2195 replies to this topic

[Turnbuckle]

In the human study they didn't use lethicin or cocoa - just heated it in milk and on consumption it caused fusion to occur in the cells they measured it in. So as far as I'm concerned further enhancement of bioavailability beyond this is unecessary.

 

 

This is their recipe--

 

Preparation of the banana shakes

For the C18:0 drink, 24 g of C18:0 intended for human consumption (stearic acid, Sigma-Aldrich W303518) were mixed with 100 ml of low-fat milk. This amount of C18:0 was selected by calculating the C18:0 content of a high fat meal. The mixture was microwaved to emulsify the fatty acid. One small banana was added and the whole mixture was homogenized with a hand blender. The volume was completed to 250 ml with more low-fat milk. The mock drink was prepared the same way without fatty acids. For the C16:0 drink, 21.56 g (an equal molar amount to 24 g of C18:0) of C16:0 intended for human consumption (palmitic acid, Sigma-Aldrich W283207) was added instead. Milkshakes were prepared approximately 90 min before consumption.

https://www.nature.c...467-018-05614-6

 

 

 

As always when dealing with stearic acid, you have to question what exactly this is. The stearic acid from Sigma-Aldrich appears to be a free acid (though this is not explicitly stated), whereas everything available to the public is a triglyceride. Expect a free acid to reversibly bond with components of the shake, whereas triglycerides would not. Once the shake cooled off, globules of stearic acid triglycerides would then solidify into particles again.

[QuestforLife]

I've only used the Sigma stuff once, but unlike the Mango butter stuff it melts all at once and solidifies again all at once when it cools off. I'd put this down to its purity, but perhaps the fatty acid form is also different to other formulations people are using. 

[Turnbuckle]

I've only used the Sigma stuff once, but unlike the Mango butter stuff it melts all at once and solidifies again all at once when it cools off. I'd put this down to its purity, but perhaps the fatty acid form is also different to other formulations people are using. 

 

"Stearic acid" triglycerides are normally a mixture of stearic (S) and palmitic acids (P) and positional isomers thereof -- such as SSP, SPS, PSP and PPS -- so it will not have an exact melting point. Mango butter is even more complicated with several other fatty acids.

[Nate-2004]

References:

 

Phospholipid emulsifying properties improve bioavailability and are a good delivery system not just for fats like DHA and EPA but drugs and even stearic acid.

https://www.scienced...es/stearic-acid

 

Cocoa contains phospholipids

https://www.ncbi.nlm...les/PMC4786564/

 

Soy lecithin is a mixture of phospholipids

https://en.wikipedia.org/wiki/Lecithin

Edited by Nate-2004, 11 December 2018 - 10:23 PM.

[Rocket]

In the human study they didn't use lethicin or cocoa - just heated it in milk and on consumption it caused fusion to occur in the cells they measured it in. So as far as I'm concerned further enhancement of bioavailability beyond this is unecessary.

 

I have read the same things. Cooking is not required. I will continue to mix into protein shakes. I think that I would notice if my body was not digesting the stearic acid that didn't get broken down by the blending process!

[capob]

If the effort is to reach small enough mito for QC, and sleeping (natural melatonin, small fast) would result in fusion, why not attempt to maximize fission on a single day by condensing the first two days (2g N + 2g R, 3hr to exercise, then repeat)?  And, perhaps increase N + R to 3g each (which is, afaik, the max tested regular dose (https://www.ncbi.nlm...pubmed/11126400 1940 Hoffer at 6g/day))

[Turnbuckle]

If the effort is to reach small enough mito for QC, and sleeping (natural melatonin, small fast) would result in fusion, why not attempt to maximize fission on a single day by condensing the first two days (2g N + 2g R, 3hr to exercise, then repeat)?  And, perhaps increase N + R to 3g each (which is, afaik, the max tested regular dose (https://www.ncbi.nlm...pubmed/11126400 1940 Hoffer at 6g/day))

 

 

You can do a one day mitophagy treatment, no problem. I spread it out to more than one day to take advantage of the fact that NAD+ will be raised for a while, and it's only possible to eliminate a fraction of the defective mitochondria in one day. The QC process is not just limited to labelling of defective mitochondria for recycling, but includes the digestion in lysosomes. Lysosomes can handle only so many mitochondria and digesting them can take a while. I had a large load of defective mitochondria initially due to statins, and it took many many months of cycling mitophagy with biogenesis to correct the problem.

