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Life Extension says it's been proven diabetics have mitochondrial deficiency

triffid113

Day of the Square Peg
Messages
831
Location
Michigan
I know there are those here who strongly disagree, but I believe that long term diabetics (not young ones) have CFS (mitochondrial dysfunction). I know the diagnosis criteria EXCLUDES diabetics but I think this is rather unfair and arbitrary as if people can only have one ailment at a time (ludicrous in fact). I can attest that my father had MANY ailments all at the same time...

I have always thought CFS ran in my family (long before I knew there was a name for it) and I used to think of it in terms of "some kind of problem with B vitamins" before I knew about the methyl cycle (so like 45 years ago). So now I had my and my father's genes mapped and we both have 18 of 30 genetic defects mapped, many in the methyl cycle (yes, I was right all those years, we have a B vitamin issue). We did not have all the same defects nor the same severity, yet the general screwed-up-edness was similar. He did not have allergies so I suspect I have additional genetic problems he did not have.

The thing is that I could look right up my Dad's side of the family tree and see severe fatigue issues everywhere there (and none on my mother's side - my Dad lucked out on marrying someone with the energy to take care of him). The diabetes in my family is ALSO all up my Dad's side. Medical science just dismissed their life-altering fatigue as diabetes, yet every other diabetic I knew growing up had plenty of energy (rode frequently in bike marathons, waitressed in busy restaurants, etc). So I told my Dad and my Aunt long time ago that I thought they had some kind of fatigue issue in addition to diabetes. My father's side of the family didn't use wheelchairs, they just never went anywhere or did anything...they didn't WANT to, because depression went along with the fatigue.

So I am just saying that it is proven now that diabetics have the same mitochondrial issues that CFSers have, possibly different cause, although I think you'll find there are multiple causes even among classical CFSers. Those who dismiss this as diabetes think that those with diabetes and low numbers of mirtochondria (which sounds like eventually all diabetics have) only have to eat 'properly' to have this problem go away, but I can speak from experience that it's not so easy as that. If diabetes is in your genes eating a certain way might never do the trick nor be possible. If you can't absorb sugar or utilize it properly you would be surprised at how useless a "supposed to" or "should" diet is. (I have been diabetic twice and beat it - because I was young and it THEN was caused by too much stress (divorce) and its effect on my diet / self - care), but over 50 w/o hormonal (gene expression) help, I don't think diet would help enough to - well - help. I developed inability to break down glycogen (panic/low blood sugar) forever after age 50 and I couldn't play around with that with little things that may/may not have effect in a million years so I jumped right on hormone replacement until I found a strategy that works. So I have had some sort of blood sugar issue I have had to fight all my life - as a kid it took little to fend off, but as I got older it got HARDER. I do not believe w/o hormones it would have been possible.

So, I am making the case that diabetes as a cause of CFS is just as relevant as any Epstein-barr or lyme or any other cause. The end result is mitochondrial dysfunction. And the path there is not remotely easy to fix. (So for instance insulin did NOTHING to fix it). I think it's bogus to exclude diabetics from having CFS. It's just some arbitrary rule w/o basis in what's really going on at the cellular level. I'm just putting this out there. My opinion. Unsolicited so we know what that's worth.
 

triffid113

Day of the Square Peg
Messages
831
Location
Michigan
http://www.lef.org/magazine/mag2011/feb2011_Our-Aging-Mitochondria_01.htm

Mitochondria Insufficiency Promotes Type 2 Diabetes

Type 2 diabetes is often caused by overeating, but some people lose the ability to control glucose because of hereditary factors or physical inactivity.
A study looked at young, lean, sedentary children with insulin resistance whose parents had developed type 2 diabetes. Compared to similar children of non-diabetic parents, muscle biopsies showed that mitochondrial density was reduced by 38% in the offspring of diabetic parents.73
This study also showed that these insulin-resistant children exhibited increased amounts of fat content in their muscles, which also contributes to insulin resistance. These findings support the concept that hereditary mitochondrial dysfunction contributes to the development of insulin resistance and subsequent type 2 diabetes.
The encouraging aspect to this study is that those genetically predisposed to type 2 diabetes may be able to avert this calamity through either rigorous physical exercise and/or supplementation with PQQ, both of which have been shown to promote mitochondrial biogenesis.15,18 (Note that certain anti-diabetic drugs like metformin and thiazolidinediones also induce mitochondrial biogenesis through additional mechanisms.)17,74-76
...
How Mitochondrial Structure Deteriorates

Altered (glycated) proteins can bind to mitochondria and compromise their function.79,80
The accumulation of dysfunctional mitochondria results in a vicious cycle whereby increased oxidative and glycation reactions disable more mitochondria, eventually leading to a cell’s demise.81 The mitochondria in cells of elderly people are mostly dysfunctional, whereas young individuals have virtually no mitochondrial damage.82,83
A fascinating report published in 2010 describes the lethal cascade that occurs as inactive mitochondria accumulate in cells and how carnosine, acetyl-L-carnitine, and resveratrol can protect against these longevity-shortening molecular interplays.84
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The above bit is interesting because Alex is working with resveratrol now with significant success.
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Life EXtension proposes the following strategy to reverse mitochondrial dysfunction: CoQ10, shiajit (which supposedly restores CoQ10 so it can be used again), and PQQ (creates new mitochondria). I don't think this is enough as I think antioxidants and potentially things that destroy pathogens (like olive leaf extract) are important to stopping the destruction, and substances that reduce cellular protein glycation (important in dibetics but also in the AVERAGE AMERICAN - as the average American has too high a fasting blood sugar), are important. But I think LEF is on to something anyway: http://www.lef.org/magazine/mag2013...trategy-to-Reverse-Mitochondrial-Aging_02.htm
 

triffid113

Day of the Square Peg
Messages
831
Location
Michigan
http://www.lef.org/magazine/mag2013...ses-of-Aging-Conference-in-Tokyo-Japan_01.htm
Reducing Methylation

