Rest periods and can CFS people get really well?

[Kimsie]

I wonder why nicotinamide is a SIRT1 inhibitor, when NAD+ is a SIRT1 activator? Feedback loop? We definitely want SIRT1 activation, not inhibition. But if both forms interconvert, I guess it doesn't matter.

It seems that substances such as resveratrol are dependent on SIRT1 to raise NAD+ and improve mito function. At the same time, SIRT1 is also dependent upon NAD+?

SIRT1 Is Required for AMPK Activation and the Beneficial Effects of Resveratrol on Mitochondrial Function

The study was in vitro, so it really is hard to know how much it applies to in vivo. I suppose that niconiamide inhibits SIRT 1 to avoid draining the NAD pool too much. Maybe the regulation depends on the NAD/nicotinamide ratio.

This study seems to confirm that a lack of NAD+ is bad news for neurons under duress:

Nicotinamide prevents NAD+ depletion and protects neurons against excitotoxicity and cerebral ischemia: NAD+ consumption by SIRT1 may endanger energetically compromised neurons.

Just thinking whether SIRT1 activators would be helpful or not. I guess that still depends on rest, if I understand correctly.

There doesn't seem to be a lot of information on SIRT, so it's hard to know. I think it might be helpful to keep the NAD pool up with the NAD recipe, or at least with niacinamide and D-ribose.

 

[Strawberry]

Anyone who has any coexisting OI issues with this is far better off laying then sitting when resting. The heavy in leg feel could be going along with extra blood pooled within the legs due to OI.

I'm not sure I have OI though? I have high blood pressure, and it seems most OI/POTS have low BP... I could be wrong though.

 

[Kimsie]

I apologize in advance if my knowledge is very poor and I ask rather bad questions. But...

1. The mitochondry membrane is the only one - I read - that countains in its inner part cardiolipin (as 20% of total lipids there), and it was found in a study (*) that 95% of CFS patients have anti-cardiolipin antibodies.

(I belong to the group with elevated IGM anticardiolipin antibodies - and the number increased with the severity of the symptoms from 1998 to now).

2. From wikipedia :
Cardiolipin serves as proton trap for oxidative phosphorylation[edit]
During the oxidative phosphorylation process catalyzed by Complex IV, large quantities of protons are transferred from one side of the membrane to another side causing a large pH change. CL is suggested to function as a proton trap within the mitochondrial membranes, thereby strictly localizing the proton pool and minimizing the changes in pH in the mitochondrial intermembrane space.

This function is due to CL’s unique structure. As stated above, CL can trap a proton within the bicyclic structure while carrying a negative charge. Thus, this bicyclic structure can serve as an electron buffer pool to release or absorb protons to maintain the pH near the membranes.[7]

Other functions[edit]

• Cholesterol translocation from outer to the inner membrane of mitochondrial
• Activates mitochondrial cholesterol side-chain cleavage
• Import protein into mitochondrial matrix
• Anticoagulant function

==> so my question is :
Could this anticardiolipin antibodies - which are present in a lot of CFS/ME patients - impair the way our mitochondries work ?
If yes, what can be done about it?
Perhaps it is another point - beside the rest and the supplementation - that has to be examined in order to make ATP ?

I have no scientific background, so please, forgive me in advance if it is a silly question,
Thanks

(*) Hokama Y, Campora CE, Hara C, Kuribayashi T, Le Huynh D, Yabusaki K. Anticardiolipin antibodies in the sera of patients with diagnosed chronic fatigue syndrome. J Clin Lab Anal. 2009;23(4):210-2.

No need to apologize, this is entirely new to me. I started looking into it and it's almost like trying to read a new foreign language because there are so many words I haven't seen before! It will probably be a day or two before I can give any kind of a response.

 

[Gingergrrl]

@Kimsie I have had trouble keeping up with this thread but have a question for you re: the sulfate/cysteine ratio kit. I looked through all the tests on the Genova website and there is nothing with this name. However, there are many tests which do test for both of those items and one of them is the "Oxidative Stress Analysis" test (for urine or blood.) Is this the kit you are ordering for your sons?