[lost69]

today i tried the original recipe from the study and it is by far extremely easy and fast to prepare.the taste is amazing, easy to drink and digest

i first made an extremely fine powder of Sigma-Aldrich W303518 by a coffee grinder.it is easy to mix and eat 24g by making a very fine powder

 

i put some milk on the powder, mixed a little and microwaved to reach boiling point

 

in a separate bowl i did banana milk shake

 

i added the hot stearic acid/milk to the banana shake and blended some more and drank straight away.

 

 

i did not use all the milk like in the study (i think they used 500ml in total) but much less maybe about 250ml in total, the stearic acid was not solid even if it was not hot while drinking

i think that boiling in microwave until milk becomes a tranparent liquid and blending it well with this liquid, or remaining concentrated milk, makes it possible to drink it not hot and not solid.i guess as turnbuckle said it bonds to the milk molecules and this way it stays liquid some more when cooling off

 

i don t know if this recipe can work with the commercial stearic acid, the sigma is very diiferent in the way it melts and solidifies again

 

 

 

Edited by lost69, 16 December 2018 - 05:16 PM.

[Rocket]

today i tried the original recipe from the study and it is by far extremely easy and fast to prepare.the taste is amazing, easy to drink and digest
i first made an extremely fine powder of Sigma-Aldrich W303518 by a coffee grinder.it is easy to mix and eat 24g by making a very fine powder

i put some milk on the powder, mixed a little and microwaved to reach boiling point

in a separate bowl i did banana milk shake

i added the hot stearic acid/milk to the banana shake and blended some more and drank straight away.


i did not use all the milk like in the study (i think they used 500ml in total) but much less maybe about 250ml in total, the stearic acid was not solid even if it was not hot while drinking
i think that boiling in microwave until milk becomes a tranparent liquid and blending it well with this liquid, or remaining concentrated milk, makes it possible to drink it not hot and not solid.i guess as turnbuckle said it bonds to the milk molecules and this way it stays liquid some more when cooling off

i don t know if this recipe can work with the commercial stearic acid, the sigma is very diiferent in the way it melts and solidifies again

Seems to work fine with my commercial grade. It does leave a nasty white film to wash out of the glass.

I really don't notice a difference between cooking it or eating it raw in my shake.

[sumguy90]

Sorry if this was answered already, I've been following the thread sporadically.

Given the safety and purity concerns with the easily available stearic acid products, is consuming straight cocoa butter or mango butter a good alternative?

For a while I was adding a handful of cocoa butter wafers to my bullet proof coffee now and then and it was delicious.

Edited by sumguy90, 24 December 2018 - 12:03 PM.

[jgkyker]

If I understand correctly, adding a substance that damages mitochondria could result in higher rates of fission.

 

Is it possible that "promoting fission" is actually damaging mitochondria? From what I'm gathering, mitochondria undergo fission when they are damaged. Certain changes occur to prevent them from fusing properly. Therefore, my wonder is whether promoting fission is actually a good idea. Perhaps, "fission promotion" is actually "mitochondria damage promotion."

 

I was reading this, when the thought occurred to me:

Mitochondrial Fission, Fusion, and Stress

"Low levels of damage might be corrected by complementation through mitochondrial fusion, but badly damaged mitochondria will contaminate other mitochondria if they are allowed to rejoin the mitochondrial network before their elimination by autophagy. Several mechanisms are at work to stop this from happening. A first line of defense is provided by a built-in requirement of the mitochondrial inner membrane fusion machinery for membrane potential (30). Vertebrates have elaborated on this mechanism by providing a second line of defense through proteolytic inactivation of the inner membrane fusion dynamin OPA1. Proteolysis is mediated by the mitochondrial inner membrane protease OMA1, which is rapidly activated by low membrane potential and low levels of ATP (31, 32). The outer membranes of these mitochondria can still fuse, even without functional OPA1 or membrane potential, but the inner membrane–bound matrix compartments do not fuse, resulting in several matrix compartments surrounded by a common outer membrane, like peas in a pod.The last line of defense is provided by the Pink1 and Parkin pathway through the ubiquitination of the mitochondrial outer membrane fusion proteins Mfn1 and Mfn2. Ubiquitination of these proteins leads to their extraction from the membrane by p97 and their degradation by proteasomes (16). In addition, Pink1 and Parkin disrupt mitochondrial motility by degrading the small GTPase Miro, which serves as an adaptor for kinesin-dependent transport and is also needed for mitochondrial fusion (33). Ultimately, uncoupled mitochondria lose both their inner and outer membrane fusion machineries, thereby preventing them from fusing with and poisoning the healthy mitochondrial network."

 

"Fission segregates the most seriously damaged mitochondria to preserve the health of the mitochondrial network in addition to regulating morphology and facilitating mitochondrial trafficking."

