2195 replies to this topic

[Nate-2004]

This is off topic but quickly:

 

1) Start slow and low in terms of dosage. Slowly increase to 3 tbsp and I'm still experimenting with it. I am still unsure of how much of the effect was purely caprylic acid and how much was keto. Could be synergistic, not sure.

2) Speaking of coffee I think it might be good for me to cut back on caffeine, as it doesn't help the tremor for sure. I'll figure it out though. Just buy viva naturals MCT and put a tsp in your coffee at first. Don't waste money on bulletproof.

3) I know there's a number of apps on Android just search tremor, I use iPhone and the app is called "My Tremor" and the other app for spiral tests is called Progress or something, I can't see the full title because the developer is an idiot.

4) The link I posted explains the mechanism of action hypothesis. I am still trying to understand it but it is very similar to what ethanol does.

 

UPDATE:

 

Today is my 2nd day of fusion and the 5th or 6th cycle through this (though this time I'm following pretty much what Turnbuckle's most recent suggested protocol (3 fission 3 fusion except 1.5g NR not N+R)). I can say without a doubt my energy is way up and I feel more and more like everything seems effortless to do, relative to what I was used to. Riding my bike anywhere I can hit some fast speeds if I can get a straight away with no traffic. It feels like I'm not even trying. I don't know if this is rejuvenation or what. I ran a lot faster on the treadmill with no more effort than a couple weeks ago at a much lower speed. I am at pretty much sprint speed but as safely as possible given treadmill sprints can be pretty dangerous if you trip. I wanna build up that lactic acid. Anyway, the HIIT today was easy yet intense.

 

I tested my A1C today and it was 5.3% down from 5.5% last year. Oddly though my fasted blood glucose was really high this morning but I drank last night and then ate a key lime pie not long before bed, breaking some rules heh. However, when I was out at the concert I noticed just how much energy I had to basically dance forever.

Edited by Nate-2004, 11 October 2017 - 10:28 PM.

[Heisok]

To give this thread less clutter, I moved mine to Nates Keto thread

 

http://www.longecity...e-2#entry829814

Edited by Heisok, 11 October 2017 - 11:03 PM.

[able]

I think you saw this on another thread Nate, but not totally sure so thought I'd mention here also.

 

These studies show BHB may be the reason CR extends life and health span (and also boosts NAD+)

 

I think it's likely at least part of the reason your recent improvements with ET.

 

You're producing a lot more BHB with the mct oil AND keto diet.

 

Will be interesting if your condition is stable after leaving ketosis. 

 

 

 

Ketone bodies mimic the life span extending properties of caloric restriction

 

β-Hydroxybutyrate: A signaling metabolite in starvation response

[Nate-2004]

Supplement for fusion: C18:0 — stearic acid.

 

See: Regulation of mitochondrial morphology and function by Stearoylation of TfR1 — “We find that animal cells are poised to respond to both increases and decreases in C18:0 levels, with increased C18:0 dietary intake boosting mitochondrial fusion in vivo.”

 

I would love to know exactly how much of a relative increase in stearic acid it takes to promote fusion and to what degree. I tried reading that study and it's a doozy when it comes to understanding everything explained. We get a lot of stearic acid in just about everything we eat that has any fat in it. For instance, even flaxseeds have 300mg of stearic acid per serving. Just a 1/4 lb of grass fed beef (112g) contains 19g of stearic acid. Peanut butter has just about the same as flaxseed, 300mg per serving.

 

The only things I can find that don't have very much are breads, pastas and beans and pretty much most fat free foods.

 

I wanna make sure I'm getting the most out of my fission days. Did you pay attention to these things on fission days or did you rely more on the N+R/Fisetin/AMPK activator induced/assisted fission?  

 

You once said taking broccomax with NR might as well be throwing it away, wouldn't it also be the same case for taking NR on days with fatty foods?

Edited by Nate-2004, 13 October 2017 - 05:03 PM.

[aconita]

If things were to be as black or white as sometimes we tend to think life on the planet would be impossible at least.

 

Reality is more kind of grey shades.

 

Would eating meat (fusion) dressed with a turmeric (fission) sauce lead to disruption of the fission/fusion process?