I also got a cursory list of doctors in my area who Genova recommends and am also going to call Genova for additional referrals. I am looking for a local doctor since I no longer see my naturopath and I do not have a PCP (GP.) I was given a recommendation for a functional medicine doctor, who also was on the list from Genova, and thinking about seeing him in the new year.

 

[adreno]

I have several other ideas for mitochondrial antioxidants, namely idebenone, mitoq, methylene blue and c60. Perhaps @Hip can help here, as he seem to have an interest in exotic compounds. First up, idebenone:

Recently, we and others described that certain short-chain quinones are able to bypass a deficiency in complex I by shuttling electrons directly from the cytoplasm to complex III of the mitochondrial respiratory chain to produce ATP.

Features of Idebenone and Related Short-Chain Quinones that Rescue ATP Levels under Conditions of Impaired Mitochondrial Complex I

The biochemistry is a bit beyond me, but would this bypassing help us? Isn't impaired mitochondrial complexes the main issue?

 

[Hanna]

Was idebenone the sort of CoQ10 that Dr Cheney was recommending ?

 

[Hanna]

@Kimsie thanks for looking at this, as it is far beyond my understanding, and perhaps, this cardiolipin thing may be one more piece of the puzzle.

 

[Mij]

Was idebenone the sort of CoQ10 that Dr Cheney was recommending ?

http://www.dfwcfids.org/medical/cheney/hrt04lng.htm

I found this in my files:

CoQ10 within the mitochondria and Lipoic Acid in the cytoplasm bind excess superoxide so it's unavailable to couple with nitric oxide to produce peroxynitrite. Taking sufficient CoQ10 under certain redox state conditions, would allow you to make more energy and not get creamed with peroxynitrite. [Redox will be discussed in another article.] But, if you keep raising CoQ10 in an inappropriate redox state you may actually generate more superoxide, and that's when the CoQ10 bites you. [Some patients who cannot tolerate CoQ10 find that its analogue, Idebenone, works better.]

 

[adreno]

I'm not sure I have OI though?

You are not sure whether you have OI? You'd know it if you had it, believe me.

 

[Kimsie]

@Kimsie I have had trouble keeping up with this thread but have a question for you re: the sulfate/cysteine ratio kit. I looked through all the tests on the Genova website and there is nothing with this name. However, there are many tests which do test for both of those items and one of them is the "Oxidative Stress Analysis" test (for urine or blood.) Is this the kit you are ordering for your sons?

I also got a cursory list of doctors in my area who Genova recommends and am also going to call Genova for additional referrals. I am looking for a local doctor since I no longer see my naturopath and I do not have a PCP (GP.) I was given a recommendation for a functional medicine doctor, who also was on the list from Genova, and thinking about seeing him in the new year.

Here is a link to the sample for the test. It is the oxidative stress blood test, not the urine test. It has some other helpful information on it, too, such as lipid peroxides.

 

[Kimsie]

1. The mitochondry membrane is the only one - I read - that countains in its inner part cardiolipin (as 20% of total lipids there), and it was found in a study (*) that 95% of CFS patients have anti-cardiolipin antibodies.
.

I have found that these anti-cardiolipin antibodies have been found in other illnesses that I believe are caused by this mitochondrial dysfunction - schizophrenia, Alzheimer's, depression, RA, etc., but at lesser rates than that CFS study. My take on this is that in CFS the severity of the symptoms correlates more directly with the amount of damage to the ETC, where in the other illnesses the severity of the symptoms relates to other factors.

The fact that people with these illnesses may or may not have these antibodies makes me think that the antibodies are a response to high levels of damaged cardiolipin and not the cause of it.

It looks to me like the cardiolipins are responsible for several things relating to the function of the ETC, including passing the protons either to the complexes and supercomplexes, and supporting the structure of the supercomplexes. (They appear to be involved in many other functions, too)

Because of their position in and next to the complexes they would be inevitably damaged by superoxide even in a healthy person, so there must be a mechanism for their constant repair (this part in bold is my own idea, I haven't found any study about this yet). They are known to be damaged by ROS.