Juleen Zierath, PhD (Head of the Section of Integrative Physiology, Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden), like Dr. Rando, is interested in control of DNA expression (epigenetics, as distinct from genetics, which studies the effects of DNA differences). Dr. Zierath is specifically investigating the relationship between gene expression and type II (formerly called adult-onset) diabetes.
An important mechanism of epigenetics is addition of methyl molecules (methylation) or removal of methyl molecules (demethylation) to regulatory areas of DNA.14,15 Methylation of biomolecules is an essential biochemical reaction required for maintaining the integrity of biological membranes,16 synthesis of neurotransmitters,16 visual acuity,17 increasing glutathione synthesis in the brain to protect against oxidative stress,18 and protection against depression19 ― among many other vital functions. Methylation and demethylation of DNA is a means by which control is exerted over which genes are expressed and which genes are not. If DNA were completely methylated, no genes would be expressed, whereas if there were no DNA methylation there would be chaotic overexpression of too many genes. Both excessive and inadequate DNA methylation have been associated with cancer.20
Dr. Zierath has been studying DNA methylation effects in type II diabetes. As background, Dr. Zierath described twin studies. Identical twins are genetically identical because they have the same DNA and continue to have the same DNA throughout their lifetimes. Identical twins are epigenetically identical at birth, but become increasingly epigenetically distinct as they become subject to different environmental influences.21 She cited a study which showed that epigenetic effects due to smoking and dietary behavior can be inherited.22
In 2009 Dr. Zierath’s laboratory published a study showing that fatty material in the bloodstream causes methylation of DNA regulatory areas that results in a reduction of mitochondria (and resultant reduction of cellular energy).23 This study was an advance in providing a molecular mechanism that would explain why patients with type II diabetes have fewer mitochondria in their cells. The following year,her team published research indicating that exercise induces epigenetic changes that induce mitochondria function and fat utilization.24
Dr. Zierath has called exercise “the first line of defense against the development of insulin resistance in type II diabetes.” Vigorous exercise at least once per week has been shown to reduce the risk of type II diabetes by 33%.25 Most recently Dr. Zierath’s group published a study showing that exercise increases gene expression of sections of DNA that induce mitochondrial formation.26
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As we know, exercise is not possible for many - SPECIFICALLY THOSE WITH LESS MITOCHONDRIA! (So LEF touts PQQ to replace exercise as a way to generate mitochondria).
 

August59

Daughters High School Graduation
Messages
1,617
Location
Upstate SC, USA
I'm a Type 2 diabetic within the only last two years. The envelope was one to slowly open with the fasting sugar level inching up. My triglycerides have been very sporadic over the last 10 years and still are. My LDL always borderlines high and HDL is always low.

My type 2 diabetes made it's debut when I was trying to get a refill on my Androgel and between my endo and the Patient Assistant Program I went a month without any and it just so happen to be when I was going to my primary doctor during that time and asked him to test my total T and it was down to 86 or 91 (I can't remember!) and it usually between 450 and 550. My thyroid TSH also went up to 4.850 and he upped my Levothyroxine for 75 mcg to 88 mcg.. I received my 3 month supply of Androgel. This has been months ago and I'm looking for good endocrinologist that will take Medicare and I still want to use my Integrative doctor. See if I can get my endocrinologist to run any normal labs that my Integrative doctor wants run.

After being back on my Androgel for about a month I started getting bad anxiety, sweating worse than I already do. Side note - If I could cut my sweating in half I would be a happy man. I sweat around my hairline and down the center of back and on my chest just brushing m teeth (I use a pretty good Oral-B electric toothbrush). My eyes felt very tired, bulging. I went and had my Primary doctor order another TSH and it was .001 which is as low as it will read. He immediately dropped me back to 75mcg. This why I will not let a doctor manipulate more than one hormone at a time anymore. I followed up with primary again for normal yearly physical and had him run my total and free testosterone and as well my TSH, free T4 and free T3.

What are possible food and drug interactions associated with Synthroid?

If Synthroid is taken with certain other drugs, the effects of either could be increased, decreased, or altered. It is especially important to check with your doctor before combining Synthroid with the following: amiodarone, androgens (male hormones), antacids and antigas medications, antidepressants such as imipramine and sertraline, blood pressure drugs, blood-thinners such as heparin and warfarin, cancer drugs (such as 5-fluorouracil, 6-mercaptopurine, mitotane, and tamoxifen), chloral hydrate, cholesterol-lowering drugs, diabetes drugs such as glyburide and insulin, digoxin, estrogen products and oral contraceptives, furosemide, growth hormones, hormone inhibitors such as aminoglutethimide and methimazole, interferon, interleukin, iodide/iodine, kayexalate, ketamine, lithium, methadone and heroin, metoclopramide, NSAIDs such as ibuprofen and naproxen, Parkinson's drugs such as levodopa/carbidopa, propylthiouracil, seizure medications (such as carbamazepine, phenobarbital, and phenytoin), steroids such as dexamethasone and hydrocortisone, stimulants such as epinephrine, sucralfate, tranquilizers, tuberculosis drugs, and theophylline.

This is a well written "Prescribing Information" section if you ever want you really read what all thyroid medication goes through in the body:

http://www.pdr.net/full-prescribing-information/synthroid?druglabelid=26#Drug_Interactions

The reason I posted this that my subtle changes in different areas turn into a fireball real quick known as "Metabolic Syndrome X".

This all came together over the last year.

Keep your guard up so it doesn't sneak up on you because doctors do not know how to treat it correctly. It can be cured for the most part, as usual a doctor is going to treat symptoms and that's all.
 

xchocoholic

Senior Member
Messages
2,947
Location
Florida
Diabetes is common in untreated celiac disease. Many
who eliminate gluten lose their diabetes dx.

I have hyperinsulinemia so my bg runs low. I heard this
is a precursor to diabetes so I need to get checked.

Oxalates either damage block mitochondria. I can't
remember right now. And flouroquinolones damage
mitos. Imho, it's ridiculous how often these meds
are prescribed still.

great info. tx. x
 

August59

Daughters High School Graduation
Messages
1,617
Location
Upstate SC, USA
I'm with triffid113 in her support of the idea that any of us that are very inactive, don't have the greatest will power on their diet need to think seriously about the possibility of Type 2 diabetes and/or Metabolic Syndrome.

Some may or may not have a hereditary link to and I don't think you have to have one. I can't find one anywhere in my family tree going back a couple of generations on both sides.

