2503 replies to this topic

[Turnbuckle]

turnbuckle

i was thinking about adding epimedium extract to the protocol because according to these studies it promotes stemcells proliferation and helps in tendon injuries.when should i add this, before stearic acid or at end after c60?

could it make interference with the rest of the protocol?

 

i had tecar therapy same days as protocol with stearic acid and shoulder felt ok until next day, while having c60 only i felt good during tecar but felt the same few hours later

Effects of Epimedium flavonoids on proliferation and differentiation of neural stem cells in vitro https://www.ncbi.nlm...pubmed/19703337   Icariin Promotes Tendon-Bone Healing during Repair of Rotator Cuff Tears: A Biomechanical and Histological Study

https://www.ncbi.nlm...les/PMC5133781/

 

 

I've tried icariin with stearic acid but without C60. See here. Using it with C60, I'd take it one hour before.

[QuestforLife]

Anyhow, if c60 is a backdoor to stem cell activation then there clearly must be a mechanism to shut it - otherwise, those on high doses would just burn through their stem-cells on paradise island to one day find the tide has just gone way, way out. But it is not what happens. They haven't, I haven't. Perhaps in your case that shut-down response was slow and so achieved remarkable results through ravaging your reserves; in Sensei's case maybe only brut force could liberate the pool.

Any substance that you use repeatedly (and often) you will eventually become insensitive to. I don't doubt that repeatedly stimulating stem cells, whether that be with AFA, Sea Buckthorn, C60, or something else, you'll eventually be left with a whole bunch of stem cells remaining that are insensitive to the substance you're using. So it makes sense that stimulating coincident with fusion is actually increasing the pool of stem cells sensitive to the substance you are using.

This is actually a testable hypothesis. If you were to add other stem cell stimulants to this (fusion)protocol, you should see a magnified effect.

[Turnbuckle]

 

Anyhow, if c60 is a backdoor to stem cell activation then there clearly must be a mechanism to shut it - otherwise, those on high doses would just burn through their stem-cells on paradise island to one day find the tide has just gone way, way out. But it is not what happens. They haven't, I haven't. Perhaps in your case that shut-down response was slow and so achieved remarkable results through ravaging your reserves; in Sensei's case maybe only brut force could liberate the pool.

 

 

 

It's not a back door, it's the front door, opened by a different means. And I suppose I'll have to explain this again and again forever, but the usual case of stem cell replication is mostly asymmetric (one estimate is 80% asymmetric and 20% symmetric). Asymmetric division produces one new stem cell and one new somatic cell, with no net gain of stem cells, while symmetric division (self-renewal) produces a net gain of one stem cell. This ratio appears sufficient to keep stem cell niches filled for a long time in spite of losses, but eventually it falls behind, partly because of the build up of senescent stem cells that no longer divide at all, and partly due to large numbers of somatic cells reaching senescence when one reaches geriatric age. Then forcing stem cell replication with a bias to symmetric division has a decided advantage.

 

Here the front doors are the UCP2 pores, which allow protons to leak out and stop ATP production, thereby keeping mitochondria (and stem cells that contain them) quiescent. Normally those pores disappear just prior to stem cells waking up. C60 appears to have the right geometry, size and predilection for mitochondria to block those pores and thus produce the same effect, waking up stem cells so they can divide. Stearic acid acts in a hormone-like fashion to  fuse mitochondria, and fusion has been found to bias stem cells to divide symmetrically, thus increasing the pool of stem cells when used with C60.

 

C60 also blocks UCP2 pores in somatic cells (which have many fewer of them) and this produces temporary strength gains in the gym. Likewise with the antioxidant properties, which are temporary. 

Edited by Turnbuckle, 16 January 2020 - 07:56 PM.

[Andey]

I dont see how it means that Turnbuckle`s hypothesis is wrong if mikey feels good taking c60 for a long time. Thats quite a stretch.

The hypothesis could be wrong but this is not a way to rebuke it.

[ambivalent]

With respect, you didn't need to repeat what was said because it wasn't relevant or contested.  We don't need a semantic discussion on biological door-entry metaphors - if you're right c60 is acting exogenously to bring cells out of quiescence through blocking UCP2 pores. Evidently this doesn't continue til depletion because high dose users haven't Benjamin Buttoned before Dorian Graying. By your assertion they should have. Why haven't they? That's all, it is a straight forward point - the effects didn't wear off because you ran full out of stem cells. C60 no longer woke them up - for whatever reason. 

