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Manipulating mitochondrial dynamics

nad nad+ c60 mito fission fusion stearic acid mtdna methylene blue

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#1531 Turnbuckle

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Posted 08 March 2020 - 09:22 AM

Could this be a good source of stearic acid?

https://www.amazon.c...customerReviews

 

It does indeed deliver stearic acid and works rapidly. And that may create a problem with those sensitive to it or suffering from hypertension. So if you try it, start with a very low dose and work up, monitoring your BP. I expect that one gram may be all you need. 



#1532 PAMPAGUY

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Posted 08 March 2020 - 01:43 PM

It does indeed deliver stearic acid and works rapidly. And that may create a problem with those sensitive to it or suffering from hypertension. So if you try it, start with a very low dose and work up, monitoring your BP. I expect that one gram may be all you need. 

I have been taking 5 gm in your protocol.  Stearic Acid was difficult to obtain here in Europe.  Have you made a change?



#1533 Turnbuckle

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Posted 08 March 2020 - 03:34 PM

I have been taking 5 gm in your protocol.  Stearic Acid was difficult to obtain here in Europe.  Have you made a change?

 

 

No, I haven't changed it. I expect the pharmacology of glycerol monostearate to be different from food grade stearic acid. It acts far faster, and likely won't last as long. It might be fine for some, but I don't use it because of its speed, which pushes up BP very rapidly.



#1534 Biotochandron

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Posted 19 March 2020 - 12:39 PM

As a sufferer from FQAD ("Fluoroquinolone-associated disability") I use TB's protocol to heal my severe mitochondrial damage. FQAD patients suffer from a severe (and irreversible), disabling multisymptom profile involving peripheral neuropathy, tendinopathy, joint pain, muscle weakness, autonomic dysfunction and other symptoms after prescribed antimicrobial fluoroquinolone treatment. Some scientists (Golomb et al.) call it an exposure-induced mitochondrial neurogastrointestinal encephalomyopathy.

And we are a living example of the effectiveness of this protocol to induce strong mitophagy.

 

The severely damaged patients in our european forum using this protocol need as little as 300-400mg N+R in the initial rounds of cycling. We believe to have nearly 100% damaged mtDNA that can only be differentiated into heavy, medium or slightly oxidized mtDNA.

 

Most of us live with constant nerve, tendon and muscle pain. In the initial years of having FQAD (or being "floxxed") it is a normal phenomenon to have constant, painful flare-ups due to extreme oxidative stress induced mitophagy - as an attempt of the body to heal the mitochondrial damage. However after months or years of burning in the hell and a small to moderate improvement of symptoms, the flare-ups eventually stop, still leaving even young FQAD patients in the body of a 90 year old chronic pain patient with persistent neuropathies and multiple other conditions.

What is very interesting is that we experience a (temporary) worsening of symptoms (probably due to the drop of ATP) and often also flare-ups of old symptoms many days later after the N+R dose (even if it was as little as 400mg / one day fission). The peak of what we call "mitophagy pain" usually hits around day 4-6 (while we notice little no nothing on day 1-2 - in fact, I feel nice on N+R), then the symptoms slowly decline until day14, and some residual pain (like burning of the achilles tendon) sometimes persists even after 14 days. I myself do fusion/biogenesis for many days but haven't managed to accelerate this process.

The delay of mitophagy might be because of the limited capacity of the lysosomal system and the great number of labeled mtDNA in each cycle.

 

However there is light at the end of the tunnel and one of us who got painful flareups and frightening shivering in his initial cycles with 500mg NAM+R tolerates now 2x2g NAM+R and he's already doing a lot better.

 

Personally I still have a lot defective mtDNA to catch in the dose range of 500-700 N+R - but I'm still in my early cycles which seem to be the worst...

I do biogenesis with 5g GMS, 20mg PQQ and 5g Leucine 24h after N+R, however I'm not quite sure if it would be better to wait with biogenesis until the biggest load of mitophagy hits and is overcome (around day 7) so the enzymatic system of the mitochondria is not overwhelmed.

 

One thing to contribute to the GMS stearic/palmitic acid discussion: Bulkpowders.co.uk claim their GMS consists of 95% stearic alpha-monoester of glycerol, 2,5% free stearic acid and 1% glycerol. So no palmitic acid in there, it seems. If anyone knows where to obtain stearic acid in europe, please let me know.

 

This protocol is a godsend and ticket out of hell. I am hopeful that I will be a lot better in less than a year and finally achieve full healing which was unimaginable until this protocol.


Edited by Biotochandron, 19 March 2020 - 12:57 PM.

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#1535 Turnbuckle

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Posted 19 March 2020 - 01:25 PM

 

This protocol is a godsend and ticket out of hell. I am hopeful that I will be a lot better in less than a year and finally achieve full healing which was unimaginable until this protocol.

 

Excellent news!

 

I do biogenesis with 5g GMS, 20mg PQQ and 5g Leucine 24h after N+R, however I'm not quite sure if it would be better to wait with biogenesis until the biggest load of mitophagy hits and is overcome (around day 7) so the enzymatic system of the mitochondria is not overwhelmed.

 

 

For glycerol monostearate (GMS), you may not even need 5g, as its action is so rapid. This can be a problem if you have high blood pressure, as it can raise it faster than oral dosing of medications can control it. This may be especially acute if you do what I did--mix it into a hot chocolate drink.

 

If you have a high level of damage requiring many cycles, you might want to try the faster cycle I mentioned in this post. Two caveats: I haven't tried it myself as my mito damage is now in the past, and it depends on biogenesis without fusion, or with sulforaphane, which has a shorter half-life than stearic acid but might not be available in Europe. Lysosomes may take 24 hours to digest defective mitochondria, and biogenesis is similar. So alternating days might work, and if that is too fast, a blank day could be sandwiched between each (which should work with stearic acid). Either way you will get more cycles faster.


Edited by Turnbuckle, 19 March 2020 - 01:55 PM.

