2287 replies to this topic

[eigenber]

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 -- 

 

 

 

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--

I'm probably not interpreting the article correctly, but it it suggesting that significant mitophagy only occurs after about 5 days of continuous N+R (the fission/mitophagy phase of the protocol)?

[Turnbuckle]

I'm probably not interpreting the article correctly, but it it suggesting that significant mitophagy only occurs after about 5 days of continuous N+R (the fission/mitophagy phase of the protocol)?

 

 

Keep in mind that the experiment was in vitro, so it is only suggestive of what will happen in vivo.

 

The work shows that nicotinamide produced more than 20% decline in mtDNA mass in one day, 50% in 5 days, and 60% in 7 days (Fig 1. C). This result is strange, as the cells were taken from a newborn, and one would expect the level of mito damage to be small. So why was the mtDNA level reduced so much? Is nicotinamide capable of removing good (non-depolarized) mitochondria  as well as bad mitochondria? Or were the mitochondria of these cells somehow damaged prior to the experiment? In any case, I expect the results in vivo will depend on your level of mito damage. If you have a lot, then you will feel it strongly. If you have none, you will feel virtually nothing. 

 

If you have a lot of damage, you will feel it rather quickly because fission isolates bad mtDNA, and if they aren't producing all the enzymes needed they will fail to produce any energy at all. In the fusion state, by contrast, bad loops can cover for each other as long as the damage in not in the same gene.

Edited by Turnbuckle, 29 March 2020 - 10:04 PM.

[Andey]

What do you think about adding Spermidine to the protocol? and where it makes more sense to add it - in the fission or fusion part?

I take it once a week anyway, so want to place it properly.

[Turnbuckle]

What do you think about adding Spermidine to the protocol? and where it makes more sense to add it - in the fission or fusion part?

I take it once a week anyway, so want to place it properly.

 

 

Since spermidine increases PINK1, you would use it with fission. However, it may not make a difference as the NAD+/NADH ratio is already driving the QC process. Try it with and without and see if you can tell the difference.

Edited by Turnbuckle, 31 March 2020 - 05:28 PM.

[Andey]

Since spermidine increases PINK1, you would use it with fission. However, it may not make a difference as the NAD+/NADH ratio is already driving the QC process. Try it with and without and see if you can tell the difference.

 

   Thank you, I will try it. I think I feel similar while taking big doses of N+R and spermidine, its a subtle thing and more about mental side of things so will see if it gets amplified and if it will than I will stick to it.

[eigenber]

Should nicotinamide plus ribose be taken at any time other than during fission/mitophagy? 

[Turnbuckle]

Should nicotinamide plus ribose be taken at any time other than during fission/mitophagy? 

 

 

That's like asking should I do fission/mitophagy when I'm not doing fission/mitophagy. You could do it with fusion, perhaps, in which case the fission/mitophagy aspect would be overridden, but not the increase in NAD+. This might give you more energy, but I haven't experimented enough to give any guidance. 

Edited by Turnbuckle, 01 April 2020 - 01:55 PM.

[eigenber]

So, all instances of ingesting nicotinamide+ribose, NMN, NR, are inducing fission/mitophagy?

And because chronic induction of mitophagy is problematic, it's foolish to be supplementing with any of the NAD+ precursors outside of the 3-day fission/mitophagy phase of the Protocol?

 

[Turnbuckle]

So, all instances of ingesting nicotinamide+ribose, NMN, NR, are inducing fission/mitophagy?

And because chronic induction of mitophagy is problematic, it's foolish to be supplementing with any of the NAD+ precursors outside of the 3-day fission/mitophagy phase of the Protocol?

 

The natural process is for mitochondria to fuse and fission constantly. This is sufficient for mito QC except in extraordinary circumstances, such as when large numbers of defective mtDNA loops are present due to any number of factors--drugs and disease being most common. Cells may get so far behind in QC that they may never catch up. In this protocol, fission and fusion are driven to extremes cyclically to boost QC far beyond what naturally occurs. To do only the fission side won't do the job.

 

As long as the NAD+/NADH (oxidized/reduced) ratio is boosted sufficiently, fission will occur. But what happens in the chronic case isn't clear. Seems to me that ultimately the ratio must decline and fission will decrease. So you will get the best fission/mitophagy results with intermittent use.

Edited by Turnbuckle, 01 April 2020 - 09:50 PM.