 

Anyhow, I'm not spoiling for an argument for the sake of it - theories should be tested not protected, that's how we progress, we all want that. Unfortunately many far more qualified in that effort than I are long gone. 

 

Quest I agree, that makes sense, which is why I hope with optimism those using c60 say for antioxidant benefits probably aren't running down there stem cell levels - which is pretty important to the masses not using TB's stem cell renewal protocol.

 

Anyhow, this sub-discussion has probably run its course. 

Edited by ambivalent, 16 January 2020 - 08:25 PM.

[ambivalent]

I dont see how it means that Turnbuckle`s hypothesis is wrong if mikey feels good taking c60 for a long time. Thats quite a stretch.

The hypothesis could be wrong but this is not a way to rebuke it.

 

Andey, I'm not suggesting the self-renewal protcol is wrong, based on mikey's experience, rather contesting TB's suggestion that taking c60 without stem cell renewal will empty the bank and so rapidly accelerate aging - that's all, that it won't burn our reserve of stem cells twice as bright for half as long.

[Turnbuckle]

Andey, I'm not suggesting the self-renewal protcol is wrong, based on mikey's experience, rather contesting TB's suggestion that taking c60 without stem cell renewal will empty the bank and so rapidly accelerate aging - that's all, that it won't burn our reserve of stem cells twice as bright for half as long.

 

 

Remind me where I said it would "rapidly accelerate aging." What I am saying is that you may ultimately end up worse off. This could take years, and will to some degree depend on your diet. Whereas if you use a fusion agent, you can reverse aging, very likely dramatically. (That said, at least one person experienced a rapid negative response without fusion, as noted in post #1106.)

 

 

I have said that telomerase enhancers can rapidly accelerate epigenetic aging, as I have see it myself. Lengthening telomeres result in cells becoming older without being cleared at the normal rate.

 

 Evidently this doesn't continue til depletion because high dose users haven't Benjamin Buttoned before Dorian Graying.

 

 

You won't achieve a Benjamin Button situation in any case, as this epigenetic age reversal requires the replacement of senescent cells with near zero age somatic cells derived from stem cells. Thus you can only go so far as non-senescent cells aren't going to be replaced and you end up with an average of very young cells and old but not yet senescent cells.

Edited by Turnbuckle, 16 January 2020 - 09:10 PM.

[dlewis1453]

Any substance that you use repeatedly (and often) you will eventually become insensitive to. I don't doubt that repeatedly stimulating stem cells, whether that be with AFA, Sea Buckthorn, C60, or something else, you'll eventually be left with a whole bunch of stem cells remaining that are insensitive to the substance you're using. So it makes sense that stimulating coincident with fusion is actually increasing the pool of stem cells sensitive to the substance you are using.

This is actually a testable hypothesis. If you were to add other stem cell stimulants to this (fusion)protocol, you should see a magnified effect.

 

This point you made, which I highlighted in bold, makes a lot of sense to me and I think its relevant to the discussion. 

 

I have seen you allude to a positive experience with AFA and Sea Buckthorn in one of your posts on your Alternative Telomere Lengthening protocol thread. Could you share your experiences with those substances? It could give Turnbuckle some ideas for future iterations of his protocol. 

[Turnbuckle]

This point you made, which I highlighted in bold, makes a lot of sense to me and I think its relevant to the discussion. 

 

I have seen you allude to a positive experience with AFA and Sea Buckthorn in one of your posts on your Alternative Telomere Lengthening protocol thread. Could you share your experiences with those substances? It could give Turnbuckle some ideas for future iterations of his protocol. 

 

 

Let's not go off topic here. This is an anti-telomere-lengthening zone.

[QuestforLife]

This point you made, which I highlighted in bold, makes a lot of sense to me and I think its relevant to the discussion.

I have seen you allude to a positive experience with AFA and Sea Buckthorn in one of your posts on your Alternative Telomere Lengthening protocol thread. Could you share your experiences with those substances? It could give Turnbuckle some ideas for future iterations of his protocol.

