2288 replies to this topic

[jgkyker]

Well nicotinamide is a powerful activator of mitophapgy via raising NAD as per various references upthread, and it's difficult to imagine NR or NMN would have a different effect.

In Vivo studies make it hard to work out the exact mechanism, but if the impaired mice in the study had their mitochondria rescued by improved mitophagy, upregulated fusion proteins might result as a consequence of lower ROS, for example.

I certainly wouldn't take NMN as part of Turnuckle's stem cell protocol. I'd stay away from curcumin too if I were you, as it's a well known nrf2 activator, which encourages differentiation.

 

Excellent thoughts. Thank you for sharing them. Clearly, I have still much to learn, and I will research this further.

 

My first thought, though, is that I want any stem cells created to be immediately used, if at all possible, to restore degraded tissues. Therefore, I believe (please correct me if I am wrong) that I would want to encourage differentiation on stem cell creation days. Also, it seems to make sense to encourage differentiation on mitochondria fusion days as general cellular function is likely on an upswing, probably providing more "activity" that can be utilized for differentiation.

 

I'll try to read the NMN study a little more to see if I can get a better idea of what they were saying.
 

[stephen_b]

I've had really good results taking NMN. I presume that the beneficial effects are due to fusion promotion. It's the opposite feeling of the blahs when taking N+R. I wonder if NMN or NMN + curcumin might replace stearic acid in this protocol.

[QuestforLife]

Excellent thoughts. Thank you for sharing them. Clearly, I have still much to learn, and I will research this further.

My first thought, though, is that I want any stem cells created to be immediately used, if at all possible, to restore degraded tissues. Therefore, I believe (please correct me if I am wrong) that I would want to encourage differentiation on stem cell creation days. Also, it seems to make sense to encourage differentiation on mitochondria fusion days as general cellular function is likely on an upswing, probably providing more "activity" that can be utilized for differentiation.

I'll try to read the NMN study a little more to see if I can get a better idea of what they were saying.

Differentiation (i.e. nrf2 or ROS driven) is asymmetric stem cell division, so it's best separated in time from increasing stem cell numbers.

[Turnbuckle]

Excellent thoughts. Thank you for sharing them. Clearly, I have still much to learn, and I will research this further.

 

My first thought, though, is that I want any stem cells created to be immediately used, if at all possible, to restore degraded tissues. Therefore, I believe (please correct me if I am wrong) that I would want to encourage differentiation on stem cell creation days. Also, it seems to make sense to encourage differentiation on mitochondria fusion days as general cellular function is likely on an upswing, probably providing more "activity" that can be utilized for differentiation.

 

I'll try to read the NMN study a little more to see if I can get a better idea of what they were saying.
 

 

 

See the first post of my stem cell thread-- https://www.longecit...with-c60/page-1

[jgkyker]

Hey, guys, thanks for helping me understand your perspective. I realize I need to do some further studies, namely stem cell creation and differentiation and how they relate to each other. If I understand those better, it will make sense why I would need to separate stem cell pool repletion and stem cell use (differentiation). My initial thought is to ramp up both, and this is also part of why I am supplementing amino acids, non-stop.

 

The first post in the thread seems to indicate that stem cells lose their ability to differentiate as we age and that this may happen due to a decrease in number. To carry that thought further, if there are fewer stem cells around, whatever queues them to differentiate probably queues them less often, or it could even be more complex than that, of course, in that stem cells may have some kind of unknown mechanism that naturally causes them to stop differentiating. Turnbuckle seems to think the mitochondria are closely related to this process, and I agree with that thought. I definitely believe, at this stage, that age issues are stemming from:

1. Mitochondria dysfunction

2. DNA damage

3. Stem cell depletion and a lower frequency of differentiation

4. I haven't got this far yet.

Edited by jgkyker, 01 February 2019 - 02:25 PM.

[Graviton]

Differentiation (i.e. nrf2 or ROS driven) is asymmetric stem cell division, (...)

I am not sure why you say that

 

Differentiation is a general term that can be either case

 

Also, if you don't mind, could you clarify the story about NRF2?