 

I don't think so, biology works in a much smarter way or we should all be dead since long time.

 

Certainly we can sort of shift emphases on certain aspects but in a relatively limited way when talking about food, with supplements and various compounds things gets trickier but I seriously doubt eating your steak close to N+R will defy the purpose of it, actually it might just avoid too much shift on one aspect which might not be all that bad.

 

Being aware of certain mechanisms is certainly smart but over complicating things might not.

 

I would take care with supplements and their pairing but a much more relaxed approach about food.

 

Anyway, luckily enough, you can't have just fission or just fusion.

 

Maybe what we are doing isn't 100% efficient toward our goal...so what?

 

We likely aren't going to know for sure anyway and it might only mean a few months more to compensate the eventual lack of efficiency.

 

Theory only goes so far in biology, even for very smart researchers.

 

Usually practice tells different stories, often quite counter intuitive ones.

 

Lets keep it in perspective avoiding to be carried away too far. 

[Andey]

 

 

 

The [NAD+]/[NADH] ratio is reciprocally regulated by the [pyruvate]/[lactate] ratio...

https://www.ncbi.nlm...les/PMC3365962/

 

 

 

Or equivalently, lactate/pyruvate is high when NAD+/NADH is high.

 

 

 Isn't it the opposite?

 https://www.ncbi.nlm...034525.g001.jpg

[Turnbuckle]

 

 

 

 

The [NAD+]/[NADH] ratio is reciprocally regulated by the [pyruvate]/[lactate] ratio...

https://www.ncbi.nlm...les/PMC3365962/

 

 

 

Or equivalently, lactate/pyruvate is high when NAD+/NADH is high.

 

 

 Isn't it the opposite?

 https://www.ncbi.nlm...034525.g001.jpg

 

 

You are right. In fact, adding lactate to fusion side might be a good idea--

 

Surprisingly, lactate treatment resulted in an increase in the mitochondrial contents of both the control and NAM-treated cells in a dose-dependent manner. This indicates that lactate itself or the lactate-induced decrease in the [NAD+]/[NADH] ratio increases the mitochondrial content.

 

[Andey]

 

 

 

You are right. In fact, adding lactate to fusion side might be a good idea--

 

Surprisingly, lactate treatment resulted in an increase in the mitochondrial contents of both the control and NAM-treated cells in a dose-dependent manner. This indicates that lactate itself or the lactate-induced decrease in the [NAD+]/[NADH] ratio increases the mitochondrial content.

 

 

 

  Yep, and in your first take on protocol exercise definitely increases lactate (esp pump type)

 I am kinda puzzled with similarities between  NAM+R+exercise and KAATSU = BFR. In KAATSU small weight (20-30% of 1RM) combined with 30+ reps gives systemic (almost bodywide) anabolic effect due to the accumulation of metabolic byproducts in blood flow of restricted limb. (kinda nice training modality BTW coz it should affect many small muscles that are hard to train, also while injured etc). Your protocol with exercise sounds familiar but without the need to restrict blood flow and possibly even more systemic.

[Ovidus]

Big Bump to Kaatsu training; it indeed the best way to increase lactic acid and other byproducts in a muscle and known to be an extremely effective training method. I highly recommend it and am wondering whether Nate or Turnbuckle would incorporate it into their fission /fusion regimens. 

Here is a link to KAATSU:

 

An additional question is about the use of DNP (more specifically the 2,4 isomer of Dinitrophenol). I know that pretty much anyone here would not touch this not approved for human consumption and has lead to deaths resulting from an overdose. But essentially this substance results in significantly decreased ability of mitochondria to build up ATP reserves. The mitochondria keep working to turn ADP to ATP, but are far less efficient in doing so and the energy wasted during this process is given off as heat. This is why this drug heats you up significantly. 

Would DNP constitute an effective tool to use somewhere in your fusion/fission protocol and if you were to utilize it (this is entirely a theoretical discussion; I do not advocate anyone use it and do not think the posters in this thread will consider doing so -however, it must be added that DNP has extended lifespan in more than one species and is a very well studied substance... a whole different discussion which we best shouldn't get into in order not to dilute this thread), where would you do so?