I was sick long before I started down the road towards Type 2 diabetes and Metabolic syndrome except for maybe the slightly elevated triglycerides which were easily control by diet. You have to fast at least 12 hours to get an accurate triglycerides test. (Some labs or doc will say 8 hours which is fine for sugar, but not triglycerides)

If you start picking up that small spare tire around the middle. Nip in the bud because is a strong sign that some processes are changing. If you can't exercise like me sometime, i'll stretch instead and sometimes I'll stretch on purpose. I'll get a massage sometime, but I'm right up front that they have to listen to me as far as pressure goes.

Thanks triffid113 for bringing Diabetes Type 2 to the forum as either a cause or a product of our disease.
 

triffid113

Day of the Square Peg
Messages
831
Location
Michigan
Wow...no hate mail from anyone for bringing up diabetes as a cause for mitochondrial dysfunction! Well, August59, you say 'do your best to get rid of the spare tire' blah, blah, blah. But remember, some are born with less mitochondria (children of diabetics like my Dad, like me). I am not saying don't try, but only that to assume there is a point where you coulda caught it by exercise is IMHO wrong for at least some people. However I do believe there are other ways to catch it. I am taking PQQ every day now. The way I read it, PQQ is like exercise in a bottle. I don't expect miracles from any one supplement, it's only part of my regime with P5P to prevent some glycation, and anti-oxidants and pathogen killers like olive leaf extract to keep down potential sources of mitochondrial destruction.

I measure my energy level by my house. If I start to win on keeping up with the house then my energy level is improving. Well I started taking PQQ and have not taken a full bottle yet but my house is getting cleaner. If I ever get it all under control I will shout PQQ to the rafters. But I don't improve things one at a time...I think too many things would break while I waited for that strategy...if I read that something makes sense for me I try it. So right now I am taking new stuff: PQQ, coleus, and berberine. (The berberine I just started today). As you point out this can cause inability to isolate what causes problems, but still that is how I work. I rely on knowledge to make choices more than what it makes me feel like because I do not believe in a single magic bullet and if it worked for others in tests but did not work for me, I don't just discard it as I tend to then think it's part of the fix but not the whole fix and that those 'other guys' did not have their biochemistry as screwed up as mine. (So for instance, mB12 alone may fix you up, but I have a lot of genetic defects in the methyl cycle and mB12 alone would not do it for me but is still part of the solution).

I don't want to imply btw that I do not houseclean, but I do less than the minimum to get by in that if something goes wrong, it stays wrong a long while because I cannot summon extra energy to deal with it. So if I put a can of cat food on the stove burner to warm it a bit before serving an outdoor cat and it explodes plastering my wall and ceiling with baked on cat food, it will stay so-decorated for sometimes years before I actually deal with it. New paint design.

Oh yes, what I said was not about will power. If you are having blood sugar issues / panic attack, you cannot function at all for more than a few minutes. You can pass out, die, etc. So you do not have the luxury of 'willpower on a diet.' you gotta do what you gotta do. THAT was what I was saying. I don't think saving your own life is 'not exercising willpower'.
 
Messages
15,786
I measure my energy level by my house. If I start to win on keeping up with the house then my energy level is improving.
I'm confused. A couple years ago, you were stating outright that you don't have ME/CFS. Some months ago, you were talking about doing rather extended and intensive exercise on a regular basis.

What causes your difficulty in keeping up with your house now, since it doesn't seem to be a consistent physical disability? And how are your experiences with those extreme fluctuations relevant to ME/CFS patients?
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
I think diabetes is a syndrome. I think diabetic syndrome can occur in ME. I have been thinking about this off and on for years now. Many of us have metabolic syndrome. Many of those develop diabetes. I have mild diet controlled diabetes that should be almost symptom free. It definitely does not account for PEM or severe fatigue and brainfog. I have two other "exclusionary" conditions too, but neither explain my symptoms. These two are now also treatable.

I developed severe hypoglycemic attacks on a trial metformin. I had to overeat to compensate, usual dietary regulation failed, such as small regular meals.

Any deficit in mitochondrial function or glycolysis may induce a diabetic syndrome. Its not always the same disease as found in most diabetics though. When doctors treat diabetes they are usually treating symptoms or associated pathophysiology. The cause is still not really understood, and even talk of "the" cause might be an issue, as its probably multifactorial and heterogeneous. There is however oodles of research on contributing factors, one of which is obesity.

So I consider the mitochondrial dysfunction in ME to be a risk factor for a diabetic syndrome. Along the way there is serious risk of metabolic syndrome.
 

triffid113

Day of the Square Peg
Messages
831
Location
Michigan
I think diabetes is a syndrome. I think diabetic syndrome can occur in ME. I have been thinking about this off and on for years now. Many of us have metabolic syndrome. Many of those develop diabetes. I have mild diet controlled diabetes that should be almost symptom free. It definitely does not account for PEM or severe fatigue and brainfog. I have two other "exclusionary" conditions too, but neither explain my symptoms. These two are now also treatable.

I developed severe hypoglycemic attacks on a trial metformin. I had to overeat to compensate, usual dietary regulation failed, such as small regular meals.

Any deficit in mitochondrial function or glycolysis may induce a diabetic syndrome. Its not always the same disease as found in most diabetics though. When doctors treat diabetes they are usually treating symptoms or associated pathophysiology. The cause is still not really understood, and even talk of "the" cause might be an issue, as its probably multifactorial and heterogeneous. There is however oodles of research on contributing factors, one of which is obesity.

So I consider the mitochondrial dysfunction in ME to be a risk factor for a diabetic syndrome. Along the way there is serious risk of metabolic syndrome.
I am not sure what you are saying here exactly. I see that you say the conditions can co-exist (but the medical criteria for diagnosing CFS does not agree as far as I understand it), despite which I believe is wrong. I am not diabetic myself and yet I have significantly less than normal energy (lifelong, not just as an adult) and I am not obese. I have been diabetic twice (stress) and recovered, but I have had lifelong low blood sugar issues that got totally unmanageable (could not stop shaking!) after age 50 w/o hormonal help. This, of course, has nothing to do with CFS, but I only mention it to show that although I have some sort of blood sugar issue it is not the cause of my energy issues except as inherited. My father also had energy issues his whole life, before he became diabetic, and he was not obese either. But I don't really think the state of how one got there is as important as recognizing the deficiency of mitochondria exists and needs to be dealt with. For instance, I have seen in my Dad's family that healthy people assume you did it to yourself and can get yourself out of it with exercise...like my Aunt was refused a wheelchair when she could no longer walk because her doctor wanted to FORCE her to exercise. She could not so she became housebound.
 

triffid113

Day of the Square Peg
Messages
831
Location
Michigan
Well I was going to post more about mitochondrial dysfunction, but maybe someone else would rather. Feel free.
 