 

It sounds like mitochondria have built-in mechanisms to automatically prevent fusion when they become damaged (low membrane potential for instance). If this is the case, promoting fission sounds like a bad idea. Whatever is inducing fission may be damaging mitochondria. Could this be why "fission" is promoted? Adding a substance that damages mitochondria would result in higher rates of fission. More damaged mitochondria (i.e. lower membrane potentials) will cause more fission to occur.

 

Any thoughts? I fully admit that I may be misunderstanding this, and I appreciate any elucidation. If there is something I am misunderstanding, please point me to the appropriate material, and I will research further.

Edited by jgkyker, 25 December 2018 - 04:01 AM.

[jgkyker]

If I understand correctly, adding a substance that damages mitochondria could result in higher rates of fission.

 

Is it possible that "promoting fission" is actually damaging mitochondria? From what I'm gathering, mitochondria undergo fission when they are damaged. Certain changes occur to prevent them from fusing properly. Therefore, my wonder is whether promoting fission is actually a good idea. Perhaps, "fission promotion" is actually "mitochondria damage promotion."

 

I was reading this, when the thought occurred to me:

Mitochondrial Fission, Fusion, and Stress

"Low levels of damage might be corrected by complementation through mitochondrial fusion, but badly damaged mitochondria will contaminate other mitochondria if they are allowed to rejoin the mitochondrial network before their elimination by autophagy. Several mechanisms are at work to stop this from happening. A first line of defense is provided by a built-in requirement of the mitochondrial inner membrane fusion machinery for membrane potential (30). Vertebrates have elaborated on this mechanism by providing a second line of defense through proteolytic inactivation of the inner membrane fusion dynamin OPA1. Proteolysis is mediated by the mitochondrial inner membrane protease OMA1, which is rapidly activated by low membrane potential and low levels of ATP (31, 32). The outer membranes of these mitochondria can still fuse, even without functional OPA1 or membrane potential, but the inner membrane–bound matrix compartments do not fuse, resulting in several matrix compartments surrounded by a common outer membrane, like peas in a pod.The last line of defense is provided by the Pink1 and Parkin pathway through the ubiquitination of the mitochondrial outer membrane fusion proteins Mfn1 and Mfn2. Ubiquitination of these proteins leads to their extraction from the membrane by p97 and their degradation by proteasomes (16). In addition, Pink1 and Parkin disrupt mitochondrial motility by degrading the small GTPase Miro, which serves as an adaptor for kinesin-dependent transport and is also needed for mitochondrial fusion (33). Ultimately, uncoupled mitochondria lose both their inner and outer membrane fusion machineries, thereby preventing them from fusing with and poisoning the healthy mitochondrial network."

 

"Fission segregates the most seriously damaged mitochondria to preserve the health of the mitochondrial network in addition to regulating morphology and facilitating mitochondrial trafficking."

 

It sounds like mitochondria have built-in mechanisms to automatically prevent fusion when they become damaged (low membrane potential for instance). If this is the case, promoting fission sounds like a bad idea. Whatever is inducing fission may be damaging mitochondria. Could this be why "fission" is promoted? Adding a substance that damages mitochondria would result in higher rates of fission. More damaged mitochondria (i.e. lower membrane potentials) will cause more fission to occur.

 

Any thoughts? I fully admit that I may be misunderstanding this, and I appreciate any elucidation. If there is something I am misunderstanding, please point me to the appropriate material, and I will research further.

 

Nevermind, I see my mistake. Fission does not imply degradation. According to Mitochondrial Fission, Fusion, and Stress, fission induces a stress test that can "mark" a degraded mitochondria for elimination.

 

"In most fission events, one daughter mitochondrion is transiently hyperpolarized while the sister mitochondrion is hypopolarized, suggesting that fission embodies a “stress test” that could push a daughter mitochondrion to completely depolarize if it functions suboptimally. Mitophagy could be prevented with a dominant-negative mutant of Drp1, suggesting that fission is required for mitophagy (19). Photodamaged mitochondria undergo selective mitophagy (20), which is also consistent with the model that fission provides a form of quality control by segregating damaged parts of mitochondria and targeting them for elimination by autophagy (Fig. 2). Recent work on two gene products mutated in familial Parkinson’s disease, PINK1 and Parkin, yields insight into a molecular mechanism of quality control via the elimination of damaged mitochondria (Fig. 3). The abundance of the kinase PINK1 is constitutively repressed in healthy mitochondria by import into the inner mitochondrial membrane and degradation by the rhomboid protease PARL. When a mitochondrion becomes uncoupled, protein import to the inner mitochondrial membrane is prevented so PINK1 is diverted from PARL and accumulates on the outer mitochondrial membrane. This yields a sensor of mitochondrial damage that can flag an individual impaired mitochondrion in a milieu of healthy ones. PINK1 on a damaged mitochondrion, through its kinase activity, recruits the E3 ligase Parkin from the cytosol specifically to that impaired mitochondrion (Fig. 3). Once there, Parkin ubiquitinates outer mitochondrial membrane proteins and induces autophagic elimination of the flagged mitochondrion (21)."