My take on all this is that these antibodies are a response to the high levels of cardiolipin damaged by ROS, and that the damaged cardiolipin probably contribute to the problems, but is not the underlying cause. I expect that as ROS levels decline, the damage to cardiolipins will also decline and so will the antibodies.

So this aspect needs the same treatments as the other aspects - rest periods, antioxidants, etc.

Linoleic acid is critical to cardiolipin synthesis, but the vast majority of the linoleic acid that people eat is from processed foods where the linoleic acid is probably damaged already and I wonder if this does not contribute to these problems. I repeat what I have said earlier - vegetable oils are highly processed, dangerous substances. Stick to raw nuts, milk and meat that is naturally grown and not over cooked at high temperatures. Sunflower seeds are a good source but only the raw should be eaten.

That's all I have at this point.

 

[Kimsie]

I have several other ideas for mitochondrial antioxidants, namely idebenone, mitoq, methylene blue and c60. Perhaps @Hip can help here, as he seem to have an interest in exotic compounds. First up, idebenone:


Features of Idebenone and Related Short-Chain Quinones that Rescue ATP Levels under Conditions of Impaired Mitochondrial Complex I

The biochemistry is a bit beyond me, but would this bypassing help us? Isn't impaired mitochondrial complexes the main issue?

Well, first of all, the purpose of the electron transport chain is to pass protons into the intermembrane space, not to change O2 into H2O. The O2 to H2O part is to get rid of the electron that is left after most of the energy is used up in the rest of the chain. Bypassing complex I and III (as one study says methylene blue does) would decrease ROS, but how much energy would be produced (i.e. protons passed)? and how would the excessive amounts of energy be dealt with when the electrons go straight to complex IV without having their energy level reduced first? Bypassing complex I is OK because that is what complex II already does, but I am not sure about bypassing complex III.

I have a feeling that methylene blue has multiple effects, and it may not really be passing electrons to complex IV as the people who did that study said it did. In another place it was said that it dis-inhibits complex IV, which would probably be good. Another site said that it bypasses only I and II. Pretty confusing. Besides that, one study showed that it can increase H2O2 in the mitochondria, which is the opposite of what we want.

The MitoQ looks interesting, except I would like to see some results in a clinical trial. I don't think the mouse model trials really tell us anything helpful.

Supposedly the MitoQ can take electrons from Complex II and pass them to ROS to neutralize them, but it if was able to do that in vivo then it should have had a positive effect on Parkinson's disease, but it didn't have any effect on it at all. However, one possibility is that it was given in too large of an amount in the studies because it has a small window between the antioxidant and pro-oxidant effects and perhaps it is only a pro-oxidant in very small doses and the pro-oxidant effects overcame the anti-oxidant effects.

Has anyone seen what the doses they used in the trials were?

As I understand it, CoQ10 can normally only give electrons to Complex III. Apparently these CoQ analogs can give electrons to ROS. (Or create ROS if they don't find a desired substrate quickly enough.)

That's all I have so far.

 

[adreno]

@Kimsie, you may find this blog highly interesting:

NAD+ an emerging framework for health and life extension — Part 1: The NAD World

NAD+ an emerging framework for life health and life extension — Part 2: Deeper into the NAD World, hopeful interventions

This topic is immensely complicated, but is seems the author is of the opinion that nicotinamide riboside (NR) is more effective at raising NAD+ than regular niacinamide.

 

[adreno]

It seems nicotinamide (Nam) can follow two pathways, where only one is conducive to NAD+ synthesis. Either it's converted by Nam PRTase to NMN (and later NAD+), or it's cleared by methyl groups to N-methylnicotinamide. Apparently it can also accumulate and inhibit sirtuins. So it would seem there are advantages to NR (although some of it can be cleaved to Nam). With NR, it seems we wouldn't have to worry about folate (methyl groups) inhibiting the NMN pathway, or accumulation and SIRT inhibition. We also wouldn't need ribose, if I understand correctly.

