Mitochondria (including Naviaux): what are the implications for resting schedules?

Sasha

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"Aggressive resting therapy" has a long history in ME/CFS and some people have done well on it - others, not so much.

Until now, the rationale for how much you rest and when hasn't been based on the details of our biology (AFAIK).

Is there now a chance to do that?

In the light of the Naviaux findings, I was interested to read the posts below, from an old thread that resurfaced in the past few days. In the first post, @Kimsie proposed these ideas about mitochondria and what schedule we should therefore use when we rest:

Kimsie said:
The majority of energy in the body is produced by oxidative phosphorylation, which is when the electron transport chain takes electrons and uses the energy it gets from the electrons to move protons into the intermembrane space of the mitochondria, and the ATP synthase enzyme uses the energy to release ATP. This energy of the protons in the intermembrane space can be referred to as the proton motive force. This proton motive force is also used to make NADPH through the NNT enzyme.

I show the protons as dollar signs instead of H+ after they move into the intermembrane space because I think of them like money in the bank that you can spend for healing or for activity. (and I am from the USA)

The electron transport chain (ETC) is inhibited because it is full of iron-sulfur clusters, and iron-sulfur clusters are damaged by ROS, or reactive oxygen species, which include nitric oxide (NO) and hydrogen peroxide (H2O2) among others, i.e. oxidative stress. This is why you can't make enough ATP to have a normal life - the ETC is inhibited.

The ETC also produces ROS; this is normal. A healthy person can create enough proton motive force to make ATP andenough NADPH to get rid of the ROS, but a person with CFS can't. There are other pathways to make NADPH in the mitochondria, but NNT is the major one and probably normally produces about 50% of the NADPH.

So we have to keep ROS levels as low as possible to allow the body to produce ETC complexes (those are the ETC enzymes) with fewer damaged iron-sulfur clusters. Every minute of consecutive activity the ROS levels are increasing, and the rest breaks give the body a chance to lower the ROS levels. Long periods of consecutive activity will spike the ROS levels to a more damaging high.

Of course this diagram is probably exaggerated, but you get the idea.

It takes a little over 2 weeks to replace most of the ETC clusters, so every 2 weeks we want to see an improvement in the function of the ETC clusters, and that means the electron transport chain will work a little better every two weeks, as long as the person does not increase activity levels which will draw the extra energy into ATP instead of NADPH!

How does NADPH get rid of ROS? NADPH is used to recycle GSSH back to GSH, or glutathione. So this is what is causing those low GSH/GSSH ratios. And the ratio you get when you are tested is the whole cell, not just the mitochondria, so you can be sure that your GSH/GSSH ratio in your mitochondria are worse than what the tests show.

This problem with glutathione is also why detox becomes such an issue.

So activity uses up the energy that could be used to fix the electron transport chain. By having frequent rests to allow the body to produce NADPH and lower ROS levels, the function of the ETC should improve over time, as long as the person doesn't use the extra energy for activity.

Total bed rest is unhealthy, so some activity is needed. If a person has a large enough window of activity, they can decrease their activity time somewhat to speed up recovery. A 6 hour activity day could be decreased to 4 hours spread out over the whole day in little increments. If a person is at 3 hours or less, they should probably not decrease their activity, but just try to keep the activity periods very short as much as possible.

There are other things that can be done to increase energy production such as supplements, which I talk about in other posts. The supplements will do no permanent good if the rest periods are not taken seriously.
A useful summary here from Hip:

Hip said:
The hypothesis you are presenting appears to be the following (please correct if wrong):

You are pointing out that the energy produced in mitochondria can either be used to make ATP, the universal energy molecule, or to make the pro-antioxidant NADPH. NADPH is important to make because it protects certain delicate mitochondrial machinery (the iron-sulfur proteins) from being damaged by hydrogen peroxide.

Hydrogen peroxide is always being produced as a by-product of mitochondrial function: operating mitochondria generate the potent ROS superoxide, and this superoxide is then converted into the less potent ROS hydrogen peroxide by the enzyme SOD2 within the mitochondria. But if this hydrogen peroxide is not itself neutralized, it will cause damage.

NADPH facilitates the neutralization of hydrogen peroxide by ensuring that there is plenty of glutathione available in the mitochondria; it is glutathione which actually performs the job of neutralizing hydrogen peroxide. NADPH ensures glutathione is available by constantly regenerating the "spent" glutathione back into "fresh" glutathione again, ready to neutralize more hydrogen peroxide. Glutathione gets "spent" when it neutralizes hydrogen peroxide, being converted into glutathione persulfide (GSSH) during this neutralization process; but NADPH converts this "spent" glutathione, ie the GSSH, back into "fresh" glutathione.