 

Thanks to all

[ambivalent]

Last year when taking NR I expereinced like many pains in my feet but also fingers and eye socket. Also one morning I awoke feeling dizzy, something of a common occurrence when I was younger with a particularly poor diet. It wasn't diagnosed but I wonder if it might have been hyperglycemia. I noticed one person posted it the experience thread that NR had triggered their hyperglycemia.

 

I've been on the fusion/fission protocol for several days and added NR on some of those occasions. It was going very well I felt improved skin, increased alertness and very energised on occasions. However, I started noticing the giddyness one afternoon, which didn't last, as well as the pain-flashes in the extremeties as in last year which have persisted for a few days. So I stopped last night (nights fission, days fusion). After a short while I awoke to excrutiating left lower back pain for a couple of hours and was close to calling for some medical help. Oddly enough drinking plenty of water rid the pain and when it returned more water solved it

 

I remember reading in the miraculous effects of vitamin D the author hypothesising why so many diabetics have extremtities amputated and I believed he reasoned it the body additional sugar in those areas as a protective method for hybernation (lower the freezing point). Anyway, a bit off track but it made me wonder whether NR or N+R was effecting blood-sugar levels. Another symptom I could feel my abscess playing up as it does when taking in high sugar. My diet hasn't been greater latetly either so there will likely have excacerbated the sugar-levels.

 

I found a thread where lower back pain was relieved by drinking water - there no firm conclusions as to the cause most speculations are kidney stones. It seems highly likely it my pain is related to the NR, N+R experiment.   

 

Any thoughts?

Edited by ambivalent, 15 October 2017 - 08:32 PM.

[Heisok]

ambivalent,

 

I regularly test my blood sugar levels, and have never gotten obvious indications of hyperglycemia from NR.Thanks for mentioning that. During the time frame, I had multiple ways of eating from SAD American eating, to South Beach, LCHF and Ketogenic.  I took NR for close to 2 years at 100 mg, 1 time per day. I then started 225 mg per day all the way up to about 250 mgs in the AM and 250 mgs in the afternoon. I am currently at 250 mgs in the AM maybe 3 or 4 times a week. I will be adding a periodic dose of NMN. I used to take 5 to 10 gms per day of D-Ribose, but stopped for a couple years. Unfortunately, in tests of 2 sources,  I have developed an apparent reverse reaction to D-Ribose. I get a spike in BG, instead of a lowering which seems to be expected. I wonder if the NR to D-Ribose in the blood could be the culprit for you.

 

 

Edited by Heisok, 15 October 2017 - 09:03 PM.

[Turnbuckle]

 

Would DNP constitute an effective tool to use somewhere in your fusion/fission protocol and if you were to utilize it (this is entirely a theoretical discussion; I do not advocate anyone use it and do not think the posters in this thread will consider doing so -however, it must be added that DNP has extended lifespan in more than one species and is a very well studied substance... a whole different discussion which we best shouldn't get into in order not to dilute this thread), where would you do so?

 

 

 

Uncouplers would be interesting in combination with exercise and fission, but as you point out, DNP has problems--

 

The protonophore 2,4-dinitrophenol (DNP), which enjoyed extensive use as an obesity treatment in the 1930s prior to its discontinuation due to toxic side effects (Colman, 2007), has been increasingly utilized as a putative DR mimetic. Promisingly, in flies and mice, DNP has recently been shown to increase lifespan, accompanied by decreases in oxidative damage (Padalko, 2005; Caldeira da Silva et al., 2008). In mice, DNP particularly affected respiration in the brain, though whether this occurred through increased concentration or enhanced activity is unclear (Caldeira da Silva et al., 2008). However, DNP equilibrates proton concentration and membrane potential across not only mitochondrial, but also endosome and plasma membranes, and therefore does more than simply uncouple mitochondria. Additionally, the small therapeutic range, sub-lethal side effects, high variability of optimal dose, and non-specific distribution of DNP in the body are important caveats when considering its application toward lifespan extension.