[Ken Mark]

If tristearin is easily available in 99% purity, you can convert it to sodium or magnesium stearate at home using lye. This is essentially soap making. You can convert the soap back to free fatty acid (FFA) using vinegar (acetic acid), if desired.

If you don't want to eat soap, you can transesterify tristearin with ethanol and lye. This is basically the process used to make biodiesel. The ethyl stearate formed will most probably be liquid, and if so, may be more bioavailable just because of it's physical form.

Making soap (or FFA) or ethyl ester seems best way to me, if indeed 99% pure stearic acid is available. I read somewhere in this thread that it is available.

If high purity tristearin is not available, fully hydrogenated Soy oil (aka soy wax, used in candle making) or fully hydrogenated cottonseed oil or sunflower oil will have upwards of 80% stearic acid in form of tri-ester. In fact any oil containing high % of oleic, linoleic or linolenic acid will upon full hydrogenation yield high stearic tri-ester. The concern with fully hydrogenated oils is the heavy metal content (used in catalytic hydrogenation), so ask suppliers about that. Avoid partially hydrogenated oils, as they will contain trans fats. After you get your hands on fully hydrogenated high stearic oil/wax, you can convert it to soap, FFA or ethyl ester.

GMS seems to be made from industrial stearic acid, meaning it contains about half palmitic. Some pharmacopoeia have specifications for GMS80 which means at least 80% stearic ester. If you get your hands on high stearic GMS and don't want to use it as such, you can always convert it to soap, FFA or ethyl ester.

What I want to say is, obtaining upwards of 80% stearic acid is easily and economically possible with some kitchen hacks, if you so desire.

All of above are my opinions based on basic chemistry.

Further, low fat vegan diet that excludes stearic acid on it's own promotes fission, as was shown in nature paper that found stearic acid promotes fusion in 90% human subjects. So those who don't want to take high does NR or N + R (for sensitivity or whatever reason) may still take benefit of this finding to cause fission. As most fats have some stearic acid, just avoid fats to achieve fission.

From this thread, I understand that fusion seems to be a mechanism evolved to overcome the ATP scarcity/depletion resulting from damage to mtDNA, in which case fusion will happen automatically after you induce fission. Fusion seems to be the normal state, fission needs to be forced.

Is my understanding of fission-fusion written in above two paragraphs correct?

I have one more question.
The nature paper claimed that fusion resulted into higher rate of fat oxidation. There are other papers that say stearic acid reduced visceral fat in mice. Have those of you using stearic acid for fusion experienced visceral fat loss?

[kurt9]

Have those of you using stearic acid for fusion experienced visceral fat loss?

 

I'm on week 10 of the protocol and am experiencing this big time.

 

I've got two more weeks to go. Yes, I'm doing fission as well. I am in a situation where my risk of getting COVID-19 is pretty minimal, even though I'm still working like crazy (I'm in the automation business).

[Turnbuckle]

Have those of you using stearic acid for fusion experienced visceral fat loss?

 

I'm on week 10 of the protocol and am experiencing this big time.

 

I've got two more weeks to go. Yes, I'm doing fission as well. I am in a situation where my risk of getting COVID-19 is pretty minimal, even though I'm still working like crazy (I'm in the automation business).

 

 

Your observation is in line with a study in mice--

 

Our main finding was that dietary stearic acid leads to dramatically reduced visceral adipose tissue (VAT). Our data also indicated that total body fat was reduced by 25% compared to the low fat diet group when standardized to total body weight. Specifically, when VAT was normalized to total body weight, the stearic acid group had 67%±4% (SEM) less VAT as compared to the other diet groups. A conservative estimate of the normal percentage of VAT compared to total mouse fat is 60% [21] and a 67% reduction in VAT would reduce total body fat by 40% which is more than enough to account for the 25% loss of total body fat measured by DXA (which was also standardized to total body weight). Thus our data strongly point to VAT as being the primary fat depot being affected by dietary stearic acid. However we did not measure possible changes in other fat depots and cannot rule out rule out the possibility that fat was lost or gained from other depots. Also we don't know the long term effects of dramatically reducing VAT. Nevertheless it is clear that excess VAT is not healthy and a diet that reduces VAT in a setting of excess VAT may be beneficial.

https://www.ncbi.nlm...les/PMC4164353/

 

[Turnbuckle]

From this thread, I understand that fusion seems to be a mechanism evolved to overcome the ATP scarcity/depletion resulting from damage to mtDNA, in which case fusion will happen automatically after you induce fission. Fusion seems to be the normal state, fission needs to be forced.

