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Manipulating mitochondrial dynamics

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

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#1621 Turnbuckle

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Posted 11 July 2020 - 02:23 PM

I have a question about the Leucine.  In the protocol it suggest cooking it into food, but the taste is bad and I prefer ketogenic foods rather than oatmeal, so I'm wondering if it is OK to just mix it in a cup of cold water and toss it down?  In other words, not cooking it.

 

Another question. I got the glycerol monostearate to use, and have cooked it into oatmeal (once a week isn't so bad).  I accidentally put in twice the amount, using a rounded tablespoon instead of a rounded half table spoon.  It seems to have not been a problem.  I was concerned about the possible blood pressure rise, and I don't have any blood pressure lowering medicines here, except for a twenty year old bottle of Cardiotone, of which the main ingredient is Rawolvia, which has a powerful blood presure lowering effect.  In fact it's so powerful it can reduce a person's blood pressure to zero.

 

So the question here is, what is the danger of taking 10G of glycerol monstearate rather than 5G?  Also, since it is labeled as causing fusion, is it OK to take it on both the first and second days of fusion?

 

 

The protocol doesn't advocate cooking leucine, only stearic acid. As for GMS, the bioavailability may be low if you just add it to cold water, as it is insoluble in water and melts at a temperature substantially higher than body temperature. Mixing it into hot chocolate does produce a rapid effect however, and that's the problem. It can increase BP so fast that it can get dangerous before you can do anything about it. If anything, you can (and should) use less GMS than stearic acid triglyceride. 

 

My only experience with GMS suggest that several grams could be fatal in some people.

 

Since stearic acid has a long half-life, taking more of it on a second day of fusion may not be necessary. This allows you to move on to fission sooner than otherwise possible, as stearic acid driven fusion appears to trump NAD+ driven fission.


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#1622 stephen_b

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Posted 11 July 2020 - 07:58 PM

Reports from bodybuilders I've read say that they have found really thorough hydration necessary for GMS to have its desired effects, which were described as deep cellular hydration and a pump during workouts. One report said they got their pump at 6 grams.

 

During my last cycle I did 2 rounds of 2 g GMS. I didn't have a large blood pressure rise, but maybe it comes down to the individual.



#1623 stephen_b

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Posted 12 July 2020 - 04:19 PM

Starting fusion. I took 2g of GMS with water and 2g in coffee.

 

Blood pressure last night: 123/72. Blood pressure after GMS: 147/97, which is really unusual for me.

 

I guess it pays to measure. I could see where this might be an issue for someone with higher baseline BP. I just took some taurine/arginine to counteract.



#1624 stephen_b

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Posted 14 July 2020 - 10:04 PM

Anyone have thoughts on whether magnesium stearate could work for fusion, perhaps avoiding any blood pressure issues?



#1625 Turnbuckle

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Posted 14 July 2020 - 11:35 PM

Anyone have thoughts on whether magnesium stearate could work for fusion, perhaps avoiding any blood pressure issues?

 

I expect the results with metal stearates to be poor unless measures are taken to increase the bioavailability. Cooking them into brownies, for instance. The MP for magnesium stearate is considerably lower than all the others at 191 F, so it might work. Calcium stearate is too high at 311 F, sodium stearate is 490 F, and potassium stearate is around 500 F.

 

Compare this to free stearic acid at 157 F, and food grade stearic acid triglyceride (which is roughly half palmitic acid), which is about the same.


Edited by Turnbuckle, 14 July 2020 - 11:36 PM.

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#1626 Starjumper7

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Posted 17 July 2020 - 04:20 PM

The protocol doesn't advocate cooking leucine, only stearic acid. As for GMS, the bioavailability may be low if you just add it to cold water, as it is insoluble in water and melts at a temperature substantially higher than body temperature. Mixing it into hot chocolate does produce a rapid effect however, and that's the problem. It can increase BP so fast that it can get dangerous before you can do anything about it. If anything, you can (and should) use less GMS than stearic acid triglyceride. 

 

My only experience with GMS suggest that several grams could be fatal in some people.

 

Since stearic acid has a long half-life, taking more of it on a second day of fusion may not be necessary. This allows you to move on to fission sooner than otherwise possible, as stearic acid driven fusion appears to trump NAD+ driven fission.