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#1536 Unclebob

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Posted 19 March 2020 - 02:57 PM

One thing to contribute to the GMS stearic/palmitic acid discussion: Bulkpowders.co.uk claim their GMS consists of 95% stearic alpha-monoester of glycerol, 2,5% free stearic acid and 1% glycerol. So no palmitic acid in there, it seems. If anyone knows where to obtain stearic acid in europe, please let me know.

 

This protocol is a godsend and ticket out of hell. I am hopeful that I will be a lot better in less than a year and finally achieve full healing which was unimaginable until this protocol.

 

Hi

 

I just picked up this off Amazon UK

 

Naissance Stearic Acid 200g 100% Pure

 

Says external use but that seems par for the course.

 

If its 100% pure not really sure what any issues may be.  If anyone knows let me know but I intend to make some keto chocolate brownies using this in place of some of the coconut oil.

 

Cheers Bob  

 

#1537 Turnbuckle

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Posted 19 March 2020 - 04:05 PM

 

 

 

Naissance Stearic Acid 200g 100% Pure

 

 

 

 

 

100% purity? Very unlikely. In any case, "stearic acid" in the trade is generally a triglyceride with 40-60% stearic acid moieties and the rest palmitic acid. Tristearin can be obtained with >99% stearic moieties, but that has very low bioavailability. There is also stearic acid as a free acid, and glycerol monostearate (GSM), which is glycerine with a single stearic acid moiety. In no case can you assume that the fatty acids of any of these products are 100% stearic acid without a certificate of analysis. This problem has been discussed here for several years. The bottom line is that food grade stearic acid is okay. The palmitic part doesn't seem to interfere. It must of course be prepared properly to get a reasonable bioavailability--in brownies, for instance, as you can't just eat the crystals. GSM can be stirred into a hot beverage, but the rapid onset can be dangerous to those with hypertension.

 

I've posted this before several times for making stearic acid brownies: Using a box mix that calls for 1/2 to 2/3 cups of oil, eliminate the oil and add 120 grams of stearic acid flakes or granules, leaving the rest of the recipe unchanged. Mix at room temp using a power mixer, bake according to directions on the box, then divide 3x4 and freeze most of it for later use. Use ½ to 1 brownie for this protocol.

 

I typically dust them with flower to keep them from getting sticky, and store them in the freezer. They need not be thawed to consume.

 


Edited by Turnbuckle, 19 March 2020 - 04:22 PM.


#1538 eigenber

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Posted 19 March 2020 - 07:02 PM

As a sufferer from FQAD ("Fluoroquinolone-associated disability") I use TB's protocol to heal my severe mitochondrial damage. FQAD patients suffer from a severe (and irreversible), disabling multisymptom profile involving peripheral neuropathy, tendinopathy, joint pain, muscle weakness, autonomic dysfunction and other symptoms after prescribed antimicrobial fluoroquinolone treatment. Some scientists (Golomb et al.) call it an exposure-induced mitochondrial neurogastrointestinal encephalomyopathy.

And we are a living example of the effectiveness of this protocol to induce strong mitophagy.

 

The severely damaged patients in our european forum using this protocol need as little as 300-400mg N+R in the initial rounds of cycling. We believe to have nearly 100% damaged mtDNA that can only be differentiated into heavy, medium or slightly oxidized mtDNA.

 

Most of us live with constant nerve, tendon and muscle pain. In the initial years of having FQAD (or being "floxxed") it is a normal phenomenon to have constant, painful flare-ups due to extreme oxidative stress induced mitophagy - as an attempt of the body to heal the mitochondrial damage. However after months or years of burning in the hell and a small to moderate improvement of symptoms, the flare-ups eventually stop, still leaving even young FQAD patients in the body of a 90 year old chronic pain patient with persistent neuropathies and multiple other conditions.

What is very interesting is that we experience a (temporary) worsening of symptoms (probably due to the drop of ATP) and often also flare-ups of old symptoms many days later after the N+R dose (even if it was as little as 400mg / one day fission). The peak of what we call "mitophagy pain" usually hits around day 4-6 (while we notice little no nothing on day 1-2 - in fact, I feel nice on N+R), then the symptoms slowly decline until day14, and some residual pain (like burning of the achilles tendon) sometimes persists even after 14 days. I myself do fusion/biogenesis for many days but haven't managed to accelerate this process.

The delay of mitophagy might be because of the limited capacity of the lysosomal system and the great number of labeled mtDNA in each cycle.

 

However there is light at the end of the tunnel and one of us who got painful flareups and frightening shivering in his initial cycles with 500mg NAM+R tolerates now 2x2g NAM+R and he's already doing a lot better.

 

Personally I still have a lot defective mtDNA to catch in the dose range of 500-700 N+R - but I'm still in my early cycles which seem to be the worst...

I do biogenesis with 5g GMS, 20mg PQQ and 5g Leucine 24h after N+R, however I'm not quite sure if it would be better to wait with biogenesis until the biggest load of mitophagy hits and is overcome (around day 7) so the enzymatic system of the mitochondria is not overwhelmed.

 

One thing to contribute to the GMS stearic/palmitic acid discussion: Bulkpowders.co.uk claim their GMS consists of 95% stearic alpha-monoester of glycerol, 2,5% free stearic acid and 1% glycerol. So no palmitic acid in there, it seems. If anyone knows where to obtain stearic acid in europe, please let me know.

 

This protocol is a godsend and ticket out of hell. I am hopeful that I will be a lot better in less than a year and finally achieve full healing which was unimaginable until this protocol.

What specific tests were you given to diagnose FQAD?



#1539 Biotochandron

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Posted 20 March 2020 - 06:58 PM

 

For glycerol monostearate (GMS), you may not even need 5g, as its action is so rapid. This can be a problem if you have high blood pressure, as it can raise it faster than oral dosing of medications can control it. This may be especially acute if you do what I did--mix it into a hot chocolate drink.

 

Then maybe it would be wise to spread the dosage of GSM over the day (like 3x2g) to equalize GSM with the half-life of food grade (triglyceride) stearic acid, so that fusion is guaranteed for the full cycle of biogenesis.

