2287 replies to this topic

[able]

There is a formula to convert murine dosages to human dosages.  I'm sure Dr. Sinclair is very aware that to reproduce similar results in humans that he got in mice you have to use a certain dosage.  That said, the first trial is a small trial to check the safety of the drug, so they could be trying the max dose for that purpose.  Remember, that Sinclair and his family have been on this for quite a while now and I'm sure have had many blood tests to check the NAD+ levels and the other parameters. 

 

I agree with you Brenner's presentation skills are very lacking.

 

The 2016 long term study says the 100mg/kg a day was better than 300mg/kg a day for some parameters and not as effective at others.

 

They say the 100mg/kg a day equals 560mg a day for humans, which maybe why Sinclair says 500mg a day.

 

The 30 day study for safety that Sinclair mentions isn't posted on clinical trials.

 

Anyone know if he was talking about the Japanese study that was supposed to start late last year or what?

 

This one  is a different study:

 

https://clinicaltria...cond=nmn&rank=1

 

8 weeks of supplementation at 250mg a day, then following the subject for 2 years to judge the long term effects.

 

 

"This study is is looking at the effect of the dietary supplement "Nicotinamide mononucleotide" (NMN) on key cardiovascular and metabolic functions, specifically those that are important risk factors for diabetes and cardiovascular disease. Accordingly, the investigators will evaluate the effect of NMN on how well (a) the hormone insulin works to control blood sugar, (b) the body produces insulin, and © blood vessels dilate (get wider). The investigators will also look at the effects of NMN on blood lipids; body fat and liver fat; and other blood, fat tissue and muscle tissue markers of cardiovascular (heart) and metabolic health. Data from studies conducted in rodents have shown that NMN supplementation has beneficial effects on cardiovascular and metabolic health, but this has not yet been studied in people."

Edited by able, 03 November 2017 - 06:18 PM.

[PAMPAGUY]

Just when we thought that we had the NAD+ mechanism all figured out, then something else pops up.  In this article from a very esteemed lab it seems that we have a new term - HSF1.  Is now the time to head to the nearest Sauna to up your body core temp to at least 42 C?

 

It seems that heat as well as fasting stresses the body to produce life extending transcription factors.

 

If all the phenotypes of HSF1-deficient livers derive from an NAD+ crisis, it should be expected that recovering NAD+ levels would reverse the phenotypes of HSF1-null hepatocytes. To test this hypothesis, Qiao et al. (2017) performed a series of elegant experiments using Nampt-independent NAD+ precursors, such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). The treatment with either NR or NMN was enough to fully rescue intracellular NAD+ levels, mitochondrial respiration, and ATP levels in HSF1-deficient hepatocytes. Further, NR also improved hepatic glucose production capacity in HSF knockout mice, based on pyruvate tolerance tests. These experiments certified the relevance of NAD+ as the central element driving the metabolic decline caused by HSF1 deficiency. Overall, the work of Qiao et al. (2017) shows that HSF1 depletion affects the transcriptional regulation of Nampt levels. Lower amounts of Nampt lead to lower amounts of NAD+, which in turn dampen sirtuin activity and thereby mitochondrial biogenesis and oxidative capacity (Fig. 1). 

 

http://jcb.rupress.o...701093.full.pdf

[Nate-2004]

I've been using the sauna at 80 degrees celsius, 4x a week for at least 20 mins for about a year now. I've been trying to aim for fission days when I go but it doesn't always fall on the right day for that.

Edited by Nate-2004, 04 November 2017 - 04:23 PM.

[able]

Interesting article.

 

I've also been doing sauna followed by cold shower, 2 cycles, on 3 gym days a week for 6 months or so.  

 

Lots of studies on both heat and cold stress being beneficial. 

 

Edited by able, 04 November 2017 - 04:23 PM.

[Nate-2004]

Honestly I've read or been told that heat shock therapy should be separate from cold shock therapy. Ideally you would do cold shock on fusion days (biogenesis) and heat shock on fission days (HSF1). It's also important to space them out as the the effects of either are more potent up to an hour after exposure. So either warming up slowly or cooling down slowly is important.