I will reply to this on my thread.

[ambivalent]

You won't achieve a Benjamin Button situation in any case, as this epigenetic age reversal requires the replacement of senescent cells with near zero age somatic cells derived from stem cells. Thus you can only go so far as non-senescent cells aren't going to be replaced and you end up with an average of very young cells and old but not yet senescent cells.

 

Then perhaps this is why Mikey's benefits have persisted. If DMSO, which he takes everyday, triggers apoptosis then why wouldn't those destroyed cells be replaced by younger ones bringing his said average down? In addition Longo's research on fasting should encourage this process, assuming the cleared cells are not just (or at all if Michael is to be believed) senescent.

 

https://news.usc.edu...-immune-system/

 

If Michael is right about fasting what other mechanism is there, apart from senolytics, to clear out s-cells? I understood you were benefitting with this therapy and c60 before deploying senolytics.

 

- It remains unclear to me as to why from your explanation the c60 stem-cell inductive effect would wear off - why it stopped working - when there are still stores of stem cells waiting to be woken. But we, or certainly not I, have anything more to add to this.

Edited by ambivalent, 17 January 2020 - 07:43 AM.

[Turnbuckle]

Then perhaps this is why Mikey's benefits have persisted.

 

 

If mikey is your evidence, why not invite him to post here and assert he has not seen fading? The last I recall, he was considering upping his dose to 20 mg/day (from 10 mg/day). That is a very high dose, in my opinion, and when people start taking that much, it's a sure sign they are trying to recapture the mojo. Even ten mg/day is 25 times what I take. He's also looking at many other things, some 200, I understand. So it sounds like he's still looking for the solution to aging.

 

It remains unclear to me as to why from your explanation the c60 stem-cell inductive effect would wear off - why it stopped working - when there are still stores of stem cells waiting to be woken.

 

 

Stem cells niches become populated with senescent cells even as the demand for new stem cells increases with age. Asymmetric division (the typical situation) does not increase SC numbers and cannot make up for loses, but symmetric division does.

Edited by Turnbuckle, 17 January 2020 - 10:56 AM.

[ambivalent]

If mikey is your evidence, why not invite him to post here and assert he has not seen fading? Or at least link to recent posts saying this. The last I recall, he was considering upping his dose to 20 mg/day. That is a very high dose, in my opinion, and when people start taking that much, it's a sure sign they are trying to recapture the mojo.

 

I'm not sure why you've turned in to this cu-de-sac - he may have been doing so or like you and many others always trying to reduce aging further. And he does experiment, besides no one is suggesting c60 will singularly stop aging. The point is and I've thought this for a long time why did he, like you, get so much out of c60 where others didn't.

 

It was your comment on the somatic cell barrier to cell replacement which led thoughts on apoptosis, DMSO, mikey and fasting. So put simply, could encouraging apoptosis improve your protocol further, replacing older somatic cells with youthful ones?

[lost69]

I've tried icariin with stearic acid but without C60. See here. Using it with C60, I'd take it one hour before.

 

thanks i ll definitely add icariin too.i also received vitalzym (bromelain,papain,rutin,amylase,protease,lipase,amla, serrapetase) is this best on days off stearic acid+c60 protocol?

[ambivalent]

Stem cells niches become populated with senescent cells even as the demand for new stem cells increases with age. Asymmetric division (the typical situation) does not increase SC numbers and cannot make up for loses, but symmetric division does.

 

I understand and I understand this is what your protocol is addressing - I'm not railing against the idea that c60 + stem cell renewal is better than c60, just that simply the c60 stem cell effect didn't cease in you and others because there were no more stem cells to wake up. They were there it seems but couldn't be stimulated (for some reason). When you increased the stem cell pool, then the c60 effect started up, suggesting there was some surplus or allocating mechanism. Those on high doses over long periods may have gained through c60's other properties present at those levels but hopefully weren't running down their stem cell pools.

 

To be honest though your renewal theory is dependent on long term depletion of stem cell pools via extensive c60 usage, if it works it works, but it does matter to those long term c60 users not on your protocol.  