Edited by Graviton, 01 February 2019 - 04:30 PM.

[QuestforLife]

I am not sure why you say that

Differentiation is a general term that can be either case

Also, if you don't mind, could you clarify the story about NRF2?

No differentiation implies loss of stemness, so it must be assymmetrical. Symmetrical division produces two stem cells.

Nrf2 is a well known part of the antioxidant response element, so if it is being activated conditions are likely not right for stem cells to increase their number (in fact they'll probably be needed to repair damage).

Think it was mentioned near the start of the thread, as Turnbuckle said.

[Turnbuckle]

It's differentiation (stem cells creating somatic cells) vs proliferation (stem cells creating only stem cells). This can happen is symmetrically or asymmetrically: One stem cell can divide to become 2 somatic cells or 2 stem cells (symmetric division), or one stem cell can become one stem cell plus one somatic cell (asymmetric division). In normal situations the last possibility is most common (perhaps 80%), while the first is the least common. The second is proliferation (self-renewal). In some tissue types (as in skin and intestines) there are transit amplifying cells, which are intermediate between stem cells and somatic cells, and carry most of the workload of producing new somatic cells. These cells can age and die.

 

 

Edited by Turnbuckle, 01 February 2019 - 08:49 PM.

[zorba990]

I've had really good results taking NMN. I presume that the beneficial effects are due to fusion promotion. It's the opposite feeling of the blahs when taking N+R. I wonder if NMN or NMN + curcumin might replace stearic acid in this protocol.

I seem to be observing mild hair growth effects from topical nmn but it's early.....

[jgkyker]

I think I get it guys.

 

From Mitochondrial Dynamics Impacts Stem Cell Identity and Fate Decisions by Regulating a Nuclear Transcriptional Program:

"Changes in mitochondrial dynamics regulate stem cell fate decisions by driving a physiological reactive oxygen species (ROS)-mediated process, which triggers a dual program to suppress self-renewal and promote differentiation via NRF2-mediated retrograde signaling."

 

"Furthermore, acute RNAi-mediated loss of the mitochondrial inner membrane fusion protein OPA1 (Meeusen et al., 2006) resulted in decreased primary and secondary neurospheres, which provide an estimation of stem cell self-renewal capacity (Figure 1J)."

"Acute short hairpin RNA (shRNA)-mediated knockdown of the fusion protein OPA1 in Sox2⁺ uncommitted cells, in the context of a healthy wild-type developing cortex, caused a significant cell-autonomous increase in the number of GFP⁺ electroporated cells that had committed to a neuronal fate (GFP⁺/DCX⁺ cells) at the expense of the Sox2 population (GFP⁺/Sox2⁺ cells) after only 48 hr (Figures 1L and 1M)."

 

In other words, eliminating the "fusion machinery" reduced the population of the stem cells. The "system" seems to choose either a self-renewal state or a differentiation state based on fusion or fission.

 

This makes sense to me because, when fission occurs, damaged mitochondria are flagged for elimination, and from what I understand, this can lead to cell elimination as well. To say that the body would ramp up differentiation in a fission state makes sense to me because there are probably cells that need to be replaced. On the other hand, fusion is almost like a "rest-state" for the fission machinery. Since fission and differentiation go together, they have their own machinery, and this is off, when fusion rules the day.

 

Okay, I'll buy that I don't want differentiation during fusion. Makes perfect sense to me, and I have to emphasize my thanks to those that are patiently trying to explain this to me. I appreciate it!

 

Here is what doesn't make sense:

Protective effects of a natural product, curcumin, against amyloid β induced mitochondrial and synaptic toxicities in Alzheimer's disease

 

"In contrast, curcumin enhanced mitochondrial fusion activity and reduced fission machinery, and increased biogenesis and synaptic proteins."

 

However (same paper), we do see here it also increases mitochondrial biogenesis through Nrf2:

"mRNA levels were significantly increased for PGC1α (2.1 fold decrease, p=0.003), Nrf1 by 2.1 fold (p=0.003), Nrf2 by 1.4 fold (p=0.04) and TFAM by 1.8 fold (p=0.03) in curcumin treated cells relative to untreated cells (table 4). These observations indicate that curcumin increases mitochondrial biogenesis activity."