My BP is usually 120/80 and GSM fortunately doesn't raise my BP - but once I tried 14g GSM for experimental reasons to test if I can actually feel fusion. And I can definitely feel fusion and agree with you that being hyperfused (after too much stearic acid) feels weird - additionally my skin feels itchy on high-dose GSM which is also weird (as I usually don't have food allergies).

 

 

If you have a high level of damage requiring many cycles, you might want to try the faster cycle I mentioned in this post. Two caveats: I haven't tried it myself as my mito damage is now in the past, and it depends on biogenesis without fusion, or with sulforaphane, which has a shorter half-life than stearic acid but might not be available in Europe. Lysosomes may take 24 hours to digest defective mitochondria, and biogenesis is similar. So alternating days might work, and if that is too fast, a blank day could be sandwiched between each (which should work with stearic acid). Either way you will get more cycles faster.

 

 

Thanks for your advice, actually I just wanted to try this approach anyway (cycling faster with lower doses below the threshold that will lead to flare up of symptoms). Already ordered Thorne Sulforaphane from US and it arrived today.

As doses above 500mg N+R trigger symptoms that flare up 5 days later (despite of blank days and/or fusion+biogenesis days in between), my new dosing regime will be like 2x 200mg N+R per day, and maybe I won't even stop N+R at all, taking it every day for 2-3 weeks and just take 3x2g GSM now and then (with PQQ for biogenesis) as it should inhibit the fission while the maintained increased NAD+/NADH ratio will still provide high-energy levels on which my system seems to run much better. It also stabilizes the membrane potential of the remaining mitochondria and reduces ROS. There is some magic to N+R for me. So why stop taking N+R at all if stearic acid overrides any fission? (Of course I don't mean to take N+R every day for the rest of my life, but maybe low-dose for a few weeks)

If Lysosomes take 24 hours to digest defective mitochondria, how do you explain that I feel the drastic effects of mitophagy only 5 days later? - and that it so interesting because this time-delay phenomenon is coherent with all the other mito-damaged FQAD people who use the protocol.

I can't comprehend it. If I take 500mg NAM+R on Day1, the labeling (and lysosomal digesting) of defective mtDNA loops should be completed about 24 hours later (this is the assumption). As the labeled mtDNA loops can't fuse anymore and should also be too damaged to produce ATP, the drop of ATP and flare-up of symptoms should normally happen instantly or at least on the same day - as this seems to be the case with all the people in this forum, but not with us FQAD folks. We don't notice anything the first days after N+R - but then on day4: Boom: Intensified muscle, tendon and nerve pain etc.

Do you have an explanation for that?
 

 

 

 

I just picked up this off Amazon UK

 

Naissance Stearic Acid 200g 100% Pure

 

Says external use but that seems par for the course.

 

 

I also ordered Stearic Acid on Amazon UK because it was labeled as food grade. When I asked the shop they said it was a labeling mistake and refunded my money. Now I have 500g of this "non foodgrade" stearic acid at home, but I don't think that I'm going to use it.

 

 

What specific tests were you given to diagnose FQAD?

 

There are no specific tests, the diagnose is purely anamnestic. You take Cipro for a week and might be messed up for life immediately. I got "floxxed" 8 years ago at the age of 22. It normally starts with tendon and muscle pain all over your body (since the tendons only have a few copies of mtDNA loops). Fluoroquinolone-associated tendon ruptures are a recognized complication, but all other collagen-associated adverse events may also be possible like aortic ruptures.

If you suspect that you are a victim of Cipro the following review about FQAD is good to start with:

https://www.ncbi.nlm...les/PMC5632915/

However, while Michalak et al. mention PQQ for biogenesis as a possible treatment option and many in the FQAD-scene talk about anti-oxidative therapy, they are all missing the whole point of this very thread: mitochondrial quality control and mitophagy. In the very acute phase of FQAD anti-oxidants may be useful to prevent some damage but in the long run they will also prevent quality control of mitochondria. Supplementing with PQQ alone will grow an even greater pool of defective mtDNA.

I would recommend stopping the antioxidants for a while and starting with TB's protocol with a very low dose (like 250mg N+R). Don't redose too soon as you will begin to feel worse after several days. The flare-up of the first cycles can be very scary and can last for up to a month as the worst (possible zombi)-mitochondria get cleared. Later it becomes easier and goes faster and eventually you will be rewarded for your courage.

Note that Fluoroquinolones bind to divalent cations and forming chelates with Mg, Zn, Mn etc. which lead to mitochondrial dysfunction through a big big cascade of ROS (like a nuclear ROS bomb). The regeneration of the intracellular cation deficit especially of the strongly chelated Mg seems to be one of the most important and immediate measures. I would strongly advise against taking chelating agents like gluthatione, ALA or phytochelatins as they often irreversibly aggravate the condition further. No one knows why, either because they also induce a cation deficit and thus start a cascade of ROS / oxidative mtDNA damage again or the severely damaged mtDNA can't handle the mobilization of heavy metals (which reduce gluthatione and in this way also lead to further ROS and mtDNA damage). Redox before Detox should be the motto.

 


Edited by Biotochandron, 20 March 2020 - 07:11 PM.


#1540 Turnbuckle

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Posted 20 March 2020 - 07:37 PM

 

If Lysosomes take 24 hours to digest defective mitochondria, how do you explain that I feel the drastic effects of mitophagy only 5 days later? - and that it so interesting because this time-delay phenomenon is coherent with all the other mito-damaged FQAD people who use the protocol.

I can't comprehend it. If I take 500mg NAM+R on Day1, the labeling (and lysosomal digesting) of defective mtDNA loops should be completed about 24 hours later (this is the assumption). As the labeled mtDNA loops can't fuse anymore and should also be too damaged to produce ATP, the drop of ATP and flare-up of symptoms should normally happen instantly or at least on the same day - as this seems to be the case with all the people in this forum, but not with us FQAD folks. We don't notice anything the first days after N+R - but then on day4: Boom: Intensified muscle, tendon and nerve pain etc.

Do you have an explanation for that?