 

https://www.ncbi.nlm...les/PMC2924931/

 

 

Ursolic acid might be safer--

 

...the effects of 0.4-200 ng/mL ursolic acid (1) on the functions of isolated rat heart mitochondria oxidizing either pyruvate and malate, succinate, or palmitoyl-l-carnitine plus malate were investigated. It was found that 1 induced a statistically significant uncoupling of oxidative phosphorylation. A statistically significant decrease in H₂O₂ production in the mitochondria was observed after incubation with 5 ng/mL 1. This effect was comparable to the effectiveness of the classical uncoupler carbonyl cyanide 3-chlorophenylhydrazone. Since mild mitochondrial uncoupling has been proposed as one of the mechanisms of cardioprotection, the present results indicate that ursolic acid (1) has potential use as a cardioprotective compound.

 

https://www.ncbi.nlm...pubmed/21648406

 

[ambivalent]

ambivalent,

 

I regularly test my blood sugar levels, and have never gotten obvious indications of hyperglycemia from NR.Thanks for mentioning that. During the time frame, I had multiple ways of eating from SAD American eating, to South Beach, LCHF and Ketogenic.  I took NR for close to 2 years at 100 mg, 1 time per day. I then started 225 mg per day all the way up to about 250 mgs in the AM and 250 mgs in the afternoon. I am currently at 250 mgs in the AM maybe 3 or 4 times a week. I will be adding a periodic dose of NMN. I used to take 5 to 10 gms per day of D-Ribose, but stopped for a couple years. Unfortunately, in tests of 2 sources,  I have developed an apparent reverse reaction to D-Ribose. I get a spike in BG, instead of a lowering which seems to be expected. I wonder if the NR to D-Ribose in the blood could be the culprit for you.

 

Thanks Heisok.

 

There do seem to be some similarities between hyper/hypo most notably dizziness. Perhaps it was hyper when I was young, and hypo with NR, N+R. I've certainly noticed my BO has suffered recently (increased sweating is a symptom of hypo). I've also noticed increased hunger (as did a friend of mine when trialling NR for a couple of days) another hypo symptom.

 

http://www.diabetes....oglycaemia.html

[Ovidus]

 

Uncouplers would be interesting in combination with exercise and fission, but as you point out, DNP has problems--

 

 

 

Ursolic acid might be safer--

 

...the effects of 0.4-200 ng/mL ursolic acid (1) on the functions of isolated rat heart mitochondria oxidizing either pyruvate and malate, succinate, or palmitoyl-l-carnitine plus malate were investigated. It was found that 1 induced a statistically significant uncoupling of oxidative phosphorylation. A statistically significant decrease in H₂O₂ production in the mitochondria was observed after incubation with 5 ng/mL 1. This effect was comparable to the effectiveness of the classical uncoupler carbonyl cyanide 3-chlorophenylhydrazone. Since mild mitochondrial uncoupling has been proposed as one of the mechanisms of cardioprotection, the present results indicate that ursolic acid (1) has potential use as a cardioprotective compound.

 

https://www.ncbi.nlm...pubmed/21648406

 

 

 

I very strongly believe that Ursolic Acid is NOT safer. This is a topic that I have discussed for years and I am very intimately familiar with DNP. Again, not reallya discussion fit for this particular thread as it would take forever to resolve this debate and -as has happened in several discussions where DNP was debated- it will likely be impossible to reach a definitive conclusion. However if used reasonably, DNP is a very safe and non-toxic compound. What confuses people (not referring to you Turnbuckle, because I know you are far more sophisticated a thinker than that) is that the dose -response curve is very steep. Low doses, and a lot of very pleasant things happen, high dose and very bad things happen. People quote the research where high doses were used and will label it as bad, simply because people cannot accept that something can be good or bad depending on circumstances and means of administration. It has to be universally good or bad in their minds.
(happy to elaborate over PM)

 

Now all of this aside, if one were to THEORETICALLY use this to remodel mitochondria, what exercise modality and other supplements might we be combining with this?

[Fafner55]

Here is support for a causal relationship between accumulated dysfunctional mitochondria and the phenotypes of aging.

"Premature ageing in mice expressing defective mitochondrial DNA polymerase" (2004) https://www.nature.c...ature02517.html

 

Regarding transitioning from improving one's population of mitochondria to a maintenance mode, what are the opinions for how often a 60+ year old individual might need a treatment to invoke mitophagy?