 

I noticed my mistake about cooking the leucine, I wrote it down wrong while putting it into some desk notes, next time I'll just mix it in some cold water and toss it down.  Taking ten grams of glycerol monostearate seems to have not been a problem, but concerning the blood pressure issue (my pressure measuring machine broke) would it be OK to divide up the five gram dose of glycerol monostearate to twice a day.

 

I'm guessing that the fusion is something that will happen more or less naturally if someone has just done the fission, even if nothing is taken for fusion, maybe just more slowly?

 

Also, what is your opinion about taking TMG with the niacin/niacinamide & ribose during fission,  would it block the fission process?


Edited by Starjumper7, 17 July 2020 - 04:21 PM.

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#1627 stephen_b

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Posted 23 July 2020 - 03:56 AM

I've decided to ditch the glycerol monostearate. After my 3rd cycle was complete, I had persistent high blood pressure (30 points higher than normal) still several days after. My blood pressure returned to normal after starting the next cycle with fission.



#1628 lost69

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Posted 23 July 2020 - 11:17 AM

I've decided to ditch the glycerol monostearate. After my 3rd cycle was complete, I had persistent high blood pressure (30 points higher than normal) still several days after. My blood pressure returned to normal after starting the next cycle with fission.

 

BP spikes can be very dangerous, if you remember last year i had an ischemic stroke using 24g of pure stearic acid from sigma and pure sulpharophane since then i lowered dose to 10g and no problems.

no lasting damage and mri showed few cells being abnormal (they could not say what that was exactly), 1year later those cells look almost normal



#1629 yz69

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Posted 23 July 2020 - 04:38 PM

I tried emulsifying 2g GMS with some boiling milk and cream and took it around 9:00AM yesterday.  My BP before taking it was 98/60, @9:10AM it was 101/63, @9:15 it was 105/63 @9:20 BP dropped to 90/53 @9:40 BP was 93/58. I only experienced a small bump in BP, not sure it was caused by GMS.



#1630 stephen_b

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Posted 23 July 2020 - 10:47 PM

Another anecdotal report: my best running day during the cycles (now starting on number 4 with 1 or 2 days break between cycles) has been the first day of fission. I'm not sure why...


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#1631 theobromananda

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Posted 27 July 2020 - 01:03 PM

Aging shifts mitochondrial dynamics toward fission to promote germline stem cell loss  (2020)

 

Abstract

Changes in mitochondrial dynamics (fusion and fission) are known to occur during stem cell differentiation; however, the role of this phenomenon in tissue aging remains unclear. Here, we report that mitochondrial dynamics are shifted toward fission during aging of Drosophila ovarian germline stem cells (GSCs), and this shift contributes to aging‐related GSC loss. We found that as GSCs age, mitochondrial fragmentation and expression of the mitochondrial fission regulator, Dynamin‐related protein (Drp1), are both increased, while mitochondrial membrane potential is reduced. Moreover, preventing mitochondrial fusion in GSCs results in highly fragmented depolarized mitochondria, decreased BMP stemness signaling, impaired fatty acid metabolism, and GSC loss. Conversely, forcing mitochondrial elongation promotes GSC attachment to the niche. Importantly, maintenance of aging GSCs can be enhanced by suppressing Drp1 expression to prevent mitochondrial fission or treating with rapamycin, which is known to promote autophagy via TOR inhibition. Overall, our results show that mitochondrial dynamics are altered during physiological aging, affecting stem cell homeostasis via coordinated changes in stemness signaling, niche contact, and cellular metabolism. Such effects may also be highly relevant to other stem cell types and aging‐induced tissue degeneration.

 


Edited by theobromananda, 27 July 2020 - 01:03 PM.

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#1632 p75213

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Posted 27 July 2020 - 07:00 PM

I remember reading (I think on this thread) sulforaphane inhibits mitochondrial fission.

https://www.ncbi.nlm...les/PMC5126150/

#1633 Empiricus

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Posted 30 July 2020 - 05:48 PM

Been taking glycerol monostearate in doses of 5-15g (divided doses) per day for 3 days.  No noticeable negative effects, though I don't own a blood pressure monitor.  Though I don't have a history of high blood pressure, I'm wondering if there is a way to know if you're overdoing it with the GM without using a bp monitor.    