 

So, how can curcumin enhance mitochondria fusion, which enhances stem cell self-renewal, and also increase Nrf2?

 

Perhaps, Nrf2 acts on stem cells to promote differentiation, according to previous posts, and separately on mitochondria to promote biogenesis. In other words, you do not have to have Nrf2 acting in both roles. Just because it is present doesn't mean it is promoting differentiation, for instance. I guess what I am getting at is perhaps Nrf2 can be directed specifically at mitochondria biogenesis and not stem cell differentiation. This is why curcumin can enhance fusion, which promotes stem cell self-renewal, and increase Nrf2.

 

Thoughts?

Edited by jgkyker, 02 February 2019 - 02:54 AM.

[jgkyker]

Maybe this is the key (from my words above):

 

"On the other hand, fusion is almost like a 'rest-state' for the fission machinery. Since fission and differentiation go together, they have their own machinery, and this is off, when fusion rules the day."

 

So, something with the fusion state prevents Nrf2 from acting toward differentiation. When fission kicks in, Nrf2 knows to ramp up differentiation. My guess is there is something happening in the cell elimination state that utilizes Nrf2 to prod stem cells to differentiate. I would not be surprised that the body uses Nrf2 for 2 different things, in the same place (using the system state to determine its use). Although it has nothing even remotely similar here, the idea reminds me of how starch and cellulose are both made of different glucose stereoisomers. Nature amazes me at how it can, in the glucose case more or less, use the same building block for 2 different functions.

[QuestforLife]

Nrf2 is basically a hormetic response. It might end up resulting in more fused mitochondria, but only because it overcompensated for increased ROS, for example. But it might also be a signal for differentiation because it is a damage signal. Resveratrol causes upregulation in the mitochondrial sirtuins (3//4/5), which increase fusion, but it does this by (I believe) damaging Mitochondria.

So again, I don't think this is ideal for stem cell renewal, but it isn't totally clear. If you get great results then fine. Just want to point out the difference between good conditions for stem cell renewal, and compensating for bad conditions.

[jgkyker]

Nrf2 is basically a hormetic response. It might end up resulting in more fused mitochondria, but only because it overcompensated for increased ROS, for example. But it might also be a signal for differentiation because it is a damage signal. Resveratrol causes upregulation in the mitochondrial sirtuins (3//4/5), which increase fusion, but it does this by (I believe) damaging Mitochondria.

So again, I don't think this is ideal for stem cell renewal, but it isn't totally clear. If you get great results then fine. Just want to point out the difference between good conditions for stem cell renewal, and compensating for bad conditions.

 

Excellent points. Thank you again for sharing.

 

If I understand you correctly, you suspect we may be seeing false positives, in a sense. In other words, we believe resveratrol does good things to the body, but really it is damaging the body. In that process, the body reacts haphazardly to offset the damage, and we are reading the symptoms of damage rather than the symptoms of positive healing. Fascinating.

 

Can you share why you believe this? I am sure you have explained it before. Is there a post you can share? I would be interested in reading those thoughts.

 

As far as great results go, there is always room for improvement. I seem to think it is the amino acid supplementation that is doing the most for me. Nevertheless, I will say that in the last 6 months or so, through NR and NMN supplementation (initially I bounced between them), among other things, I feel like I have crystal clear vision most of the time and also that my mind is fresher than it has been in years. I'm actually very happy about it because I didn't think this would be possible. Now, if I can only heal my hip joint, I would be very happy. Went ahead and bought a brace for that to see if it will help with progress. Hip injuries are stubborn things.

[QuestforLife]

Sirtuins are well known for being repair and defense enzymes. Resveratrol is the most famous sirtuin activator but many of the plant extracts work in a similar fashion - basically they are mild poisons.

NMN etc raise NAD available to the sirtuins, so it's not the same mechanism as resveratrol. But it's still effectively simulating conditions of no food. I assume this evolved because cells needed sirtuins to keep going in starvation conditions, but when the NADH level went up (food) it was more important to grow and divide cells, etc. and repair was down regulated.