You are hypothesizing that when ME/CFS patients engage in too much activity, most of the energy produced in the mitochondria is directed towards making ATP, in order to provide the energy needs of the body and brain; but this manufacture of ATP is done at the expense of NADPH manufacturing, which means that there will not be enough NADPH around to protect against the damage that hydrogen peroxide can inflict on the delicate iron-sulfur proteins found in the electron transport chain of the mitochondria.

This lack of NADPH then leads to further damage of the mitochondrial iron-sulfur proteins, resulting in even lower mitochondrial energy output, resulting in even less energy being spare to make the protective NADPH, and this is the basis of your proposed vicious circle of mitochondrial damage.

You are suggesting that if the ME/CFS patient only engages in short periods of energy expenditure, punctuated by periods of rest, then this will ensure that the levels of hydrogen peroxide will not rise too high, and will also allow breathing space for the mitochondria to direct their energy output to make the all-important protective NADPH.

I have to admit that on re-reading this thread, this hypothesis is intriguing. I guess a lot hinges on whether the damage inflicted by hydrogen peroxide on the iron-sulfur proteins in the mitochondria does actually lead to reduced mitochondrial energy output, as this is the basis of the vicious circle. And as with any mitochondrial theory of ME/CFS, it depends on whether reduced mitochondrial output and increased ROS can be shown to give rise to the symptoms observed in ME/CFS.

Incidentally, there is a theory by Dave Whitlock not dissimilar to yours, which hypothesizes ME/CFS is caused by lownumbers of mitochondria. The average mitochondrion has a lifespan of around 1 month, after which it must be replaced. Whitlock thinks that in ME/CFS not enough new mitochondria are being made to replace the old ones. So ME/CFS patients are running on old, worn out mitochondria, which become leaky, thereby producing more reactive oxygen species and less energy output. More info here.
Note that Kimsie suggests not just "loads of rest" but keeping periods of activity very short (this is key), and alternating with periods of complete rest (not just reclining watching TV, etc.), with timings based on what might be the underlying biology.

Wondering what people think of this, especially in the light of the Naviaux findings.

What would be the ideal rest/activity schedule? It's really tough to do 15 mins on / 15 mins off (I've done it today and I feel stunned, groggy and weakened).

How soon should one see effects, if this is true?

If you manage to stick to a good schedule (whatever that is) but then blow your budget one day, are you back to square one?

Lots of questions.

Please don't take this thread off-topic by discussing supplements or the impossibility of following this programme if you're too sick. Please start other threads for those topics - I'd like this thread to stick to REST ONLY. :)
 

Mij

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"So activity uses up the energy that could be used to fix the electron transport chain. By having frequent rests to allow the body to produce NADPH and lower ROS levels, the function of the ETC should improve over time, as long as the person doesn't use the extra energy for activity."

So basically investing that "extra" energy from resting to reinvest long term to create more energy?

I don't understand this:

"It takes a little over 2 weeks to replace most of the ETC clusters, so every 2 weeks we want to see an improvement in the function of the ETC clusters, and that means the electron transport chain will work a little better every two weeks, as long as the person does not increase activity levels which will draw the extra energy into ATP instead of NADPH!"

How do we know that it takes a little over 2 weeks? Are we supposed to feel this difference? I've done this and I still feel as though my "energy bank" remains the same.
 

ahmo

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I think I've been really influenced by these posts from Kimsie. I'm no longer pushing myself. (And I've also had no emergencies which have forced me to push.) And I've had no crashes for at least 2 years. Mind, I don't do much. I'm pretty self-sufficient, take care of my own shopping weekly.

But I've also stopped pushing to increase my exercise, much as I'd like to. OTOH, I feel like there's an immediate benefit to the minimal resistance exercises I do. OTOH, I don't seem to be able to repeat my few repetitions of arm, leg, abd exercises for many days. And if there's anything else going on, either mental effort, emotional upset, or physical demands, no way I can exercise.

My exercise tolerance does not seem to be improving. But I'm also not deteriorating, as far as I can tell. I'm unclear whether my most pressing symptoms are from oxidative stress or POTS-lite: light-headed, shortness of breath, generalized feeling of yuk. Antioxidants help somewhat, but I'm not really able to keep these symptoms at bay.
 

Sasha

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I've done this and I still feel as though my "energy bank" remains the same.
When you say "I've done this", what exactly did you do?

I think I've been really influenced by these posts from Kimsie. I'm no longer pushing myself.
But what Kimsie was talking about goes a long way beyond not pushing yourself. Did you do what she suggested?
 

Mij

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I enjoy power walking when I'm rested and able because I don't use up mental energy or use my arms and can be outdoors. I know from experimenting that I can walk for an hour or a little less and not experience delayed PEM the next day. I'm using this as my guide line.

If only I can see what is going on in my cells :D then maybe, just maybe I would do the 15 min on and then off.
 

