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"In very low concentrations—the equivalent of a few raindrops in four Olympic-sized swimming pools—the drug slows cellular aging and enhances the function of cellular “power plants” called mitochondria"
"The group found methylene blue could prevent or slow mitochondrial decline, specifically that of an important enzyme called complex IV. Mitochondria are the main energy suppliers to animal and human cells."
Complex IV is the last link in the mitochondrial respiratory chain in which "heme a" is involved to adduce oxygen for the production of ATP. Statins inhibit production of farnysyl and since heme a is made by the farnesylation of proto-heme we can expect heme a depletion to be an inevitable result of statinization in the same way that Coenzyme Q10 is reduced.
I contacted Dr Ames regarding this several months ago and his team could find NO RESEARCH AT ALL into this little-known aspect of statin "collateral damage". Hopefully this new finding may prove of benefit to us seekers!
BTW other agents that adversely affect heme a are carbon monoxide and potassium cyanide!!
This could be our electron transport chains' major weak link from statin damage since the gene (heme a), which is likely one of the few remaining onsite genes inside the mitochondrial genome, would constantly be trying to runoff working copies and would therefore be the most vulnerable to "successful" oxidative attack -- particularly with the lack of CoQ10 in the vicinity.
How did you know Dr. Ames was working with heme a and/or M. blue?
The part about it being inexpensive is troublesome though: No Profits?! No Way!!
Well, on the other hand, maybe it can be made a little less effective and a little less safe with a patentable slight alteration to its molecular structure as happened with to the natural statins...
Joined: 13 Dec 2006 Posts: 1136 Location: Fort Worth, Texas
Posted: Thu Aug 21, 2008 12:30 am Post subject:
This is a very interesting find. M-Blue however is not available OTC and good luck getting a Dr. to administer it or provide it as an Rx. Any thoughts as to how this could become a part of our arsenal? Can we order this from our Canadian cousins?
Joined: 24 Oct 2006 Posts: 683 Location: Ongar, UK
Posted: Thu Aug 21, 2008 1:45 am Post subject:
Dr Ames is THE World expert on heme deficiencies through his work at the Oakland Childrens' Hospital. I contacted him last year re heme a and he and one of his team were very helpful, sending me papers and looking to see if there was any work being done anywhere looking at statin-induced heme a deficiency and its treatment. Of course there was none at all. I got the uneasy feeling that I, a layman, seemed to be the only person aware of the importance of this neglected corollary of down-regulated farnesyl pyrophosphate production resulting from HMG-CoA inhibition. This can be clearly seen in this diagram...
MVP is Most Valuable Player -- a term used in football (the oval variety) and baseball here in the States.
"Heme a" is a very complicated molecule, in fact it's actually a protein complex, as you know, therefore my assertion of it's having a corresponding gene is inappropriate (as you likely also know). There would be many genes associated with its creation -- one or more of which is likely coded for in the mitochondria. Many hemes, probably including this one, are constructed in stages with the aid of innumerable enzymes and are shuttled in and out of the mitochondria for various stages of construction. The mitochondrial genome's contribution might easily be the weak link (e.g., a mutated genetic code for it's partial construction). I have not had time to study your or Brook's links and may not for some time, but I look forward to doing so and the matter appears promising.
On the MVP issue again, adec is again a runner up in my estimation. I like his distinction regarding the many natural REGULATORY HMG CoA Reductase Inhibitors in the body including magnesium (of many others, including some of our hormones) as opposed to "Artificial and Imposed" HMG CoA Reductase Inhibitors exemplified by our drug industry statins.