Hope you find a way to sort out your hip; the only things I can think of off the top of my head are anti inflammatories and most of all, lose weight. You might find your hip can heal when it's bearing less weight (obviously I've no idea of your weight, you could be super thin for all I know).

[Arcanist]

I've only just discovered this massive thread and will catch up stp by step since it seems to be full of intriguing musings and findings.

 

So sorry for crashing a bit and this has probably been adressed before:

 

Turnuckle uses Niacinamide and d-Ribose as supps instead of Nicotinamide-Riboside. Is it consensus that these both substances will act similar as the the compound? Especially regarding the longevity aspects of SIRT. Niacinamide is reported to inihibit sirtuins, while NAmide-Riboside enhance them (very basic). Is supplemting Niacinamide and d-Ribside at the same time resulting in a net enhancement despite Niacinamides effects?

 

If somebody is willing to adress that question I'd appreciate it very much!

 

Concering the previous post: I've also read a publication sometime ago that claimed Homo sapiens used to "tolerate" some parasites like roundworms becuase they'd produce niacine. With better food conditions, that changed.

[Rocket]

Hey, guys, thanks for helping me understand your perspective. I realize I need to do some further studies, namely stem cell creation and differentiation and how they relate to each other. If I understand those better, it will make sense why I would need to separate stem cell pool repletion and stem cell use (differentiation). My initial thought is to ramp up both, and this is also part of why I am supplementing amino acids, non-stop.

 

The first post in the thread seems to indicate that stem cells lose their ability to differentiate as we age and that this may happen due to a decrease in number. To carry that thought further, if there are fewer stem cells around, whatever queues them to differentiate probably queues them less often, or it could even be more complex than that, of course, in that stem cells may have some kind of unknown mechanism that naturally causes them to stop differentiating. Turnbuckle seems to think the mitochondria are closely related to this process, and I agree with that thought. I definitely believe, at this stage, that age issues are stemming from:

1. Mitochondria dysfunction

2. DNA damage

3. Stem cell depletion and a lower frequency of differentiation

4. I haven't got this far yet.

 

Item 4 could be, glycation, protein folding, calcium channel degredation, ELLP damage, or many other things.

[jgkyker]

I've only just discovered this massive thread and will catch up stp by step since it seems to be full of intriguing musings and findings.

 

So sorry for crashing a bit and this has probably been adressed before:

 

Turnuckle uses Niacinamide and d-Ribose as supps instead of Nicotinamide-Riboside. Is it consensus that these both substances will act similar as the the compound? Especially regarding the longevity aspects of SIRT. Niacinamide is reported to inihibit sirtuins, while NAmide-Riboside enhance them (very basic). Is supplemting Niacinamide and d-Ribside at the same time resulting in a net enhancement despite Niacinamides effects?

 

If somebody is willing to adress that question I'd appreciate it very much!

 

Concering the previous post: I've also read a publication sometime ago that claimed Homo sapiens used to "tolerate" some parasites like roundworms becuase they'd produce niacine. With better food conditions, that changed.

 

Turnbuckle will probably answer this question. I know he has definitely answered it before, as I have seen him post about it. Therefore, you will find the answer in the thread, if not. From what I remember, he claims that the large doses of each forces the body to create NR out of the separate N+R molecules. The key is the large dose, which for some apparently, provides issues initially. In other words, you have to build up to the large dose.

 

I am not speaking from experience as I have not opted to go this route yet. Ribose is a fascinating compound though. It is embedded in so many important things like NAD, RNA, and DNA, for instance. So, I consider it more and more, day by day.

[jgkyker]

Reminder of Protocol

- Fission (NR) and Senescence Clearance (Quercetin) Day

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

 

 

I made a mistake on the quoted post. Cinnamon can be used for senescence clearance, if I recall Turnbuckle's post correctly. Therefore, I incorrectly had it slated for use on the Fusion Day. Realized my mistake today. I haven't really habitually incorporated it into everything yet. I keep forgetting it (only remembered once maybe). Need to set it out on the counter.

