonished when it cleared up my skin.
I was concerned that the formula was merely masking the underlying problem by speeding up my turnover of skin cells, but it appears the formula – including the molybdenum – is actually affecting the cause of the problem too, because this same formula is essential to lower homocysteine and provide adequate methylation reactions. I’m not sure how essential A & D are to this process, but they were important for my skin.
Other methyl donors might help too, including SAMe (s-adenosyl-l-methionine), DMG (dimethylglycine), and TMG (trimethylglycine).