Supplemental antioxidants reportedly failing to show life extension effects per studies performed in the past (something of which I would like to know more about) could be explained on a similar basis. I suspect our bodies have evolved to use oxidants as cellular regulatory mechanisms at times which we may short circuit with supplementation at times. (I know you read the same book on mitochondria as I did where this was examined.) But I am mainly still in the "supplemental camp," and particularly with Vitamin C. I took adec's suggestion regarding Astaxanthin some months ago. This is the stuff that is believed to make salmon so unusually healthful (besides its important fats) and is what gives the fish its color -- in fact, it is added to farmed salmon either before (e.g., in their feed) or after (before shipping the fillets). I read that it is what adds twenty percent to the cost of buying salmon. The stuff is bizarre. Put a tiny scoop of the powder, which is green / gray in color, in your mouth and a few seconds later you will believe you must have cut yourself and are bleeding in your mouth. It turns seriously red. I did some experiments with it. Added to alcohol (e.g., rubbing) it is very color reactive -- but much less so in water. But it sure likes saliva. Add a tiny amount to your soup, and it is pink/orange in no time. I got mine at Beyond a Century. Twenty grams. Very concentrated. Makes for hundreds of servings. I was unsure of the directions on the bottle (because you are to use so little of t per serving) so actually called them and talked to a knowledgeable employee -- a scientist of some sort; it was months ago. He was a straight shooter (not a salesman-type at all) and was also impressed with the stuff. You have to keep it in the refrigerator after opening it. Does it do good things, and not stop other good things from happening? Don't know. I estimate the odds at being in favor of it.
Joined: 24 Oct 2006 Posts: 683 Location: Ongar, UK
Posted: Fri Aug 22, 2008 2:36 am Post subject:
I don't know about "MVP" Biologist, "MPP" more likely - Most Pessimistic Player! This is because at heart we are dealing with politics, not science.
If you haven't done so already please read Naomi Klein's "The Shock Doctrine", a book which thoroughly peels the stinking onion. This puts our problem in brutal context.
Like everyone here I am downing a complex cocktail of compounds (20 or so) every day, including astaxanthin capsules (4mg twice a day) in ignorance of my body's quantitative needs. Am I downregulating some processess(es) by overloading? I have no idea. A truly science-based medicinal practice would involve a spectrum of blood assays taken when we are young and healthy to provide a template for assessing imbalance throughout our lives. Then we would have a rational base for our dosing.
Actually such a thing is available in France (looking at 52 indicators) but when I enquired if the company had any UK contacts the answer was (surprise, surprise) negative. Brooks' experience with Langjoens a while back in which "overdose" of Vitamin E was identified is an example of what should be.
Mitochondrial health should be the first priority of any treatment regime but obviously this would be bad for business.
Joined: 14 Sep 2006 Posts: 262 Location: New York City
Posted: Sat Aug 23, 2008 10:37 am Post subject:
We've definitely assembled a great group here. Far more intellectually curious than many doctors, but then, they aren't the ones being experimented on for monetary gain. Only their livelihoods are at stake. We have a lot more at risk. We also benefit from the very same scientific databases and studies they no longer have any impetus to monitor or review. They take their patients and this information age for granted. These are both the best and worst of times.
Anyway, I'd be indeed very curious to see the effects astaxanthin has on your HDL levels. My mom experienced record high HDL levels after supplementing with astaxanthin. I only care about greatly raising HDL, and lowering oxidized cholesterol and triglycerides. Astaxanthin is one of the few substances capable of all these things, while helping maintain a healthful cholesterol profile.
Myself, I'm just trying to keep my head above water. I've been thinking a lot about the core of mitochondrial dysfunction lately, it would appear both me and Brooks. We don't even need to think outside the box, as much as going scientific dumpster diving. I hope to add a little food for thought.
I had seen this metylene blue story come down the pike a few days ago. The chemical sounded vaguely familiar to me. Turns out it's often found as an anti-fungal agent in aquatic enviornments like fishtanks. Also used by scientists to stain and examine DNA under a microscope. So this should be very easy to purchase at very little expense -- maybe even pharmaceutical grade, administered at just a few drops daily. I had no idea about its use as a mitochondrial pathway reviver. Though metylene blue seems to have served various uses throughout the history of medicine.
Apparently part of the promise of metylene blue is as a treatment for Alzhemier. For starters, I never believed tau protein (or beta amyloid) to be the actual cause of Alzheimer's, instead only a resulting collateral damage to the brain's arterial wall. Totally eliminating these proteins has done very little to reverse the symptoms of Alzheimer's, recent studies are more than suggesting this.
I do believe that statins leave the reminents of mitochnodrial dysfunction in their wake. This is perhaps further compounded by our own drug-induced manifistations to predisposed genetic mutations. And reversing this is the central element in abating those statin side effect symptoms... above all else.