[Arcanist]

Thanks for your reply. I've found Turnbuckle mentioning that NR is metabolized into it's separate components before it is synthesized again in cells - so coming from that, there should

not be a different in taking NA+Ribose or NR apart from the price.

 

I'm a bit skeptical about high doses Niacinamide myself becuase of the SIRT issue, though Ray Peat has been a proponent of Niacinamide for a long long time now for example.

 

Considering Ribose too, givn that my diet would no lack b3 maybe supplemetnal Ribose helps forming mito-benficial compounds when and where needed.

 

Sorry, I know this is an undercomplex approach in light of this thread, but I'm here to learn and gain insight

[Graviton]

No differentiation implies loss of stemness, so it must be assymmetrical. Symmetrical division produces two stem cells.

Nrf2 is a well known part of the antioxidant response element, so if it is being activated conditions are likely not right for stem cells to increase their number (in fact they'll probably be needed to repair damage).

Think it was mentioned near the start of the thread, as Turnbuckle said.

Well, I meant the story of NRF2 regarding this protocol. This protocol includes NRF2 activators in the fusion time.

 

It could be case by case for NRF2/KEAP1 pathway.

 

Please take a look about this study.

 

https://www.ncbi.nlm...les/PMC4165656/

 

 

 

Nrf2 expression is highly enriched in hESCs and dramatically decreases upon differentiation. Nrf2 inhibition impairs both the self-renewal ability of hESCs and reestablishment of pluripotency during cellular reprogramming. Nrf2 activation can delay differentiation. During early hESC differentiation, Nrf2 closely co-localizes with OCT4 and NANOG. As an underlying mechanism, our data show that Nrf2 regulates proteasome activity in hESCs partially through proteasome maturation protein (POMP), a proteasome chaperone, which in turn controls the proliferation of self-renewing hESCs, three germ layer differentiation and cellular reprogramming.

Edited by Graviton, 05 February 2019 - 08:33 PM.

[QuestforLife]

Well, I meant the story of NRF2 regarding this protocol. This protocol includes NRF2 activators in the fusion time.

It could be case by case for NRF2/KEAP1 pathway.

Please take a look about this study.

https://www.ncbi.nlm...les/PMC4165656/

Interesting study Graviton, thanks for that - but enhanced Nrf2 in stem cells could just mean they are resistant to the effects of elevated ROS (which might otherwise cause excessive differentiation). Rather than being a switch we might want to press to encourage stemness.

At this point it is a chicken and egg argument - but I'd still err on the side of caution and avoid nrf2 activators when trying to encourage stem cell symmetric division.

[Graviton]

Astragalus, PQQ, sulforaphane can be NRF2 activators although it is not a generalization. So, do you take them when you are in the fusion period?

Edited by Graviton, 05 February 2019 - 10:02 PM.

[jgkyker]

Astragalus, PQQ, sulforaphane can be NRF2 activators although it is not a generalization. So, do you take them when you are in the fusion period?

 

At this time, I have decided to continue taking fusion inducing supplements that also activate NRF2. I take them during the fusion state. However, this does not mean that I understand NRF2 and how it is utilized. Based on the study you posted and the one I posted on curcumin, it seems like NRF2 supports mitochondria biogenesis and stem cell self-renewal. The other study posted indicated NRF2 supports differentiation.

 

To me, it makes sense that mitochondria biogenesis (self-replication) and stem cell self-renewal are functions that cooperate with fusion. Mitochondria biogenesis is shown to enhance endurance, which is also associated with fusion, if I understand correctly.

 

There is also this study:

The Interaction of Mitochondrial Biogenesis and Fission/Fusion Mediated by PGC-1α Regulates Rotenone-Induced Dopaminergic Neurotoxicity.

"Further experiments proved that inhibition of mitochondrial fission or promotion of mitochondrial fusion has protective effects in rotenone-induced neurotoxicity and also promotes mitochondrial biogenesis."

