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Oxidative Stress and Mitochondrial Injury in Chronic Multisymptom Conditions

Discussion in 'Other Health News and Research' started by Marco, Feb 4, 2012.

  1. Marco

    Marco Old blackguard

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    This is a very interesting paper which I would urge everyone to read.

    Currently it appears on Nature Precedings as a pre-publication manuscript (to stimulate discussion etc). I can only hope it is subsequently published.

    While written from the perspective of Gulf War Illness, she proposes similar physiological processes underlying a range of 'overlap' illnesses with non-specific and protean symptoms including ME/CFS.

    Predisposition to oxidative stress, stressor triggers, inflammation/oxidative stress, mitochondrial dysfunction etc will be very familiar I'm sure.


    http://precedings.nature.com/documents/6847/version/1/files/npre20126847-1.pdf

    While this may at first sight appear to be a slightly controversial 'think piece', Beatrice Golomb is a very experienced researcher and 'mainstream' as evidenced by her CV :

    http://cnl.salk.edu/~bgolomb/

    It would be great to get her 'onboard' with ME/CFS research.
  2. justy

    justy Senior Member

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    Hi Marco, there is another thread on this, sorry i dont know how to do the link thingy - its a great piece though and has moved my understanding forwards a lot - especially as i have had the mito profile test which shows all these abnormalities
  3. justy

    justy Senior Member

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  4. Marco

    Marco Old blackguard

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    Thanks Justy.

    I admit I was surprised it hadn't been picked up so apologies for missing it.
  5. Marco

    Marco Old blackguard

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    Just to bump this.

    I think this is of more general interest than might be implied by a thread under detox/methylation etc.
  6. justy

    justy Senior Member

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    Hi Marco, im surprised that no one seems interested in this as well. It really is worth a read and i would love to hear what others think about it. I for one was surprised at how closely the mito dysfunction in GWI realted to my (M.E) mito dysfunction as shown on tests doen at Acumen - I don't understand why this isnt being morte closely researched and investigated - these are clear abnormalities that are showing up AND explain many of the symptoms of these illnesses. I wonder if people have tried to make ties with GWIV in the US and U.K - do you know if anyone has tried this - would the reasearch be taken more seriously if GW vets were lobbying for it (i suppose thats naive of me, as they must allready be doing this - but i wonder iof we should join forces a bit more)
    Hmm, Justy.
  7. mellster

    mellster Marco

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    I agree, good info - mito dysfunction as one of the root issues/causes could also explain the wide range of severity of CFS/ME/FM, from very mild to very severe vs a solely infecting agent or clear genetic disorder which would - eventually - likely bring most patients very close to the same level. I started taking PQQ a while ago which seems to be the new hot item for mito repair. cheers
  8. Marco

    Marco Old blackguard

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    Hi Justy

    If you scan Beatrice Golomb's CV you will see that her primary focus is on GWI

    But this extends to other conditions with overlap symptoms and other conditions with elevated 'co-morbidity' in Gulf War Illness such as CFS, fibro, MCS and ALS.

    You can see this from a quick glance at the range of research presented annually to Congress by the Department of Veterans Affairs (and they have a UK Liaison - so its not as if the UK authorities are unaware of these overlaps) :

    http://www.research.va.gov/resources/pubs/docs/GulfWarRpt07.pdf

    I would imagine that at least some ME/CFS researchers also keep a close eye on related fields.

    What I don't know is the extent (if any) of primarily 'CFS' research that might be federally funded in relation to GWI.
  9. Marco

    Marco Old blackguard

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    Hi mellster.

    It certainly covers all the bases (various triggers, various onset patterns, individual and changing symptoms) and ties in well with the 'multi-hit' hypothesis.

    It also unfortunately suggests that, without appropriate intervention (whatever that might be), it is likely to be a progressively deteriorating condition which has certainly been my experience.
  10. Marco

    Marco Old blackguard

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    Good catch mellster.

    Exercise in a pill :

    http://www.anti-agingfirewalls.com/...gc-1alpha-sirt3-and-mitochondrial-biogenesis/

    It will be interesting to hear how you get on with pqq. One difficulty is that many of us have been taking various mito support compounds for many years (I remember reading up on CoQ10 and trying it twenty plus years ago) with no 'cure' obviously. Its difficult to know at what point you need to intervene. Do you support mito function with substrate compounds (which ones, all of them?) or at the PPAR signalling end as per pqq, or will preventing oxidative stress via antioxidants prevent mito dysfunction?

    Unfortunately we patients can't really trial these things systematically.
  11. Abha

    Abha Abha

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    Hi everybody,
    Mito dysfunction is a major problem in my case too(like Justy).Acumen Lab tests(Dr Myhill) have shown that.Professor Behan(Glasgow)now retired spoke about this in the recent Alba Tv programme(see other threads here).Professor Behan did a lot of research work on this from 1985 till about 2000+(?)Dr Chas Shepherd (ME advisor)was one of Prof Behan's patients then.
    Mellester, like Marco, I'll be very interested to see how you get on with PQQ.Where do you purchase it?
  12. justy

    justy Senior Member

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    Hi, a few questions - what is PQQ? and what effect if any did the coq10 have for you Marco- i am taking it but cant tolerate a high enough dose, i know i am deficient from my tests.