[QuestforLife]

Turnbuckle a question - are not all senolytic chemicals acting via mitochondria in some way (and in some cases, i.e. azithromycin, it is impicitly stated that the substance causes metabolic stress on mitochondria), and therefore could prolonged or extreme mitophagy not be a very good senolytic?

 

The following paper (https://www.ncbi.nlm...pubmed/16939485) has a fascinating account of the effect of long term culture on cells with nicotinamide. In particular the effect of adding nicotinamide to already mature cells paints a picture whereby cells are mitochondrially stressed to the extent that only healthy cells go on to survive in culture, improving the growth rate back to youthful levels, see Fig 3c:

 

And on a related note, all cancer cells seem to have mitochondria that are damaged or abnormal in some way - so mitophagy/senolytics may well be a universal cancer therapy perhaps?

 

 

 

 

Attached Files

•  nicotinamide added to mature cell culutre.png   375.95KB   0 downloads

Edited by QuestforLife, 09 January 2019 - 01:49 PM.

[Turnbuckle]

 

 

It sounds like mitochondria have built-in mechanisms to automatically prevent fusion when they become damaged (low membrane potential for instance). If this is the case, promoting fission sounds like a bad idea. Whatever is inducing fission may be damaging mitochondria. Could this be why "fission" is promoted? 

 

 

In reality it's the mtDNA that are damaged, not the mitochondria. Mitochondria typically have several loops of mtDNA and can perform reasonably well even with every loop damaged, as they cover for each other, producing enough of all the necessary enzymes to keep the citric (aka Krebs) cycle going. (As there are 37 genes in mtDNA, it is unlikely they would all be damaged in the same place.) By fissioning mitochondria to the smallest possible size--with only one loop--deficiencies in individual loops soon become apparent. If even one of 37 genes is defective, membrane potential (ΔΨm) goes to zero and the mitochondria are marked with a pair of special proteins (PINK1 and Parkin) for mitophagy. So fission is necessary to clean up defective genes. Normally fission and fusion go on all the time, but eventually these prove inadequate and defective mtDNA build up anyway, reducing ATP production and making all cellular processes less efficient. This fission/fusion protocol is like a spring cleaning vs a weekly light dusting. It is not in principle different from the natural process, just more extreme.

 

Edit: I see you answered your own question.

Edited by Turnbuckle, 09 January 2019 - 04:41 PM.

[Turnbuckle]

And on a related note, all cancer cells seem to have mitochondria that are damaged or abnormal in some way - so mitophagy/senolytics may well be a universal cancer therapy perhaps?

 

Most cancer cells are like stem cells, they shut down their mitochondria and subsist on glycolysis (the Warburg effect). Mitochondria act like a switch -- turn them off and cells can become immortal, turn them on and they become mortal again. So to deal with cancer cells--most of them, anyway--you want to do the exact opposite of what you suggested. You want to turn their mitochondria on.

 

Some have looked at using senolytics to kill cancer cells, for instance -- https://www.fightagi...erapy-succeeds/

 

And yes, fissioning mitochondria for apoptosis is good. In fact, it is essential.

Edited by Turnbuckle, 09 January 2019 - 05:00 PM.

[jgkyker]

It looks like optimal mitochondrial fusion/fission cycles may be an important part of enhancing senescence. I'm contemplating taking quercetin on fission promotion days due to this.

 

From Targeting Mitochondria to Counteract Age-Related Cellular Dysfunction

"Since mitochondria play such a critical role in an organism’s process of aging, they also offer promising targets for manipulation of senescent cellular functions."

"In addition, the byproducts of mitochondrial respiration, reactive oxygen species (ROS), are key determinants in the initiation of cellular senescence when present in high concentrations [14]. Moreover, changes in mitochondrial dynamics in fusion and fission, as well as alterations in the mitochondrial membrane potential [15] have been reported to cause cellular dysfunctions during senescence [16]."

 

Lower membrane potential is part of what flags a fissioned mitochondria for autophagy (clean-up).

 

From the same study:

"Accordingly, the first senolytic agents discovered all affected mitochondria, including dasatinib, quercetin, and navitoclax [12]."