[able]

Interesting.  I thought it was the shock/stress to the body that does the trick.  

 

A longer, colder cold bath is supposed to be more effective than a cold shower, but as you mentioned previously is difficult.   

 

I notice a very relaxed feeling after, followed by increased energy/euphoria if I refrain from eating for a few hours afterwards.

 

I'll try separating the hot and cold and see how that does.

 

The article does say that heat therapy was more effective in a fasted state, which does line up with the theories I have been following on exercise while fasted.  

Edited by able, 04 November 2017 - 04:37 PM.

[PAMPAGUY]

All the discussion about Alive by Nature selling NMN for a lot of money and this study comes out and says the following.

 

"The treatment with either NR or NMN was enough to fully rescue intracellular NAD+ levels, mitochondrial respiration, and ATP levels in HSF1-deficient hepatocytes. Further, NR also improved hepatic glucose production capacity in HSF knockout mice, based on pyruvate tolerance tests."

[able]

Yes, it seems another data point that NR is likely more effective than NMN at raising NAD+ in the liver.

 

The study that quote came from is here:

 

https://www.ncbi.nlm...les/PMC5350514/

 

I found this more interesting:

 

"NAM treatment in vitro and in vivo could not reverse the NAD+and ATP-decline or restore the diminished glucose production capacity of hepatocytes caused by HSF1 loss"

Edited by able, 04 November 2017 - 06:39 PM.

[able]

Bummer.  That research was almost all in vitro - introducing liver cells to different compounds.  Except one where they injected 400mg/kg of NAM.

 

And none compared effect of NR to NMN at all.  

 

They did some experiments exposing cells to NMN, and some different ones exposing cells to NR.  Hence the statements that article made about the precursors showing some benefits, but were not comparisons.

 

So is extremely difficult to draw conclusions on efficacy of oral supplementation of the different precursors based on that study.

 

 

Edited by able, 04 November 2017 - 07:31 PM.

[Iporuru]

'Manipulating mitochondrial networks inside cells — either by dietary restriction or by genetic manipulation that mimics it — may increase lifespan and promote health'

https://news.harvard...asing-lifespan/

[PAMPAGUY]

An interesting video on ageing research made for the masses.  Also, a website on similar videos.

 

http://www.popularme.../aging-science/

 

https://www.youtube....ltHxD1rDPwtNM8Q

[William Sterog]

Just when we thought that we had the NAD+ mechanism all figured out, then something else pops up.  In this article from a very esteemed lab it seems that we have a new term - HSF1.  Is now the time to head to the nearest Sauna to up your body core temp to at least 42 C?

 

It seems that heat as well as fasting stresses the body to produce life extending transcription factors.

 

If all the phenotypes of HSF1-deficient livers derive from an NAD+ crisis, it should be expected that recovering NAD+ levels would reverse the phenotypes of HSF1-null hepatocytes. To test this hypothesis, Qiao et al. (2017) performed a series of elegant experiments using Nampt-independent NAD+ precursors, such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). The treatment with either NR or NMN was enough to fully rescue intracellular NAD+ levels, mitochondrial respiration, and ATP levels in HSF1-deficient hepatocytes. Further, NR also improved hepatic glucose production capacity in HSF knockout mice, based on pyruvate tolerance tests. These experiments certified the relevance of NAD+ as the central element driving the metabolic decline caused by HSF1 deficiency. Overall, the work of Qiao et al. (2017) shows that HSF1 depletion affects the transcriptional regulation of Nampt levels. Lower amounts of Nampt lead to lower amounts of NAD+, which in turn dampen sirtuin activity and thereby mitochondrial biogenesis and oxidative capacity (Fig. 1). 