[Turnbuckle]

An experimental protocol for epigenetic age reduction (updated) —

 

Caveats:

 

1. This is a work in progress.

2. It is intended as a geriatric treatment for age reversal.

3. One should avoid alcohol during this treatment.

4. A link to the latest protocol can always be found on my profile page.

 

  

 

Part 1: Stem cell self-renewal

 

 

Time 0 —

¹Stearic acid — 5-10 g (food grade, in brownie)

 

  

Time 3:00 —

²Sulforaphane — 50 mg

³Liposomal glutathione — 1 g

⁴SAM-e — 500 mg

⁵Resveratrol — 300 mg

 

Time 3:30 —

⁶C60 — 3 mg (in oil)

⁷Amino acids: Lysine — 2 g, Methionine — 1 g, Leucine — 1 g

 

These amino acids should be repeated as necessary every couple of hours.

 

 

Part 2: Senescent cell replacement (24 hours later)

 

⁸Nicotinamide — 2g, Ribose — 2g

⁹Curcumin (liposomal or phytosomal) — 2g

⁷Lysine — 2 g, Methionine — 1 g, Leucine — 1 g

 

These amino acids should be repeated as necessary every couple of hours, and the entirety of Part 2 may be repeated the next day as well.

 

 

 

Notes:

 

(1) This is for mito fusion, which directs SCs to self-renewal. Food grade stearic acid is a waxy triglyceride with about 50% stearic acid moieties. It has a high melting point and will have very poor availability unless properly prepared. Baking it into brownies is one option: Using a box mix that calls for 1/2 to 2/3 cups of oil, eliminate the oil and add 120 grams of stearic acid flakes or granules, leaving the rest of the recipe unchanged. Mix at room temp using a power mixer, bake according to directions on the box, then divide 3x4 and freeze most of it for later use. Use ½ to 1 brownie for this protocol. With the addition of sulforaphane, I've been using ½. Stearic acid has much longer half life than sulforaphane (11 vs 4 hours), and thus may interfere with subsequent senescent cell replacement, which requires mito fission. It may be possible to use sulforaphane alone, but I've been content with just cutting it back.

 

(2) Sulforaphane penetrates the BBB to produce mito fusion there, while stearic acid is blocked. 50 mg caps can be obtained from Amazon — Thorne Research - Crucera-SGS - Broccoli Seed Extract for Antioxidant Support - Sulforaphane Glucosinolate (SGS)

 

(3) Primary antioxidant.

 

(4) Methyl group donor.

 

(5) Stimulates stem cells and protects from apoptosis

 

(6) UCP2 blocker. A teaspoon of commercially available C60 oil.

 

(7) These can be used in caps or tablets, though I use a commercial blend of essential amino acids here, adding extra lysine, methionine and leucine. Pluripotent cells have a special need for these three. I would spread out the doses as indicated, to avoid nausea.

 

(8) Used together, nicotinamide and ribose rapidly increase NAD+, which drives mitochondrial fission, required for senescent cell apoptosis and replacement.

 

(9) Senolytic

 

 

 

 

 

Edited by Turnbuckle, 17 January 2020 - 01:12 PM.

[Andey]

Thank you

What is the rationale to initiate Stem cell renewal before SC replacement and not other way around?

[Turnbuckle]

Thank you

What is the rationale to initiate Stem cell renewal before SC replacement and not other way around?

 

 

Homeostatic mechanisms are at play. So when you overfill a stem cell niche, the body will eliminate the excess. Thus best to use SCs profitably before such mechanisms kick in. 

 

Here is one example: Niche induced cell death and epithelial phagocytosis regulate hair follicle stem cell pool

[yz69]

Hi Turnbuckle,

Just started your latest protocol, thanks!  two questions,

 

Why is  threonine not needed in the latest protocol? 

Is resveratrol here to activate sonic hedgehog gene?

 

 

[lost69]

Turnbuckle

 

today i checked shouldler by mri and tendons are perfectly repaired already.

i dont know if it was badly damaged and recovered so fast by your protocol, the ultrasound said " structural changes on supraspinatus tendon insertion on....with fine lamellae calcifications".i am not expert on this but i read calcifications on tendons are not a good sign.anyway all tendons are now perfect

 

mri found: intraspongous acromion-clavicle bone contusion from direct impact (minimal fluid present)

 

i'll see the specialist tommorow, from what i understand it is something broken inside the bone and it is treated by high dose IV bisphosphonate and recovers complitely by 3 months on 80% cases if treated early when edema is still present.