 

Started taking it for chronic infectious disease related symptoms, not specifically for this protocol.  Initial round went sufficiently well that I am looking at continuing to take it for a longer duration.  

 


Edited by Empiricus, 30 July 2020 - 06:08 PM.


#1634 Turnbuckle

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Posted 30 July 2020 - 07:06 PM

Been taking glycerol monostearate in doses of 5-15g (divided doses) per day for 3 days.  No noticeable negative effects, though I don't own a blood pressure monitor.  Though I don't have a history of high blood pressure, I'm wondering if there is a way to know if you're overdoing it with the GM without using a bp monitor.    

 

Started taking it for chronic infectious disease related symptoms, not specifically for this protocol.  Initial round went sufficiently well that I am looking at continuing to take it for a longer duration.  

 

 

I strongly urge you to get one. They can be had for under $30, and high BP generally produces no symptoms until it is too late.


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#1635 Empiricus

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Posted 31 July 2020 - 08:13 AM

I strongly urge you to get one. They can be had for under $30, and high BP generally produces no symptoms until it is too late.

 

I will definitely get one then before taking any more.  (Good to know about the price, I had imagined they must cost hundred of dollars).

 

What reading would you say is too high and you need to cut back the dose?   As a person with normal blood pressure, does only high pressure pose a danger, or is it hazardous to go a certain amount over my personal baseline level?   



#1636 DragosR

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Posted 31 July 2020 - 10:19 AM

HI! I am willing to try this protocol fighting against my antibiotics associated mtDna damage. I want to add the following two substances, Luteolin and Palmitoylethanolamide. I've been researching them in terms of mitochondrial dynamics, trying to figure out where to take them ( fission vs fussion ).

The main reasons i want to take these are: https://www.ncbi.nlm...les/PMC7139331/

 

I'll post here all the research i did along with a conclusion, waiting for you guys please to tell me if i am wrong or not.

 

--- LUTEOLIN ---

 

1) Luteolin-fisetin => Sirts + Foxo3a activation ( https://www.ncbi.nlm...les/PMC5621366/ ) 

The above findings suggest that fisetin and luteolin inhibited high glucose-induced ROS production in monocytes through the activation of SIRTs and FOXO3a.

 

2) FOXO3 is most frequently associated with autophagy induction. FOXO3 controls the expression of genes involved in autophagosome biogenesis [81, 85–87].

   Thus, in addition to regulating autophagy, FOXO3 regulates genes involved in mitophagy and may be a critical regulator of mitochondrial turnover in NSPCs.

https://www.ncbi.nlm...les/PMC6478346/

 

3). Two recent studies delineate a role of FOXO3a in modulating mitophagy. In the first study, mitochondrial proteotoxic stress activates UPRmt and elevates sirtuin-3 (SIRT3) expression (Figure 2(a)). SIRT3 is another member of the sirtuin family that is localized to the mitochondria and plays predominant roles in mitochondrial processes. A study found that increased SIRT3 levels lead to FOXO3a deacetylation and activation [88]. Active FOXO3a induces the transcription of genes involved in mitophagy, including lc3, atg9, and bnip3l/nix [88]. Notably, the study observed that only the fragmented mitochondria were engulfed by autophagosomes whereas the remaining mitochondrial network was unaffected [88]. This observation is consistent with the notion of mitophagy, where only the damaged mitochondria are targeted for autophagic clearance. It was also observed that Parkin expression levels remained unchanged, suggesting that SIRT3-FOXO3a-mediated mitophagy is independent of Parkin [88]. It appears that the Parkin-independent mitophagy induced by SIRT3-FOXO3a is a peculiar response to mitochondrial UPR. In contrast, another study reported that SIRT3-FOXO3a signalling upregulated Parkin expression to mediate enhanced mitophagy to protect against diabetic cardiomyopathy in mice [89]. This shows that SIRT3-FOXO3a activation can induce different mitophagy mechanisms, possibly determined by the type of mitochondrial stress.