 

 

 

I worked this protocol out to treat myself, as I had long standing damage from a few months of statin use. My first experiences were dramatic wipe outs that could persist for days, recovering completely when I moved on to fusion. But I was using much more N+R than you are -- 2 grams of each. Likely the NAD+/NADH ratio in my case was sufficient to produce complete fission, but your dosage may be insufficient for that...unless you are taking N+R each day for several days, then the ratio may be increasing day by day and fission along with it.

 

I suspect your 500 mg N+R dose is not producing complete fission initially, and that's why you are using it. Otherwise it could be dangerous for a person with high levels of damage. So are you using it only on the first day, or on every day?

 

That fusion eliminated the fission effect for me is evidence that stearic acid driven fusion trumps NAD+ fission, something I noted subjectively many times. It probably also trumps Parkin, forcing labeled mitochondria to fuse with others. If it doesn't work that way for FQAD people, then that will be interesting.

 

Edit: If you are getting increasing effects day by day after only one dose of N+R, then you may be experiencing a build up of glycogen and waste materials that lysosomes are tasked with dealing with. Normally there is spare capacity, but that may disappear with a heavy load of defective mitochondria.


Edited by Turnbuckle, 20 March 2020 - 08:19 PM.


#1541 eigenber

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Posted 20 March 2020 - 09:22 PM

Then maybe it would be wise to spread the dosage of GSM over the day (like 3x2g) to equalize GSM with the half-life of food grade (triglyceride) stearic acid, so that fusion is guaranteed for the full cycle of biogenesis.

My BP is usually 120/80 and GSM fortunately doesn't raise my BP - but once I tried 14g GSM for experimental reasons to test if I can actually feel fusion. And I can definitely feel fusion and agree with you that being hyperfused (after too much stearic acid) feels weird - additionally my skin feels itchy on high-dose GSM which is also weird (as I usually don't have food allergies).

 

 

Thanks for your advice, actually I just wanted to try this approach anyway (cycling faster with lower doses below the threshold that will lead to flare up of symptoms). Already ordered Thorne Sulforaphane from US and it arrived today.

As doses above 500mg N+R trigger symptoms that flare up 5 days later (despite of blank days and/or fusion+biogenesis days in between), my new dosing regime will be like 2x 200mg N+R per day, and maybe I won't even stop N+R at all, taking it every day for 2-3 weeks and just take 3x2g GSM now and then (with PQQ for biogenesis) as it should inhibit the fission while the maintained increased NAD+/NADH ratio will still provide high-energy levels on which my system seems to run much better. It also stabilizes the membrane potential of the remaining mitochondria and reduces ROS. There is some magic to N+R for me. So why stop taking N+R at all if stearic acid overrides any fission? (Of course I don't mean to take N+R every day for the rest of my life, but maybe low-dose for a few weeks)

If Lysosomes take 24 hours to digest defective mitochondria, how do you explain that I feel the drastic effects of mitophagy only 5 days later? - and that it so interesting because this time-delay phenomenon is coherent with all the other mito-damaged FQAD people who use the protocol.

I can't comprehend it. If I take 500mg NAM+R on Day1, the labeling (and lysosomal digesting) of defective mtDNA loops should be completed about 24 hours later (this is the assumption). As the labeled mtDNA loops can't fuse anymore and should also be too damaged to produce ATP, the drop of ATP and flare-up of symptoms should normally happen instantly or at least on the same day - as this seems to be the case with all the people in this forum, but not with us FQAD folks. We don't notice anything the first days after N+R - but then on day4: Boom: Intensified muscle, tendon and nerve pain etc.

Do you have an explanation for that?
 

 

 

I also ordered Stearic Acid on Amazon UK because it was labeled as food grade. When I asked the shop they said it was a labeling mistake and refunded my money. Now I have 500g of this "non foodgrade" stearic acid at home, but I don't think that I'm going to use it.

 

 

 

There are no specific tests, the diagnose is purely anamnestic. You take Cipro for a week and might be messed up for life immediately. I got "floxxed" 8 years ago at the age of 22. It normally starts with tendon and muscle pain all over your body (since the tendons only have a few copies of mtDNA loops). Fluoroquinolone-associated tendon ruptures are a recognized complication, but all other collagen-associated adverse events may also be possible like aortic ruptures.

If you suspect that you are a victim of Cipro the following review about FQAD is good to start with:

https://www.ncbi.nlm...les/PMC5632915/

However, while Michalak et al. mention PQQ for biogenesis as a possible treatment option and many in the FQAD-scene talk about anti-oxidative therapy, they are all missing the whole point of this very thread: mitochondrial quality control and mitophagy. In the very acute phase of FQAD anti-oxidants may be useful to prevent some damage but in the long run they will also prevent quality control of mitochondria. Supplementing with PQQ alone will grow an even greater pool of defective mtDNA.

I would recommend stopping the antioxidants for a while and starting with TB's protocol with a very low dose (like 250mg N+R). Don't redose too soon as you will begin to feel worse after several days. The flare-up of the first cycles can be very scary and can last for up to a month as the worst (possible zombi)-mitochondria get cleared. Later it becomes easier and goes faster and eventually you will be rewarded for your courage.

Note that Fluoroquinolones bind to divalent cations and forming chelates with Mg, Zn, Mn etc. which lead to mitochondrial dysfunction through a big big cascade of ROS (like a nuclear ROS bomb). The regeneration of the intracellular cation deficit especially of the strongly chelated Mg seems to be one of the most important and immediate measures. I would strongly advise against taking chelating agents like gluthatione, ALA or phytochelatins as they often irreversibly aggravate the condition further. No one knows why, either because they also induce a cation deficit and thus start a cascade of ROS / oxidative mtDNA damage again or the severely damaged mtDNA can't handle the mobilization of heavy metals (which reduce gluthatione and in this way also lead to further ROS and mtDNA damage). Redox before Detox should be the motto.

 

So, are you suggesting to use only the fission/mitophagy phase of the protocol for a month, then use the fusion/biogenesis phase? 

And re: your last paragraph, what is your practical recommendation regarding supplementing with minerals?



