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NAD-TERT: Using NAD and Resveratrol for Telomerase activation

telomeres nad nampt ampk resveratrol allicin methylene blue nmn sirtuins statin

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#1 QuestforLife

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Posted 04 September 2018 - 03:18 PM


NAD-TERT
Using NAD+ and Resveratrol for Telomerase activation

This thread is to draw together mine and others’ research on resveratrol, Sirtuins, NAD and telomeres. I now believe we can rejuvenate cells and possibly ourselves by combining NAD uplift (using NAD precursors, NAMPT and AMPK) and telomerase activation via SIRT4 using a bioavailable form of resveratrol.

I have placed this thread in under the Telomeres Subforum because I believe that it is telomerase that is key to rejuvenating cells beyond that achieved by raising NAD alone. It could equally be placed under resveratrol or NAD subforums, however.  It is my decision to place it here however, partly to draw attention back to the importance of telomeres, whilst arguing that extending telomeres, particularly using this method (via Sirtuins) is not a route to cancer but to youth.

The protocol is still very much under development. But early signs are promising.

Rejuvenation is via NAMPT, NAD, SIRT 4 and HTERT

The key finding of this thread is that increasing NAD+ (either directly or via NAMPT) is a necessary but not sufficient step for cellular rejuvenation. A combination of a NAD and/or NAMPT booster with resveratrol however permits SIRT4 to use elevated NAD to re-activate telomerase in cells.

We know that if you raise NAD, this is used by the body for various processes to repair and protect our DNA and cells. It is the specific hypothesis of this thread that SIRT4 (and to a lesser extend SIRT1) can use NAD to reactivate telomerase when prompted by Resveratrol, and that this offers benefits beyond increasing NAD alone.

Here is the research evidence followed by my personal experiences with this protocol, which I call NAD-TERT

References

Resveratrol has been shown to be able to rejuvenate cells in vivo at low doses via modulation of splicing factors and re-extension of telomeres.
Ref: https://bmccellbiol....2860-017-0147-7

Resveratrol has been shown to reduce endothelial progenitor cell senescence through HTERT (telomerase) activation
Ref: https://bpspubs.onli...38/bjp.2008.272

Resveratrol has been shown to have different effects on early and late passage mesenchymal stem cells, and this is mediated by the presence or absence of SIRT1
Ref: https://www.scienced...006291X1530721X

Resveratrol appears to exert its effects on HTERT via SIRT4
Ref: http://www.oncotarge...580&path[]=7251

This last paper shows that SIRT4 is dependent on NAMPT. But lower doses of resveratrol can raise telomerase levels without raising NAMPT, suggesting background levels of NAMPT can be used up by this process. This suggests that the short term upregulation of HTERT seems to be due to the non-sustainable rise of NAMPT produced by dosing with resveratrol alone.

Other supplements can more sustainably increase NAMPT, for example Hydrogen sulphide (which can be induced in cells by allicin supplementation).
Ref: https://journals.plo...al.pone.0164710

Note H2S was more effective at boosting NAMPT than Resveratrol but less effect at boosting HTERT, probably because it acts primarily through SIRT1 not SIRT4

Sinclair et al. has also recently shown that the benefits of a H2S donor are additive in mouse studies using NMN
Ref: https://www.cell.com...?code=cell-site

Linking this back up to splicing factors, H2S donors alone also were able to achieve partial rejuvenation of old cells
Ref: https://www.ncbi.nlm...les/PMC6075431/

and that this is achieved by upregulating SRSF2 (and one other) splicing factor, which is interesting as this splicing factor is within 10MB of the telomere on chromosome 17 and likely affected by the shortening of the telomere via the Telomere Position Effect over long distance (TPE-OLD)

https://onlinelibrar...1111/acel.12646

https://journals.plo...al.pbio.2000016

Methylene Blue can postpone cellular senescence via boosting NAD (but not NAMPT), so this might also be a synergist pathway with the action of resveratrol and Allicin.
Ref: https://www.scienced...213231715001159

(Note: other NAD precursors may also be as or more effective, but in my experience this has not been the case).

Personal experience

I am a 39 year old male with no major health issues.

 

All the findings reported or conclusions drawn below are to be considered highly provisional.

I took 2 drops (~1mg) of Methylene blue for the first time in 2 months. This was in addition to my normal AM supplements that include Allicin, Vitamin C and Ashwaghanda. Within 4 hours I felt unusually fatigued and had a headache. The experience was similar to using Turnbuckle’s mitochondrial fission Nicotinamide and Ribose protocol for the first time (https://www.longecit...drial-dynamics/ ), but which has subsequently and even recently failed to elicit the same effect, even when combined with the same supplements. I have not experienced this fatigue when using MB alone.