 

4) Luteolin, a flavonoidal compound derived from Lonicera japonica Thunb. and Chrysanthemum indicum L., has been reported to show anti-inflammatory, anti-oxidative and anti-carcinogenic effects. ----> (4) Luteolin inhibited PMA-induced phosphorylation and nuclear translocation of nuclear factor kappa B (NF-κB) p65. This result suggests that luteolin can regulate the secretion, production and gene expression of mucin by acting on airway epithelial cells via regulation of NF-kB signaling pathway.  ( https://pubmed.ncbi....h.gov/25285988/ ) 

In a study by Liu et al. (2004), inhibition of NF-κB alone in macrophages resulted in the release of cytochrome c. Recall that cytochrome c is responsible for shuttling electrons from Complex III to Complex IV and that the release of cytochrome c into the cytoplasm, an activator of caspases, is a key step in triggering apoptosis.

 

5) Found this also somewhere on this topic ->  Mitochondrial Fusion by increasing cytochrome c oxidase

 

Conclusion : Luteolin in FISSION days. (please correct me if i am wrong)

 

--- Palmitoylethanolamide ---  (PEA)

 

1) PEA -> Its antinflammatory, analgesic and neuroprotective actions have been however associated with peroxisome proliferator-activated receptor-α (PPAR-α) activation.

 

2) PPAR α activity is induced by fasting and its molecular consequences overlap with the effects of calorie restriction and ketogenic diet (CRKD). CRKD induces increase of NAD+/NADH ratio and drop in ATP/AMP ratio. The first one is the main stimulus for enhanced protein deacetylase SIRT1 activity; the second one activates AMP-dependent protein kinase (AMPK). Both SIRT1 and AMPK exert their major metabolic activities such as fatty acid oxidation and block of glycolysis and protein, nucleotide and fatty acid synthesis through the effector protein peroxisome proliferator activated receptor gamma 1 α coactivator (PGC-1α). PGC-1α cooperates with PPAR α and their activities might contribute to potential anticancer effects of CRKD, which were reported for various brain tumors. Therefore, PPAR α activation can engage molecular interplay among SIRT1, AMPK, and PGC-1α that provides a new, low toxicity dietary approach regimen.

 

3) Physiologically, SIRT1 and AMPK are concomitantly activated under conditions of reduced nutrient availability such as; glucose restriction, fasting, chronic calorie restriction, and exercise

 

4)  PEA and Sirtuin-1, sharing a common target or a direct interaction?

 

 PEA and Sirt1 share a common mechanism, consisting in the activation of PPAR-α [146-148]. Sirt1 potentiates the effect of PPAR-α, the main target of PEA involved in the antinflammatory, analgesic and neuroprotective effects [82,90,94,100]. Pertinent to this, PEA and Sirt1 could play a PPAR-α mediated sinergic action. Resveratrol as well plays antinflammatory and neuroprotective actions with beneficial effects in neurological disorders including neuropathic pain [140,146,149,150].

 

The molecular target through which PEA plays its anti-inflammatory, analgesic and neuroprotective role is PPARα [82,158], even if several indirect mechanisms, known as the “entourage effect” have been demonstrated. The entourage effect includes the endocannabinoid-mediated activation of CB1, CB2 and TRPV1 receptors [114,159] or PPARα-mediated TRPV1 desensitization [60,160]. Moreover, the PPARα direct activation by PEA does not exclude the contribution of the entourage effects thus justifying the multiple and the large spectrum effects of PEA. The development of novel formulations such as m- or um-PEA or the combination with the flavonoid luteolin with antioxidant property has improved the clinical efficacy of PEA. Moreover, PEA was avoided of adverse reactions worthy of notes in clinical studies. Preclinical and clinical studies about PEA efficacy in neurological disease report encouraging outcomes and are considerably multiplying in these last years, which is already a clear sign of its enormous therapeutic potential.

(http://www.jneuropsy...-12915.html#153)

 

Should i include them both in fission days? Thank you!

 

 

Also, while researching this i came across this, a new potential supplement for fission along with LUTEOLIN and PEA (for me): Yes, i know, the fewer the supplements the better the protocol, but eh :D

 

Here, we described a new mechanism of mitochondrial fragmentation induced by bioenergetic/metabolic stress that at an early time point proceeds in a Drp1-independent fashion, driven mainly by the actin cytoskeleton and the deacetylation of cortactin by SIRT1. At later time points, AMPK prevails and orchestrates the phenomenon (Figure 7).