 

From another study, Quercetin and the mitochondria: A mechanistic view

"Quercetin is now recognized as a phytochemical that can modulate pathways associated with mitochondrial biogenesis, mitochondrial membrane potential, oxidative respiration and ATP anabolism, intra-mitochondrial redox status, and subsequently, mitochondria-induced apoptosis."

 

It looks like senolytic agents and mitochondrial dynamics go hand-in-hand. In other words, to promote senescence, one probably also needs to "clean" their mitochondria, perhaps by promoting fission.

 

I don't like the idea of taking NR exclusively because it promotes fission and reduces exercise performance. NMN apparently promotes fusion. (See this post.)

 

So, I plan to cycle these.

- Fission (NR) and Senescence (Quercetin) Day

- Fusion Day (NMN, Sulforaphane, C60, Stearic Acid in the form of cocoa butter) - higher exercise activity on this day

Edited by jgkyker, 09 January 2019 - 09:29 PM.

[QuestforLife]

Most cancer cells are like stem cells, they shut down their mitochondria and subsist on glycolysis (the Warburg effect). Mitochondria act like a switch -- turn them off and cells can become immortal, turn them on and they become mortal again. So to deal with cancer cells--most of them, anyway--you want to do the exact opposite of what you suggested. You want to turn their mitochondria on.

My view is somewhat different. If a cell is damaged it either dies or may become senescent. Senescent cells are damaged (and become increasingly so over time) but not enough to die. All such cells are potential cancer cells because their mitochondria are damaged and this then leads to greater ROS. Once a cell acquires the nuclear mutations to go rogue, it may then manipulate the mitochondria further. But they are not 'switched off', more adjusted for another purpose, such as producing the material needed for cellular mitosis.

One interesting this is that cancer cells cannot run on fats. They have to run on glucose (or glutamine). So a ketogenic diet may well starve cancer cells. They can still make glutamine unfortunately, but perhaps this could be blocked in the future by a small molecule (for the short time the rest of your body can do without it).

Also, even if cancer cells prove able to survive standard Senolytics (we know dasatinib works to some extent on both, for example), senescent cell clearance is likely to decrease the chance of any senescent cells going rogue.

[jgkyker]

It looks like optimal mitochondrial fusion/fission cycles may be an important part of enhancing senescence. I'm contemplating taking quercetin on fission promotion days due to this.

 

From Targeting Mitochondria to Counteract Age-Related Cellular Dysfunction

"Since mitochondria play such a critical role in an organism’s process of aging, they also offer promising targets for manipulation of senescent cellular functions."

"In addition, the byproducts of mitochondrial respiration, reactive oxygen species (ROS), are key determinants in the initiation of cellular senescence when present in high concentrations [14]. Moreover, changes in mitochondrial dynamics in fusion and fission, as well as alterations in the mitochondrial membrane potential [15] have been reported to cause cellular dysfunctions during senescence [16]."

 

Lower membrane potential is part of what flags a fissioned mitochondria for autophagy (clean-up).

 

From the same study:

"Accordingly, the first senolytic agents discovered all affected mitochondria, including dasatinib, quercetin, and navitoclax [12]."

 

From another study, Quercetin and the mitochondria: A mechanistic view

"Quercetin is now recognized as a phytochemical that can modulate pathways associated with mitochondrial biogenesis, mitochondrial membrane potential, oxidative respiration and ATP anabolism, intra-mitochondrial redox status, and subsequently, mitochondria-induced apoptosis."

 

It looks like senolytic agents and mitochondrial dynamics go hand-in-hand. In other words, to promote senescence, one probably also needs to "clean" their mitochondria, perhaps by promoting fission.

 

I don't like the idea of taking NR exclusively because it promotes fission and reduces exercise performance. NMN apparently promotes fusion. (See this post.)

 

So, I plan to cycle these.

- Fission (NR) and Senescence (Quercetin) Day

- Fusion Day (NMN, Sulforaphane, C60, Stearic Acid in the form of cocoa butter) - higher exercise activity on this day

 

Yes, sorry, to clarify I meant optimal mitochondrial fusion/fission enhances senescence clearing, not senescence in and of itself. The meaning probably came clear through the post, but just to be safe...

[Ovidus]

Have you guys seen this?
https://actu.epfl.ch...to-fight-aging/

 

It is not something we can replicate, but is very exciting.

[Turnbuckle]

Have you guys seen this?
https://actu.epfl.ch...to-fight-aging/

 

It is not something we can replicate, but is very exciting.

 

 

It's very easy to fission mitochondria with N+R, though this research does supply another reason why defective mitochondria build up--having an age-associated reduction of mito fission factor.

Edited by Turnbuckle, 11 January 2019 - 11:29 AM.