Is my understanding of fission-fusion written in above two paragraphs correct?

 

 

 

This is incorrect. The normal state is dynamic, with mitochondria constantly fissioning and fusing. This protocol takes the normal state of mixed fusion and fission and pegs them out in each direction in a cyclic fashion.

Edited by Turnbuckle, 03 April 2020 - 10:12 AM.

[Ken Mark]

Have those of you using stearic acid for fusion experienced visceral fat loss?

I'm on week 10 of the protocol and am experiencing this big time.

That's amazing. There aren't many things that can help reduce visceral fat. Reducing visceral fat itself would make one much healthier.

If I may ask you, what's your age, which stearic acid (as in pure or stearic palmitic mixed?) you take and what's your dose?

Your observation is in line with a study in mice--

Yes, that's the mouse study I was referring to. Did you expect this visceral fat loss effect yourself, Turnbuckle? You have most experience with stearic acid. Nature paper says stearic acid induced fusion accelerated fat oxidation. Also, in the mice study, the mice were fed stearic acid all the time, so they may have been in fusion all the time and they were healthier than control mouse. This stearic acid may turn out to be a wonder molecule.

This is incorrect. The normal state is dynamic, with mitochondria constantly fissioning and fusing. This protocol takes the normal state of mixed fusion and fission and pegs them out in each direction in a cyclic fashion.

Of course. Normal wasn't the perfect word. May be fusion is a 'preferred' state, instead of normal. If not preferred, let's say baseline state. Of course both fission and fusion occur simultaneously, all the time. I understand your rationale behind cyclic fission-fusion but body does fission and fusion to solve a purpose. One of the two processes require higher resources and thus body would do it no more than absolutely required. I assumed it would be fission. So body would need to be coerced to do fission but then eventually body will come back to it's baseline state. Like there's elevated heart rate and there's resting heart rate (baseline). No matter how many times you exercise, the body will come back to resting heart rate. You wouldn't try to decrease your heart rate below resting, would you. So I was thinking you force the body to do fission and it comes back to fusion automatically.

Understanding this isn't important to do your MMD protocol and I have tried the fission side several times but I don't feel much, may be I don't have many damaged mitochondria. But I want my parents and grandparents to try this, so trying to understand as much as possible before pitching the idea before them.

Although stearic acid has wonderful positive effects, especially the reduction in visceral fat if it's robustly replicated, my dad and grandma have mild hypertension, so I was just trying to avoid the fusion side, at least initially. They do fast frequently, so I was hoping that would take care of fusion.

I want my elders to eventually try all your protocols, and much reading I have to do for the same. Thanks for sharing these protocols for others' benefits.

[Turnbuckle]

Yes, that's the mouse study I was referring to. Did you expect this visceral fat loss effect yourself, Turnbuckle? You have most experience with stearic acid. Nature paper says stearic acid induced fusion accelerated fat oxidation. Also, in the mice study, the mice were fed stearic acid all the time, so they may have been in fusion all the time and they were healthier than control mouse. This stearic acid may turn out to be a wonder molecule.

 

 

 

The paper says this--

 

In conclusion, dietary stearic acid leads to dramatically reduced visceral fat likely by causing the apoptosis of preadipocytes.

 

 

While they found it likely, I find it unlikely, as apoptosis requires fission. In 2014 they would not have appreciated that stearic acid drives fusion. A better explanation is the reduction of appetite due to mitochondria running more efficiently in fusion mode. With stearic acid driven fusion I've noted lower hunger and thus greater ease in losing weight with dieting and exercise. Red light applied to visceral fat also reduces hunger, presumably by stimulating mitochondria of fat cells and increasing the release of triglycerides into the blood.

[kurt9]

That's amazing. There aren't many things that can help reduce visceral fat. Reducing visceral fat itself would make one much healthier.

If I may ask you, what's your age, which stearic acid (as in pure or stearic palmitic mixed?) you take and what's your dose?

 

I am 57 years old and do "bodybuilder" weight training  (two day split, four days a week). I'm taking regular food grade steric acid baked into brownies, just like the way Turnbuckle has specified in the protocol. I am doing the mitochondrial fission/fusion protocol, again the one specified by Turnbuckle here. I started at the beginning of the year and am finishing up week 10 today. I have skipped the weeks that I travelled (two weeks) since the beginning of the year.