 

Intensified Drp1 activation resulted in increased fragmentation and mitochondrial oxidative stress, promoting apoptosis

 

Also, using live cell imaging, Kanki’s group show that upon induction of mitophagy, mitochondria makes a bud that is wrapped and excised without the participation of Drp1 by an isolation membrane formed on the mitochondrial surface (Yamashita et al., 2016). Altogether, these works confirm the existence of Drp1-independent mitochondrial fragmentation mechanisms, and the mechanistic details await to be unveiled.

 

The supplement who increase drp1 is Silibinin.

 

Silibinin Induces G2/M Cell Cycle Arrest by Activating Drp1-Dependent Mitochondrial Fission in Cervical Cancer ( https://www.frontier...2020.00271/full )

 

Silibinin (INN), also known as silybin (both from Silybum, the generic name of the plant from which it is extracted), is the major active constituent of silymarin, a standardized extract of the milk thistle seeds, containing a mixture of flavonolignans consisting of silibinin, isosilibininsilichristinsilidianin, and others.

 

 

 

 

 


Edited by DragosR, 31 July 2020 - 10:43 AM.


#1637 hsibai

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Posted 01 August 2020 - 03:40 AM

Anyone have thoughts on whether magnesium stearate could work for fusion, perhaps avoiding any blood pressure issues?

My first experience with GMS was not good as I experienced elevated BP for most of the day. However, before ditching GMS, I decided to give it one more shot. This time however, I preloaded the night before on a cocktail of Arginine. Citruline, Taurine (4,1,2 grams). In the morning, I repeated the cocktail an hour before taking 2.5g of GMS in hot chocolate and then repeated the hot chocolate/GMS an hour later. This time around I did not observe any meaningful fluctuation in my BP. Summary is, as Turnbuckle advised, if you’re going to use GMS, do your research and use with caution. 



#1638 QuestforLife

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Posted 01 August 2020 - 07:08 AM

My first experience with GMS was not good as I experienced elevated BP for most of the day. However, before ditching GMS, I decided to give it one more shot. This time however, I preloaded the night before on a cocktail of Arginine. Citruline, Taurine (4,1,2 grams). In the morning, I repeated the cocktail an hour before taking 2.5g of GMS in hot chocolate and then repeated the hot chocolate/GMS an hour later. This time around I did not observe any meaningful fluctuation in my BP. Summary is, as Turnbuckle advised, if you’re going to use GMS, do your research and use with caution.


Do we know that it is the GMS that is causing the BP rises or is it the combination with hot chocolate cocoa? I don't have a BP monitor (yet) but I definitely felt some pressure behind the eyes on making a GMS hot chocolate, which was significantly reduced by adding taurine. But I don't notice the same with GMS (or pure stearic acid) mixed in other things like butteroll or brownies. The cocoa could be part of the problem, also being high in stearic acid.

#1639 Turnbuckle

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Posted 01 August 2020 - 09:58 AM

HI! I am willing to try this protocol fighting against my antibiotics associated mtDna damage. I want to add the following two substances, Luteolin and Palmitoylethanolamide. I've been researching them in terms of mitochondrial dynamics, trying to figure out where to take them ( fission vs fussion ).

The main reasons i want to take these are: https://www.ncbi.nlm...les/PMC7139331/

 

 

 

Are you trying to treat mito dysfunction, or something else? If the former, and if you suspect severe mtDNA damage, I suggest you proceed cautiously at first. Too much fission and too much mitophagy for a person with severe mito damage could be dangerous. As for luteolin, it likely won't do much of anything anyway, due to its poor bioavailability.


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#1640 Empiricus

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Posted 02 August 2020 - 08:28 AM

Do we know that it is the GMS that is causing the BP rises or is it the combination with hot chocolate cocoa? I don't have a BP monitor (yet) but I definitely felt some pressure behind the eyes on making a GMS hot chocolate, which was significantly reduced by adding taurine. But I don't notice the same with GMS (or pure stearic acid) mixed in other things like butteroll or brownies. The cocoa could be part of the problem, also being high in stearic acid.