In the very least, for statin suffers, I now place mitochondrial regneration only below stem cell therapy. And yet, the mitchondria are at the very heart of stem cell differentiation… and therefore tissue regneration and recovery. I'd easily pit mitchondrial dysfunction against some of the largest known mechanisms of cellular aging: inflammation, glycation, free radicals, oxidation, hormonal disruption, autoimmunity etc. Reducing these biomarkers might still only get you to the point of original damage. Not a bad beginning, but at best incomplete. This is current medical science in a nutshell.
Here's my main point. Scientists continue to look at the degradative functions, or the afteraffects in the wake of damage. But they never bother looking at the non-degradative function of organelles... which uridine sythesis is a major biosythetic function. More on uridine later.
Likely the clearest start in combating mitchondrial disorders would be solving the very causes of mitchondrial waste and lipid peroxidation debris that chokes systems. These aging, literally bloated mitochondria produce less energy and more superoxide, free radicals, excitotoxins like glutamate, cytokines and certainly other damaged proteins. Decreases in cellular efficiency causes a lethal disruption in the networking between organs. Eventually this communication breakdown leads to many of these statin-induced illnesses. That's the theory, at least.
You might say mitochondrial dysfunction is a direct byproduct of errors created in purine and pyrimidine metabolism. These manefest themselves as mutations in mitchondrial DNA and RNA. Purine and pyrimidines are, in fact, the most vital substances of all living cells as precursors of DNA and RNA. They are directly involved in signalling and providing energy in the form of ATP, through the the metabolism of carbohydrates, as in the biosynthesis of glycogen and sucrose. These defects of metabolism are already known to cause human disease.
On a side note, more of the damage might then come in the form of overproduction of uric acid, as the end-product of purine catabolism. Perhaps other problems could be related to iron deficiency anemia in hemoglobulin, but especially iron overload disorder. We already know heme to contain iron, and serve in many biochemical processes involving a crucial release of oxygen. You could say this relates directly to a heme deficiency.
I highly suspect the most curative solution of mitchondrial dysfunction is to increase levels of pyrimidine nucleotide precurors, or uridine (and to a smaller extent purine nucleotide precursors or inosine) in the body and brain. This is as close to a magic bullet for mitochondrial dysfunction as currently exists. For maximal effectiveness, uridine should be taken away from inosine, as they compete for the same metabolic pathway.
Uridine supplementation would provides nucleotides, or the very structural units of mt/DNA and mt/RNA. Mitochondrial diseases, such as Autism, ALS, Alzheimer's, Huntington's, Parkinson's, MS often arise from a genetic defect in mitochondrial DNA. We could also implicate diseases and disorders such as Epilepsy, Leukemia, Leukodystrophy, liver renal and heart failure, impared eyesight, myopathy, neuropathy etc.
Uridine itself is formed by the more potent attachment of uracil to a ribose ring, the very building block of RNA. We know that Ribose as a natural sugar is responsible for cellular energy metabolism or ATP. Choline, as a B vitamin, is an important precursor of the neurotransmitter aceytlcholine. Without Ach brain activity would surely cease. Both choline and uridine have been suggested for Alzheimer's and Parkinson's. From my brief reading, it appears metylene blue only helps delay mitchondrial aging, while uridine provides the very energy needed to reverse abnormal DNA sythesis. This would aid the bodies ability to transcode RNA from DNA.
Perhaps together both uridine and metylene blue might work well in synergy, at the very heart of mitchondrial dysfunction. Who knows. Both metylene blue and uridine already have been studied for decades. Otherwise, both are being suggested to revive mitchondrial pathways. Uridine itself serves as a carrier of nutrients to the center of the mitchondria, similar to the effect of orotic acid.
Interestingly, as for brain disorders, uridine very effectively crosses the blood-brain-barrier.... from what I'm reading, unlike metylene blue. Perhaps it's time to revisit these natural non-patentable substance, those abandoned long ago for much more lucrative ones. In fact, both a uridine variant and metylene blue have recently received US patents. Uridine might certainly have more of a biological basis in mitochondrial disorders. There’s also a very high tolerance to higher doses of uridine, while metylene blue could be potentially brain damaging in doses well above several drops daily. There's definitely a slight caution here.
The bottom line is that mitchondria are dependant on uridine due to pyrimidine sythesis. The primary biosynthetic pathway of the mitochondria is that of pyrimidine. Those cells suffering from mitchondrial dysfunction are dependant on uridine for their very growth and survival. This would include over 250 known cell-types comprising the entire human body. Those cells cannot make the RNA and DNA to grow with properly functioning mitchondria. Pyrimidine constitutes more than half of the base needed for RNA and DNA, with a secondary role played by purine bases adenine, guanine, xanthine. It's a vicious cycle.