[longcity90]

Since ALCAR is an AMPK /PGC-1a activator, why is it recommended in fusion and not in fission?

 

Second question that I have not received an answer ... does this type of protocol impact only MTdna or also in the DNA of the nucleus? we know that mitochondrial DNA is of maternal origin while nuclear DNA comes from both parents.

 

Thanks

[Turnbuckle]

 

Since ALCAR is an AMPK /PGC-1a activator, why is it recommended in fusion and not in fission?

 

Second question that I have not received an answer ... does this type of protocol impact only MTdna or also in the DNA of the nucleus? we know that mitochondrial DNA is of maternal origin while nuclear DNA comes from both parents.

 

Thanks

 

 

 

See the latest protocol here. There is no ALCAR, which is not tolerated by some people.

 

This protocol is for mtDNA, not nuclear DNA. Mitochondrial DNA has a clearance mechanism for QC that is amplified by cycling mito fusion and fission. The corresponding mechanism for nuclear DNA is apoptosis, whereby the entire cell is removed and replaced. I have a protocol for that too. Check my profile page for "Stem cell self-renewal with C60."

[Biotochandron]

"The ROS Theory of Obesity" from Dr. Michaels Eades deals with the discussed topic (why stearic acid may be able to reduce visceral fat). The core of his hypothesis is that reverse electron transport (as a signal to induce local insulin resistance) happens in adipose cells using saturated fats with a specific F/N (FADH2:NADH) ratio (-> 0.48) such as stearic and palmitic acid. Giving the adipose cells the flexibility to be insulin resistance as opposed to having yet-more fat stuffed into them constantly by insulin.

 

(You can skip to 31:10 to get directly to the "math".)

 

In this blog the issue is discussed further:

 

http://high-fat-nutr...s-and-mufa.html

 

http://high-fat-nutr...53-formula.html

Someone even made a spreadsheet that calculate the F/N ratio for many oils with pure stearic acid having the perfect ratio for reverse electron transport:

 

https://docs.google....t#gid=438622257

 

 

[Turnbuckle]

Michael Eades has quite the complicated idea. One way to test it would be to compare pure stearic FFA with pure palmitic FFA. Stearic acid has an almost hormonal effect on mitochondria, driving them to fusion, while palmitic does not.

 

....our previous work in cell culture showed that mitochondrial fusion is very specifically induced by C18:0 and not by any other fatty acid such as C16:0, C18:1, or C20:0, because there is a dedicated signaling pathway that senses C18:0

https://www.ncbi.nlm...les/PMC6081440/

 

 

 

If the reduction of hunger is due to mito fusion, then palmitic acid (or any other fatty acid except stearic) will not work.

 

Palmitic acid and palmitates are bad actors that drive mitochondria to fission and higher ROS (which is typical of fission)--

 

...long-term exposure to palmitate (> 8h) enhances ROS generation, which is accompanied by loss of the mitochondrial reticulum and a pattern suggesting increased mitochondrial fission. 

https://www.ncbi.nlm...les/PMC5756120/

 

 

--yet the body converts excess carbs into palmitic acid, with body fat being about 1/4 palmitic acid.

Edited by Turnbuckle, 04 April 2020 - 10:40 AM.

[Ken Mark]

Thanks Kurt for answering my questions.

Biotochondron, the video + website you linked and discussions therein propose that insulin resistance is good. That's shocking to say the least. The F:N ratio hypothesis sounds interesting but if the hypothesis is true, why does fructose cause insulin resistance with F:N ratio of 0.2? Exercise is good for us and it improves insulin sensitivity, not insulin resistance.

The body metabolises each fatty acid differently because each fatty acid is a different chemical so has different property, so all saturated fats can't be bad and all unsaturated fats can't be good, and viceversa. But the hyperlipid approach goes on to generalize all unsaturated fats bad and all saturated ones good. F:N ratio doesn't seem very sound hypothesis. But I'll read what hyperlipid site has to say. There must be some interesting info about fats I haven't come across yet. Thanks for posting that.

Turnbuckle, in the stearic acid mouse study, the caloric intake of stearic acid fed mice was highest, so the mechanism for visceral fat loss may not be lack of hunger. The reason they claim in study about lipotoxicity of stearic acid to adipocytes causing apoptosis doesn't sound convincing to me too. If searched, a paper would be found showing all fatty acids, aminoacids and carbohydrates causing apoptosis in adipocytes.