As my headache grew worse I decided to try and trigger mitochondrial fusion by ingesting 20g of fish oil (ref: https://www.ncbi.nlm...les/PMC3963938/ ). I gave it two hours to work but the effect was minimal. I lay down for a rest. Letting my mind wonder over various papers I’d read recently the potential synergy of resveratrol with high NAMPT/NAD occurred to me. I took 10ml (180mg) of liposomal resveratrol from Actinovo that I had lying about. This liposomal resveratrol supplement had not previously produced any significant positive results, and I had taken it at various doses from 180mg to 4 g a day.

Within 10 minutes not only did I feel better, but I felt euphoric. I ran down the stairs and played with my kids in the garden with a renewed and fresh energy. I continued to feel fantastic for the rest of the day. That night I vigorously made love to my partner (we are sexually active but this an unusual enough event to comment on).

The following day I again took 1mg of MB with my normal AM supplements. I again grew fatigued by early afternoon, but only had the beginnings of a headache. I lay down for a rest, intending to take resveratrol as soon as a headache set in, but I fell asleep for several hours. When I woke I remembered to take the 180mg liposomal resveratrol. I again felt restored and fresh but the effect was less pronounced than on the previous day. Perhaps the sleep had already restored me, or the NAD/NAMPT levels had begun to fall.

The following and third day of treatment I once again took MB with my morning regime. Because I was to be out all day I took the liposomal resveratrol only 1 hour later; I had not yet begun to feel fatigued. I did not experience the fatigue or the headache induced previously, but neither did I experience an obvious boost or euphoria. I was able to drive for 4 hours that day without more than slight fatigue, and I did note that my skin looked unusually good that evening, in particular some small but annoying cysts that had appeared over the previous year on my left cheek were reduced in size.

After a week’s break I intend to repeat the protocol with various changes to determine to best combinations. I will continue to report back in this thread.

 

Many others here have been experimenting with various NAD, NAMPT and AMPK boosters, with and without resveratrol, whether liposomal or not, with various timings. It would be great to see if we can work out what the best combinations are.

 


Edited by QuestforLife, 04 September 2018 - 03:27 PM.

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#2 Phoebus

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Posted 05 September 2018 - 05:02 PM

Interesting!

 

now what i noticed is that you had the greatest effect following 20 g fish oil followed by liposomal resveratrol

 

Resv.'s problem has always been bioavailability. So what I am wondering is if you found a way to create maximum resv bioavailability using mega dosing of fish oil + lipid soluble resv. 

 

maybe it was that combo that created the energy rush? 

 

also...20 grams? thats a crazy high amount of fish oil. if I did that i would be weeping fish oil from my facial pores for the next three weeks! ha! 

 

anyway would be interesting to try just that combo again and see what kind of result you get. 

 

 

 

Due to its chemical characteristics, resveratrol can interact with fatty acids. Recent studies in vitro show that more than 90% of freetrans-resveratrol binds to human plasma lipoproteins. This binding is also found in vivo, as shown by the presence of dietary polyphenolic compounds detected in isolated LDL in blood samples of healthy human volunteers [3132].

Fatty acids facilitate a lipophilic environment, which favors resveratrol binding [33]. Normally they are employed as vectors because of their high affinity for the liver and their efficient cellular uptake, resulting from specific interactions with transmembrane transporters.

https://www.ncbi.nlm...les/PMC4499410/


Edited by Phoebus, 05 September 2018 - 05:14 PM.

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#3 QuestforLife

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Posted 05 September 2018 - 10:07 PM

That's possible Phoebus, and another thing for me to look into. It's liposomal resveratrol so it should be fairly bioavailabile anyway, but I'm going to trial this protocol again starting tomorrow, but without fish oil.

Incidentally, 20g is only about 20ml of Seven Seas fish oil.

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#4 jorgy72

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Posted 09 September 2018 - 07:21 PM

How about NAC for H2S production ?
https://www.cell.com...9456(18)30033-3
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#5 QuestforLife

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Posted 10 September 2018 - 01:09 PM

How about NAC for H2S production ?
https://www.cell.com...9456(18)30033-3

 

Certainly NAC helps, or if you can afford it, (liposomal) glutathione, as this boosts H2S very effectively, atleast in vitro (and my experiences suggest also in vivo)

 

http://www.pnas.org/...nt/104/46/17977

 

I've yet to recreate the initial dramatic effects of taking liposomal resveratrol to alleviate the effects of methylene blue. I am certain it was mitochondrial fission that caused the headache/tiredness -as I've experienced this before with N+R, and I expect MB penetrates the blood-brain barrier much better, which is why the headache was so bad and more noticeable that with N+R. And I also have to assume that my various previous efforts with mitochondrial fusion were successful, in that a sudden fission of mutated mitos caused me to feel so bad. At this point the feeling of mitochondrial fission is a useful symptom rather than the point of this thread - but I'd like to recreate it. A good bet for the culprit is my repeated doses of allicin plus liposomal glutathione over the summer, so I might try this for a few weeks and then repeat the MB and resveratrol experiment.