 

I acquired a quality BP monitor.  I have since discovered that 5ml (grams?) of GMS powder melted into 15g of imported "75% chocolate with cocoa nibs" made into hot chocolate with the addition of hot milk has no adverse affect on my BP.  In fact, my BP went down a little.  I have repeated the experiment twice. 

Here's a mystery. We know that dark chocolate is high in stearic acid.  Yet, hypertensives don't seem to be dropping dead from chocolate, quite the contrary, there are many reports that chronic consumption of dark chocolate results in lowered BP in persons with hypertension.  So it would seem that the flavonoids in dark chocolate counteract chocolate's high stearic acid content.  I wonder if such a tendency might explain my own results.   

 

Incidentally, my previous implementations of Turnbuckle's mitochondrial protocol (several years ago) had always involved substituting large amounts of dark chocolate where the protocol called for stearic acid. 



#1641 Turnbuckle

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Posted 02 August 2020 - 09:03 AM

I acquired a quality BP monitor.  I have since discovered that 5ml (grams?) of GMS powder melted into 15g of imported "75% chocolate with cocoa nibs" made into hot chocolate with the addition of hot milk has no adverse affect on my BP.  In fact, my BP went down a little.  I have repeated the experiment twice. 

Here's a mystery. We know that dark chocolate is high in stearic acid.  Yet, hypertensives don't seem to be dropping dead from chocolate, quite the contrary, there are many reports that chronic consumption of dark chocolate results in lowered BP in persons with hypertension.  So it would seem that the flavonoids in dark chocolate counteract chocolate's high stearic acid content.  I wonder if such a tendency might explain my own results.   

 

Incidentally, my previous implementations of Turnbuckle's mitochondrial protocol (several years ago) had always involved substituting large amounts of dark chocolate where the protocol called for stearic acid. 

 

 

The cocoa butter in chocolate bars is a triglyceride with palmitic, stearic, and oleic moieties. Roughly 1/3 is stearic. Food grade "stearic acid" is also a triglyceride, with roughly half stearic and half palmitic moieties. The rate of digestion is dependent on the mix of fatty acids and their position on the glycerol backbone. Tristearin, for instance, is a triglyceride with three stearic acid moities. It has very low bioavailability. GMS is a monoglyceride and thus is essentially pre-digested. I will be absorbed much more quickly than any of the others. The rapid absorption of GMS seems to be the driver of hypertensive effects, for those who are sensitive to it.

 

Note that most products sold as "stearic acid" also contain palmitic acid. They may even contain more palmitic acid than stearic acid. GMS typically contains both stearic and palmitic acids, some portion of which are diglycerides. As one example --

 

GLYCEROL MONOSTEARATE 40-55
Glyceroli monostearas 40-55
DEFINITION
Glycerol monostearate 40-55 is a mixture of
monoacylglycerols, mainly monostearoylglycerol,
together with variable quantities of di- and triacylglycerols. It
contains 40.0 per cent to 55.0 per cent of monoacylglycerols,
30.0 per cent to 45.0 per cent of diacylglycerols and
5.0 per cent to 15.0 per cent of triacylglycerols, obtained
by partial glycerolysis of vegetable oils mainly containing
triacylglycerols of palmitic or stearic acid or by esterification
of glycerol with stearic acid 50 (type I), stearic acid 70
(type II) or stearic acid 95 (type III) (see Stearic acid (1474)).
The fatty acids may be of vegetable or animal origin.

 

 

 


Edited by Turnbuckle, 02 August 2020 - 09:35 AM.

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#1642 QuestforLife

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Posted 03 August 2020 - 01:02 PM

 

The cocoa butter in chocolate bars is a triglyceride with palmitic, stearic, and oleic moieties. Roughly 1/3 is stearic. Food grade "stearic acid" is also a triglyceride, with roughly half stearic and half palmitic moieties. The rate of digestion is dependent on the mix of fatty acids and their position on the glycerol backbone. Tristearin, for instance, is a triglyceride with three stearic acid moities. It has very low bioavailability. GMS is a monoglyceride and thus is essentially pre-digested. I will be absorbed much more quickly than any of the others. The rapid absorption of GMS seems to be the driver of hypertensive effects, for those who are sensitive to it.