 

Stem cell self-renewal makes sense in the fusion state, to me, because fission is a mechanism that supports elimination of damaged mitochondria and even cells. If you have damaged cells, you differentiate stem cells to replace the damaged cells. Therefore, self-renewal is probably more likely to occur when there is less fission (fewer damaged cells to be replaced).

 

In other words, maybe NRF2 is state-functional. It determines its function by the state of the system. I have no data to back this up other than the conflicting study results we several seem to be jockeying. If one study indicates NRF2 supports differentiation in the fission state and then another study indicates NRF2 supports self-renewal in the fusion state.... well, it seems logical to conclude its function is dependent on an uncited variable. We do not fully understand it or have not explained it, in the least, through our discussions yet.

Edited by jgkyker, 06 February 2019 - 03:40 AM.

[QuestforLife]

Astragalus, PQQ, sulforaphane can be NRF2 activators although it is not a generalization. So, do you take them when you are in the fusion period?

 

Posted before in this thread, but worth re-reading:

 

https://www.ncbi.nlm...pubmed/27889639

 

Sulforaphane is a Nrf2-independent inhibitor of mitochondrial fission.

Abstract
The KEAP1-Nrf2-ARE antioxidant system is a principal means by which cells respond to oxidative and xenobiotic stresses. Sulforaphane (SFN), an electrophilic isothiocyanate derived from cruciferous vegetables, activates the KEAP1-Nrf2-ARE pathway and has become a molecule-of-interest in the treatment of diseases in which chronic oxidative stress plays a major etiological role. We demonstrate here that the mitochondria of cultured, human retinal pigment epithelial (RPE-1) cells treated with SFN undergo hyperfusion that is independent of both Nrf2 and its cytoplasmic inhibitor KEAP1. Mitochondrial fusion has been reported to be cytoprotective by inhibiting pore formation in mitochondria during apoptosis, and consistent with this, we show Nrf2-independent, cytoprotection of SFN-treated cells exposed to the apoptosis-inducer, staurosporine. Mechanistically, SFN mitigates the recruitment and/or retention of the soluble fission factor Drp1 to mitochondria and to peroxisomes but does not affect overall Drp1 abundance. These data demonstrate that the beneficial properties of SFN extend beyond activation of the KEAP1-Nrf2-ARE system and warrant further interrogation given the current use of this agent in multiple clinical trials.

 

Upshot: sulforaphane causes fusion via drp1 interference and this is completely independent of its nrf2 activation.

[jgkyker]

Today, I have been contemplating two things:

1. Some additional dental work I had done yesterday, and how fast it healed.

2. Turnbuckle's "Exercise Like a Girl" thread.

 

In #2, Turnbuckle notices that promoting a heavy fission state causes him to gain muscle mass more quickly (if I recollect correctly). Another way to frame this is that he is tearing his muscles more quickly and/or with less resistance, while in a state of fission. This is probably why there is an exercise performance decrease during fission heavy states. Since more muscle is torn, more muscle is built back up in the long haul. The way I am beginning to think of this is, "In fission promotion, the body injures more easily." This is a profound statement, if true, because it is applicable to more than just exercise. It is also applicable to surgery, competitions, and so on, where less injury is better.

 

Regarding #1, I had some additional dental work done yesterday. It was my fusion promotion day. The work was more extensive, to my understanding, than the previous work I mentioned here. Since the previous work I had done was very painful, I was not looking forward to this week. I fully expected to be eating soup for a few days, possibly, or in the least a bit handicapped in terms of eating.

 

For a quick reminder, I had my previous dental work done on Jan. 15th, which was a fission day for me! I definitely had pain going into the 2nd week, but was only at maybe a 95% pain-free state at around that time (mostly during chewing or after eating tough things like peanuts). Now, this work was done around a sensitive tooth. Therefore, it may have been the reason it took that much time to heal. I had to take naproxen on multiple occasions to fight the pain in the first week.

 

Today, I am hardly handicapped at all, in terms of eating. I had more dental work done done yesterday (other side of mouth), on a fusion day. Today, I am probably at a 90% pain-free state! BLOWS MY MIND. I took 2 naproxen when I got home yesterday at around 9:30 AM. Therefore, those 2 naproxen are long out of my system by now, which is about 12:38 PM local time. I don't need any more and have taken none today!