August59

Daughters High School Graduation
Messages
1,617
Location
Upstate SC, USA
Well I was going to post more about mitochondrial dysfunction, but maybe someone else would rather. Feel free.

If you have some information that you would like to share, then I wish you would. I think many of us have mitochondrial dysfunction, but I don't think we all get there the same way. Any information could be of value to someone else.

Thanks
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
There are thousands of skinny type 2 diabetics in every big city. Its not a disorder of obesity, obesity is just a big risk factor. The problem is that the medical model used in early and often later research was obesity. Since this appears in most models and patient groups, they have conflated obesity with diabetes. When I was in medical tutorials when studying biochem, the med students all thought you could only get type 2 diabetes when obese. Yet when I put this to a researcher who worked with an endocrinologist, at first he thought no, they must be obese. Then he realized just how many skinny diabetics they were treating in a big hospital (main hospital for their country, don't want to say where).

Obesity can trigger type 2 diabetes. Ergo, that is all they consider. What about the other triggers? There is not much research there, but enough to show that there are other causes, and what we call diabetes is a final common pathway of many different diseases.
 

triffid113

Day of the Square Peg
Messages
831
Location
Michigan
If you have some information that you would like to share, then I wish you would. I think many of us have mitochondrial dysfunction, but I don't think we all get there the same way. Any information could be of value to someone else.

Thanks
Well...thanks. I don't think I have any real information. I just like to explore together. So like find something and see if it sparks ideas and just study together. But maybe I should go study on my own. I think of this as like email where you write whatever you think but apparently I need to become an expert before I say a word. I...read fast and write fast and I don't often realize how much work it can be for others to read so much. So...condense, condense, condense. But then it's like work of course. I have to go now anyway. It's quite late and I have to drive home...Take care.
 

triffid113

Day of the Square Peg
Messages
831
Location
Michigan
- IF YOU HAVE NO INTEREST, SIMPLY DO NOT READ -

Alex made me look into resveratrol because he said it would helo with asthma, something I had never heard before. Well, it so happens that resveratrol GENERATES MITOCHNODRIA:


Resveratrol causes creation of significant amounts of new mitochondria in endothelial cells, improves endothelial dysfunction and vascular inflammation in diabetes (suspected (and later proven) via SIRT1): http://ajpheart.physiology.org/content/297/1/H13

Resveratrol increase GSH in a dose-dependent manner and significantly reduces cellular ONOO: http://ajpheart.physiology.org/content/297/5/H1876

Resveratrol significantly increases mitochondria in skeletal muscle and liver: http://ajpheart.physiology.org/content/297/1/H13

Resveratrol lowers oxidative stress at the mitochondria (which are large generators of oxidative stress), lowres high blood sugar, raises glutathione: http://ajpheart.physiology.org/content/297/5/H1876

Resveratrol improves mitochondrial function: http://www.sciencedirect.com/science/article/pii/S0092867406014280

Resveratrol raises AMPK (like berberine? ), B3 levels, and mitochondrial levels ad function, via SIRT1: http://www.sciencedirect.com/science/article/pii/S155041311200143X

Resveratrol affects the following P450 pathways (thus serious drug-herb interactions likely): http://cancerprevres.aacrjournals.org/content/3/9/1168.short

Resveratrol, what is an effective clinical dose? (fyi, Alex lists his effective dose on his blog, and interestingly only needs it once a week): http://www.dynamicchiropractic.ca/mpacms/dc_ca/article.php?id=55474

Resveratrol: What Is an Effective Clinical Dose?

By Kerry Bone, BSc (hons), Dipl. Phyto.

Currently resveratrol is probably the most actively researched phytochemical worldwide and many favorable properties have been demonstrated in pharmacological models.




A PubMed search in June 2011 retrieved more than 4,000 articles on resveratrol, which demonstrates an amazing array of favorable pharmacological activities including antioxidant, cardioprotective, antidiabetic, anticancer, antiviral, neuroprotective, antiplatelet, anti-inflammatory and modulation of fat metabolism. Resveratrol inhibits cancer development at all the three known phases of chemical carcinogenesis, namely initiation, promotion and progression. The development of other chronic diseases might also be reduced by resveratrol, based on the many lab studies. These diseases include cardiovascular disease, dementia, type 2 diabetes and osteoarthritis.1-2 In addition to its indirect effects on the aging process via SIRT1, this one simple molecule has the potential to directly prevent most of the chronic diseases associated with aging.

However, the relative lack of clinical research raises questions about the effective and safe human dose, especially for health maintenance. A landmark animal experiment and subsequent discussions over dosage, together with three recent human trials, provide some insights into the appropriate human dosage of resveratrol.

The Pharmacological Study

The important pharmacological study was published in the journal Nature in 2006. Rather than giving resveratrol to normal mice to see if it simulated calorie restriction, the effect of resveratrol on a high-calorie diet (HCD) was studied. Middle-aged (1-year-old) male mice on a HCD were given resveratrol and compared to untreated mice on the same diet or a standard diet.3 The administered doses of resveratrol were either 5.2 or 22.4 mg/kg/day for six months, but only results for the higher dose were reported.

The mice receiving the HCD became overweight, whether they were receiving resveratrol or not. However, a clear survival benefit from resveratrol was evident: Survival rates for mice on the HCD plus resveratrol diet were the same as those for the mice on the standard diet (SD).

Although resveratrol increased survival, it was also important to understand if quality of life was maintained. This was determined by the rotarod test, which measures balance and coordination. Surprisingly, the resveratrol-fed mice on the HCD steadily improved their motor skills as they aged, to the point that they were indistinguishable from the SD group. Resveratrol also corrected the following parameters in the overfed mice to levels similar to those observed in the SD mice: plasma insulin, fasting glucose, plasma albumin, plasma amylase, liver weight, aortic elastic lamina morphology and mitochondria levels in liver tissue. Furthermore, resveratrol opposed the effects of the HCD on 144 of 153 significantly altered metabolic pathways.