[Turnbuckle]

 

Regarding transitioning from improving one's population of mitochondria to a maintenance mode, what are the opinions for how often a 60+ year old individual might need a treatment to invoke mitophagy?

 

Mitophagy is a normal process in cells that tends to become less effective with age as QC declines and defective mitochondria build up--degenerative processes that likely feed on each other in a death spiral--so this protocol was intended to turn the clock back by taking fission/mitophagy to an extreme that doesn't normally occur. Does this actually reestablish QC to a more youthful level? In my case it seems likely, but I haven't given it enough time to know for sure. And though I said recently that I was transitioning to a maintenance mode, I didn't do that for very long as I'm addicted to fission-amplified exercise. In any case, I will be surprised if there is any particular schedule that will fit everyone. 

[MikeDC]

Here is support for a causal relationship between accumulated dysfunctional mitochondria and the phenotypes of aging.
"Premature ageing in mice expressing defective mitochondrial DNA polymerase" (2004) https://www.nature.c...ature02517.html

Regarding transitioning from improving one's population of mitochondria to a maintenance mode, what are the opinions for how often a 60+ year old individual might need a treatment to invoke mitophagy?

Mitophagy become dysfunctional as we age because NAD+ level decreases with age. Restoring NAD+ Levels with NR restores mitophagy.

[Turnbuckle]

 

Here is support for a causal relationship between accumulated dysfunctional mitochondria and the phenotypes of aging.
"Premature ageing in mice expressing defective mitochondrial DNA polymerase" (2004) https://www.nature.c...ature02517.html

Regarding transitioning from improving one's population of mitochondria to a maintenance mode, what are the opinions for how often a 60+ year old individual might need a treatment to invoke mitophagy?

Mitophagy become dysfunctional as we age because NAD+ level decreases with age. Restoring NAD+ Levels with NR restores mitophagy.

 

 

 

 

Does restoring NAD+ to youthful levels get rid of zombie mitochondria as well? It's very doubtful you can do that without taking NAD+/NADH to a level higher than youthful levels. The trials with animals did that, and that's what we are doing here. It's also clear that you can't just raise NAD+ levels all the time. There is a purpose to mito fusion as well.

 

Also, simply saying that NAD+ declines with age is not sufficient. It's important to consider why that actually happens. One theory is that declines of mito output results in a decline of mitophagy, which produces a death spiral--

 

I suggest that as mitochondrial ATP output drops, cells respond by further inhibiting mitophagy, leading to a further decrease in ATP output in a classic death spiral. I suggest that this increasing ATP deficit is communicated by progressive increases in mitochondrial ROS generation, which signals inhibition of mitophagy via ROS-dependent activation of insulin signaling. This hypothesis clarifies a role for ROS in aging, explains why insulin signaling inhibits autophagy, and why cells become progressively more oxidized during aging with increased levels of insulin signaling and decreased levels of autophagy. 

 

Evidence that a mitochondrial death spiral underlies antagonistic pleiotropy

https://www.research...tic_pleiotropy 

 

 

 

The details seem overly convoluted. I think it more likely that the decline of mito function directly lowers cellular NAD+ levels, which directly lowers mitophagy, which results in more defective mitochondria, and so on with a death spiral. If that is the case, then breaking that spiral by clearing the cellular load of defective mitochondria should restore health for a while. 

 

Edited by Turnbuckle, 16 October 2017 - 09:05 PM.

[Fafner55]

 

The details seem overly convoluted. I think it more likely that the decline of mito function directly lowers cellular NAD+ levels, which directly lowers mitophagy, which results in more defective mitochondria, and so on with a death spiral. If that is the case, then breaking that spiral by clearing the cellular load of defective mitochondria should restore health for a while. 

 

 

There is ample support for Turnbuckle's view - 

1. “Nicotinamide-induced mitophagy: event mediated by high NAD+/NADH ratio and SIRT1 protein activation” (2012)  http://www.jbc.org/c.../23/19304.long 
2. "Nicotinamide enhances mitochondria quality through autophagy activation in human cells" (2009) http://onlinelibrary...9.00487.x/full 

[aconita]

as mitochondrial ATP output drops, cells respond by further inhibiting mitophagy

 

I was a bit reluctant to enunciate my hypothesis but because of the above it might not be totally unreasonable.