 

do you think your protocol can still help on this?

i believe the little pain was always from the bone and not tendon.your protocol reduced this pain, actually all pain was gone by your protocol and first PRP injection and came back immediately as i took an antibiotic pill (i had to take clarithromycin 4 days)

 

thank you

[Mr Matsubayashi]

I haven't read the whole thread so my apologies if this has already been hashed out, I found this article interesting. 

 

https://sci-hub.tw/h...pubmed/30087348

 

Abstract

"Unexpectedly, feeding C18:0 to Drosophila animals also regulated mitochondrial fusion in vivo, and led to organismal consequences: dietary supplementation with C18:0 was able to partially rescue the impaired locomotion and reduced lifespan resulting from mitochondrial dysfunction caused by mutations in the Parkinsons genes Pink1 or parkin16. This indicates that flies can sense and respond to levels of C18:0 in their diets. Humans, however, ingest more lipids than flies17,18. Furthermore, humans, like flies, express Elovl6, which elongates C16:0 to C18:0 thereby providing an endogenous source of C18:0. Hence it is unknown whether in humans this C18:0 sensing mechanism is saturated with dietary and/or endogenous lipids, or if it is poised to sense changes in dietary C18:0 intake, responding by altering mitochondrial morphology and function. To test this, we undertook here a clinical study, manipulating dietary C18:0 intake in both healthy and diabetic subjects, and assayed mitochondrial morphology and function in vivo. We found a surprisingly robust response, with C18:0 ingestion causing fusion of mitochondria in 90% of all tested subjects. C18:0 intake also led to a drop in circulating acylcarnitine levels, suggesting increased fatty acid beta-oxidation in vivo. This identifies C18:0 as a lipid metabolite sensed in humans, and raises the possibility that dietary C18:0 activates part of the physiological response through which the human body handles lipids."

 

Other fun bits

"C18:0 levels peak in blood 3 h after ingestion"

"24 g of C18:0, roughly equivalent to the amount of C18:0 present in 200 g of milk chocolate"

"Dietary stearic acid (C18:0), however, does not increase atherosclerosis risk, and, if anything, actually reduces LDL cholesterol"

"When C18:0 levels are low, the Transferrin Receptor TfR1 activates JNK signaling, leading to ubiquitination and inhibition of Mitofusin 2 and hence mitochondrial fragmentation and reduced oxygen consumption"

"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"

"Ingestion of the C18:0 drink caused mitochondria to fuse, both 3 and 6 h after ingestion: the fraction of neutrophils with fragmented mitochondria dropped significantly from 50 to 25% while the fraction of neutrophils with fused mitochondria increased significantly from 7 to 27%"

"dietary C18:0 rapidly induces mitochondrial fusion in human neutrophils. Although we did not assay mitochondrial morphology in other tissues, we previously published that various different human and Drosophila cell types respond to C18:0 in tissue culture"

"circulating levels of C18:0 are responsive to acute changes in diet, and that they are more responsive than C16:0."

"in addition to fatty acids, we also measured other metabolites and markers in the blood samples including cholesterol, glucose, insulin, methylglyoxal (MG), iron, ferritin, transferrin, and hepcidin. None of them showed C18:0-dependent changes in levels"

"We noticed that the mitochondria in some people fused particularly strongly in response to C18:0 ingestion, whereas the mitochondria in 10% of the people did not respond"

"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"

 

"C18:0 ingestion reduces circulating acyl-carnitines"

"Acylcarnitines are fatty acids coupled to carnitine that are ready for mitochondrial import for betaoxidation"

"When beta-oxidation is impaired relative to the fatty acid supply, these long chain acylcarnitines accumulate and are released into the blood where they can be detected"

"Interestingly, we found that serum long chain acylcarnitine levels increase significantly after a 2-day low-fat vegan diet"

"suggesting that C18:0 intake increases fatty acid beta-oxidation in vivo"

 

"A diet rich in C16:0 could be particularly bad because it provides lipids to the body without activating the mitochondrial response that C18:0 does"

 