These dramatic results provoked worldwide attention and the observation that with resveratrol, "you can eat your cake and not have it." However, they also led to considerable discussion as to whether the amount of resveratrol given to the mice was realistically achievable in humans. Many media sources at the time stressed that the doses used could be interpreted to mean several hundred or even thousands of litres of wine per day in human equivalent doses (HEDs).4

A 2007 paper pointed out that this was a serious misinterpretation of the results, leading to unnecessary scepticism of this important research.4 It reflected a general ignorance of the scientific community and public regarding appropriate methods of dosage extrapolation between animal species, which should be based on surface area rather than body weight.4 In other words, the HED for a 130 lb (60 kg) human adult from a mouse dose of 22.4 mg/kg is not 60 times 22.4 mg (1,344 mg), but instead works out to just 109 mg. While not reasonably achievable through the consumption of wine (which typically contains 2-3 mg resveratrol per litre), this dose of resveratrol is readily reached by the use of an extract of the herb Polygonum cuspidatum (giant knotweed).

Human Clinical Trials

Information about the appropriate human dose of resveratrol also comes from recent clinical trials. Nineteen overweight/obese men and postmenopausal women (BMI 25-35 kg/m2) with untreated borderline hypertension consumed three different single doses of resveratrol (30, 90 or 270 mg) or a placebo at weekly intervals in a double-blind, randomized, crossover comparison.5 One hour after the resveratrol consumption, its level in plasma and its impact on flow-mediated dilatation (FMD) of the brachial artery were assessed. Impaired FMD is associated with several cardiovascular risk factors, including hypertension and obesity.

With increasing doses of resveratrol, there were proportional increases in plasma resveratrol concentrations. FMD was significantly increased by all doses of resveratrol compared to placebo (p < 0.05), but the higher doses had only a marginally greater impact than the 30 mg dose.

Two groups (10 in each) of normal-weight healthy participants were randomized to placebo or a Polygonum cuspidatum extract containing 40 mg/day resveratrol for six weeks.6 In mononuclear cells taken from participants after six weeks, the extract had induced significant antioxidant and anti-inflammatory effects (p < 0.05). Also, it significantly reduced plasma concentrations of TNF-alpha (tumor necrosis factor-alpha), IL-6 (interleukin-6) and C-reactive protein (p < 0.05).

In a third study, 19 patients with type 2 diabetes received just 10 mg/day of resveratrol for four weeks in a double-blind, placebo-controlled, randomized clinical trial.7 By the end of the trial, resveratrol had significantly decreased insulin resistance (homeostasis model of assessment for insulin resistance, HOMA-IR) compared with placebo (p = 0.044). The time to maximum plasma glucose after a test meal was also significantly delayed by resveratrol (p = 0.03 versus placebo). Mechanistic investigations suggested the improvement in HOMA-IR might be due to a resveratrol-induced decrease in oxidative stress leading to more efficient insulin signalling, rather than enhanced pancreatic beta-cell function.

Suggested Dosing

Based on these studies, an effective long-term human dose for resveratrol probably ranges from 10 to 120 mg/day. While higher doses up to 200 mg/day could be considered where the need exists, doses beyond this limit might not only be unnecessary, but could also prove to be unsafe with prolonged usage. There are still many uncertainties in the resveratrol research and it would be wise to exercise caution at this stage. A daily dose of resveratrol of 100 mg from Polygonum cuspidatumis certainly within the range of the traditional doses used for Chinese herbs.

One of the issues with resveratrol is that it is rapidly metabolized and has limited bioavailability as such. However, resveratrol metabolites (mainly phase II conjugates) might also be bioactive or act as a reservoir of resveratrol at target tissues. One study found that to maximize plasma resveratrol levels it should be taken with a standard breakfast and not with a high-fat meal.8The high-fat breakfast was observed to reduce its bioavailability by about 45 percent.

References

1. Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov,2006;5(6):493-506.

2. Shakibaei M, Harikumar KB, Aggarwal BB. Resveratrol addiction: to die or not to die. Mol Nutr Food Res,2009;53(1):115-128.

3. Baur JA, Pearson KJ, Price NL, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature, 2006;444(7117):337-342.

4. Reagan-Shaw S, Nihal M, Ahmad N. Ahmad N. Dose translation from animal to human studies revisited. FASEB J, 2007;22(3):659-661.

5. Wong RH, Howe PR, Buckley JD, Coates AM, Kunz I, Berry NM. Acute resveratrol supplementation improves flow-mediated dilatation in overweight/obese individuals with mildly elevated blood pressure. Nutr Metab Cardiovasc Dis, 2010 Jul 29. [Epub ahead of print]

6. Ghanim H, Sia CL, Abuaysheh S, et al. An antiinflammatory and reactive oxygen species suppressive effects of an extract of Polygonum cuspidatum containing resveratrol. J Clin Endocrinol Metab, 2010;95(9):E1-E8.

7. Brasnyó P, Molnár GA, Mohás M, et al. Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the Akt pathway in type 2 diabetic patients. Br J Nutr, 2011 Mar 9:1-7.

8. la Porte C, Voduc N, Zhang G, Sequin I, Tardiff D, Singhal N, Cameron DW.. Steady-state pharmacokinetics and tolerability of trans-resveratrol 2000 mg twice daily with food, quercetin and alcohol (ethanol) in healthy human subjects. Clin Pharmacokinet, 2010;49(7):449-45.
 

triffid113

Day of the Square Peg
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But actually that was even a side note because I ran across this from Martin Pall, which strikes me as much more consolidated that priorly from him:

New Theory on Explanations for Chronic Fatigue Syndrome


By Dr. Martin L. Pall • www.ProHealth.com • February 13, 2001

Editor's Note: Dr. Martin L. Pall, Ph.D., received his Ph.D. in Biochemistry and Genetics from Caltech after receiving his B.A. degree at Johns Hopkins University. He is a professor of Biochemistry and Basic Medical Sciences at Washington State University. He teaches medical students and is the chief instructor at Washington State University in the medical biochemistry course for first year medical students.

Dr. Pall writes that he came down with CFS in June/July 1997 after a severe bout of Varicella zoster infection.
"My CFS was diagnosed by my primary care physician and my case did meet the 1994 CDC criteria. So this was, in many ways, a typical case of post-viral fatigue syndrome, sudden onset. However, I have had an excellent recovery, over about a year and a half (possibly due to self-medication?), and consider myself cured. So, I don't view myself as a CFS patient. It was only after recovery from the severe cognitive dysfunction that I was able to dedicate myself to understanding the basis of CFS."