[Ovidus]

It's very easy to fission mitochondria with N+R, though this research does supply another reason why defective mitochondria build up--having an age-associated reduction of mito fission factor.

 

But are you able to achieve optimal levels of fission? 
Can you say that achieving a greater degree of fission -by way of some other mechanism (possibly yet undiscovered) - would not be more beneficial?
 

[Turnbuckle]

But are you able to achieve optimal levels of fission? 
Can you say that achieving a greater degree of fission -by way of some other mechanism (possibly yet undiscovered) - would not be more beneficial?
 

 

For rapid repair, an optimal level of fission is 100%, cycled with fusion. This can be achieved with supplements, but does not occur naturally.

[Ovidus]

For rapid repair, an optimal level of fission is 100%, cycled with fusion. This can be achieved with supplements, but does not occur naturally.

 

Can you please provide evidence for the underlined part?
I have read the thread, but have done so over a long period of time; so if this has been posted in the thread I would really appreciate if you can mention a few keywords I can use to search this thread.

Has research actually shown that 100% fission can be achieved with supplements IN VIVO -as in actual human cells in a living human (and even if so, it is nearly unthinkable that 100% can be achieved in a wide variety of cells across several tissue types)?

 

Thank you 

[Turnbuckle]

The object of the present protocol is to drive mito morphology to cyclic extremes. Nothing about this is unnatural, just rare and ephemeral —

 

The network architecture is rather diverse and flexible, is able to adjust itself on a time scale of minutes depending on the actual physiological condition, and is highly variable among different cell types. In the fully interconnected state, the network edges are approximately of cylindrical shape with a typical diameter a few hundred nm and highly varying lengths up to more than 10 µm [10]. The opposite extreme is the fully fragmented condition, where the mitochondria are roughly spherical vesicles with diameter similar to that of the aforementioned cylinders. In the majority of situations, a cell contains many networked clusters of varying sizes along with numerous individual mitochondria, thus representing an intermediate state between the two extremes.

https://journals.plo...al.pcbi.1002745

 

 

 

As has been discussed before, there are supplements that can be used to control morphology. Stearic acid is known to drive mitochondria to fusion, while NAM drives them to fission.

 

Induction of mitochondria fragmentation (fission) by NAM treatment—

 

... a more prominent change in the MitoTracker signals is the disappearance of the filamentous structures and appearance of dots and puncta suggesting mitochondrial fragmentation. This occurred as early as in day 3 [Fig. 4A(b); Fig. S4]. Interestingly, at day 15, most of the signal was in the form of circles (or rings) with a diameter range of 1–2 μm.

https://onlinelibrar...26.2009.00487.x

 

 

And a later paper by the same researchers—

 

Removal of dysfunctional mitochondria requires the activation of autophagy coupled with ongoing mitochondrial fission (7). Our current and previous studies show that both of these processes can be induced by NAM treatment. The earlier part of this study showed that the effect of NAM was exerted through an increase of [NAD+]/[NADH] ratio.

https://www.ncbi.nlm...pubmed/22493485

 

 

 

Since NAD+ requires ribose and ribose is a rare commodity in the body, it makes sense to supply it along with NAM and raise NAD+ levels more rapidly.

 

Neither fusion nor fission need be 100%, but fission should be substantially more than normal for efficient detection and labeling of mitochondria with defective mtDNA. Actual disposal is limited by the lysosomal capacity in any case. Thus when there are a large fraction of defective mtDNA, many cycles of destruction and creation are needed. The level of defective mtDNA can get very high before it is noticed as multiple mtDNA loops in individual mitochondria cover for each other. My mitochondria were damaged by statin treatment to the point I could barely get out of bed, and thus the level of damage was very high. After years of excruciatingly slow and incomplete recovery,  I applied this cyclic method and finally got back to where I was before statins.

 

A separate problem is the appearance of zombie mitochondria, which are resistant to the normal levels of mitophagy —

 

When normal mitophagic organelle elimination (Figure 7A) is suppressed by Parkin insufficiency, abnormal undead or zombie mitochondria accumulate and (as zombies will do) contaminate the normal mitochondrial population by fusing with normal organelles (Figure 7B). Mitochondrial fusion that is ordinarily protective, therefore, becomes the mechanism for a general contagion of mitochondrial dysfunction. Interrupting mitochondrial fusion prevents contamination of functionally normal mitochondria by virulent zombie mitochondria (Figure 7C), sequestering abnormal mitochondria that can then be removed by alternate, albeit almost certainly less efficient, elimination pathways.

https://www.ncbi.nlm...les/PMC4392818/

 

 

 

 

 

 

[Fafner55]

What available substances besides cinnamon extract might activate PINK1 and Parkin to help rid cells of zombie mitochondria?