 

Taking allicin, MB and resveratrol daily for 4 days caused the initial fresh, energetic feeling to be replaced with early afternoon tiredness, though I have to say my skin, hair and eyes look very good.  I definitely feel I need to take a break from this protocol though, so it's probably something to cycle.


Edited by QuestforLife, 10 September 2018 - 01:10 PM.


#6 QuestforLife

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Posted 17 October 2018 - 10:59 AM

Another way to raise NAMPT is troxerutin.

 

https://www.ncbi.nlm...pubmed/25026599

 

(full text on sci-hub)

 

Bear in mind that any oxidative stress (that activates DNA repair) will increase PARP and use up NAD and NAMPT. So a nice antioxidant will always help and this study showed troxerutin could cancel out the negative effects of having lots of oxidized lipids in the blood and liver of rats.



#7 QuestforLife

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Posted 17 October 2018 - 12:41 PM

I've continued this line of research (Resveratrol appears to exert its effects on HTERT via SIRT4) with the finding that SIRT4 reinforces cellular arrest during DNA repair via inhibition of glutamine synthesis. Interesting SIRT4 is activated by rapamycin and deactivated by mTOR. There is more detail here (https://www.longecit...ns/#entry859169), but I'm not sure whether or not this ability of SIRT4 is causally related to its activation of HTERT, which is not a known target of rapamycin.

One possible link is the requirement for glutamine to create a protein required by telomerase to fasten onto the DNA strand it is elongating:

https://www.ncbi.nlm...les/PMC2744565/

Whether or not this increases telomerase via activation of HTERT or just increases the affinity of telomerase for DNA is not clear to me. In either case we’d expect glutamine users to have longer telomeres. Do we see this in bodybuilders that use it?

 

 



#8 QuestforLife

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Posted 18 October 2018 - 07:48 AM

For a while I’ve been pursuing several telomerase activation leads. One is via resveratrol and the Sirtuins. The other is via statins and inhibition of the mevalonate pathway. These two lines of investigation have finally converged somewhere in the mysterious signalling mechanisms of the mitochondria.

 

The potential of statins (and sartans) to activate telomerase (in vivo!) and repair the cardiovascular system was first brought to my attention by this paper:

https://www.ncbi.nlm...pubmed/26214555

 

Subsequent research revealed that this was a fairly well known pleitrophic affect, independent of the cholesterol lowering effects of statins and seems to be related to melavonate pathway inhibition and consequent AKT activation. The upshot is, people on statins have longer telomeres: 

https://www.ncbi.nlm...pubmed/25127175

https://www.ncbi.nlm...les/PMC5043056/

https://www.ncbi.nlm...pubmed/12676819

 

Further work strengthened the link to mitochondria. Inhibiting the mevalonate pathway leads to mitochondria fusion:

https://www.ncbi.nlm...les/PMC5104693/

 

This next paper draws a tentative link between mitochondrial fusion, low ROS and AKT (and therefore telomerase upregulation)

https://www.ncbi.nlm...pubmed/29378182

 

So how does this link us to the SIRTUINS and resveratrol? Well we know SIRT3 – SIRT5 are mitochondrial sirtuins. And Sirt4, the ‘culprit’ supposedly behind resveratrol’s telomerase activation, I have now found upregulates Opa1 – an important inner membrane fusion protein.

https://www.ncbi.nlm...ing-09-2163.pdf

 

(This might, just might, explain my massive energy boost when I took resveratrol after 20g of fish oil, as fish oil also upregulates Opa1 – so maybe the combination is synergistic after all, see https://www.ncbi.nlm...pubmed/24663492 Fig 4d. Could this also explain why those who eat fish generally have longer telomeres, too?)

 

So there we have it: resveratrol via NAMPT and SIRT4* and Statins via melvonate pathway inhibition, lead to increases in mitochondrial fusion. And somehow this is leading to an upregulation in AKT and telomerase.

The research continues.

 

* in fact all the mitochondrial sirtuins seem to upregulate fusion and downregulate fission (Sirt3 and 5 do it via the other mito fusion proteins), which makes sense – as the sirtuins are supposed to resist stress (which generally causes mito fission and an increase in ROS).