    You raise the question Marco of how to address these issues and wether it can be curative. I agree with you that it seems to be a degenaritive situation, especially as it seems that the MD can then affect gene expression, causing further MD in another way. Eg for me i now have my Gene for Mn SoDase partially blocked - which is causing massive problems with antioxidant status - evn if i take them. For me giving antioxidant cover with injected B12 has really helped a lot with functioning i imagine by reducing oxidative stress? this si the type of intervention you talk about above i suppose, without the antioxidants, everything i do seems to cause more damage in my body. but what will happen once i stop them? or will i have to do it forever?

    I know Dr Myhills approach is to throw everything at the mitos - antioxidants by the bucketload as well as Things like D Ribose and Acetyl l carnitine, as well as placing importance on rest to allow recovery. Then when some progress is made she advocates the right sort of exercise (strength training essentailly rather than stamina or long distance) which helps to actually promote the growth of ATP. My main problem is that i can make ATP but im not recycling it properly and i have partially blocked genes and problems with the mito membranes (energy transport system)

    What about remmission? i improved to about 70=80% functioning for nearly10 years. but then lost it again after a nasty virus - how does that tie in? it really is very complex. Do you think all PWME have mito dysfunction or do you think it is a subset thing?
    Why do you suppose that M.E is not being treated as an acquired mitochondrial disorder? after all they are now known to exist. I actually showed my mito results to my GP in the hope that he would prescribe co q10 (it is prescribable in the uk) but he refused saying that it wasnt indicated for CFS (despite my results in front of him) and that the tests i had had were purely experimental and finally that he didnt understand it. That shouldnt be too hard, after all he has done 7 years of medicl school and i only did science until i was 13 and then gave it up for a life of humanities.

    Of course there are researchers in the UK looking inot both CFS and GWI - unfortunately its Professor wessley! i imagine hes hoping to save the uk govt a bundle by lumping them in with other somatoform disorders such as M.E.
    Sorry for the garbled post, it sort of comes out on the page as it does in my mind and i dont have the energy to make it more coherent.
    Justy.
  13. Marco

    Marco Old blackguard

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    Mellster might be able to give you more details on PQQ Justy. Its new to me but appears to be a natural compound that can boost the genetic signalling mechanisms that boost mito function and stimulate the production of new mitochondria - as exercise does if only we could do it.

    As for CoQ10, at the time it only one of many therapies touted for ME/CFS and back then 'fatigue' wasn't the biggest problem for me. Plus I have a low tolerance for the placebo effect. So I probably tried it for a week or so, found little difference and moved onto something else. Nowadays I find a consistent positive effect from taking acetylcysteine but I only take it occasionally as a 'rescue' remedy for PEM and heat intolerance.

    What Dr Golomb seems to be suggesting is that certain individuals are predisposed to develop a range of illlnesses due to having a comparatively weak or inefficient antioxidant system or perhaps are depleted of antioxidants. Perhaps these vulnerable individuals use up their antioxidant capacity at a faster rate? Once depleted then there is the likelihood of increased damage and depletion in response to ongoing stressors. Whether of not you can restore and maintain antioxidant capacity and regain health or whether the damage that is already done can't be repaired is the big question. Some animal studies I've come across suggest that some degree of restoration is possible.

    I'm not familiar with Dr MyHill's protocol but it sounds sensible to rest and restore capacity before attempting any activities that increase oxidative stress, although longer term, exercise, if tolerated, can induce improved mito function even in those with genetic mitochondrial diseases. Perhaps Rich can answer on the APT recycling?

    My take on it is, as above, that antioxidant capacity and mito function varies as an individual difference with a proportion of the population at risk of developing a range of conditions depending on genetic predisposition, environment, external stressors of any type inclusing viruses. Didn't the Dubbo study conclude that only a proportion of those exposed to (West Nile?) virus went on to develop PVFS, ME/CFS? Anything that creates additional oxidative stress poses a risk of relapse and potentially avoiding stressors might allow some regaining of capacity and remission.

    So I think this proposed mechanism could easily explain all cases of ME/CFS and could also account for the much maligned 'TATTs' who may be in a state of teetering on the edge of developing full blown ME/CFS or another condition. I also personally think that this mechanism can also account for a much wider range of illlnesses that those overlap conditions reviewed by Dr Golomb.

    Where to start? Your GP's reaction is hardly surprising given that most GPs merely provide a triage service and the 'experts' are hardly convinced of the 'evidence base' even for a physiological cause of ME/CFS. I"m also not surprised that a GP might be unwilling to step outside NICE guidelines.

    Its been quite a while since I read any of the UK GWI research but given that I haven't seen any reports of 'X causes GWI' then I would assume that the various pathogens/toxins/other risk factors were examined and not found to have a direct association with GWI. In other words, not all those exposed to X developed GWI and not all of those who developed GWI were exposed to X.

