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Old human cells rejuvenated in breakthrough discovery on ageing

senescent cells rejuvenation

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#31 greenwich

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Posted 09 December 2017 - 07:25 PM

I think an injectable form is the way to go! I've been thinking about buying some resveratrol and grapefruit juice from the grocery store for a few days now.....

What would happen if someone were to mix R with DMSO and apply to skin? Would the R get to where it is needed for rejuvenation like in the study?

Good idea. I've got a bottle of 99% DMSO right here. So here goes!

 

It dissolves amazingly well. Better than other things I've tried. The color of the DMSO is now a dark, reddish brown.

 

Now it's painted over the veins of my forearm. Will I wake up 10 years younger? That will be so hard to explain to my friends.


Edited by greenwich, 09 December 2017 - 07:35 PM.

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#32 Nate-2004

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Posted 09 December 2017 - 07:31 PM

 

 

HaplogroupW says "Unless I missed something big (always a possibility), there were 6 that they showed the effects of. #1 of 6 was resveratrol itself, and it had roughly similar effects as all the other resveralogues." I haven't read the article yet, but

  • It appears that in vitro 5 micromolar resveratrol for 24 hours resulted in dramatic reversal of cellular senescence and doubling of telomere length.
  • The oral bioavailability of resveratrol is almost zero due to rapid and extensive metabolism and the consequent formation of various metabolites 
  • The metabolism of trans-resveratrol into metabolites in vivo is catalyzed primarily by CYP1A2  ref
  • If we keep CYP1A2  inhibited for 24 hrs while dosing with 5 umol/L of resveratrol, in theory we can clear our senescent cells
  • Under CYP1A2 Wikipedia lists some of the inhibitors, one or more of which may work
  • Molar weight of resveratrol = 228 g/mol.  (5 umol/L)(228 g/mol) = 1.14 g/L. = 5.6 g/5 L of blood = 44.8 g/40 L of body fluids

 

Of the strong inhibitors, the fluoroquinolones shouldn't be used. However fluvoxamine looks promising, st. John's Wort could be useful, and in the unspecified potency section, grapefruit juice has been known to cause serious side effects with some drugs which would to me suggest that it's quite potent as a CYP1A2 inhibitor.

 

That's also quite a bit of resveratrol, but I guess if you don't have to use it for long...

 

 

St. John's Wort does not inhibit these enzymes in humans and even induces them in Women specifically.


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#33 YOLF

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Posted 09 December 2017 - 09:50 PM

 

I think an injectable form is the way to go! I've been thinking about buying some resveratrol and grapefruit juice from the grocery store for a few days now.....

What would happen if someone were to mix R with DMSO and apply to skin? Would the R get to where it is needed for rejuvenation like in the study?

Good idea. I've got a bottle of 99% DMSO right here. So here goes!

 

It dissolves amazingly well. Better than other things I've tried. The color of the DMSO is now a dark, reddish brown.

 

Now it's painted over the veins of my forearm. Will I wake up 10 years younger? That will be so hard to explain to my friends.

 

We're your friends, make sure we know if it works, we're easy to explain things to.


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#34 Nate-2004

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Posted 09 December 2017 - 10:31 PM

@Oakman I added 2% resveratrol to a 50% solution of DMSO & distilled water with 2% urea and 2% nicotinamide. We shall see what happens on skin.


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#35 Rocket

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Posted 10 December 2017 - 01:45 AM

You should try to apply to scars and things like that which would noticable faster

#36 Rocket

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Posted 11 December 2017 - 02:11 AM

I am not a biochemist, but from something I read here on longecity, glucuronidation and sulfation in the digestive process is the problem with resveratrol and Grapefruit juice won't inhibit that.

So it seems i won't be mixing the 2 with any results.

How are you doing, Nate?

Edited by Rocket, 11 December 2017 - 02:12 AM.


#37 Nate-2004

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Posted 11 December 2017 - 04:02 AM

You should try to apply to scars and things like that which would noticable faster

 

Scars form from excess collagen and generally grows only in one direction. Collagen doesn't get replaced or removed with skin cell turnover. There's no reason why it would affect scars that I can imagine at the moment.

 

@Rocket I'm pretty sure you're right:

 

 


A variety of other molecules have been demonstrated to have synergistic and additive effects when combined with resveratrol for in vitro models, and such interactions may potentially enhance bioavailability. Protecting resveratrol from rapid metabolization in the gastrointestinal tract and liver is one general mechanism which can increase bioavailability. Given that CYP, UGT, and SULT are the key enzymes which conjugate resveratrol, any intervention which decreases their rate of reaction on trans-resveratrol should increase concentration of the parent compound. For this reason, it has been suggested that combining resveratrol with other polyphenols which are targeted by these enzymes may increase bioavailability.

Piperine, a polyphenol found in black pepper, has been shown to substantially increase serum Cmax and AUC of resveratrol in rats [59]. In coadministration in an oral gavage of 100 mg/kg and 10 mg/kg piperine, Johnson et al. showed a 1000% increase of peak plasma levels for resveratrol while delaying a major glucuronide resveratrol metabolite [59]. Consequent research in cellular [60] and animal [61] models has indeed shown piperine to potentiate the effects of resveratrol. However, only one human study has explored this combination, and found that piperine may enhance resveratrol’s effects on cerebral blood flow, yet does not increase its bioavailability [62]. The failure to increase bioavailability may be due to a lower mg/kg dosage in humans for piperine and resveratrol, which prevented a saturation of the UGT enzyme and had no effect on the rate of metabolite formation. Alternatively, this may be a difference in human and rat UGT1A1 isoforms, where piperine may not inhibit UGT in humans as has been observed in rodent models [63].