"We had four vegetarians in our study (Supplementary Data 1). Since vegetarians eat no meat, but still eat dairy products, both of which are rich in C18:0, there is the possibility that vegetarians could have reduced serum C18:0 levels. However, we did not see any differences between vegetarians and omnivores in either basal C18:0-TAG levels (Fig. 4c, d) or mitochondrial fusion (Fig. 4b). This lack of an association could be due to the small sample size, however, it could also be due to compensatory intake of C18:0 from dairy products in vegetarians, or from increased endogenous biosynthesis. Hence it is possible that long-term constitutive differences in dietary C18:0 intake might be buffered by changes in endogenous biosynthesis."

 

I'll increase my chocolate consumption. 

[Mr Matsubayashi]

Sounds like NMN/NR+/N+R supplementation might increase fusion and mitochondrial oxygen consumption by increasing C18:0 synthesis. 

 

https://www.ncbi.nlm...ubmed/25003994/

 

"In vitro FA elongation assays using membrane fractions demonstrated that ELOVL6 activity was enhanced ∼10-fold in the presence of NADPH, although ELOVL6 itself did not require NADPH for its catalysis. On the other hand, KAR does use NADPH as a reductant in its enzyme reaction"

 

Maybe a low fat vegan diet should be part of the fission protocol. 

Edited by Mr Matsubayashi, 04 February 2020 - 03:34 AM.

[Mr Matsubayashi]

A study in mice where injected NMN increased brain NAD+ and increased fusion.

 

https://www.ncbi.nlm...pubmed/30801823

[Mr Matsubayashi]

Sorry for the spamming. 

 

What's the purpose of Curcumin in the stack? The three known effects i've found while trawling through the literature are;

 

Whole cell autophagy

Mitochondria biogenesis 

Mitochondria survival

 

https://sci-hub.tw/h...pubmed/27143655

https://www.ncbi.nlm...pubmed/30669284

 

 

[Mr Matsubayashi]

To answer my own questions on NAD+ fission and fusion, 

 

NMN supplementation = fusion

NR/N+R supplementation = fission

 

https://www.cell.com...1247(18)30742-3

 

"In our model systems, NR ameliorated mitochondrial function and rescued mitochondrial quality control. We also observed an increased expression of BNIP3L/NIX after NR treatment. In line with this, mitochondrial content decreased after 24 hr of NR treatment, which points toward increased mitophagy. However, prolonged NR treatment boosted mitochondrial content and increased TFAM, which underlines the dual role of NAD+ and sirtuins in maintaining mitochondrial biogenesis and quality control. Furthermore, supporting an increase in mitophagy, NR positively regulated autophagic function."

 

Is this right?

[Turnbuckle]

To answer my own questions on NAD+ fission and fusion, 

 

NMN supplementation = fusion

NR/N+R supplementation = fission

 

https://www.cell.com...1247(18)30742-3

 

"In our model systems, NR ameliorated mitochondrial function and rescued mitochondrial quality control. We also observed an increased expression of BNIP3L/NIX after NR treatment. In line with this, mitochondrial content decreased after 24 hr of NR treatment, which points toward increased mitophagy. However, prolonged NR treatment boosted mitochondrial content and increased TFAM, which underlines the dual role of NAD+ and sirtuins in maintaining mitochondrial biogenesis and quality control. Furthermore, supporting an increase in mitophagy, NR positively regulated autophagic function."

 

Is this right?

 

 

NR, N+R and NMN all increase NAD+ and the NAD+/NADH ratio. According to the paper below, the oxidized/reduced ratio increases fission in cells, and fission increases mitophagy and clearance of defective mitochondria.

 

Removal of dysfunctional mitochondria requires the activation of autophagy coupled with ongoing mitochondrial fission. 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...les/PMC3365962/

 

 

The supplements driving the ratio up shouldn’t much matter. With chronic use, however, one would expect NAD+ to be reduced to NADH and the NAD+/NADH ratio to fall, the effect on fission falling along with it. Mito mass should then tend to increase again.

 

The new paper Mr Matsubayashi linked to suggests that raising NAD+ in the brain has the opposite effect on mitochondria.