    Of course Dr Golomb's explanation is that the exact X doesn't matter. There are a range of 'stressors' that can cause oxidative stress/mito dysfunction and thus cause GWI (or ME/CFS) in those with a predisposing vulnerability.


    Not at all Justy. All very pertinent questions that I wish we had answers to.
  14. mellster

    mellster Marco

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    Honestly I am fairly new to the mito dysfunction field, but I do use antioxidants (as part of my food and as supplements such as green tea, asthaxanthin and others) besides the PQQ daily. My recovery from my worst point (being a 5-6) last April is now more than 10 months in and I can work out almost as vigorously as before (I give myself an 8.5 now) - however I deplete faster than I used to, which has been always a problem for me, but it worsened when I got FM/IBS in 2009 after the viral trigger and then the CFS/PVFS crash in April. It means that I hit patches of fatigue and exhaustion and foggy/heavy head - luckily towards the end of the day but sometimes intermittently - esp. after exercise and I need to go to bed between 9 and 10 pm to catch 8-9 hours of sleep at the minimum. I hope the PQQ (which I take at night to not add to any stress) does at least half of what it promises and I am constantly researching what else can be done. I believe I could close to completely recover if I were by myself and had the luxury to dynamically reduce my daily stress and exertion to my needs but I do have to support a family and the daily stress makes a complete recovery almost impossible. I agree with the difficulty to know what to take and when, but I hope if we could start a supplements/drugs thread tailored specifically to mito dysfunction this might be a good start. I also just started the KMAF drops and will see where this will take me. We are left to experiment with ourselves as I do think as well that inaction with this is worse than careful trial and error. cheers
  15. justy

    justy Senior Member

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    Lots to think about in your posts above. I'm going to check out your link tomorrow Melster - thanks!
    I think a thread on recovery from mito dysfunction would be a good idea!
    Justy - brain tired now.
  16. Dreambirdie

    Dreambirdie work in progress

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    Hey Mellster--

    How much of the PQQ do you take... what dose, and how often? And did you notice any strange effects from it, especially initially?

    Upon trying out some of the strong anti-oxidants, like astaxanthin (and another one that was for mitochondrial support... that I can't remember right now), I became very revved up. I had to stop because of this. Some of these come in gel caps, so it's very hard to take 1/4 or 1/2 of the capsule.
  17. mellster

    mellster Marco

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    Hi Dreambirdie - currently I don't take strong anti-oxidants either but it's just laziness as I take quite a few supplements and some are more important. Regarding the PQQ, I am still on my first bottle from Life Extension and I take one cap (= daily suggested dosage) at night if I can remember, which has 10 mg in it. I haven't noticed anything so far, no side effects and no direct energy effects, but I am in good shape exercise-wise now. However since this is my first jar I don't know whether the PQQ helped that but I am hoping it will have a long term effect and aid in general endurance (by repairing and creating new mitochondria) and exercise recovery and which is still quite more sluggish (fatigue and occasionally very mild PEM which goes away if I get a good nights sleep) for me than before I got sick. I also just started the KMAF, so lots of new variables, did 12 vials of blood work today, let's see what comes out.. cheers
  18. Legolas

    Legolas

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  19. justy

    justy Senior Member

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    Thanks for the link to the book, i've just read some of the pages, what he is saying is EXACTLY the same as what Dr Myhill says. You can download her e book for free from here

    http://drmyhill.co.uk/wiki/CFS_-_CFS_Book_published_by_Dr_Sarah_Myhill

    She covers all the same ground to do with how the mitochondrial damage may have occured - toxins, viruses etc and how to adress them, it really is a remarkably similar book.
  20. richvank

    richvank Senior Member

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    Hi, all.

    For what it's worth, I still believe that the mito dysfunction in ME/CFS is caused by the vicious circle mechanism that involves glutathione depletion, in turn caused by various stressors (many involving oxidative stress, but others conjugating glutathione or interfering with its synthesis), a B12 functional deficiency caused by the glutathione depletion, a partial block in the methylation cycle caused by the B12 functional deficiency, and folate loss caused by the "methyl trap" mechanism due to the partial methylation cycle block, combined with reaction with peroxynitrite that has been allowed to rise because of the glutathione depletion.

    This combination causes a number of problems for the mitochondria, which produces their dysfunction. These include the following:
    1. Inhibition of enzymes in the Krebs cycle and the respiratory chain by the oxidative stress and the glutathione depletion.
    2. Buildup of toxins due to the glutathione depletion, which block enzymes and produce adducts on DNA.
    3. Deficiency of adenosyl B12 because of the functional B12 deficiency, which inhibits feeding of several substances which are normally fuel for the mitochondria.
    4. Depletion of coenzyme Q-10, carnitine, phosphatidylcholine, and creatine because of the methylation deficit, interfering with mito function in several ways.
    5. Damage to the phospholipid membranes of the mitochondria by the oxidative stress, when glutathione is depleted.

    Because of this, it is my view that it will not be possible to restore the mitochondria to normal operation in ME/CFS unless the partial methylation cycle block is lifted, which will break the vicious circle mechanism and allow glutathione to come back up.

    Best regards,

    Rich

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