#1542 longcity90

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Posted 21 March 2020 - 10:08 AM

A doubt has arisen ... in the event of mutations at the nuclear DNA level, is this protocol useless?



#1543 Biotochandron

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Posted 21 March 2020 - 10:40 AM

I was using much more N+R than you are -- 2 grams of each. Likely the NAD+/NADH ratio in my case was sufficient to produce complete fission, but your dosage may be insufficient for that...unless you are taking N+R each day for several days, then the ratio may be increasing day by day and fission along with it.

 

I suspect your 500 mg N+R dose is not producing complete fission initially, and that's why you are using it. Otherwise it could be dangerous for a person with high levels of damage. So are you using it only on the first day, or on every day?

 

That fusion eliminated the fission effect for me is evidence that stearic acid driven fusion trumps NAD+ fission, something I noted subjectively many times. It probably also trumps Parkin, forcing labeled mitochondria to fuse with others. If it doesn't work that way for FQAD people, then that will be interesting.

 

Edit: If you are getting increasing effects day by day after only one dose of N+R, then you may be experiencing a build up of glycogen and waste materials that lysosomes are tasked with dealing with. Normally there is spare capacity, but that may disappear with a heavy load of defective mitochondria.

 

I was using only one dose of N+R on the first day.

 

I experimented with different approaches like:

Day 1 (Fission): 500mg N+R

Day 2 (Fusion/Biogenesis): 5g GMS, 5g Leucine, 2x20mg PQQ (No symptoms or: Very, very slight symptoms begin to occur like burning of the achilles tendon)

Day 3 (Fusion/Biogenesis): 5g GMS, 5g Leucine, 2x20mg PQQ (Same as Day2)

Day 4 (Fusion/Biogenesis): 5g GMS, 5g Leucine, 1x20mg PQQ (Mitophagy kicks in: Intensified muscle, tendon and nerve pain etc.)

Day 5 (Fusion/Biogenesis): 5g GMS, 5g Leucine, 1x20mg PQQ (Same as Day4)

Day 6 (Blank day): Symptoms gradually decline until Day 10 - 14, some tissues need even longer, especially the achilles tendon

 

or without so much biogenesis/fusion and more blank days:

 

Day 1 (Fission): 500mg N+R

Day 2 (Blank day): No symptoms or: Very, very slight symptoms begin to occur like burning of the achilles tendon

Day 3 (Blank day): Same as Day2

Day 4 (Blank day): Mitophagy kicks in: Intensified muscle, tendon and nerve pain etc.

Day 5 (Fusion/Biogenesis): 5g GMS, 5g Leucine, 1x20mg PQQ (Symptons: Same as Day4)

Day 6 (Fusion/Biogenesis): 5g GMS, 5g Leucine, 1x20mg PQQ (Symptoms gradually decline until Day 10 - 14, some tissues need even longer, especially the achilles tendon)

 

And I did the protocol even without fusion/biogenesis with almost the same results.

 

I do believe that fusion with GMS attenuates the symptoms a little bit, but (in my special case) it was not a switch or emergency brake as I suspected it to be. I also believe that biogenesis accelerates the regeneration but again: it was not so noticeably significant I suspected it to be.

 

The mitochondrial damage in FQAD people may differ from the damage of Statin people because different types of tissue could be affected. For FQAD people especially tendons, cartilage and connective tissue are affected (or symptomatically affected). As these are bradytrophic tissues they may take longer to regenerate than tissues with a larger number of mtDNA loops.

 

I consider the same hypotheses as you:

1) The heavy load of defective mitochondria overwhelms the limited capacity of the lysosomal system, therefore it takes longer for the peak of mitophagy (and thus drop of ATP) to become symptomatic.

2) Labeled mitochondria are able to fuse with others (with stearic acid and maybe also without) so that the overwhelmed mitochondrial system can maintain its energetic level for some time.

 

I got some 30:1 cinnamoon extract today. So taking 2g of that would be equivalent to 60g cinnamoon which should upregulate Pink/Parkin quite a bit. I'm curious to see if this changes anything.

 

I agree with you that 500mg N+R might most likely be insufficient for complete fission of mitochondria to their minimal size (with only one mtDNA loop). However, just the slight raising of NAD+ from 500mg N+R seems to induce enough fission to catch many defective mitochondria (as there might be many heavily oxidized in FQAD people).

 

In my initial cycles I was too enthusiastic and did 2g N+R for two days one time. Because I felt nice and energetic in these two days (N+R makes me very euphoric and relaxxed)

and I didn't know at the time that the symptoms will occur time-delayed I did many pushups (but unfortunately not like a girl - which was stupid - I even exceeded my usual performance limit this day). I woke up next morning with a very painful tendon/muscle-strain in my pectoralis which is healing slowly for a few months now (I currently do some exercise like a girl, prolotherapy and TB500 to heal that injury).

 

Speaking of months, I'm only in my ninth or tenth cycle as I stopped the protocol for a long time since I meanwhile had to deal with a severe gastritis. I have just started again.

 

Since three days I'm trying a different low-dose approach (taking 150mg N+R in the morning and evening) and I haven't developed symptoms yet, but it maybe still will hapen later as the NAD+/NADH ratio and fission may be increasing day by day. However I hope that the mitophagy will be retarded this way. I can save the high dose N+R approaches for later in the future then, to catch the modest and medium oxidized mtDNA loops).


Edited by Biotochandron, 21 March 2020 - 10:50 AM.


#1544 Biotochandron

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Posted 21 March 2020 - 11:06 AM

So, are you suggesting to use only the fission/mitophagy phase of the protocol for a month, then use the fusion/biogenesis phase? 

And re: your last paragraph, what is your practical recommendation regarding supplementing with minerals?

 

A high potency multi-vitamin and mineral supplement should be fine, along with 600mg Magnesium per day (I use Mg-glycinate) + ALCAR + Q10. Maybe inject 1g Mangesium Sulphate per week (I.M) or more often. Stop everything on fission days. I'm currently trying a low-dose approach (2x150mg N+R) per day and will do fusion days on maybe two times a week with 3x2g GSM+5g Leucine+2x 20mg PQQ. I try this for 2-3 weeks. Afterwards I will use the normal TB version of the protocol again, gradually increasing the dose to 2g N+R.