Edited by QuestforLife, 18 October 2018 - 07:56 AM.

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#9 MikeDC

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Posted 20 October 2018 - 04:26 PM

NAD+/Sirt1 appears to be a powerful telomerase activator. H2S also increases NAMPT/NAD+/Sirt1.
Look at the big jump in htert at the right H2S level. NR/NMN should have bigger effect.

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#10 QuestforLife

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Posted 07 November 2018 - 02:56 PM

Just a quick update.

 

I am now pursuing the low dose, intermittent statin-sartan protocol outlined in these papers 

 

 

https://www.ncbi.nlm...pubmed/26214555

 

https://www.ncbi.nlm...les/PMC4533138/

 

With addition of Vit D and Q10, which according to my research should not interfere with the desired arterial wall rejuvenation effects.

 

So the topic title should probably be changed to 'Methods of Activating Telomerase'. Perhaps the moderators will permit me to change it (it will still remain in the Telomeres subforum)?

 

I am not currently pursing the NAD-Resveratrol angle, mainly because any persistent (or intermittent large dose) use of resveratrol or pterostilbene destroys my sex drive and makes me feel generally low. Happy the statin-sartan protocol does not have this effect! But I believe that the mechanism that activates telomerase is probably the same, i.e. a low ROS environment (sartan or antioxidant) combined with mitochondrial fusion (statin via the mevalonate pathway or SIRT3/4/5). 


Edited by QuestforLife, 07 November 2018 - 03:00 PM.

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#11 Fafner55

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Posted 14 November 2018 - 02:39 AM

That's possible Phoebus, and another thing for me to look into. It's liposomal resveratrol so it should be fairly bioavailabile anyway, ...

 

Resveratrol is hydrophobic and doesn't lend itself to liposomal encapsulation. My attempts at making liposomal resveratrol have all failed. I suspect that what is marketed as liposomal resveratrol are actually emulsions. You could verify this by diluting a sample with 8 or 10 times the amount of water and placing it in a refrigerator for a few days. Excess water will break down an emulsion and the resveratrol will precipitate to the bottom.



#12 QuestforLife

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Posted Yesterday, 03:58 AM

Resveratrol is hydrophobic and doesn't lend itself to liposomal encapsulation. My attempts at making liposomal resveratrol have all failed. I suspect that what is marketed as liposomal resveratrol are actually emulsions. You could verify this by diluting a sample with 8 or 10 times the amount of water and placing it in a refrigerator for a few days. Excess water will break down an emulsion and the resveratrol will precipitate to the bottom.


I will do this experiment.

#13 QuestforLife

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Posted Yesterday, 04:16 AM

Another update. My statin-sartan experiment is going well. I feel good on the protocol and I am almost 3 weeks into the 4 week cycle.

I have continued to research the link with fusion and believe that C18 (stearic acid) is signalling in a similar manner to a statins to trigger fusion. I believe this is done via a PPAR agonist pathway, which makes the body think that it should burn fats and not store or manufacture them. In this way it is similar to a ketogenic diet. With statins it is via blockade of SREBP (creation of chloresterol). With ingestion of C18 it is stimulation via direct fatty acid oxidation. The connection with a ketogenic diet and PPAR suggests that one should limit intake of carbohydrates, particularly when taking the stearic acid or statins, to avoid the conflicting signals from PPAR and SREBP.

REFERENCES:

https://www.nature.c...467-018-05614-6
(Previously posted reference in the stem cell protocol thread regarding human in vivo fusion with stearic acid. Note the mention of fatty acid B oxidation, which doesn't occur with ingestion of palmitic acid, only with stearic).

https://www.liebertp...journalCode=rej
(Excellent overview on PPAR and SREBPs by Karen Kurtak. Need sci-hub).

I have previously experimented with adipocyte generation using pioglitazone, a potent PPAR agonist. Now I think this could be a good addition to a future fusion protocol.
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#14 QuestforLife

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Posted Yesterday, 09:06 AM

Further evidence my hypothesis is correct:

https://www.ncbi.nlm...ubmed/11226238/

This paper discusses how PPAR is activated by liver fatty acid binding protein (L-FABP), upregulated by statins (or fatty acids).

The only missing piece of the puzzle is how does this then lead to upregulated mitofusin and fused mitochondria? My bet is it is to do with the PPAR switch to burning fats means they are not available for making chloresterol to go into cell or mitochondrial walls, hence the mitochondria need to reduce overall surface area. Just a guess though. It could equally just be an adaptation to starvation, which is when your body would normally start burning fats





Also tagged with one or more of these keywords: telomeres, nad, nampt, ampk, resveratrol, allicin, methylene blue, nmn, sirtuins, statin

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