The downfall begins as defects in mitchondrial enzymes, missing enzymes, or the reduced or inefficient expression of certain enzymes. These main mitchondrial disorders are classified according to their effects on mitochondria-specific pathways, which could be aided by uridine, and a secondary treatment with inosine (and perhaps even metylene blue???) These specific enzymes along the mitchondrial electron chain would yes include NADH, succinate produced from citric acid, but most importantly dihydroorotate dehydrogenase and uridine monophosphate. Clearly supplementation with CoQ10, a balanced vitamin B, vitamin C, carnitine, alpha lipoic acid is not enough.
I'm not an expert, by any means. But I know for certain my intuition continues to lead me on the correct path.
Joined: 19 Jan 2008 Posts: 242 Location: mcminnville,OR
Posted: Sat Aug 23, 2008 12:18 pm Post subject: statin drugs
adec, How come I understand almost everything you posted. Thanks for the info. We need a billionaire to fund a lab to research the damage statins due and to discover a way to correct the damage. Stem cells?
Joined: 13 Dec 2006 Posts: 1136 Location: Fort Worth, Texas
Posted: Sat Aug 23, 2008 2:10 pm Post subject:
adec: I couldn't agree more. I am and have been convinced that mito rejuvenation (if possible) is the path to wellness for us and for God knows how many other degenerative ailments. This is a concise, lucid post on the mechanics of mito recovery, and I appreciate it.
I had actually stumbled upon the power of uridine while in synergy with other supplements. Any decent choline source should have the ability to raise uridine levels. I originally used Alpha GPC to increase cholinergic brain cells and the number of acetylcholine receptors. This was an attempt to increase brain function. Eventually I started using alpha-GPC as an effective way to raise bioavailability of various supplements requiring choline. It was at this moment fairly amazing things started to occur. I only fairly recently have figured out precisely what though.
By the way, another great source of choline would be CDP-choline, as the anabolic precursor of choline and cytidine. Alpha-GPC is considered the catabolic predigested product of choline, stripped of its fatty acids for easier assimilation - especially by neurons. It appears to me that Alpha GPC is not only cheaper but more effective, with much reduced sides. Although, alpha-GPC and CDP-choline should similarly raise blood uridine levels. Of course, another side benefit is an increase in blood dopamine and receptors, which also leads to increased levels of HGH.
There was a recent study showing that: DHA in combination with uridine and choline decreased symptoms of depression. Of course, who wouldn't be depressed with poor brain and mitochondrial function. Although uridine supplementation can do so much more in helping reversing autoimmune and neurodegenerative diseases.
Uridine also does many wonderful things besides just improve mitochondrial function. As an overall neuroprotective, uridine greatly decreases neurotoxicity to drugs and chemicals (such as statin drugs,) has anti-tumor affects, greatly increases BDNF or Brain-derived neurotrophic factor (directly related to nerve growth factor.) Acetylcholine itself is also necessary for activating REM sleep, and helps keep neural membranes healthy and complete -- instead of brittle and fractured. It would also help prevent an excess build-up of amyloid protein. This is similar to the promise of methylene blue, while perhaps being safer and more biologically plausible. I'm not completely certain yet. +Although, I received an email from a registered pharmacist stating 58mcg daily should be fine.+
Now for the good part.
Apparently there's a substance created by Repligen that has received orphan drug status called PN401 or triacetyluridine. This is basically triacetylated uridine through a patented process. My mom has been using this product for over two months. Triacetyluridine increases uridine biosynthesis 5-10x better than ordinary uridine, much better than any combination of substances. This is great for anyone tired of using many supplements in synergy for mitochondrial regeneration.
I had already been using a sometimes 2x daily combination of 600mg of alpha-GPC, 100mg of orotic acid, sometimes magnesium orotate, 500mg of DHA on my mom. It was very extremely effective in clearing any residual statin-induced symptoms. Up until recently, I had always felt we were only hitting the periphery of the recovery problem. I have pretty much tried every plausible theory within reason, some even documented on the forum. In my estimation, this is the first time we have truly hit the bulls-eye. Triacytleuridine intensified her regimen and allowed for a more remarkable transformation.