But the nature paper says that stearic acid caused fusion and during fusion the rate of fat oxidation increased. So body was burning more fat. That may explain visceral fat loss in mice. As they were constantly fed stearic acid, their mitochondria were mostly in fusion and they kept on burning fat, thus they were lean despite slightly higher caloric intake. Some people in this thread have observed more energy while in fusion. Increased fat burning may be partially responsible for that.

Also, fission is favored in fed state and fusion during fasting, so may be fission is well suited for oxidation of carbohydrates plentiful in fed states and fusion for fat burning because in fasted state body has to burn stored fats.

Metochondrial dynamics may have much more to do with the diseases of plenty than simple calorie counting may suggest.

Edited by Ken Mark, 04 April 2020 - 10:19 PM.

[longcity90]

Grazie Kurt per aver risposto alle mie domande.

Biotochondron, il video + sito Web che hai collegato e discussioni in esso propongono che l'insulino-resistenza è buona. A dir poco scioccante. L'ipotesi del rapporto F: N sembra interessante ma se l'ipotesi è vera, perché il fruttosio causa insulino-resistenza con un rapporto F: N di 0,2? L'esercizio fisico è un bene per noi e migliora la sensibilità all'insulina, non l'insulino-resistenza.

Il corpo metabolizza ogni acido grasso in modo diverso perché ogni acido grasso è una sostanza chimica diversa, quindi ha proprietà diverse, quindi tutti i grassi saturi non possono essere cattivi e tutti i grassi insaturi non possono essere buoni e viceversa. Ma l'approccio iperlipide continua generalizzando tutti i grassi insaturi cattivi e tutti quelli saturi buoni. F: il rapporto N non sembra un'ipotesi molto valida. Ma leggerò cosa ha da dire il sito hyperlipid. Devono esserci alcune informazioni interessanti sui grassi che non ho ancora incontrato. Grazie per averlo pubblicato.

Turnbuckle, nello studio sul topo con acido stearico, l'apporto calorico di topi nutriti con acido stearico era massimo, quindi il meccanismo per la perdita di grasso viscerale potrebbe non essere la mancanza di fame. Il motivo che sostengono nello studio sulla lipotossicità dell'acido stearico per gli adipociti che causano l'apoptosi non sembra convincente anche per me. Se cercato, verrebbe trovato un documento che mostra tutti gli acidi grassi, gli aminoacidi e i carboidrati che causano l'apoptosi negli adipociti.

Ma il documento sulla natura afferma che l'acido stearico ha causato la fusione e durante la fusione il tasso di ossidazione dei grassi è aumentato. Quindi il corpo stava bruciando più grasso. Ciò può spiegare la perdita di grasso viscerale nei topi. Poiché venivano costantemente alimentati con acido stearico, i loro mitocondri erano principalmente in fusione e continuavano a bruciare grassi, quindi erano magri nonostante un apporto calorico leggermente più elevato. Alcune persone in questo thread hanno osservato più energia durante la fusione. L'aumento della combustione dei grassi può essere parzialmente responsabile di ciò.

Inoltre, la fissione è favorita nello stato di alimentazione e fusione durante il digiuno, quindi la fissione può essere adatta per l'ossidazione di carboidrati abbondante negli stati di alimentazione e la fusione per bruciare i grassi perché nello stato di digiuno il corpo deve bruciare i grassi immagazzinati.

La dinamica metocondriale può avere molto più a che fare con le malattie di abbondanza di quanto possa suggerire un semplice conteggio delle calorie.

 

Did you mean the opposite with regards to fusion and fission? because it is the fission that increases during a fasting state ..

If tristearin is easily available in 99% purity, you can convert it to sodium or magnesium stearate at home using lye. This is essentially soap making. You can convert the soap back to free fatty acid (FFA) using vinegar (acetic acid), if desired.

If you don't want to eat soap, you can transesterify tristearin with ethanol and lye. This is basically the process used to make biodiesel. The ethyl stearate formed will most probably be liquid, and if so, may be more bioavailable just because of it's physical form.

Making soap (or FFA) or ethyl ester seems best way to me, if indeed 99% pure stearic acid is available. I read somewhere in this thread that it is available.