 

So, to sum this up, I believe the following:

1. For training, fission possibly makes sense, as indicated in Turnbuckles "Exercise Like a Girl" thread.

2. For surgery, game-days, competitions, etc., fusion will likely decrease injury to the body, increasing endurance and more.

 

I believe everyone probably already expected #2 in terms of exercise. However, what I did not expect is injury prevention during my minor surgery (dental work).

 

Here is the most important finding for me:

- Fusion states may allow older humans to perform like younger humans in states of heavy exercise or training (e.g. grappling with 20 year olds during Brazilian jiu jitsu class).

 

That statement above is profound. If it is true, it means that we could see the average age of Olympic class athletes skew higher as this is applied.

 

NOTE: I also am taking C60 to enhance stem-cell self renewal on fusion days. So, that is likely a factor too...

[Ovidus]

Guys, 

 

Can we also use Azitromycin to manipulate mitochondrial dynamics? IT surely will have an effect; where in the whole puzzle one should integrate it is an open question of course:

 

a little quote below; full text: https://www.aging-us...cle/101633/text

 

Moreover, the effects of Azithromycin on mitochondrial oxygen consumption rate (OCR) are highlighted in Figure 9A,B. Note that the mitochondrial effects of Azithromycin were concentration-dependent and bi-phasic. At 25 μM, Azithromycin did not show any effects on OCR. However, at 50 μM, the effects of Azithromycin clearly inhibited mitochondrial metabolism, especially effecting maximal respiration and spare respiratory capacity. In contrast, at 100 μM, Azithromycin actually stimulated maximal respiration and more than doubled spare respiratory capacity. This may represent a cellular compensatory response to Azithromycin treatment, to overcome its mitochondrial inhibitory effects.

[jgkyker]

EP-1, a polysaccharide in Lion's Mane mushroom (hericium erinaceus), appears to improve mitochondria function.

 

This is a future dated paper that apparently has not been published yet, March 15, 2019.

 

"Our results showed that the treatment of EP-1 could increase SOD enzyme activity as well as decrease ROS content and oxidative damage both in vivo and in vitro. As a consequence, mitochondria function improved significantly, indicated by the increase of oxygen consumption and ATP production. In addition, increased respiration activity accelerated the elimination of excessive ROS substrate and enhanced bioenergy generation."

 

"EP-1 is a polysaccharide with a molecular weight of approximately 3100 Da, which is extracted from the cultured mycelium of Hericium erinaceus."

 

https://www.ncbi.nlm...pubmed/30543884

 

I don't have full text access to the paper and cannot read into any further details. Therefore, it is hard for me to say if this should just be generally taken to enhance mitochondria function or if it should be a part of fusion or fission specific cycles. Probably one of the latter...

Edited by jgkyker, 13 February 2019 - 05:56 PM.

[jgkyker]

Guys, 

 

Can we also use Azitromycin to manipulate mitochondrial dynamics? IT surely will have an effect; where in the whole puzzle one should integrate it is an open question of course:

 

a little quote below; full text: https://www.aging-us...cle/101633/text

 

Moreover, the effects of Azithromycin on mitochondrial oxygen consumption rate (OCR) are highlighted in Figure 9A,B. Note that the mitochondrial effects of Azithromycin were concentration-dependent and bi-phasic. At 25 μM, Azithromycin did not show any effects on OCR. However, at 50 μM, the effects of Azithromycin clearly inhibited mitochondrial metabolism, especially effecting maximal respiration and spare respiratory capacity. In contrast, at 100 μM, Azithromycin actually stimulated maximal respiration and more than doubled spare respiratory capacity. This may represent a cellular compensatory response to Azithromycin treatment, to overcome its mitochondrial inhibitory effects.

 

In the U.S., Azithromycin is a prescription drug. Therefore, for me, it is not really an option.