Mij

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When you say "I've done this", what exactly did you do?
I've tried shorter activities and rested for shorter periods of time, not exactly 15 minutes but something similar to that and overall I'm not sure if it makes any difference. Am I supposed to bank up more energy over time? I don't force myself to do more, I'm done with that.
 

ahmo

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"But what Kimsie was talking about goes a long way beyond not pushing yourself. Did you do what she suggested?
I wasn't as rigorous as suggested. Just far more mindful to rest after activity. Recently I was feeling great, but found tht instead of an hour of mild activities, which I'd expect, I was feeling poorly after 1/2 hour. Instead of pushing through, I lay down. That's the way I've implemented the resting. I'm not timing it minute for minute.
 

Sasha

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I've tried shorter activities and rested for shorter periods of time, not exactly 15 minutes but something similar to that and overall I'm not sure if it makes any difference. Am I supposed to bank up more energy over time? I don't force myself to do more, I'm done with that.
How many days in a row would you say you did 15 mins (ish) stretches of activity, alternating with rest?

Yes, the idea is that by not letting ROS get so high, your mitochondria can use the stuff it would otherwise use to repair ROS damage to heal themselves, so you'd get increasingly more efficient mitochondria and hence more energy.
 

Sasha

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I wasn't as rigorous as suggested. Just far more mindful to rest after activity. Recently I was feeling great, but found tht instead of an hour of mild activities, which I'd expect, I was feeling poorly after 1/2 hour. Instead of pushing through, I lay down. That's the way I've implemented the resting. I'm not timing it minute for minute.
So I think it's fair to say that you haven't done what Kimsie was suggesting. That's not a criticism - it's just important that we know whether any of us has tried that pretty strict set of rules and, if they have, what the results were.
 

Mij

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@Sasha I don't do these types of activities days in a row, I give myself at least 3 days of rest in between, otherwise I feel terrible and can't cook for myself etc. I spread it out, and it depends on how I'm feeling too.
 

GlassHouse

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I'm not sure what is considered rest. Is it laying down in a dark room with no sound or is it anything that's under a person's anaerobic threshold (at which point the cells switch from ox phos to anaerobic metabolism)?
 

Mij

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Yes, the idea is that by not letting ROS get so high, your mitochondria can use the stuff it would otherwise use to repair ROS damage to heal themselves, so you'd get increasingly more efficient mitochondria and hence more energy.
Do you think this applies to us though?
 

Sasha

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@Sasha I don't do these types of activities days in a row, I give myself at least 3 days of rest in between, otherwise I feel terrible and can't cook for myself etc. I spread it out, and it depends on how I'm feeling too.
I wonder if we're talking at cross-purposes, Mij. I think Kimsie is talking about doing any activity (even if it's just reading) for no more than 10-15 minutes and then having complete rest. So when you say, "types of activities", I think you must be thinking of something different.
 

Mij

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I wonder if we're talking at cross-purposes, Mij. I think Kimsie is talking about doing any activity (even if it's just reading) for no more than 10-15 minutes and then having complete rest. So when you say, "types of activities", I think you must be thinking of something different.
Yes, I was referring to body movement type activities in that post, but it also applies to resting mental activities such as talking.. I lie down, wear earplugs and a eye mask throughout the day, sometimes for 15 minutes, sometimes more.
 

Sasha

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Yes, I was referring to body movement type activities in that post, but it also applies to resting mental activities such as talking.. I lie down, wear earplugs and a eye mask throughout the day, sometimes for 15 minutes, sometimes more.
So you're resting properly... but the key thing for what Kimsie is saying is limiting the length of the active periods (reading, talking, sitting, walking, anything).
 
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When I did an activity diary for the CFS/ME centre (at a time when I was working and doing relatively well) I noticed that I tended towards quite a long warm up and cool down in activity. I mean mentally, I wasn't so well that I was working out! So I would rest, do low level activity, go to work, do medium activity, do low activity, rest, sleep.

This is sort of the opposite of the 15min on 15min off approach. But it worked for me when mild.

I find it hard to switch my mind off. Lots of tired but wired. I'd spend 15min attempting to rest then be back to activity!
 

Mij

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@Sasha yes, I was thinking a while back that I should consider only power walking for 30 minutes instead of one hour.
 
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Note that Kimsie suggests not just "loads of rest" but keeping periods of activity very short (this is key), and alternating with periods of complete rest (not just reclining watching TV, etc.), with timings based on what might be the underlying biology.

Wondering what people think of this, especially in the light of the Naviaux findings.
I am all for this "Aggressive resting therapy" concept. I think this all fits quite well with what the research is uncovering. If we can't wake up the energy production cells in our bodies, we should work to develop methods to best utilize what energy we have. If we can somehow boost our energy reserves in the process, this is a real win.