I asked Dr. Pall about his comment that he considers himself cured. Is he not afraid of a relapse in the future? Also, to what does he attribute the 'cure' and how does he stay healthy? This is his response:

I became ill with CFS in June/July 1997 and spent most of July and August in bed trying to recuperate. The following semester, I was able to perform at a minimal level in my teaching, taking lot's of sick leave, living from day to day, as most of us do. I self medicated on several things (more about that later) but had little apparent improvement. However, the following winter, I did improve substantially and by May was doing very well, not completely recovered but maybe 80% recovered. A year later, I considered myself completely recovered although I am still self-medicating, not wanting to take any chances of having a relapse. Specifically, over the past two summers, I have been able to go on a series of fairly taxing Sierra Club hikes with no post-exertional malaise. That is quite distinct from my earlier condition where I could only walk (slowly) circa 50 yards before having to sit down for a long rest.

My self medication was primarily with antioxidants (natural mixed tocopherols, vitamin C, selenium, some carotenoids, calcium/magnesium supplement, Ginkgo extract and coenzyme Q10). I also tried some black currant seed oil and some choline/inositol supplements - I did not think these helped but maybe I was wrong? I am very careful with my diet, eating nutritionally rich foods and antioxidant-rich foods (it would take a book to tell you all about the food issue). I did not have any GI tract problems so was able to tolerate both the supplements and a wide variety of foods.

The most dramatic effects that I saw, appeared to be from the Ginkgo extract (this over a period of two or more months, however) and, following that, from the Co Q10 , the latter of which was a dramatic, within 24 hours, recovery of cognitive function. I have never had a problem with cognitive dysfunction since that time and am still taking the Co Q10. I am aware that most others who have tried Co Q10 have not had as favorable a response, and I can only think that my body was primed, possibly by the other supplements and foods, to be ready to respond to it.

I have been running a clinical trial/pilot study with a physician (Dr. Albert G. Corrado) using a series of supplements based on my theory, and the results have been both encouraging and discouraging - encouraging because essentially everyone who was on the trial and was able to tolerate most of the supplements reported an improvement but all reported a modest improvement, over a 150 day period. So no one was cured over that time. I met yesterday with a group of pwcs, a few of whom were on the trial, and we are seeing some continued improvement (most people opted to continue on the supplements after
the trial was officially completed, suggesting that they felt that the supplements were helpful). One person even reported that she was "almost normal" now about 13 months after starting on the supplements. So, maybe there is hope.

With regard to your question about a possible relapse, that is, of course, the nightmare of all us who have largely or partially recovered from CFS. All I can say is that over the past two years, I have functioned on a completely normal level - but then, I am still self-medicating and plan to continue doing so indefinitely. Some of the hikes I have been on have been quite taxing - 8 1/2 to 9 mile fairly tough hikes, with substantial elevation gains - and the results have been some fatigue afterwards, but normal fatigue, just requiring normal resting. So I am hopeful that this functional
recovery is permanent.

Dr. Pall's hypothesis follows below:

Novel chronic fatigue syndrome (CFS) theory finally produces detailed explanations for many CFS observations

A novel theory of the cause of CFS has been published which is supported by diverse biochemical and physiological observations of CFS, while providing explanations for five of most difficult puzzles about this medical condition. The theory has been published by Dr. Martin L. Pall (Professor of Biochemistry and Basic Medical Sciences, Washington State University) in several publications (1-4,9).

The theory starts with the observation that infections that precede and may therefore induce CFS and related conditions act to induce excessive production of inflammatory cytokines that induce, in turn, the inducible nitric oxide synthase (iNOS). This enzyme, in turn, synthesizes excessive amounts of nitric oxide which reacts with another compound (superoxide) to produce the potent oxidant peroxynitrite. Peroxynitrite acts via six known biochemical mechanisms to increase the levels of both nitric oxide and superoxide which react to produce more peroxynitrite. In this way, once peroxynitrite levels are elevated, they may act to continue the elevation, thus producing a self-sustaining vicious cycle. It is this cycle, according to the theory, that maintains the chronic symptoms of CFS and it is this cycle, therefore, that must be interrupted to effectively treat this condition.

Twelve different observations on chronic fatigue syndrome and its symptoms provide support for this theory:

1. The levels of neopterin, a marker for the induction of the inducible nitric oxide synthase are reported to be elevated in CFS(1).

2. Mitochondria are reported to be dysfunctional in CFS and mitochondria are known to be attacked by peroxynitrite and also by nitric oxide (1).

3. Both cis-aconitate and succinate levels are reported to be elevated in CFS and the enzymes that metabolize these two compounds are known to be inactivated by peroxynitrite (1).

4. The four inflammatory cytokines implicated have been reported to been reported to be elevated in 10 different studies of CFS (1,2).

5. These same inflammatory cytokines have been reported to induce fatigue when injected into humans (1).

6. An animal (mouse) model of CFS has "fatigue" induced by a bacterial extract that can induce both the inflammatory cytokines and also the inducible nitric oxide synthase.

7. Polyunsaturated fatty acid pools are reported to be depleted in CFS and such polyunsaturated fatty acids are known to be oxidized by oxidants such as peroxynitrite.

8. Anecdotal evidence has suggested that antioxidants such as coenzyme Q-10, flavonoids and glutathione precursors may be useful in CFS treatment, consistent with a role for an oxidant such as peroxynitrite.

9. Women are reported to produce more nitric oxide than men, possibly explaining the gender bias seen in CFS. A similar gender bias is seen in autoimmune diseases characterized by excessive peroxynitrite (i.e. lupus, rheumatoid arthritis).

10. Cases of CFS are associated with high levels of deleted mitochondria DNA, suggesting but not proving that mitochondrial dysfunction can produce the symptoms of CFS (1).

11. Biochemical similarities – depletion of glutamine and cystine pools – have been reported in CFS and several diseases characterized by elevated peroxynitrite levels, suggesting a similar biochemical basis for all of these conditions (1).

12. Because peroxynitrite is a potent oxidant, this theory predicts that oxidative stress will be elevated in CFS. There was no direct evidence for this when the theory was published but three subsequent papers have reported substantial evidence for such oxidative stress in CFS (5-7). These results, may therefore, be considered to confirm important predictions of the theory, although the authors were unaware of this theory when they initiated these studies.