#1545 Turnbuckle

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Posted 21 March 2020 - 12:42 PM

I was using only one dose of N+R on the first day.

 

I experimented with different approaches like:

Day 1 (Fission): 500mg N+R

Day 2 (Fusion/Biogenesis): 5g GMS, 5g Leucine, 2x20mg PQQ (No symptoms or: Very, very slight symptoms begin to occur like burning of the achilles tendon)

Day 3 (Fusion/Biogenesis): 5g GMS, 5g Leucine, 2x20mg PQQ (Same as Day2)

Day 4 (Fusion/Biogenesis): 5g GMS, 5g Leucine, 1x20mg PQQ (Mitophagy kicks in: Intensified muscle, tendon and nerve pain etc.)

Day 5 (Fusion/Biogenesis): 5g GMS, 5g Leucine, 1x20mg PQQ (Same as Day4)

Day 6 (Blank day): Symptoms gradually decline until Day 10 - 14, some tissues need even longer, especially the achilles tendon

 

 

Day 1 (Fission): 500mg N+R
Day 2 (Blank day): No symptoms or: Very, very slight symptoms begin to occur like burning of the achilles tendon
Day 3 (Blank day): Same as Day2
Day 4 (Blank day): Mitophagy kicks in: Intensified muscle, tendon and nerve pain etc.
Day 5 (Fusion/Biogenesis): 5g GMS, 5g Leucine, 1x20mg PQQ (Symptons: Same as Day4)
Day 6 (Fusion/Biogenesis): 5g GMS, 5g Leucine, 1x20mg PQQ (Symptoms gradually decline until Day 10 - 14, some tissues need even longer, especially the achilles tendon)

 

 

 

 

 

Keep in mind that symptoms you attribute to mitophagy might be something else entirely, such as the potential lysosomal problem I referred to above. Without available lysosomes to take out the garbage for several days, cells can be stressed in ways that can be misinterpreted. The pain symptoms you describe I haven't experienced, and don't sound like mitophagy. 

 

The mitochondrial damage in FQAD people may differ from the damage of Statin people because different types of tissue could be affected. 

 

 

 
Possibly, but I expect a genetic basis is making certain individuals more sensitive to statins or fluoroquinolones, and underlying genetic differences may have to be treated differently. For instance, mutations of the SCN4A gene can alter AMPK activity, with negative outcomes. 

higher activation levels of AMPK may be a general feature of mouse models carrying Scn4a mutations presenting with intermittent immobility attacks.

 

 

So I suggest dropping the leucine, which is an AMPK activator. This may not be the problem, but no need to muddy the waters.  I would also cut back the fusion/biogenesis to just one day.

 

Speaking of months, I'm only in my ninth or tenth cycle as I stopped the protocol for a long time since I meanwhile had to deal with a severe gastritis. I have just started again.

 

 

If you have very high levels of damage, this could take many cycles. The number required will vary between cells, and cells with 100% damage cannot be fixed this way--not directly, anway. For a cell with 95% damage and 10% removal of mitochondria each cycle, the first cycle will decrease the defective load by only a small amount -- to 94.5%. Progress will be slow at first, but will accelerate with each cycle. At 50% damage and 10% removal, one cycle will reduce the damage level to 44%. At 10% damage, only one cycle will be needed to get rid of it all.

 

This is all just theoretical, of course, based on the premise that all fissioned mitochondria have one loop and only defective loops are removed, and also that biogenesis duplicates loops equally, without regard to mutations, and the number of mtDNA loops is restored to the original number during biogenesis.

 

With 100% damage, cells might still be rescued by autotransplanted mitochondria. Free mitochondria exist in the blood, both naked and encapsulated in microvesicles, and hypothetically could seed cells with good mitochondria. Of course, circulating mitochondria will probably reflect the same level of damage as the body as a whole, and thus this won't be helpful until you get the overall level of damage down to reasonable levels.

 

we report here that blood contains intact cell‐free full‐length mitochondrial DNA in dense and biologically stable structures over 0.22 µm in diameter and that these structures have specific mitochondrial proteins, double membranes and a morphology resembling that of mitochondria. We further demonstrate that these structurally intact cell‐free mitochondria in the blood circulation are respiratory competent. We estimate that there are between 200 000 and 3.7 million cell‐free intact mitochondria per mL of plasma

https://faseb.online.../fj.201901917RR

 


Edited by Turnbuckle, 21 March 2020 - 01:29 PM.

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#1546 Biotochandron

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Posted 21 March 2020 - 03:53 PM



Keep in mind that symptoms you attribute to mitophagy might be something else entirely, such as the potential lysosomal problem I referred to above. Without available lysosomes to take out the garbage for several days, cells can be stressed in ways that can be misinterpreted. The pain symptoms you describe I haven't experienced, and don't sound like mitophagy.

 

That's an interesting theory and I was looking for another explanation, thanks. If the number of mtDNA loops is restored within 24-48h the flareup of symptoms days later cannot be explained due to the drop of ATP.

 

The described pain symptoms are typical symptoms of FQAD. Every FQAD patient is a bit different, but almost everyone has problems with the achilles tendons and calve muscles, as well as peripheral neuropathies in specific weak areas of the body. The flareup following N+R is simply a temporary aggravation of these symptoms. Some experience also CFS symptoms but I don't. However my general energy level, motivation and mental clarity has greatly improved after the first couple of cycles, while the tendons and nerves seem to need longer to heal. You might not have experienced these specific tendonpains because you didn't have these symptoms in the first place.

 

 

 

The number required will vary between cells, and cells with 100% damage cannot be fixed this way--not directly, anway.

 

With 100% damage, cells might still be rescued by autotransplanted mitochondria. Free mitochondria exist in the blood, both naked and encapsulated in microvesicles, and hypothetically could seed cells with good mitochondria. Of course, circulating mitochondria will probably reflect the same level of damage as the body as a whole, and thus this won't be helpful until you get the overall level of damage down to reasonable levels.