Speaking of orotic acid, also considered (by some) vitamin B13... orotic acid is another good way to increase uridine, being as its chemical makeup is almost identical to that of uracil. However, orotic acid alone would be inefficiently diffused into the cells. Yet orotic acid bound to another element would act as an efficient transporter along the pentose phosphate pathway. For instance a chemically charged orotate, such as magnesium orotate, would not only help a neutrally charged orotic acid better entrance into the cell, but uracil and the bound magnesium as well. This makes orotic acid itself a fairly exciting and effective mitochondrial pathway reviver and transporter.
For those suffering from mitochondrial diseases, the most uniform complaint seems to be about gastric intolerances, or polygenic and genetotropic diseases: such as IBS and GI dysmotility. These appear to be compounded in part due to improper mitochondrial lipid, protein, amino, sugar digestion. Uridine or triacyteluridine helps promote the very mitochondrial pathways needed to release energy from lipids and carbs. In my mom's case, I'm talking about an improvement upon a sometimes tri-weekly bout of annoying bloating, gas, and diarrhea or loose bowels. While her long-term memory problems have now subsided, per se, difficulties in learning new short-term tasks or information (especially under duress) remained. This has also now diminished greatly with triacytleuridine treatment. Her memory recall and response times have also greatly quickened to even the most mundane or ordinary questions. Shortness of breath under mild exertion or a shuffling gate under great physical exertion has also greatly reduced. Does this sound similar? How many of those in statin recovery still complain about all these symptoms?
I would be more excited at the discovery though, if not for being so exhausted. We're talking about the very heart of DNA synthesis. Uridine nucleotides are directly coupled to the respiratory chain. In a state of lactic acidosis, the mitochondria begin to use glucose instead of oxygen. Oxygen is obviously required for proper energy production.... with hypoxia being the main cause for cellular death (both apoptosis and necrosis,) cancers, or more importantly mutations in mtDNA. For instance, a slowing DNA synthesis creates large immature red blood cells incapable of carrying oxygen and dividing. Heme would also play a role here. Purine and pyrimidine metabolism is then greatly reduced along the pentose phosphate pathway. This would further limit ribose synthesis, or the energy needed for ATP production.
Joined: 14 Sep 2006 Posts: 262 Location: New York City
Posted: Sun Sep 07, 2008 3:10 am Post subject:
Now for some supplement sources:
Cardiovascular Research Ltd of Concord, CA manufactures a dietary supplement brand of triacetyluridine in bottles of 60 capsules, 25mgs each. You can find this product being sold at Bayho.com for $20.35 and Nutrimedical.com for $16.16. 25mg 1-2x daily should be fine.
The cheapest source is found in a bulk powder supplied by 1Fast400. Solidnutrition.com is selling 50 grams for $20.44 and 150 grams for $53.39. 600mg, 1-2x daily should be fine.
The cheapest source is found in a bulk powder at beyondacenturyonline.com. They sell 200 grams bottles for $19.75.
This should be easy enough to find. For the cheapest and highest quality source, I really like wonderlabs.com. They sell 120 DHA softgels for $3.99. Or 120 Mega Omega-3 softgels with 408mg of DHA for $20.99 or 240 softgels for $40.99.
Otherwise, if you can afford only one substance to revive your mitochondria, I highly recommend triacetyluridine.
And perhaps someone will find a reliable source for pharmaceutical grade methylene blue.
Joined: 24 Oct 2006 Posts: 683 Location: Ongar, UK
Posted: Sun Sep 07, 2008 6:04 am Post subject:
This is encouraging stuff adec! Thank <deity/deities of choice> for your energy, intelligence and determination. We have a good crew here and maybe, just maybe, a small but growing light is appearing at the end of the long, dark tunnel.
Posted: Mon Jan 05, 2009 3:21 pm Post subject: URO
Brian, have been aware of this individual's writings about uridine in connection to ALS --find it intriguing and wondered why it was never followed up. She has written about this more extensively on other sites, though I do not have access to my files at present to llink them here:
I have printed off the information here, and I gave it to my MDA doc yesterday at my appointment. He said that Methalene Blue has been around for a long time, and that he had not heard anything new about it, but he said he would gladly look at the study information, and get back to me.
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