CFS puzzles explained by the elevated nitric oxide/peroxynitrite theory:

There are five different puzzles of CFS that are explained by this theory. The first of these, the chronic nature of CFS, is explained by the self-sustaining vicious cycle that is central to this theory. The second is how infection and other stress which often precede CFS may produce CFS. This theory predicts that each of these can lead into this mechanism by inducing excessive nitric oxide. Infection is not the only stress that may be involved in this way – both physical trauma and severe psychological trauma can produce excessive nitric oxide synthesis (2). In addition, tissue hypoxia may induce this cycle by increasing levels of superoxide (the other precursor of peroxynitrite) (2).

A third puzzle about CFS is how it leads to the many iochemical/physiological correlates reported to occur in CFS. This is discussed with the list of 12 such correlates described above. A fourth puzzle about CFS is how the diverse symptoms of this condition may be generated. It turns out that a variety of factors, including nitric oxide, superoxide, oxidative stress and mitochondrial/energy metabolism dysfunction may have important roles (2). For example, nitric oxide is known to stimulate the nociceptors that initiate the perception of pain, and therefore excessive nitric oxide may cause the multi-organ pain associated with CFS (2). Nitric oxide has a central role in learning and memory and so its elevation may also provide a partial explanation for the cognitive dysfunction characteristic of CFS (2).

Other symptoms explained by this theory include orthostatic intolerance, immune dysfunction, fatigue and post-exertional malaise (2). The immune dysfunction reported in CFS, may allow for opportunistic infections to develop, such as mycoplasma or HHV6 infections, which may exacerbate the basic CFS mechanism by increasing inflammatory cytokine synthesis.

What about multiple chemical sensitivity, posttraumatic stress disorder and fibromylagia?

A fifth puzzle regarding CFS is its variable symptoms and, most importantly, its association with three other conditions of equally puzzling etiology, multiple chemical sensitivity (MCS), posttraumatic stress disorder (PTSD) and fibromylagia (FM). The theory explains the variable symptoms, from one case to another, in part, by a somewhat variable tissue distribution of the elevated nitric oxide/peroxynitrite.

A common etiology (cause) for CFS with MCS, PTSD and FM has been suggested by others (discussed in refs 4,9). A common causal mechanism for these four conditions is suggested not only by the association among these different conditions (many people are afflicted by more than one) but also by the overlapping symptoms typically found in these four conditions (see refs. 4 and 9 for discussion). These overlaps raise the question about whether MCS, FM and PTSD may be caused by excessive nitric oxide and peroxynitrite. Each of these four conditions is reported to be often preceded by and possibly induced by exposure to a relatively short-term stress that can induce excessive nitric oxide synthesis.

Pall and Satterlee (4) present a substantial case for an excessive nitric oxide/peroxynitrite cause for multiple chemical sensitivity (MCS), including the following:

Organic solvents and pesticides whose exposure is reported to precede and presumably induce multiple chemical sensitivity, are also reported to induce excessive nitric oxide synthesis. Such chemicals are also reported to induce increased synthesis of inflammatory cytokines which induce, in turn, the inducible nitric oxide synthase (leading to increased synthesis of nitric oxide).

Neopterin, a marker of induction of the inducible nitric oxide synthase, is reported to be elevated in MCS. Markers of oxidative stress are reported to be elevated in MCS, as predicted if excessive peroxynitrite is involved.

In animal models of MCS, there is convincing evidence for an essential role for both excessive NMDA activity (where such activity is known to induce excessive nitric oxide) and for excessive nitric oxide synthesis itself. If one blocks the excessive nitric oxide synthesis in these animal models, the characteristic biological response is also blocked. This and other evidence shows the nitric oxide has an essential role (4).

Somewhat similar evidence is available suggesting an elevated nitric oxide/peroxynitrite mechanism for both PTSD and FM (9). PTSD is thought to be induced by excessive NMDA stimulation, which, as discussed above, is known to produce excessive nitric oxide and peroxynitrite (9). Two inflammatory cytokines known to induce increased synthesis of nitric oxide have been reported to be elevated in PTSD. PTSD animal model studies have reported an essential role for both excessive NMDA stimulation and nitric oxide synthesis in producing the characteristic biological response.

Interestingly, a recent study of FM implicates elevated nitric oxide and also elevated NMDA stimulation (8), and such NMDA stimulation is known to increase nitric oxide synthesis. As in the other conditions discussed here, there is a pattern of evidence from studies of FM patients, consistent with the proposed nitric oxide/peroxynitrite mechanism (9). The theory that elevated nitric oxide/peroxynitrite is responsible for the etiology of CFS, MCS, PTSD and FM appears to be the only mechanism to be proposed that explains the multiple overlaps among these four conditions. While the pattern of evidence supporting it cannot be considered definitive, the many types of evidence providing support for this view must be considered highly suggestive.

What does this proposed mechanism suggest about CFS treatment? As discussed in ref 1, there are a number of agents that may be useful in the treatment of CFS, based primarily on anecdotal evidence, that are expected to lower the consequences of the proposed nitric oxide/peroxynitrite mechanism. Possibly the most intriguing such mechanism relates to the widespread use of vitamin B12 injections in treatment of CFS (3). Two forms of vitamin B12 are being used here, hydroxocobalamin, which is a nitric oxide scavenger and cyanocobalamin, which is converted to hydroxocobalamin by Pall human cells (3). These observations suggest that the nitric oxide/peroxynitrite proposed mechanism for CFS makes useful predictions for effective treatment. It is hoped that this proposed mechanism may allow us to optimize the use of these and other agents for treatment of CFS and related conditions.