 

Beyond that, from what I gather, Azithromycin is a well known senolytic and, based on my understanding, could probably be paired with a mitochondrial fission state to optimize clean-up. However, my question is how do you determine the dose to manage 50 micromolar vs. 100 micromolar exposure throughout your body? That is unclear, and until that is clear, I personally would not use this to affect mitochondria changes. Without that knowledge, I would be unable to determine if I am inhibiting mitochondrial metabolism (50 micromolar exposure) or stimulating it (100 micromolar exposure).

Edited by jgkyker, 13 February 2019 - 08:13 PM.

[jgkyker]

Apparently GTP, guanosine triphosphate, is an important component of mitochondrial energy. Mitochondria produce ATP. However, apparently they use GTP for fusion events, and it looks like for other things as well.

 

Has enhancing GTP availability to mitochondria been discussed here?

 

This research is apparently available as full-text on AliveByNature's website, Mitochondrial NUDIX hydrolases: A metabolic link between NAD catabolism, GTP and mitochondrial dynamics.

Here is the NCBI link: https://www.ncbi.nlm...pubmed/28302504

 

From the AliveByNature's site with the full-text:

"Fusion is controlled by mitofusin-1 and -2 (MFN1 and MFN2), which are localized in the mitochondrial OM, and by the mitochondrial IM optic atrophy protein (OPA1) (Hoppins et al., 2007; Song et al., 2009). Since these enzymes are GTP binding proteins the efficiency of fission and fusion depends on the cytosolic and mitochondrial GTP levels. Therefore, Intra-mitochondrial GTP depletion could inhibit OPA1, while cytosolic GTP depletion could inhibit the MFNs and Drp1."

 

"Furthermore, genotoxic stress-induced mitochondrial NAD+ catabolism leads to significant reduction of GTP pools in mitochondrial matrix, suggesting a causal link between downstream NAD+ degradation products and GTP metabolism (unpublished data)."

 

I'm beginning to think that increasing GTP levels is just as important as increasing ATP. In fact, apparently, in order to sustain high ATP production, you have to provide GTP.

[jgkyker]

From what I gather, GTP is synthesized during the Krebs cycle AKA the citric acid cycle (CAC) AKA TCA cycle (tricarboxylic acid cycle). (I have no idea why we have 3 names for the same cycle.)

https://biology.stac...nesis-tca-cycle

 

What feeds the Krebs cycle? Acetyl-CoA

https://en.wikipedia...tric_acid_cycle

 

How does the body produce Acetyl-CoA? Glycolysis and Beta Oxidation

https://en.wikipedia...wiki/Acetyl-CoA

 

Glycolysis requires glucose, and beta oxidation requires fatty acids.

 

So, I'm going to state somewhat the obvious here... it looks like a key component to optimal mitochondrial function is supplying the optimal fuel supply (GTP), and that requires glucose and fatty acids, e.g. stearic acid. Glycolysis and beta oxidation then creates the fuel (Acetyl-CoA) that feeds the generation of GTP.

 

One way to get glucose in your body is to eat it, of course... However, we all know that high spikes in blood glucose levels cause insulin to spike, and that, in general, causes bad stuff to happen, like insulin resistance (type 2 diabetes), or sugar crashes. Clearly, then, the best way to boost glucose levels is with foods that have a low glycemic index, such as apples or whole grain breads.

 

Therefore, in order to have optimal mitochondrial function (read optimal fission and fusion cycles etc.), we also need to eat low glycemic indexed fruits etc. during fatty acid intake and particularly in between meals, like maybe mid-morning and mid-afternoon. So, if we are eating stearic acid for fusion promotion, for instance, we probably need to eat some fruit with it (etc.).

 

Now, the body can store glucose. Perhaps, then this is unnecessary. However, consider the mid-afternoon slump of which many of us are likely familiar. Low blood glucose levels may be partially responsible for the typical mid-afternoon slump. The body doesn't have enough glucose to power the Krebs cycle, and that means low energy levels in general. Maybe this means, generally, a mid-afternoon slump is proof our body has not stored enough glucose to operate at 100%.

 

Edited by jgkyker, 14 February 2019 - 12:04 AM.