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Intriguing idea on why resveratrol hasn't lived up to its potential

resveratrol fasting nad nr

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#1 HaplogroupW

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Posted 18 April 2018 - 03:54 PM


There's a fairly recent interview on Stemtalk with Dr. Tommy Wood:

https://www.ihmc.us/...alk/episode-48/

 

The whole thing was good, but there was one idea in particular he mentioned that I transcribed below.

 

At 0:45:10 they asked the question:

 

Do you have any thoughts on the supposedly lifespan or healthspan enhancing supplements, for example NAD or Nicotinamide Riboside to improve NAD+ levels?

 

 

[..earlier portion of answer elided..]

 

0:46:50

 

There's going to be a potential issue where people are trying to drive the fasting physiologies (that's higher levels of NAD+) in the chronically fed state (which is most sick people). And there's a similar... people will have heard of resveratrol... which was supposed to be this life enhancing or life-extending supplement. And it's activated, or activates the pathways associated with fasting. They recently showed in a clinical trial with type 2 diabetics, that high doses of resveratrol seem to make it worse. I think that's because you've taken people who are chronically fed, or over-fed (that's part of the disease process) and you try to drive fasting physiology at the same time, and you get a negative interaction. So to get the most benefit out of those supplements you also need to do the stuff that's associated with those processes which would involve sleep, occasional fasting and carbohydrate restriction.

 

I've had similar thoughts, and have been attempting to divide any supplements into at least two categories: those for anabolism/feasting, and those for catabolism/fasting.   And how these two phases map onto, say, Turnbuckle's fission/fusion protocol.


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#2 pamojja

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Posted 18 April 2018 - 05:14 PM

Interesting. Till now only divided my supplements in to those taken on empty stomach versus those taken with meal. Additionally those more stimulating in the first half of the day, those more calming in the second half. Now additional fasting/feasting and fission/fusion would seem increasingly complex. Would you like to share what you came up with?



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#3 Nate-2004

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Posted 18 April 2018 - 06:50 PM

I do intermittent fasting (a combination of the one 24 hour fast per week and time restricted feeding) and I aim to only take it on those days or times when I'm fasting. Given its bioavailability I tend to take lower doses every 3 hours to keep it running through my system all day. The in vitro studies that showed such promise had cells exposed for a fairly long time.

 

Here's one of the issues though, its bioavailability sucks and is generally improved by liposomal solutions, lipids, *and/or* competitive enzyme inhibition (apigenin, caffeine, etc). The liposomal version contains fat which kind of breaks the fast, though from what I understand reading the label, it's only 1g of fat and a couple of carbs per dose, so that's debatable. The lipid solution is the same problem. It's lipid soluble so like many supplements, food or some sort of fat solution makes it absorb. Then there's the last option which is enzyme inhibition, that won't break a fast unless you want to make a sublingual formulation and we're back to alcohol and a small amount of cream. It's like a catch 22 I think and this, along with the answer given in your post, is probably among some of the bigger reasons why it's failed.  ¯\_(ツ)_/¯

 

 


Edited by Nate-2004, 18 April 2018 - 07:05 PM.


#4 HaplogroupW

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Posted 19 April 2018 - 03:37 PM

Would you like to share what you came up with?

 

I was afraid someone might ask that :P

 

No great insights; just the relatively obvious. Multi-Vitamin and extra  A, D3, K2 on eating days. Mineral supplementation (especially magnesium and NaCl in veg broth) all the time (to keep electrolytes up, due to the natriuresis of fasting and keto), as well as occasional glycine, NAC and ALCAR.  Resveratrol, quercetin and NR on fasting days with apigenin from some stiff german chamomile tea. I was doing NR all the time (with some breaks), until I pondered the quote above.

 

And I'm pretty much a chain-drinker of grean tea, peppermint tea and coffee.

 

The timing relative to fusion/fission thing is a bit unclear to me. On the one hand, fission seems to be the natural complement to fasting, as the up-regulated mitophagy during an extended fast will dispose of the fizzed, diseased mitochondria. But on the other hand, fasting promotes the fused state of mitochondria (the ref for this is somewhere in Turnbuckle's fusion/fission thread). Does the fissile effect of nicotinamide overpower the fusion effect of fasting? Maybe better not to put them in opposition? One of the references reported that diseased fizzed mitochondria are unable to fuse, and hang around as part of a pool of dead mitochondria, waiting for the time when mitophagy gets around to them, so perhaps we can see that recycling process as asynchronous. The pipeline of dead mT gets filled up during the fissioning, and gets emptied on the next upregulation of mitophagy. So no need to time fission/fusion exactly with feating/fasting. Just my current SWAG.