 

A single dose (62.5mg/kg) of NMN, administered to male mice, increases hippocampal mitochondria NAD+ pools for up to 24 hours post-treatment and drives a sirtuin 3 (SIRT3) mediated global decrease in mitochondrial protein acetylation. This results in a reduction of hippocampal reactive oxygen species levels via SIRT3 driven deacetylation of mitochondrial manganese superoxide dismutase. Consequently, mitochondria in neurons become less fragmented...

https://www.ncbi.nlm...les/PMC6565489/

 

 

SIRT3 is overexpressed in neurons, and is known to drive fusion. It appears that when SIRT3 is stimulated with a high NAD+/NAD ratio, the result for neural mitochondria is opposite that in other tissues. Mitochondria in neurons are replicated near the cell body and are then transported long distances down axons, and for that to work, they have to be in a state of fission, thus their needs are quite different from other cells.

 

The real question is with neuronal SCs, which don’t have axons. That will take more looking into.

Edited by Turnbuckle, 04 February 2020 - 10:08 AM.

[jgkyker]

Effect of nicotinamide mononucleotide on brain mitochondrial respiratory deficits in an Alzheimer’s disease-relevant murine model

 

Furthermore, we found a shift in dynamics from fission to fusion proteins in the NMN-treated mice.

 

 

Edited by jgkyker, 04 February 2020 - 09:00 PM.

[Mr Matsubayashi]

Resveratrol appears to be a potent SIRT1 activator and promoter of fission like curcumin, should it be in part 2 of the stack?

 

Resveratrol depletes mitochondrial DNA and inhibition of autophagy enhances resveratrol-induced caspase activation.

Importantly, resveratrol depleted ATPase 8 gene, and thus, reduced mitochondrial DNA (mtDNA) content, suggesting that resveratrol induces damage to mtDNA causing accumulation of dysfunctional mitochondria triggering autophagy induction.

https://www.ncbi.nlm...pubmed/23088850

 

Resveratrol Ameliorates Mitophagy Disturbance and Improves Cardiac Pathophysiology of Dystrophin-deficient mdx Mice

In conclusion, resveratrol improved cardiomyopathy by promoting mitophagy in the mdx mouse heart.

https://www.nature.c...598-018-33930-w

 

The role of Resveratrol-induced mitophagy/autophagy in peritoneal mesothelial cells inflammatory injury via NLRP3 inflammasome activation triggered by mitochondrial ROS.

Additionally, resveratrol (RSV) treatment induced mitophagy/autophagy via adenosine monophosphate-activated protein kinase (AMPK) activation

https://www.ncbi.nlm...pubmed/26825654

[Mr Matsubayashi]

But when it comes to the brain I find the opposite.

 

Resveratrol provides neuroprotective effects through modulation of mitochondrial dynamics and ERK1/2 regulated autophagy

Resveratrol administration also recovered rotenone induced ΔΨm, mitochondria dynamics alteration, and elongated fragmented mitochondria.

https://www.tandfonl...rnalCode=ifra20

 

Resveratrol Regulates Mitochondrial Biogenesis and Fission/Fusion to Attenuate Rotenone-Induced Neurotoxicity

The results showed that resveratrol could not only promote mitochondrial mass and DNA copy number but also improve mitochondrial homeostasis and neuron function in rats and PC12 cells damaged by rotenone.

https://www.ncbi.nlm...les/PMC4684867/

[Mr Matsubayashi]

Just out of interest, endurance exercise seems to promote fission in skeletal muscle. Note that over expression of mytophagic pathways may result in decreased muscle performance. 

 

Regular Endurance Exercise Promotes Fission, Mitophagy, and Oxidative Phosphorylation in Human Skeletal Muscle Independently of Age

https://www.frontier...2019.01088/full

 

Exercise-Induced Mitophagy in Skeletal Muscle and Heart.

https://www.ncbi.nlm...pubmed/30985475

 

Effects of exercise in a cold environment on gene expression for mitochondrial biogenesis and mitophagy

https://www.scienced...011224019301294

 

This article has a nice review of young/aged mitophagy responses to exercise

https://link.springe...978-019-00041-5

 

If you're combining exercise with a fission protocol, it might pay to Exercise Like a Girl

Edited by Mr Matsubayashi, 05 February 2020 - 12:35 AM.