 

Supplementing creatine while on the protocol might help providing plenty of ATP to fully functional mitochondria avoiding the need for inhibited mitophagy while likely not making much of a dent for defective ones therefore amplifying the difference between functional and defective, especially when under stress (exercise), hopefully leading to a more efficient fission.

 

That is what I am doing, too soon to tell the outcomes but certainly something is going on quite noticeably.

 

Leave alone supplementing creatine only on fission or fusion days since creatine stores aren't going to swing from one day to another, just supplement it everyday or don't at all. 

[Nate-2004]

There is a decline in a lot of basic functions with age, collagen production and sex hormones for example, not just NAD+. There are other upstream factors to consider. There's an increase in, AGE's, SASP and CD38 which eats up NAD+ but I wouldn't dismiss other mechanisms like Turnbuckle is suggesting with the feedback loop death spiral. 

 

I'm planning on doing the fission/fusion protocol indefinitely till I see some kind of regeneration or give up on it. In terms of the hypothesis it really makes sense to me, or is making more and more sense to me as I continue to learn the details.

 

I wish I could credit this for tremor improvement but my improvement in tremor has also been pretty inconsistent and lines up more with the ingestion of caprylic acid and staying low carb more than it lines up with anything else. It could just be that the condition is most definitely not related to mitochondrial dysfunction at all and that would make sense because it began at the age of 12 for me. So I will have to look for other signs of improvement in terms of biological markers and overall fitness. I'm still only 43 and honestly I'm probably in better shape than most 30 year olds these days, so fitness is probably a bad metric to use.  This girl in orientation at my new job asked how old I was, I said 43 and she was like "no fucking way I was assuming late 20's". I never believe these things from people who know me but from people I just met it's a little more credible for some reason. Frankly she was 38 and looked 50 so I wasn't going to say anything in return lol.

 

I'm not seeing my hair thicken any nor am I seeing any huge improvement in skin youthfulness... but I'm not sure whether I can expect malar fat pad firming or zygomatic and maxilla orbital bone regrowth. This is something affected by other factors. 

 

 

 

Supplementing creatine while on the protocol might help providing plenty of ATP to fully functional mitochondria avoiding the need for inhibited mitophagy while likely not making much of a dent for defective ones therefore amplifying the difference between functional and defective, especially when under stress (exercise), hopefully leading to a more efficient fission....

 

Leave alone supplementing creatine only on fission or fusion days since creatine stores aren't going to swing from one day to another, just supplement it everyday or don't at all. 

 

I have actually been doing just that that last two cycles only during fusion and it makes me wonder if fusion shouldn't be going a bit longer than 3 days to give creatine time to do it's thing.  I don't know how creatine levels look from one day supplemented vs the next not supplemented. I did a pre-load level of creatine on day 2 and 3 of fusion which is 25g.

Edited by Nate-2004, 16 October 2017 - 09:52 PM.

[aconita]

Preloading creatine isn't smart, useless and a waste.

 

Once creatine reserves are full (the aim of supplementing) levels stays there for several days/weeks, it is a slow process to fill them up as it is a slow process to drop them.

 

Taking creatine intermittently makes no sense at all, one needs to take it everyday in order to fill up reserves which will take several days, maybe weeks, and needs keeping supplementing in order to stay there, 5g/day is the recommended dose, best after training, coupled with fast carbs (maltodextrin, for example) and baking soda (5-20g).

 

Herrings are the richest food source of creatine available with amazingly high levels (and plenty omega 3). 

[MikeDC]

Here is support for a causal relationship between accumulated dysfunctional mitochondria and the phenotypes of aging.
"Premature ageing in mice expressing defective mitochondrial DNA polymerase" (2004) https://www.nature.c...ature02517.html

Regarding transitioning from improving one's population of mitochondria to a maintenance mode, what are the opinions for how often a 60+ year old individual might need a treatment to invoke mitophagy?

Mitophagy become dysfunctional as we age because NAD+ level decreases with age. Restoring NAD+ Levels with NR restores mitophagy.