 

 

Good point. I knew GMS was (mainly) a single stearic acid chain attached to the glycerol backbone, but for some reason I hadn't appreciated that 'pure' stearic acid (I have a pure source, no palmitic acid) was in the triglyceride format rather than a free fatty acid. This totally explains the faster absorption of GMS. Having said that with a tri as opposed to mono - glyceride you're getting 3x the stearic acid, albeit over a much longer period. 



#1643 Turnbuckle

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Posted 03 August 2020 - 02:16 PM

Good point. I knew GMS was (mainly) a single stearic acid chain attached to the glycerol backbone, but for some reason I hadn't appreciated that 'pure' stearic acid (I have a pure source, no palmitic acid) was in the triglyceride format rather than a free fatty acid. This totally explains the faster absorption of GMS. Having said that with a tri as opposed to mono - glyceride you're getting 3x the stearic acid, albeit over a much longer period. 

 

Tristearin doesn't have 3x as much stearic acid as GMS per gram. It's only a small fraction more, as the glycerol content is a relatively small component. If your stearic acid source makes no specific claim about palmitic acid, it is probably a triglyceride with palmitic acid. I'm not sure what "purity" even means in that industry, but it doesn't mean no palmitic.


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#1644 QuestforLife

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Posted 03 August 2020 - 04:56 PM

Tristearin doesn't have 3x as much stearic acid as GMS per gram. It's only a small fraction more, as the glycerol content is a relatively small component. If your stearic acid source makes no specific claim about palmitic acid, it is probably a triglyceride with palmitic acid. I'm not sure what "purity" even means in that industry, but it doesn't mean no palmitic.

Yes, I should have said 3x the stearic acid per molecule, not gram. The glycerol is 90/360 g/MOL in GMS and 90/890 g/MOL in GTS.
I have 98% stearic acid from Sigma. Is that really necessary or is 50% good enough? I've no idea, but I suspect a mix with palmitic acid is fine.

Edited by QuestforLife, 03 August 2020 - 04:58 PM.


#1645 tolerant

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Posted 12 August 2020 - 02:55 AM

I'm sorry if this has already been covered, but I have several questions with respect to the protocol as follows.

1. Since stearic acid does not pass the blood brain barrier, will using it in this protocol result in brain mitochondria remaining in a state of fission (which I assume is a very undesirable outcome)? Will using sulphurophane in place of stearic acid get around this problem, and if so, what is the appropriate dosage and when should it be taken (i.e together with the other supplements or earlier)?

2. PQQ has insufficient blood brain barrier permeability, at least according to the following study: https://www.research...ibril_Formation

Does this mean that it will fail to create sufficient new mitochondria in the brain, and if so, is there a way of getting around this? Perhaps taking a larger dose?

3. If increasing NAD+ weakens you physically by promoting fission, then why do so many people find that it vastly boosts athletic performance?

Thanks.

Edited by tolerant, 12 August 2020 - 02:56 AM.


#1646 Andey

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Posted 12 August 2020 - 05:16 AM

TBH I think stearic acid passes BBB just fine, its just that neurons dont use fats as fuel and probably dont react to stearic acid as there is no fatty oxidation to switch to, on the other hand glial cells(astrocytes included) should use it no problem. 



#1647 Turnbuckle

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Posted 12 August 2020 - 09:04 AM

TBH I think stearic acid passes BBB just fine, its just that neurons dont use fats as fuel and probably dont react to stearic acid as there is no fatty oxidation to switch to, on the other hand glial cells(astrocytes included) should use it no problem. 

 

See this paper--

 

 First, discrete studies have demonstrated that cholesterol and the nonessential fatty acids, (palmitic, oleic, stearic) do not enter the brain parenchyma. These studies demonstrated that the 18 carbon-monocarboxylic fatty acids, linoleic acid with two cis-double bonds entered brain, whereas oleic acid, with one cis-double bond, did not enter brain. It was concluded the entry of essential fatty acids into brain is accomplished in a highly selective and discrete manner. 

https://pubmed.ncbi....h.gov/11478373/

 

 

 

There is still some question about this, but if it does enter the brain, it is quickly modified and does not increase the stearic acid levels there.


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#1648 Turnbuckle

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Posted 12 August 2020 - 09:21 AM

I'm sorry if this has already been covered, but I have several questions with respect to the protocol as follows.