 

 

 


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#5 HaplogroupW

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Posted 19 April 2018 - 03:47 PM

The lipid solution is the same problem. It's lipid soluble so like many supplements, food or some sort of fat solution makes it absorb. Then there's the last option which is enzyme inhibition, that won't break a fast unless you want to make a sublingual formulation and we're back to alcohol and a small amount of cream. It's like a catch 22

 

Nate, I don't think the fat or carb in liposomal formulations or enzyme inhibiting tea & cetera needs to be seen as necessarily breaking a fast. After all, Longo's FMD has close to 800 kcal/day and he has documented fasting-type response.

 


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#6 sthira

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Posted 19 April 2018 - 05:27 PM

...(I've) been attempting to divide any supplements into at least two categories: those for anabolism/feasting, and those for catabolism/fasting. And how these two phases map onto, say, Turnbuckle's fission/fusion protocol.


This is a fascinating idea, and one I've been considering, too. Five days ago I ended a 14-day water-only fast, and throughout, I kept wondering: how can I optimize this? I didn't take anything, or measure anything; but I was thinking a lot about Turnbuckle's many self-experiments, namely this:

"Fission (breaking apart, e.g., fasting)

--Nicotinamide (NAD+) — 2g
--Ribose (NAD+) — 2g
--AMPK activators (Life Extension) — 1g 
--Fisetin (Sirt1 activator) — 100mg...

Then, upon refeeding:

"Fusion ("putting together"):
 
--Stearic acid (fusion) — 5g
--Leucine (biogenesis) — 5g
--PQQ (biogenesis) — 20mg
--Hydroxytyrosol (biogenesis & antioxidant) — 25mg
Vitamin B complex (commercial mix)
Vitamin C — 1g..."

I didn't try this since fasting and refeeding seem plenty powerful to me.

But the idea of attempting to optimize a disciplined fast is compelling -- keep pushing boundaries without hurting myself, hopefully -- because clearly fasting alone just "isn't enough" for it to do what we all want to do: reverse aging.
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#7 Nate-2004

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Posted 19 April 2018 - 06:01 PM

That's some super powerful will you have there sthira, 14 days, jeeez!!! I wish my mind wasn't so obsessed with food.

 

Whenever you do this again, definitely try this idea out except use liposomal resveratrol instead of fisetin. Maybe just a 3 day fast for starters.



#8 sthira

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Posted 19 April 2018 - 08:02 PM

That's some super powerful will you have there sthira, 14 days, jeeez!!! I wish my mind wasn't so obsessed with food.


Thanks, Nate, and I wish my mind wasn't so filled with wonder about experimental fasts, like the one I just ended, are even worth the trouble. It's a big guess of investment.

Whenever you do this again, definitely try this idea out except use liposomal resveratrol instead of fisetin. Maybe just a 3 day fast for starters.


Attempting to force compounds into cells, welp, I just don't know. It's experimental, of course, and I'm obviously not discouraging anyone from trying stuff. I don't want to do more harm than good, especially in a compromised state like "fasting..." and so tend to sway toward this argument:

Philosophically, I have to wonder if we should be forcing exogenous compounds into human cells when their natural properties prevent them from entering our cells in any significant amount. Why do we think that artificially forcing ... resveratrol is in our best interest?


We're just guessing; but even if liposomal resveratrol ingestion is a step forward in slowing, stopping, or reversing some aspect of aging, we still have to wonder about the quality of the forced compound:

It is typically impossible for the home manufacturer to validate that they have created liposomes. However, we're fortunate this guy had access to a biological research lab and have used their microscopes to confirm liposome creation. 
 
http://qualityliposomalc.com/ (you can actually make your own without an ultrasonic cleaner)


Thoughts?

#9 MikeDC

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Posted 24 April 2018 - 12:01 PM

The reason why Resveratrol has not lived up to its potential is probably due to the fact that Resveratrol is not a real sirt1 activator.

It is a stress inducer. High dose of it will have negative effects.


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#10 Supierce

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Posted 24 April 2018 - 01:03 PM

The reason why Resveratrol has not lived up to its potential is probably due to the fact that Resveratrol is not a real sirt1 activator.

It is a stress inducer. High dose of it will have negative effects.

If I'm not mistaken, Sinclair found that it's due to low NAD+ in many test subjects.


Edited by Supierce, 24 April 2018 - 01:06 PM.


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#11 MikeDC

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Posted 24 April 2018 - 01:16 PM

If I'm not mistaken, Sinclair found that it's due to low NAD+ in many test subjects.


NAD+ is required for Sirt1 activity. If you take NR to increase NAD+, you don’t need Resveratrol.
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