If high purity tristearin is not available, fully hydrogenated Soy oil (aka soy wax, used in candle making) or fully hydrogenated cottonseed oil or sunflower oil will have upwards of 80% stearic acid in form of tri-ester. In fact any oil containing high % of oleic, linoleic or linolenic acid will upon full hydrogenation yield high stearic tri-ester. The concern with fully hydrogenated oils is the heavy metal content (used in catalytic hydrogenation), so ask suppliers about that. Avoid partially hydrogenated oils, as they will contain trans fats. After you get your hands on fully hydrogenated high stearic oil/wax, you can convert it to soap, FFA or ethyl ester.

GMS seems to be made from industrial stearic acid, meaning it contains about half palmitic. Some pharmacopoeia have specifications for GMS80 which means at least 80% stearic ester. If you get your hands on high stearic GMS and don't want to use it as such, you can always convert it to soap, FFA or ethyl ester.

What I want to say is, obtaining upwards of 80% stearic acid is easily and economically possible with some kitchen hacks, if you so desire.

All of above are my opinions based on basic chemistry.

Further, low fat vegan diet that excludes stearic acid on it's own promotes fission, as was shown in nature paper that found stearic acid promotes fusion in 90% human subjects. So those who don't want to take high does NR or N + R (for sensitivity or whatever reason) may still take benefit of this finding to cause fission. As most fats have some stearic acid, just avoid fats to achieve fission.

From this thread, I understand that fusion seems to be a mechanism evolved to overcome the ATP scarcity/depletion resulting from damage to mtDNA, in which case fusion will happen automatically after you induce fission. Fusion seems to be the normal state, fission needs to be forced.

Is my understanding of fission-fusion written in above two paragraphs correct?

I have one more question.
The nature paper claimed that fusion resulted into higher rate of fat oxidation. There are other papers that say stearic acid reduced visceral fat in mice. Have those of you using stearic acid for fusion experienced visceral fat loss?

 

 

Where did you read that less stearic acid intake causes fission?

[Biotochandron]

Did you mean the opposite with regards to fusion and fission? because it is the fission that increases during a fasting state ..

 

 

Is fission really increased during a fasting state? Would appreciate any references on that for further researching this issue (fasting/mitophagy). What do you mean with fasting, as there might be differences concerning mitochondrial dynamics for short term (<48h) and prolonged (>48h) fasting. I believe that prolonged fasting (>48h) increases fusion.

 

 

 

During starvation, Sirt5 deletion blunted mitochondrial elongation, resulting in increased mitophagy. Our results indicate that starvation induced mitochondrial elongation and evasion from autophagic degradation requires the energy sensor Sirt5.

https://www.ncbi.nlm...pubmed/28340937

 

 

 

 

 

In this report, we provide evidence that glucose deprivation in cultured cells and fasting in mice induces mitochondrial fusion. We show that in response to glucose starvation, HDAC6 binds and deacetylates MFN1, leading to MFN1 activation and mitochondrial fusion.

 

https://www.ncbi.nlm...les/PMC4231308/

 

 

 

 

During autophagy mitochondria elongate, are spared from degradation and sustain cell viability.

During starvation, cellular cyclic AMP levels increase and protein kinase A (PKA) is activated. PKA in turn phosphorylates the pro-fission dynamin-related protein 1 (DRP1), which is therefore retained in the cytoplasm, leading to unopposed mitochondrial fusion. Elongated mitochondria are spared from autophagic degradation, possess more cristae, increased levels of dimerization and activity of ATP synthase, and maintain ATP production. Conversely, when elongation is genetically or pharmacologically blocked, mitochondria consume ATP, precipitating starvation-induced death. Thus, regulated changes in mitochondrial morphology determine the fate of the cell during autophagy.

 

https://www.ncbi.nlm...pubmed/28340937

 

 

 

 

 

Inhibition of fusion would yield smaller fragmented or “bite sized” mitochondria that would be physically ideal for degradation in autophagosomes. Additional evidence of the importance of fragmented mitochondria for mitophagy is the fact that Drp1 (a fission mediator) knockout MEFs are impaired in fasting and uncoupling induced mitophagy [109-111]. A fundamental role for mitochondrial dynamics during mitophagy is also supported by the fact that acute fasting promotes hyper-fusion of mitochondria via protein kinase A mediated inhibition of Drp1. This hyperfused state of mitochondria is thought to prevent mitochondrial degradation by mitophagy during short periods of nutrient limitations although mitochondria are eliminated following chronic starvation conditions.

 

https://www.ncbi.nlm...les/PMC3969632/

 

 

 

But on ther other hand the last paper seems to indicate that mitochondria are eliminated following chronic starvation while acute fasting promotes hyper-fusion. (?)