 

Interesting! Other mtDNA repair mechanisms might be base excision repair (BER) and microhomology-mediated end joining (MMEJ). So there is hope.

 

https://www.ncbi.nlm...pubmed/20188838

https://www.ncbi.nlm...pubmed/29625543



#1547 eigenber

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Posted 21 March 2020 - 07:19 PM

One of the more publicized supplements targeting mitochondria is MitoQ. 

In what phase of the Turnbuckle Protocol, fission or fusion might the addition of MitoQ be advantageous, or on the other hand, not recommended at all?



#1548 Turnbuckle

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Posted 21 March 2020 - 08:01 PM

One of the more publicized supplements targeting mitochondria is MitoQ. 

In what phase of the Turnbuckle Protocol, fission or fusion might the addition of MitoQ be advantageous, or on the other hand, not recommended at all?

 

 

If you use it, use it after you've cleared out your damaged mitochondria with sufficient cycles of fission/fusion. Regular use of antioxidants can inhibit autophagy and result in cellular damage. See Antioxidants can inhibit basal autophagy and enhance neurodegeneration in models of polyglutamine disease. I expect occasional use will not be a problem, however.

 

MitoQ is known to delay replicative senescence and lengthen telomeres. Most will tell you this is a good idea, whereas I believe the opposite. If you want to live longer by replacing epigenetically old cells with epigenetically young cells derived from stem cells, delaying senescence by lengthening telomeres will work against you. Enhancenced telomeres produce resistance to replacement.


Edited by Turnbuckle, 21 March 2020 - 08:02 PM.


#1549 eigenber

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Posted 22 March 2020 - 02:52 AM

Thanks. I was thinking that might be the case. I believe I've been damaged by Cipro and am carrying a load of defective mitochondria I've done a few cycles of the protocol in the past, prior to the latest antibiotic poisoning. Yesterday and today I did a normally-dosed fission treatment, and am now feeling quite achy and dull. Not sure when to initiate the fusion cycle. 



#1550 Biotochandron

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Posted 22 March 2020 - 04:26 PM


If you are getting increasing effects day by day after only one dose of N+R, then you may be experiencing a build up of glycogen and waste materials that lysosomes are tasked with dealing with. Normally there is spare capacity, but that may disappear with a heavy load of defective mitochondria.

 

Keep in mind that symptoms you attribute to mitophagy might be something else entirely, such as the potential lysosomal problem I referred to above. Without available lysosomes to take out the garbage for several days, cells can be stressed in ways that can be misinterpreted.

 

 

Do you have any ideas how to solve the lysosomal problem and prevent the stressing of cells due do metabilic waste? Are you talking about things like accumulation of AGEs? Maybe a ketogenic diet and high-doses of l-carnitine could help prevent the AGE induced damage for people like me. I am grateful for any further ideas and thoughts.

 

 

 

L-Carnitine inhibits protein glycation in vitro and in vivo: evidence for a role in diabetic management. (2007)

Glycation-initiated changes in tissue proteins are suggested to play an important role in the development of diabetes-related pathological changes. The purpose of this study was to examine the anti-glycating effect of L-carnitine (CA) in vivo in the high-fructose diet-fed rat and to determine the potential of CA to inhibit in vitro glycation. Additionally the glucose-disposal efficiency of CA in the rat diaphragm was investigated. High-fructose diet (60 g/100 g diet)-fed rats were treated with CA (300 mg/kg/day i.p.) for 60 days. The effect of CA on glucose, fructose and fructosamine in plasma, methyl glyoxal and glycated haemoglobin in whole blood and skin and tail tendon collagen glycation were determined. The inhibitory effect of CA on the glycation of bovine serum albumin in vitro was compared with that of aminoguanidine (AG), a known antiglycation agent. Glucose utilisation induced by insulin in the control rat diaphragm was monitored in the presence and absence of CA. High-fructose feeding induced hyperglycaemia and glycation of haemoglobin and skin and tail tendon collagen. In CA-administered fructose-fed rats glycation was significantly reduced. In vitro glycation and accumulation of advanced glycation end products were mitigated by CA. CA was more effective than AG in inhibiting glycation in vitro. CA also enhanced the utilisation of glucose in the rat diaphragm. The findings of the study reveal that CA not only has antiglycation effect but also enhances glucose disposal in the rat diaphragm. These findings provide evidence for the therapeutic utility of CA in diabetes and associated complications.

 

https://www.ncbi.nlm...pubmed/17530472

 

 

 

Thanks. I was thinking that might be the case. I believe I've been damaged by Cipro and am carrying a load of defective mitochondria I've done a few cycles of the protocol in the past, prior to the latest antibiotic poisoning. Yesterday and today I did a normally-dosed fission treatment, and am now feeling quite achy and dull. Not sure when to initiate the fusion cycle. 

 

I am curious what you will report after a couple of days and whether you will expierence the delayed phenomenon. With normally-dosed, you mean 2g N+R?



#1551 eigenber

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Posted 22 March 2020 - 05:29 PM

Yes, that's the dose, along with Jiaogulan leaf, Apigenin and Fisetin. I will do one more of those today, possibly along with a half-day fast and low dose rapamycin. 

I felt pretty bad yesterday afternoon but the pain - mostly in my legs and shoulders eased a bit by late evening. I haven't experienced (yet) the phenomenon you report of very bad pain after several blank days. I'll keep you posted. I suspect all of this is guesswork within wide ranges of individual differences. 


Edited by eigenber, 22 March 2020 - 05:31 PM.


#1552 eigenber

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Posted 23 March 2020 - 05:08 AM

Within these cycles, is there an optimum time to add or subtract exogenous antioxidants, like Vitamin C, E, resveratrol, astaxanthin, etc.?


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#1553 Turnbuckle

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Posted 23 March 2020 - 12:08 PM

Within these cycles, is there an optimum time to add or subtract exogenous antioxidants, like Vitamin C, E, resveratrol, astaxanthin, etc.?