[Turnbuckle]

What available substances besides cinnamon extract might activate PINK1 and Parkin to help rid cells of zombie mitochondria?

 

Sodium benzoate.

 

Here we have explored a novel use of cinnamon in upregulating Parkin and DJ-1 and protecting dopaminergic neurons in MPTP mouse model of PD. Recently we have delineated that oral feeding of cinnamon (Cinnamonum verum) powder produces sodium benzoate (NaB) in blood and brain of mice. Proinflammatory cytokine IL-1β decreased the level of Parkin/DJ-1 in mouse astrocytes. However, cinnamon metabolite NaB abrogated IL-1β-induced loss of these proteins.

https://www.ncbi.nlm...les/PMC4167597/

 

Another useful property of NaB--

 

oral treatment of cinnamon and NaB increased spatial memory consolidation-induced activation of CREB and expression of plasticity-related molecules in the hippocampus of poor-learning mice and converted poor learners into good learners.

https://www.ncbi.nlm...les/PMC5097886/

 

 

Edited by Turnbuckle, 11 January 2019 - 02:26 PM.

[Fafner55]

Turnbuckle, what is your opinion on the importance, and possibly the necessity, of activating SIRT3 to rid cells of zombie mitochondria?

 

SIRT3 deficiency will inhibit parkin-mediated mitophagy, but it is unclear whether SIRT3 should be activated to promote the riddance of zombie mitochondria.

"SIRT3 deficiency exacerbates p53/Parkin‑mediated mitophagy inhibition and promotes mitochondrial dysfunction: Implication for aged hearts" (2018) https://www.ncbi.nlm...pubmed/29532856

 

Honokial is a SIRT3 activator. 

"Honokiol blocks and reverses cardiac hypertrophy in mice by activating mitochondrial Sirt3" (2015) https://www.nature.c...cles/ncomms7656

 

Trehalose is another SIRT3 activator and has been shown to restore parkin expression.

"Mitochondrial Quality Control and Age-Associated Arterial Stiffening" (2015) https://www.ncbi.nlm...les/PMC4252265/

"Trehalose, a Novel mTOR-independent Autophagy Enhancer, Accelerates the Clearance of Mutant Huntingtin and α-Synuclein" (2006) http://www.jbc.org/content/282/8/5641

"Trehalose ameliorates dopaminergic and tau pathology in parkin deleted/tau

overexpressing mice through autophagy activation" (2010) https://drive.google...WAUFkUjsOj/view

 

Trehalose clears lipofuscin, which like zombie mitochondria resists degradation. Seems promising.

"Trehalose upregulates progranulin expression in human and mouse models of GRN haploinsufficiency: a novel therapeutic lead to treat frontotemporal dementia" (2016) https://molecularneu...3024-016-0114-3

"Trehalose extends longevity in the nematode Caenorhabditis elegans" (2010) https://onlinelibrar...26.2010.00582.x

 

 

[QuestforLife]

 

Turnbuckle, what is your opinion on the importance, and possibly the necessity, of activating SIRT3 to rid cells of zombie mitochondria?

 

SIRT3 deficiency will inhibit parkin-mediated mitophagy, but it is unclear whether SIRT3 should be activated to promote the riddance of zombie mitochondria.

"SIRT3 deficiency exacerbates p53/Parkin‑mediated mitophagy inhibition and promotes mitochondrial dysfunction: Implication for aged hearts" (2018) https://www.ncbi.nlm...pubmed/29532856

 

Honokial is a SIRT3 activator. 

"Honokiol blocks and reverses cardiac hypertrophy in mice by activating mitochondrial Sirt3" (2015) https://www.nature.c...cles/ncomms7656

 

Trehalose is another SIRT3 activator and has been shown to restore parkin expression.

"Mitochondrial Quality Control and Age-Associated Arterial Stiffening" (2015) https://www.ncbi.nlm...les/PMC4252265/

"Trehalose, a Novel mTOR-independent Autophagy Enhancer, Accelerates the Clearance of Mutant Huntingtin and α-Synuclein" (2006) http://www.jbc.org/content/282/8/5641

"Trehalose ameliorates dopaminergic and tau pathology in parkin deleted/tau

overexpressing mice through autophagy activation" (2010) https://drive.google...WAUFkUjsOj/view

 

Trehalose clears lipofuscin, which like zombie mitochondria resists degradation. Seems promising.

"Trehalose upregulates progranulin expression in human and mouse models of GRN haploinsufficiency: a novel therapeutic lead to treat frontotemporal dementia" (2016) https://molecularneu...3024-016-0114-3

"Trehalose extends longevity in the nematode Caenorhabditis elegans" (2010) https://onlinelibrar...26.2010.00582.x

 

 

I would be cautious in assuming a particular action for SIRT3.