References:
1. Pall ML. Elevated, sustained peroxynitrite levels as the cause of chronic fatigue syndrome. Medical Hypotheses 2000;54:115-125.
2. Pall ML. Elevated peroxynitrite as the cause of chronic fatigue syndrome: Other inducers and mechanisms of symptom generation. Journal of Chronic Fatigue Syndrome, in press.
3. Pall ML. Cobalamin used in chronic fatigue syndrome therapy is a nitric oxide scavenger. Journal of Chronic Fatigue Syndrome, in press.
4. Pall ML, Satterlee JD. Elevated nitric oxide/peroxynitrite mechanism for the common etiology of multiple chemical sensitivity, chronic fatigue syndrome and posttraumatic stress disorder. Annals of the New York Academy of Science, in press.
5. Richards RS, Roberts TK, Mathers MB, Dunstan RH, McGregor NR, Butt HL. Investigation of erythrocyte oxidative damage in rheumatoid arthritis and chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome 2000;6:37-46.
6. Richards RS, Roberts TK, McGregor NR, Dunstan RH, Butt HL. Blood parameters indicative of oxidative stress are associated with symptom expression in chronic fatigue syndrome. Redox Rep 2000;5:35-41.
7. Fulle S, Mecocci P, Fano G, Vecchiet I, Vecchini A, Racciotti D, Cherubini A, Pizzigallo E, Vecchiet L, Senin U, Beal MF. Specific oxidative alterations in vastus lateralis muscle of patients with the diagnosis of chronic fatigue syndrome. Free Radicals in Biology and Medicine 2000;15:1252-1259.
8. Larson AA, Giovengo SL, Russell IJ, Michalek JE. Changes in the concentrations of amino acids in the cerebrospinal fluid that correlate with pain in patients with fibromyalgia: implications for nitric oxide pathways. Pain 2000;87:201-211.
9. Pall ML. Common etiology of posttraumatic stress disorder, fibromyalgia, chronic fatigue syndrome and multiple chemical sensitivity via elevated nitric oxide/peroxynitrite, Medical Hypotheses, in press.
 

triffid113

Day of the Square Peg
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Location
Michigan
So I did a quick search of studies for things that scavenge ONOO. In order to actually PROVE anything it would take a scientific review, which means reading every single study on the subject and coming up with a consistent theory of why any that don't agree, do not...something that I imagine takes a good year and which I doubt anyone here except a certain few (like Rich prolly) has actually done. So this is only for interest and consideration:

Things that a study somewhere has said scavenge ONOO:
melatonin (dose dependent): http://www.sciencedirect.com/science/article/pii/S0024320597000088
ascorbic acid (completely protects) http://www.sciencedirect.com/science/article/pii/S1089860399902069; http://www.sciencedirect.com/science/article/pii/S0041008X99986374
Horseradish peroxidase plus Chlorogenic acid (more on this below): http://www.sciencedirect.com/science/article/pii/S0014579398002981
resveratrol (see above note)
uric acid plus cysteine plus ascorbic acid (note, see Wiki for how to increase uric acid if necessary): http://www.sciencedirect.com/science/article/pii/S0006295205003229
ginkgo (protects brain cells against death by H2O2 (ONOO)) : http://www.sciencedirect.com/science/article/pii/S1043661899906047

Also I ran across some disturbing info, to wit, that: ONOO degrades tyrosine (which will cause thyroid, adrenal, and dopamine problems - and in myself I observe low dopamine being more tied to depression than low serotonin), and also that OOO degrades methionine (dysregulating the methyl cycle). But then we knew that free radicals, of which this is one, will dysregulate the methyl cycle - that is old knowledge. (So it stands to reason that things that quench free radicals will help un-dysregulate the methyl cycle, if, in fact, that is the ONLY way it is nonfunctional, which is not something I would personally assume). methionine: http://www.pnas.org/content/91/23/11173.short, tyrosine: http://www.sciencedirect.com/science/article/pii/S0891584997003213


Inhibition of peroxynitrite destruction of tyrosine (thus to protect thyroid etc): http://www.sciencedirect.com/science/article/pii/S0891584997003213

Peroxynitrite is a cytotoxic species generated by the reaction between superoxide and nitric oxide. In this study the ability of hydroxycinnamate antioxidants to decrease peroxynitrite-mediated nitration of tyrosine was investigated. The results obtained show that all compounds were able to inhibit nitration of tyrosine. The potency of inhibitory activity was in the order; caffeic acid ≥ chlorogenic acid ≥ ferulic acid > p-coumaric acid > o-coumaric acid > m-coumaric acid. Trolox, which was included in the study for comparative purposes, had an activity between that of ferulic acid and p-coumaric acid. The data obtained suggest that hydroxycinnamates can act by one of two possible mechanisms: preferential nitration for monophenolates and electron donation by catecholates.

Here is what Wiki lists as sources of these hydroxycinnamates:

Hydroxycinnamic acids These compounds are hydroxy derivatives of cinnamic acid.
It appears that hydroxycinnamic acids are flavanols? If so, I did not mean to list them as there appear to be studies conflicting on their benefit. Like do they scavange ONOO or just some byproducts of ONOO production... (although this has benefit in cases such as MS): http://www.sciencedirect.com/science/article/pii/S0003986100917211

Also note, this (one of many) study shows that ONOO destructs BH4, but ascorbic acid restores it (not fully): http://www.jbc.org/content/278/25/22546.short
 

August59

Daughters High School Graduation
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Upstate SC, USA
Can anyone explain to me how Metformin can be both beneficial for biogenesis or mitochondria and also considered biotoxic at the same time?

http://www.mitoaction.org/blog/medication-exposures-mitochondrial-toxicity

Ema

Very good question! I take and 50% of the information I read is in favor of it and the other 50% is not. I know the one video that is posted on PR about methylation by the Doctor that post on Seeking Health I think adamantly against taking Metformin, but I didn't hear why?
 

alex3619

Senior Member
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13,810
Location
Logan, Queensland, Australia
Along with Rich van Konyenburg I debated the biochemistry with Marty for years. We haven't done so in maybe four years or even much more though, so I am sure there have been additional developments I am not aware of. All of us were interested in the energy and antioxidant systems. Marty encouraged me to go back to uni to finish my biochem degree.This model is very old now, and has influenced docs like David Bell.

Marty's hypotheses are probably right about much of the pathophysiology. Whether or not its really causal remains unproven. I do know that some have really benefited from Marty's protocols. Some apparently don't though. There are subgroups.

I was aware of most of the claims about resveratrol. I have not investigated them so was unwilling to comment. I don't think I was aware it was claimed to induce mitochondrial replication.

I currently take resveratrol twice a week, not once a week, as it started to wear off at the end of the week. This is titrated to eliminate most of my breathing problems. So that is about 1200mg per week I take, in two doses. I have yet to test lower daily doses.

If I feel breathing issues coming on at any time, I take my next dose immediately.

The interview comment from Marty about CoQ10 and cognitive issues makes me feel like trying even higher doses some time.