 

 

See this post. I haven't changed my opinion in the intervening 4 years.



#1554 Unclebob

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Posted 25 March 2020 - 01:54 PM

You definitely don't want to do mito fission if you have any sort of virus. For colds and the flu, cells are filled up with viral particles, which are then released by cell death and rupture. Mito fission can potentially enhance both processes hijacked by viruses and make the disease worse--

 

Just asking for confirmation that with the state of the world the way it is (re CoronaVirus) Fission should be avoided until we are past this?

 

From the above post and earlier ones in this thread Virus with Fission is a bad idea.

 

OR could the enhanced supply of NAD increase the immune ability of each cell?

 

Am in the UK which is now in lock down - which is not as bad as you think - so acutely aware of how virulent this strain is.

 

By the way you were right about the Stearic acid turns out to be 40% palmeric in line with your thoughts and advice. 

 

Cheers



#1555 kurt9

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Posted 25 March 2020 - 03:57 PM

I'm on week 9 of the protocol, with three more weeks to go. Today is fission 3 day (Thursday and Friday are fusion days). Since I'm about as socially isolated as can be while still going to work (my work is not a risk factor, very large facility few people) but can't even go to the gym, I plan to finish a full 12 weeks.

 

I have a question about the fusion portion. On a fusion day, do I need to eat the steric acid brownie 3 hours prior to the fusion ingredients both morning and evening (which is what I have been doing) or can I eat the brownie only in the morning?


Edited by kurt9, 25 March 2020 - 04:02 PM.


#1556 sub7

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Posted 26 March 2020 - 09:47 PM

Turnbuckle,

 

I believe you had spoken about this but I cannot find it in the thread. How old do you think one has to be in order to notice a significant difference as a result of such a protocol?



#1557 Turnbuckle

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Posted 27 March 2020 - 08:16 AM

Turnbuckle,

 

I believe you had spoken about this but I cannot find it in the thread. How old do you think one has to be in order to notice a significant difference as a result of such a protocol?

 

The indication is mitochondrial insufficiency, not age. One way to quickly tell if you might benefit is to take N+R. If you get a strong reaction to it--like weakness in the gym--then you may have substantial damaged mitochondria. To correct it, cells must have some good mitochondria (mtDNA loops), as this protocol is only a means of expanding the good population.



#1558 sub7

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Posted 28 March 2020 - 12:06 PM

The indication is mitochondrial insufficiency, not age. One way to quickly tell if you might benefit is to take N+R. If you get a strong reaction to it--like weakness in the gym--then you may have substantial damaged mitochondria. To correct it, cells must have some good mitochondria (mtDNA loops), as this protocol is only a means of expanding the good population.

 

I actually have the weirdest reaction to NR -and get the same reaction to N+R too.

 

When I first began to take it, I felt good; nothing extraordinary but slightly fewer aches and pains and a bit of a "fresh feeling" overall, as in upbeat and a little more enrgy.

After day 10 or so, I began to get inflammed and aches and pains showed up all over. It got to the point where my gums started to be red and inflamed and even bled when brushing my teeth. I then gave it a break and restarted in 2-3 weeks time. It turns out that the body "remembers" the pre-developed sensitivity and the same inflammation started after just a few days that time. After more than a month break, I tried it one last time and same thing -after just two to three days same problems. 

 

It was bad, but the problem was inflammation, never much of a crash or weakness (maybe a slight bit)

 

This reaction is so strange and unusual that people don't believe me when I tell them.

Do you have any interpretation of this all?

Thanks a million Sir



#1559 Turnbuckle

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Posted 28 March 2020 - 01:25 PM

I actually have the weirdest reaction to NR -and get the same reaction to N+R too.

 

When I first began to take it, I felt good; nothing extraordinary but slightly fewer aches and pains and a bit of a "fresh feeling" overall, as in upbeat and a little more enrgy.

After day 10 or so, I began to get inflammed and aches and pains showed up all over. It got to the point where my gums started to be red and inflamed and even bled when brushing my teeth. I then gave it a break and restarted in 2-3 weeks time. It turns out that the body "remembers" the pre-developed sensitivity and the same inflammation started after just a few days that time. After more than a month break, I tried it one last time and same thing -after just two to three days same problems. 

 

It was bad, but the problem was inflammation, never much of a crash or weakness (maybe a slight bit)

 

This reaction is so strange and unusual that people don't believe me when I tell them.

Do you have any interpretation of this all?

Thanks a million Sir

 

 

If you create a long term state of fission, you could badly deplete your mitochondria. Stop taking it and take some PQQ, preferably with mito fusion.

 

Can depletion cause inflammation? Possibly. Fission is also necessary for apoptosis -- 

 

While apoptosis is considered a silent form of cell death, mitochondrial dysfunction (that occurs upon MOMP) is associated with inflammatory effects. For instance, mitochondrial dysfunction can lead to cytosolic exposure of several danger-associated molecular patterns (DAMPs), such as mitochondrial DNA (mtDNA) (Shimada et al., 2012; West et al., 2015) and cardiolipin (Tuominen et al., 2006). Moreover, mitochondrial ROS – increased upon disruption of mitochondrial respiratory chain function – can also promote inflammation (Nakahira et al., 2011; Zhou et al., 2011; Zorov et al., 2014). Once exposed to the cytosol, mitochondrial DAMPs are recognized by various adaptor molecules or receptors leading to an inflammatory response (Grazoli and Pugin, 2018). 

https://www.frontier...2019.00100/full

 

 

 

I can't say if this is happening, but I got a similar response to statins. After a few months I felt I was dying, and so stopped. But my doctor wanted me to try other types, and after a couple of days the terrible feelings would come roaring back. Didn't matter the statin.

 

The decrease of mtDNA mass with days of nicotinamide in vitro is shown below--

Attached Files



#1560 sub7

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Posted 29 March 2020 - 12:50 PM

I really don't think I took N+R long enough to do any of that, but that's just a guess on my part. I am talking about modest doses after less than a month showing these effects







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