1. Since stearic acid does not pass the blood brain barrier, will using it in this protocol result in brain mitochondria remaining in a state of fission (which I assume is a very undesirable outcome)? Will using sulphurophane in place of stearic acid get around this problem, and if so, what is the appropriate dosage and when should it be taken (i.e together with the other supplements or earlier)?

2. PQQ has insufficient blood brain barrier permeability, at least according to the following study: https://www.research...ibril_Formation

Does this mean that it will fail to create sufficient new mitochondria in the brain, and if so, is there a way of getting around this? Perhaps taking a larger dose?

 

 

This is likely a good thing, given the following paper --

 

Neurotoxicity and apoptosis induced by pyrroloquinoline quinone and its ester derivative on primary cortical neurons

the cytotoxic effects of PQQ and PQQE were examined in primary mouse cortical neurons. The results indicated that both PQQ and PQQE decreased neuron viability, reduced intracellular ATP level and disrupted the mitochondrial membrane potential in a concentration- and time-dependent manner, while PQQ was less potent than PQQE. PQQ and PQQE induced apoptosis

https://pubmed.ncbi....h.gov/32068067/

 

 

As I've previously noted, other biogenesis stimulants exist. One example is Leucine, which is readily crosses the BBB --

 

Leucine enters the brain from the blood more rapidly than any other amino acid. Astrocytes, which are in close approximation to brain capillaries, probably are the initial site of metabolism of leucine. A mitochondrial branched-chain aminotransferase is very active in these cells. Indeed, from 30 to 50% of all alpha-amino groups of brain glutamate and glutamine are derived from leucine alone.

https://pubmed.ncbi....h.gov/15930465/

 

 

And,

 

Leucine significantly increased mitochondrial content, mitochondrial biogenesis-related genes expression, fatty acid oxidation, SIRT1 activity and gene expression, and AMPK phosphorylation in C2C12 myotubes compared to the controls,

https://www.hindawi....me/2014/239750/

 

 

You also asked --

 

3. If increasing NAD+ weakens you physically by promoting fission, then why do so many people find that it vastly boosts athletic performance?

 

 

 
Increasing fission will definitely reduce athletic performance if you have a lot of defective mtDNA. The reason is that multiple strands of defective mtDNA in a mitochondrion cover for one another, if the same genes are not defective. With only one loop of mtDNA in a mitochondrion, only one defective gene will shut down ATP production. Also, if you produce a constant state of fission, your mito numbers will drop, reducing performance.
 
Methods
Eighteen Wistar rats were equally divided in two groups that received either saline vehicle or nicotinamide riboside at a dose of 300 mg/kg body weight/day for 21 days via gavage. At the end of the 21-day administration protocol, both groups performed an incremental swimming performance test.
 
Results
The nicotinamide riboside group showed a tendency towards worse physical performance by 35 % compared to the control group at the final 10 % load (94 ± 53 s for the nicotinamide riboside group and 145 ± 59 s for the control group; P = 0.071).

 

 

While this is a very large dose of NR, it is probably unnecessary to use this much to get a negative effect, as once total fission is achieved, you can't go any further.


Edited by Turnbuckle, 12 August 2020 - 09:39 AM.

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#1649 stephen_b

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Posted 15 August 2020 - 03:19 PM

From Mitochondrial Quality Control and Muscle Mass Maintenance (Jan 2016),

 

Altogether, Mfn2 promotes mitochondrial fusion, enhances ER-mitochondria and activates mitophagy via PINK1/Parkin pathway.

 

 

Where Mfn2 is Mitofusin 2 and ER is the endoplasmic reticulum.

 

Defects in Mfn2 can be helped by coenzyme Q (PMID: 25688136):

 

Moreover, addition of coenzyme Q to immortalized Mfn2 knockout MEFs or isolated mitochondria partially rescues the respiratory chain dysfunction, which suggests a therapeutic strategy for intervention in affected patients

 

 

This leads me to wonder if CoQ10 or ubiquinol might have a role in the program. I realize that rescuing defective mitochondria that lack Mfn2 by providing a work-around is not the same as actually promoting Mfn2.



#1650 Turnbuckle

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Posted 15 August 2020 - 03:43 PM

 rescuing defective mitochondria 

 

The object is to recycle and replace defective mitochondria, not rescue them.


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