 

http://jcb.rupress.o...701093.full.pdf

 

There are other ways to activate HSF1:

 

Here we report that SFN activates heat shock transcription factor 1 (Hsf1)-mediated heat shock response. 

http://www.jbc.org/c...jbc.M110.152686

 

Salidroside from Rhodiola seems to be one of the most efficacious substances at this regard:

 

ADAPT-232 and its active constituent salidroside induce the release of Hsp72 and NPY via a mechanism dependent on the upregulation of HSF1.

https://www.ncbi.nlm...9752/figure/F5/

 

Rhodiola has been implicated in some life extension research:

 

Rhodiola (10-25ug/mL of feed) given to nematodes (C. Elegans) for their lifetime was able to delay aging in the whole population (extending the time required for the first deaths to occur) and extend life to around 10-20%

 

The mechanism is thought to be secondary to DAF-16 nuclear translocation,[28] as DAF-16 is vital for improving heat tolerance in nematodes[29] which was also observed following dietary intake of rhodiola.[28] DAF-16 translocation is generally thought to be related to longevity and stress resistance[30][31] and the effects of rhodiola on DAF-16 is thought to be related to a hormetic mimicking of stress.[32]

 

A subsequent study on drosophilia using Rhodiola at 15-200mg/mL noted significant reductions in mortality (with only the higher doses reducing fecundity) and promoted longevity in these flies by 3.2-3.5 days,[7] which has been replicated twice elsewhere with an enhancement of life by 24%.[33][34]Longevity has also been noted to occur in yeast[35] 

 

I hope this is not considered off-topic. I don't fully understand the relation between NAD and HSF1, but I remembered reading that Sulforaphane and Salidrosides were able to activate and upregulate it. I hope this add another piece to the puzzle. 

 

I also know that Rhodiola has been found to increase mitochondrial biogenesis (among many other things): https://www.reddit.c...iew_on/debv1vi/

Edited by William Sterog, 07 November 2017 - 01:03 PM.

[PAMPAGUY]

I have still been dragging with fatigue on my Fission days with only 500 mg NR. What is the ratio of Nicotinamide to Ribose in NR? I noticed many are using twice as much Riboside as Nicotinamide. Perhaps, if I add 500-1000 mg of Riboside to my NR regime I might feel better on Fission days. I bought a lot of NR before Chromadex cut everyone off, so I need to use the NR I have before switching to N+R. Also, if this works I can up my NR dose more quickly.

One other thing. I take Metformin and Melatonin daily. How do these 2 drugs affect the Fission/Fusion cycle?

As you can see, I need help with getting everything lined up correctly. Thanks in advance for the help.

[Turnbuckle]

I have still been dragging with fatigue on my Fission days with only 500 mg NR. What is the ratio of Nicotinamide to Ribose in NR? I noticed many are using twice as much Riboside as Nicotinamide. Perhaps, if I add 500-1000 mg of Riboside to my NR regime I might feel better on Fission days. I bought a lot of NR before Chromadex cut everyone off, so I need to use the NR I have before switching to N+R. Also, if this works I can up my NR dose more quickly.

One other thing. I take Metformin and Melatonin daily. How do these 2 drugs affect the Fission/Fusion cycle?

As you can see, I need help with getting everything lined up correctly. Thanks in advance for the help.

 

I have limited experience with NR, but I don't recommend it due to the long delay time. With my early experiments of N+R I found I was sleeping a lot, and that my hypertension disappeared and was replaced with hypotension. So do measure your BP as it might be low.

 

The bigger problem may be the metformin. It acts as a mito uncoupler, so it will magnify the weakening you get from a high oxidized/reduced NAD ratio. I've found something similar using avocado oil (low stearic acid content) + urosolic acid. Both are uncouplers, and the combination with N+R wasn't particularly pleasant.

 

We show that metformin decreases mitochondrial respiration, causing an increase in the fraction of mitochondrial respiration devoted to uncoupling reactions. Thus, cells treated with metformin become energetically inefficient

https://www.ncbi.nlm...les/PMC4147388/

 

 

 

Don't know about melatonin, though it is known to alter mito function. As for more ribose + NR, who knows. Try it, but keep in mind that NR takes around 4 hours to kick in, and the extra ribose may be gone by then.

Edited by Turnbuckle, 11 November 2017 - 07:28 PM.