 

On the basis of the following abstract (fulltext not available) I would expect effective mitophagy to happen between 24h and 40h fasting, then probably fusion takes over and mitophagy declines. Please correct me, if my assumption is wrong.

 

 

 

A 24-hour fasting increased mitophagy flux as demonstrated by a 44.2% increase in the number of mitophagy events in heart sections. The average size of mitophagy events within studied myocytes increased by 13.4%. Western blot analysis showed an increase in LC3-II protein levels in both total cardiac tissue lysates and the mitochondrial fractions, suggesting that autophagy and mitophagy were enhanced in parallel. However, after 48 hours of starvation, mitophagy events decreased by 50.1% compared to events at 24 hours of fasting and decreased by 28% compared to the control fed animals. The average area of each mitophagy event after 48 hours of fasting decreased by 39.9% compared to that at 24 hours and decreased by 31.9% compared to control. Interestingly, Western Blot analysis showed that LC3-II protein levels were increased in the total cardiac tissue lysates but reduced in the mitochondrial fractions, suggesting that the 48-hour fasting enhanced general autophagy but inhibited mitophagy.

 

https://www.fasebj.o...pplement.1015.1

 

 

 

Where did you read that less stearic acid intake causes fission?

 

 

It makes perfectly sense to me that zero stearic acid intake = less fusion (= more fission).

 

Turnbuckl can you please share with us what diet you followed when you were using the protocol? If 10g food-grade stearic acid (= 5g pure stearic acid) is all what it needs to inhibit fission, then just 50g cashew nuts (1,7g stearic acid) and 50g fat/oil like olive or coconut oil (1,2g) (so 3g stearic acid altogether) could completely neutralize the hyper-fission state and so the protocol. Were you very strict and controlled your stearic acid intake through foods when doing the protocol or are saturated fats usually not on your daily menu?

 

This is particularly a great question for the FQAD folks as most of them follow a low-carb/keto diet and ingest lots of saturated fats. So my idea is to combine the protocol with a 24h fast prior to N+R. In this case the problem of lysosomal overload may also be reduced due to autophagy events that have already taken place and emptied glycogen storage.

Edited by Biotochandron, 05 April 2020 - 09:56 AM.

[Unclebob]

Just some anecdotal observations.

 

I am currently cycling through 2 days of fission followed by 2 days of fusion.  I am following Turnbuckle's simplified routine using Sulforaphane instead of the Stearic Acid with PQQ for the fusion days.  This I have been doing through February and March.  From my records I have three observations:

 

1. In terms of weight I lost 10lbs and dropped a trouser size with little or no dietary change or increase in exercise (I am keto and intermittent fasting daily with the odd 48hr fast every 4 to 6 weeks)

2. On the days of fission I experience really cold hands despite in February I was in the UAE with average temps of 22c.

3. Don't hike hot, hot steep mountainous dessert trails on fission days - that was an eye opener.

 

So with no Stearic Acid could I have experienced a similar induced weight loss?  If not what could be the underlying mechanisms that could have caused and are still causing this to happen?  (My weight is still dropping). Any thoughts on the cold hands which were reoccurring through the Fission days of the cycle?? 

Edited by Unclebob, 05 April 2020 - 02:15 PM.

[longcity90]

It is probably my mistake as I thought that during fission the NAD + / NADH ratio increases as when you are in a state of low calorie or ketogenic diet.

 

In addition, if during Fission we also keep the calories lower, AMPK / Sirti1 will also be activated ... also add high intensity exercise and you will have the maximum.

 

While during the fusion the pyruvate / lactate is higher than NAD + / NADH with higher Mtor (anabolism given by greater food) ... that's why it would make sense to insert vitamin K2 which acts by increasing the pyruvate dehydrogenase (also ALA).

 

What you point out about the diet is very important ... I am trying during fission to make a total restriction of stearic acid but it is difficult for me as I don't think that taking too much unsaturated fat is beneficial. Have you ever read what Ray Peat thinks about it? practically I would like to keep saturated without stearic acid ... and there are none ... only coconut!

 

I did not think that a fast greater than 48 hours caused the fusion, very interesting ...

Edited by longcity90, 05 April 2020 - 02:34 PM.

[Ken Mark]

Did you mean the opposite with regards to fusion and fission? because it is the fission that increases during a fasting state.

Nutrient Availability (or excess) = Fed state = Fission.
Nutrient scarcity = Fasting = Fusion.