Does restoring NAD+ to youthful levels get rid of zombie mitochondria as well? It's very doubtful you can do that without taking NAD+/NADH to a level higher than youthful levels. The trials with animals did that, and that's what we are doing here. It's also clear that you can't just raise NAD+ levels all the time. There is a purpose to mito fusion as well.

Also, simply saying that NAD+ declines with age is not sufficient. It's important to consider why that actually happens. One theory is that declines of mito output results in a decline of mitophagy, which produces a death spiral--

I suggest that as mitochondrial ATP output drops, cells respond by further inhibiting mitophagy, leading to a further decrease in ATP output in a classic death spiral. I suggest that this increasing ATP deficit is communicated by progressive increases in mitochondrial ROS generation, which signals inhibition of mitophagy via ROS-dependent activation of insulin signaling. This hypothesis clarifies a role for ROS in aging, explains why insulin signaling inhibits autophagy, and why cells become progressively more oxidized during aging with increased levels of insulin signaling and decreased levels of autophagy.

Evidence that a mitochondrial death spiral underlies antagonistic pleiotropy
https://www.research...tic_pleiotropy

The details seem overly convoluted. I think it more likely that the decline of mito function directly lowers cellular NAD+ levels, which directly lowers mitophagy, which results in more defective mitochondria, and so on with a death spiral. If that is the case, then breaking that spiral by clearing the cellular load of defective mitochondria should restore health for a while.

You can only break the spiral by supplementing NAD+. Restoring mitochandria to normal dynamics is the right thing to do. It has been proven in mice studies.

[Turnbuckle]

I would really appreciate it if Chromadex propagandists and stockholders would stop posting to this thread. Thank you.

[HaplogroupW]

This seems apropo:

 

http://onlinelibrary...acel.12434/full

 

 

 

In addition, we found that MB treatment stimulated the expression of PGC-1α (Fig. 5D) and thereby leading to a partial rescue of some of the PGC-1α targeted mitochondrial genes (Fig. S5E). We concluded that the treatment with MB significantly improves mitochondrial functional and morphological abnormalities and stimulates PGC-1α production. Notably, in contrast to the nuclear blebbing and progerin solubility analyses (Fig. 4) that appeared to be HGPS specific, the mitochondria in both normal and HGPS cells benefited from the MB treatment.

[My emphasis]

 

Figure 5 caption says they treated with "100 nM" MB.

 

[edit: removed question about molarity. nM is apparently nano-moles per liter.]

Edited by HaplogroupW, 18 October 2017 - 04:58 AM.

[Nate-2004]

PGC1a plays a strong role in biogenesis, I've been reading about methylene blue off and on for a while and much of my hesitation around it is out of concern for its MAO inhibition. There are so many negative interactions with various foods especially those containing tyrosine, they'll spike the blood pressure.

 

This is an in vitro study so I'm not so sure how we could dose it in this protocol, or if it's something that you can dip in and out of depending on fusion/fission.

 

 

[BigLabRat]

MB is a reversible MAOI, so its dangers are less than many MAOIs. Still, MAO inhibition can have unpleasant side effects (I speak from experience).

 

If anyone is inclined to fool with MB, there is a lot of info on oral dosing for infections. And, since the article cited is talking in terms of nanomolar solutions, it shouldn't take too much to get into the range used in the literature.

 

I wouldn't be inclined to mess with MB myself, but if anyone more experimental than I should do so, please report back!

 

[Nate-2004]

I'll try anything of course but I'd need some solid guidelines and methods for dosing and ingestion. I wouldn't know the first thing about how to measure out a nanomole but I realize that was for an in vitro situation.

 

You can also boost PGC1a pretty drastically with an ice bath so not sure what the difference would be on a mechanism of action level.

 

I thought about separating heat stress from cold stress relative to fission from fusion respectively.  4 mins in an ice bath is enough to induce a lot of PGC1a.

Edited by Nate-2004, 18 October 2017 - 05:44 PM.

[nikolay]

d-Ribose increases glycated hemoglobin: https://www.ncbi.nlm...pubmed/29033370

[ceridwen]

Very courageous of you to point this out. That's a whole range of supplements that should be discontinued?