[Turnbuckle]

The importance of using both fusion and fission, re cancer--

 

these observations indicate that there is a strict relationship between mitochondrial dynamics and cancer progression. In particular, impaired fusion and enhanced fission seem to contribute to the proliferation/apoptosis imbalance in cancer. Thus, a mitochondrial-targeted strategy for cancer therapy, i.e., targeting mitochondrial networking by modulating proteins involved in determining mitochondrial morphology, could represent an intriguing complementary approach to other emerging treatments (such as those targeting mitochondrial metabolism) for an efficient cancer therapy.

 

https://www.ncbi.nlm...les/PMC5439081/

 

 

[PAMPAGUY]

Thanks Turnbuckle,

Wow, I just got my first jolt from taking Stearic Acid 10 gm.  It snapped me out of fatigue right away.  I took it appx. 36 hours after the NR.  I could feel the effects 1-2 hours after taking it.  I just measured it out and took it with water.  Just like a liquid candle.  I'm 71 yo, and felt more energy and clarity of mind.  Feel, I could work all night if I had to.  Haven't felt that way in many years.  My idea is to take 1 gm. of Riboside with the NR, cut out the Metformin on Fission days.  Set up a protocol of 1 day Fission, (500 mg NR + 1 gm Riboside, 1 gm Tryptophan) 1 day Fusion, + 1 day off a week.  Will use Stearic Acid 10 mg for fusion.  Don't know if I need the PQQ, Broccoli sprout extract or the Leucine.

 

This will only leave me 24 hours between Fission and Fusion, but I'm only using 500 mg NR.  Maybe 5 gm Stearic Acid would be better?  Don't want to hamper the Mitophagy.  You want a balance. 

 

What do you think?  Feedback very welcome.

 

[PAMPAGUY]

I didn't mention it, but I have been on Rapamycin for almost a year.  No side effects, feel great and my lab work has really improved.  I take a weekly dose of 8 mg, but took 6 mg up until a month a go.  Also take low dose Statin, Metformin, BP med.  Of course, Rapa can really help protect you from Cancer.  Transplant patients rarely if ever get cancer.

[Turnbuckle]

 

Thanks Turnbuckle,

Wow, I just got my first jolt from taking Stearic Acid 10 gm.  It snapped me out of fatigue right away.  I took it appx. 36 hours after the NR.  I could feel the effects 1-2 hours after taking it.  I just measured it out and took it with water.  Just like a liquid candle.  I'm 71 yo, and felt more energy and clarity of mind.  Feel, I could work all night if I had to.  Haven't felt that way in many years.  My idea is to take 1 gm. of Riboside with the NR, cut out the Metformin on Fission days.  Set up a protocol of 1 day Fission, (500 mg NR + 1 gm Riboside, 1 gm Tryptophan) 1 day Fusion, + 1 day off a week.  Will use Stearic Acid 10 mg for fusion.  Don't know if I need the PQQ, Broccoli sprout extract or the Leucine.

 

This will only leave me 24 hours between Fission and Fusion, but I'm only using 500 mg NR.  Maybe 5 gm Stearic Acid would be better?  Don't want to hamper the Mitophagy.  You want a balance. 

 

What do you think?  Feedback very welcome.

 

 

 

See post 558 for how to take stearic acid without feeling you're drinking a candle. Remember that it isn't just fission and fusion, but fission/mitophagy and fusion/biogenesis. You are reducing the mitochondrial mass by dividing it up and exposing it to mito QC, then increasing it while in a protected fusion state. So, in my experience, 2-3 days of fission/mitophagy, followed by 3 days of fusion/biogenesis is best, using stearic acid only on the first day of fusion. 500 mg NR is not at all ideal. Consider that the 2 g nicotinamide and 2 g of ribose would be equivalent to 4 g of NR. So by all means use up your NR, but realize it may not be giving you the deep level of fission that will dice up those large zombie mitochondria.

[Ovidus]

Gentlemen,

How is the following very simplified regimen for a fission / fusion cycle.

FISSION: N+R; KAATSU Training for Maximal Lactic Acid; Fasting (cannot do 3 day fast, so as low calories as possible during those 3 days); Strong Mitochondrial Uncouplers

FUSION: Stearic Acid


- I have access to the above only. so really hoping these will suffice for an OK protocol
- Is our best guess at the moment to do 3 days of Fission followed by 3 days of fusion?