We're talking about just one side, nutrient Availability. Other side is energy demand.

Low energy demand = Fission.
High energy demand = Fusion.

It's much more complicated, of course.
I came across this review on the topic, which goes in much further details.
https://www.ncbi.nlm...les/PMC5967396/

Where did you read that less stearic acid intake causes fission?

From nature paper claiming stearic acid causes mito-fusion:

After 2 days of a low-C18:0 diet, the mitochondria in neutrophils are quite fragmented; 50% of all neutrophils had fragmented mitochondria and fewer than 10% had fused mitochondria prior to ingesting the C18:0 drink (“0 h”, Fig. 1c).
https://www.nature.c...467-018-05614-6

[longcity90]

Disponibilità di nutrienti (o eccesso) = Stato della federazione = Fissione.
Scarsità di nutrienti = digiuno = fusione.

Stiamo parlando solo di un lato, la disponibilità di nutrienti. L'altro lato è la domanda di energia.

Bassa richiesta energetica = Fissione.
Elevata domanda di energia = fusione.

È molto più complicato, ovviamente.
Mi sono imbattuto in questa recensione sull'argomento, che fornisce ulteriori dettagli.
https://www.ncbi.nlm...les/PMC5967396/


Da un documento sulla natura che afferma che l'acido stearico causa la fusione mitoconduttiva:

 

So if during a day we are doing the fission protocol ... but we go to the gym in those two hours there will be a partial fusion because the body's demand increases? sugars ... amino acids ... what do you think? it would cancel the fission scheduled for that day ... so maybe avoid both aerobics and anaerobic exercises with weights?

[Ken Mark]

So if during a day we are doing the fission protocol ... but we go to the gym in those two hours there will be a partial fusion because the body's demand increases? sugars ... amino acids ... what do you think? it would cancel the fission scheduled for that day ... so maybe avoid both aerobics and anaerobic exercises with weights?

There will always be partial fission and fusion. On fission days we try to maximize fission. That doesn't mean 100% fission. The advantage of doing exercise on Fission days is to take most benefit of exercise when mitochondria are fissioned so very inefficient in producing ATP so you overcome your muscles' capacity with less exercise. Look up Turnbuckle's "exercise like a girl" protocol to understand his rationale behind that. There will be some fusion during exercise to meet the energy demand but defective mitochondria fragmented during fission won't fuse so QC control will still happen, which is the goal of this protocol.

But of course, if you don't want to take exercise benefit, you can just stick with fission without exercise for mito QC. That's my understanding anyways.

[longcity90]

"Elongation of mitochondria is a result of increased fusion or decreased fission activity (top section). This is typical for states of increased energy efficiency (starvation, acute stress, senescence). Shortening of mitochondria is a result of decreased fusion activity or increased fission activity (bottom section). This is typical for states of reduced bioenergetic efficiency (increased respiratory leak). Since bioenergetic adaptation high energy supply requires the arrest of the mitochondria life cycle, extended exposure to excess nutrient environment is expected to impact quality control, a condition that will contribute to reduced longevity."

 

If I have not misunderstood who has defects in the respiratory chain, does greater fission prevail?

[Ken Mark]

I am currently cycling through 2 days of fission followed by 2 days of fusion. I am following Turnbuckle's simplified routine using Sulforaphane instead of the Stearic Acid with PQQ for the fusion days.

In terms of weight I lost 10lbs and dropped a trouser size with little or no dietary change or increase in exercise (I am keto and intermittent fasting daily with the odd 48hr fast every 4 to 6 weeks)

Very interesting. It tells me that there's definitely a robust physiological effect of the protocol you're doing.

So with no Stearic Acid could I have experienced a similar induced weight loss? If not what could be the underlying mechanisms that could have caused and are still causing this to happen? (My weight is still dropping). Any thoughts on the cold hands which were reoccurring through the Fission days of the cycle??

Fission is energetically very inefficient. Energy is lost as heat instead of being converted to ATP. So you burn more fuel for the same amount of energy your body needs daily. But the fuel body burns may not necessarily be fat. So extreme fission will cause weight loss, but would it be Fat loss?

Though you have lost inches from waist, so it very well may be visceral fat. I was interested in Stearic acid as it may specifically be promoting body to burn visceral fat during fusion. But if body prefers fat over carbs/proteins during fusion, irrespective of how you achieved fusion (using stearic acid, SFN or by any other means), that would be super.