 

From my research the mitochondrial SIRTUINS (3,4 & 5) all upregulate mitochondrial FUSION. And sometimes supplements that upregulate the mitochondrial SIRTUINS (i.e. cinnamon, resveratrol, and probably honokiol - I don't know about trelahose) do so by actually damaging mitochondria and spurring a hormetic response. Also increasing SIRTUIN expression in mitochondria will lead to FUSION, but increasing it in the cytosol will often lead to the reverse effect.

 

Then there is the complication that if a given supplement helps in the case of a PARKIN insufficiency, for example, we don't know whether FUSION is compensating for damaged loops of mtDNA, or whether FISSION is removing loops of damaged mtDNA (for the reasons given above).

 

Hence my advice on caution in interpreting study results regarding SIRTUIN 3/4/5.

 

SIRT4 is implicated in telomerase activation, so I did lots of research into it over on my 'Alternative methods to extend telomeres', and you can find supporting references for my arguments there.

[jgkyker]

It looks like optimal mitochondrial fusion/fission cycles may be an important part of enhancing senescence. I'm contemplating taking quercetin on fission promotion days due to this.

 

From Targeting Mitochondria to Counteract Age-Related Cellular Dysfunction

"Since mitochondria play such a critical role in an organism’s process of aging, they also offer promising targets for manipulation of senescent cellular functions."

"In addition, the byproducts of mitochondrial respiration, reactive oxygen species (ROS), are key determinants in the initiation of cellular senescence when present in high concentrations [14]. Moreover, changes in mitochondrial dynamics in fusion and fission, as well as alterations in the mitochondrial membrane potential [15] have been reported to cause cellular dysfunctions during senescence [16]."

 

Lower membrane potential is part of what flags a fissioned mitochondria for autophagy (clean-up).

 

From the same study:

"Accordingly, the first senolytic agents discovered all affected mitochondria, including dasatinib, quercetin, and navitoclax [12]."

 

From another study, Quercetin and the mitochondria: A mechanistic view

"Quercetin is now recognized as a phytochemical that can modulate pathways associated with mitochondrial biogenesis, mitochondrial membrane potential, oxidative respiration and ATP anabolism, intra-mitochondrial redox status, and subsequently, mitochondria-induced apoptosis."

 

It looks like senolytic agents and mitochondrial dynamics go hand-in-hand. In other words, to promote senescence, one probably also needs to "clean" their mitochondria, perhaps by promoting fission.

 

I don't like the idea of taking NR exclusively because it promotes fission and reduces exercise performance. NMN apparently promotes fusion. (See this post.)

 

So, I plan to cycle these.

- Fission (NR) and Senescence (Quercetin) Day

- Fusion Day (NMN, Sulforaphane, C60, Stearic Acid in the form of cocoa butter) - higher exercise activity on this day

 

Just wanted to briefly report on my experience with this cycle... I have been on it about 1-1.5 weeks.

 

About 2 months ago, I began an intense sport (Brazilian jiu jitsu), and I sprained my left wrist and also pulled my groin. I really did not feel like I was making progress healing on my wrist until this week. It seems like my mobility has substantially improved. I think it may almost be healed. Now, just 1 week ago, I was receiving INTENSE pain if I moved the wrist anywhere near its extremes. It seems like it is healing substantially faster since beginning this protocol. One thing to note, however, is that I have been particularly stubborn about wearing my wrist guard. It seems like it is beyond that though...

 

The pulled groin however seems about the same (it was much farther along than the wrist, healing-wise, before the protocol... I think). Lastly, just 3 days ago, I had some dental work done around the gums. That seems to be healing very quickly as well. I cannot recall typically how long I would deal with dental pain like that, but it seems like generally it would take weeks. I barely feel anything as I type this.

 

Some additional things I am taking that may be helping: Bromelain and BCAAs (among many other things that probably aren't)

 

The BCAAs seem to make a substantial difference in everything, and I take them before bed, when I remember (trying to make this a habit when in a state of healing). These may make a difference particularly with me because I have not eaten meat in almost 1 year. I also eat very little dairy lately. I was taking the Bromelain before this protocol when I felt like I was not healing. Therefore, it may actually be doing very little.
 

Edited by jgkyker, 18 January 2019 - 02:43 PM.

[whileitravel]

Both Dr. Sinclair & Attia say in a recent podcast that NR+ doesn't get passed the liver, therefore very little efficacy. Has anyone here seen any benefits to this protocol thus far?