Edited by Ovidus, 12 November 2017 - 04:52 PM.

[sumguy90]

I bought a lot of NR before Chromadex cut everyone off, so I need to use the NR I have before switching to N+R. Also, if this works I can up my NR dose more quickly.

This sounds like the sunk cost fallacy to me. If the NR you have isn't yielding your optimal result and N+R might then the only important question is if you can afford the minimal cost and effort of tryimg N+R. It's likely that the result would be worth the little bit of trouble to try, regardless of how much NR you've got in your closet.

I tried 500mg N + 750mg R overnight and found it too fatiguing so I found source naturals sells 100mg niacinamide I'm hoping to use to dial in a good dose. If you're going to buy d-ribose to play with the ratio in your NR you might as well buy a little niacinamide too to compare and figure out what your best possible experience is.

[sumguy90]

Gentlemen,

How is the following very simplified regimen for a fission / fusion cycle.

FISSION: N+R; KAATSU Training for Maximal Lactic Acid; Fasting (cannot do 3 day fast, so as low calories as possible during those 3 days); Strong Mitochondrial Uncouplers

FUSION: Stearic Acid


- I have access to the above only. so really hoping these will suffice for an OK protocol
- Is our best guess at the moment to do 3 days of Fission followed by 3 days of fusion?

I think you need something to raise NAD. I don't think uncouplers alone will increase fision enough to make the same difference in mitophagy.

[Turnbuckle]

Gentlemen,

How is the following very simplified regimen for a fission / fusion cycle.

FISSION: N+R; KAATSU Training for Maximal Lactic Acid; Fasting (cannot do 3 day fast, so as low calories as possible during those 3 days); Strong Mitochondrial Uncouplers

FUSION: Stearic Acid


- I have access to the above only. so really hoping these will suffice for an OK protocol
- Is our best guess at the moment to do 3 days of Fission followed by 3 days of fusion?

 

 

If you are older and are just starting this, I'd advise not using the uncouplers, as you may well find it to be too much.

 

I think you need something to raise NAD. I don't think uncouplers alone will increase fision enough to make the same difference in mitophagy.

 

 

N+R raises NAD.

[HaplogroupW]

Gentlemen,

How is the following very simplified regimen for a fission / fusion cycle.

FISSION: N+R; KAATSU Training for Maximal Lactic Acid; Fasting (cannot do 3 day fast, so as low calories as possible during those 3 days); Strong Mitochondrial Uncouplers

FUSION: Stearic Acid


- I have access to the above only. so really hoping these will suffice for an OK protocol
- Is our best guess at the moment to do 3 days of Fission followed by 3 days of fusion?

 

According to this, fasting arrests mitochondria in the fused state:

 

http://www.cell.com/...4131(13)00104-6

 

Have a look at figure 5, and accompanying discussion.

 

If so fasting would seem to be working against the fission supplements.

 

 

 

 

 

 

[stephen_b]

Where are people getting their stearic acid?

[PAMPAGUY]

Amazon, anyone, dirt cheap, 2 lbs will give you appx. 90, 10 g doses, use once a week last 1 1/2 yrs

[Ovidus]

 

If you are older and are just starting this, I'd advise not using the uncouplers, as you may well find it to be too much.

 

 

Hi Turnbuckle, 

 

We had spoken very briefly about uncouplers in this thread previously. Perhaps this is a good opportunity to say a few more words about that topic, because it is a highly relevant heading in the discussion about mitochondria. 

Now DNP has a terrible rep I know. I am not advocating its use. However, I have observed a lot of wonderful things about its effects in people who I know, even though I did not use it myself. In particular someone who I know has used it on and off at very low doses for years and got tremendous benefits. Overall it is really a very simple equation: if the dose is sufficiently low, DNP does excellent things. If the dose is too much, the effects are very unpleasant and can be fatal. Nobody has to be stupid enough to overdo it. When the person I observed dosed around 100 mg it did wonders for getting rid of fatty liver and excess bodyfat and had significant anti-inflammatory effects. At such a dose, the side effects were truly nonexistent. 
Now if, theoretically, someone were to be certain of his/her reactions to DNP and knew for a fact that he/she does very fine with a 100 mg dose per day, and also has experience using NR -also with good results- would you still be opposed to the kind of combo I have speculated about above? Would you still speculate that the combination of two such items -both benign on their own- may have very additive effects and results in undesirable outcomes when combined?