Because phosphorolysis of NR to a Nam product would compete with phosphorylation of NR to an NMN product, phosphorolysis also has the potential to be destructive to NAD+ signaling. This is the case because Nam produced by phosphorolysis can be either converted to NMN by action of Nam PRTase or cleared by methylation to N-methylnicotinamide; it can also accumulate and potentially inhibit Sirtuins and PARPs. One would expect that production of Nam and then conversion to NMN ( Revollo et al., 2004) would be constructive to NAD+ signaling, whereas conversion to N-methylnicotinamide or accumulation of Nam would inhibit NAD+ signaling. Thus, there may be conditions in which application of a Pnp inhibitor (Lewandowicz et al., 2003) with NR may improve the metabolic efficacy of NR by shunting the precursor into the Nrk pathway.

http://www.sciencedirect.com/science/article/pii/S009286740700390X

 

[taniaaust1]

You are not sure whether you have OI? You'd know it if you had it, believe me.

You'd be surprised just how many do have OI but havent realised it yet eg they may blame other things for the symptoms.

 

[taniaaust1]

I'm not sure I have OI though? I have high blood pressure, and it seems most OI/POTS have low BP... I could be wrong though.

Having high blood pressure doesnt rule OI or POTS out at all as there are different types of it, including one type which can put BP up. So dont rule out that possibility due to your BP.

I had high BP consistantly there for almost a year due to "something" the ME was doing .. (originally I'd had very low BP all my life and in my early ME years eg 80/60). Nowdays I have severely swinging BP due to the type of POTS I have which spikes my BP up when Im upright. I swing between 60/40 to 197/136 . I never know what my BP will do when I stand, it can be up that high in 1min of standing thou but has been seen to ditch too at standing.

 

[sueami]

@Kimsie, a quick question for you. DH picked up some Niacinamide for me (I already had D ribose) and I'd like to start trying to support NADH or whichever compound those support.

All I know about niacin is that it is used to quench overmethylation by sopping up methyl groups.

How do I take it in a way that won't hamper my ongoing (and pricey) methylation support, which I feel has benefited me enormously to date?

I take about 3 g mfolate a day, divided, and I have a 1 mg subq mb12 shot I take (though I've just finished a bottle and could delay starting the next) and some b12 transdermal oils (mb12 and a mb12/adb12 blend) I take that provide another 1-2g b12 absorbed, plus an 8.6 g dibencozide sublingual I take every other day or so.

 

[Kimsie]

@Kimsie, a quick question for you. DH picked up some Niacinamide for me (I already had D ribose) and I'd like to start trying to support NADH or whichever compound those support.

All I know about niacin is that it is used to quench overmethylation by sopping up methyl groups.

How do I take it in a way that won't hamper my ongoing (and pricey) methylation support, which I feel has benefited me enormously to date?

I take about 3 g mfolate a day, divided, and I have a 1 mg subq mb12 shot I take (though I've just finished a bottle and could delay starting the next) and some b12 transdermal oils (mb12 and a mb12/adb12 blend) I take that provide another 1-2g b12 absorbed, plus an 8.6 g dibencozide sublingual I take every other day or so.

I really don't think that taking 250-500 mg of niacinamide a couple times a day is going to mess up your methylation, but you will just have to see how it makes you feel. If you feel worse, then cut back. It looks to me as if you are taking plenty of B12 and folate for methylation purposes.

I think that sometimes what is referred to as overmethylation is actually just the effects of not having enough niacin because with these illnesses I think the body wants to, and needs to increase the NAD/NADH and NADP/NADPH pools.

If the niacinamide and ribose make you feel better the temptation will be to increase your activity as much as you can, but I think it would be better to keep your total activity time the same for a couple of weeks before increasing at all.

 

[Gondwanaland]

I seem to feel worse on niacinamide. I think it's because it slows down Phase I. I feel better on niacin.

 

[adreno]

I feel worse if I go over 250mg niacinamide per day, and I find that my need for folate increases dramatically. So in my experience, it can definitely interfere with methylation.