Finally, would you think that the rest of the elements suggested in my post make sense? 
How about fasting, which HaplogroupW -thanks a lot for the post- suggested may be misplaced in the cycle...

Thanks a ton

[Turnbuckle]

 

 

If you are older and are just starting this, I'd advise not using the uncouplers, as you may well find it to be too much.

 

 

Hi Turnbuckle, 

 

We had spoken very briefly about uncouplers in this thread previously. Perhaps this is a good opportunity to say a few more words about that topic, because it is a highly relevant heading in the discussion about mitochondria. 

Now DNP has a terrible rep I know. I am not advocating its use. However, I have observed a lot of wonderful things about its effects in people who I know, even though I did not use it myself. In particular someone who I know has used it on and off at very low doses for years and got tremendous benefits. Overall it is really a very simple equation: if the dose is sufficiently low, DNP does excellent things. If the dose is too much, the effects are very unpleasant and can be fatal. Nobody has to be stupid enough to overdo it. When the person I observed dosed around 100 mg it did wonders for getting rid of fatty liver and excess bodyfat and had significant anti-inflammatory effects. At such a dose, the side effects were truly nonexistent. 
Now if, theoretically, someone were to be certain of his/her reactions to DNP and knew for a fact that he/she does very fine with a 100 mg dose per day, and also has experience using NR -also with good results- would you still be opposed to the kind of combo I have speculated about above? Would you still speculate that the combination of two such items -both benign on their own- may have very additive effects and results in undesirable outcomes when combined?

Finally, would you think that the rest of the elements suggested in my post make sense? 
How about fasting, which HaplogroupW -thanks a lot for the post- suggested may be misplaced in the cycle...

Thanks a ton

 

 

Again, I'd suggest people don't add in uncouplers if they are just starting out with fission/fusion. But if later on you are brave enough to try it, please report back. My own experience was not pleasant. As for combining fasting with fission, I've never tried it. I usually take these things on an empty stomach, however that doesn't constitute "starvation," as in HaplogroupW's reference.

[BigLabRat]

 

According to this, fasting arrests mitochondria in the fused state:

 

http://www.cell.com/...4131(13)00104-6

 

Have a look at figure 5, and accompanying discussion.

 

If so fasting would seem to be working against the fission supplements.

 

 

Yes, I've puzzled over this paper, which seems to contradict many of the findings on fasting. It is widely reported that fasting increases autophagy and mitophagy, as well as quality control. Hard to see how this would be the case if starvation arrests mitochondria in a fused state.

 

This study, however, is looking at cells in culture (and only a couple of types), and many of the experiments are looking across periods of 4 hours. This might not be the best model of a a three-day fast in an organism.

 

Fasting has time-dependent effects. Longo's research on chemoprotection suggests that normal, healthy cells in the body "hunker down" after a fast of 72 hours, and become far less vulnerable to damage from outside agents (in his experiments with mice and humans, the outside agents are chemotherapy and radiation therapy for cancer. A three-day fast before treatment leaves patients with less side-effects than those who do not fast.)

 

In any case, this is a fascinating article--but I'm still not sure what it's telling me!

[Ovidus]

.
FISSION: N+R; KAATSU Training for Maximal Lactic Acid; Fasting (cannot do 3 day fast, so as low calories as possible during those 3 days); Strong Mitochondrial Uncouplers

FUSION: Stearic Acid

 

Thank you for the input Turnbuckle...

 

Now with the exception of fasting, which we are still debating, are the above classifications roughly accurate (in terms of fission vs fusion)? 

[mitomutant]

Turnbuckle took me here from here

 

In my case, where a given percentage of my mitochondria are faulty, fusion is the recommended approach:

 

 

 

 Our results provide strong experimental support for this hypothesis and suggest that mitochondrial fusion may ameliorate the clinical severity of inherited mtDNA encephalomyopathies