Similarly, attempts to increase the bioavailability of resveratrol through combining it with quercetin to inhibit SULT1A1 [64]. In an ex vivo kinetics study with cytosolic fraction of homogenized rat liver, the rate of resveratrol sulfation was reduced with the addition of purified quercetin [65]. Quercetin may reduce the rate of resveratrol sulfate formation, but this does not necessarily equate to improved bioavailability for resveratrol. In vivo, LaPorte found that adding 500 mg of quercetin to 2000 mg of resveratrol did not enhance the Cmax or AUC, and this was not influenced by the addition of ethanol [57]. This could be due to the concentration of resveratrol or quercetin never reaching the point of saturating and/or inhibiting sulfatransferases in vivo, resulting in little reduction in the rate of metabolite formation. Alternatively, the absorption of native quercetin is poor, and may not reach the liver in a concentration that will inhibit SULT in vivo [66]. 

 

Just to note I have not only been taking resveratrol on these days with 1500mg Quercetin (not just 500) but I've been taking it with roughly 500mg in addition to that under the tongue in a 50% DMSO solution. So, I'm definitely taking the more aggressive approach here but who knows.

Attached Files


Edited by Nate-2004, 11 December 2017 - 04:38 AM.


#38 Nate-2004

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Posted 11 December 2017 - 04:50 AM

Just to add a quote from the above attached review: 

 

 


A non-invasive means of resveratrol delivery, which may circumvent the constraints of the gastrointestinal tract and first pass hepatic metabolism, is oral transmucosal dosing [53,77,78]. There are multiple known limitations for the method, such as a limited dose size and difficulties achieving absorption [79–81]. Given that free trans-resveratrol can travel through the systemic circulation before being metabolized in the liver, tissue likely has greater exposure to free trans-resveratrol when it is absorbed through the oral mucosa. Blanchard et al. [78] has reported a successful proof of concept study where a Cmax of ~1.4 μM in two healthy humans following administration of a 140 mg buccal dosage of resveratrol. This is considerably greater than that reported for a standard oral dosage [47], however a direct comparison was not performed. Current concerns regarding oral transmucosal deliver center on the rapid decrease in parent compound from the plasma. Similar to Yeo et al., who reports very rapid time to Cmax using a sublingual dosage of pterostilbene in anesthetized rats, Blanchard et al. reports a high plasma concentration 15 min post-administration, but no measureable free trans-resveratrol within 30 min post-administration [78,82]. This is similar to what has been previously reported with an injected dosage of resveratrol, where rapid clearance is a result of distribution to tissues and the phase II metabolism to sulfate conjugates [9,83]. While human data demonstrates promise in oral transmucosal delivery, further work is needed in this realm 

 

This gives further reason to explore the quercetin-DMSO-resveratrol solution. Basically today what I did was put 2g quercetin in 5ml DMSO and fill the rest with distilled water, then I poured the cap of 600mg trans-resveratrol under my tongue and dumped about half that vial in with it, held it there a while. According to the hypothesis, the quercetin should limit the speed of metabolism to sulfate conjugates.

 

Most oral doses out there meant to be swallowed are around 250mg which seems low considering bioavailability and especially in light of this article. I might keep trying this route.


Edited by Nate-2004, 11 December 2017 - 04:51 AM.


#39 Rocket

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Posted 11 December 2017 - 08:43 PM

Nate - How about eye bags and crows feet?



#40 Rocket

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Posted 11 December 2017 - 08:44 PM

Nate - How about eye bags and crows feet?



#41 Nate-2004

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Posted 11 December 2017 - 10:16 PM

@Rocket I haven't noticed a damn thing appearance wise so far in all my efforts. Nothing has progressed or reversed either way. It's like I'm running on a treadmill with all this. Sometimes I think I'm rejuvenating, but usually I realize that maybe it's just the lighting or a good day or something.

 

Also though, keep in mind, I've only been trying the dmso+resv+nam+q approach for maybe 2 weeks so far. It's not been long enough. Good news is that they've found several glucosepane breakers recently this past year. 

 

 

Absolutely. Short story, we now have a bunch of glucosepane-breaking enzymes, and we are within a few months of spinning the work out into a startup.


Edited by Nate-2004, 11 December 2017 - 10:26 PM.

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#42 Rocket

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Posted 11 December 2017 - 11:53 PM

 

@Rocket I haven't noticed a damn thing appearance wise so far in all my efforts. Nothing has progressed or reversed either way. It's like I'm running on a treadmill with all this. Sometimes I think I'm rejuvenating, but usually I realize that maybe it's just the lighting or a good day or something.

 

Also though, keep in mind, I've only been trying the dmso+resv+nam+q approach for maybe 2 weeks so far. It's not been long enough. Good news is that they've found several glucosepane breakers recently this past year. 

 

 

Absolutely. Short story, we now have a bunch of glucosepane-breaking enzymes, and we are within a few months of spinning the work out into a startup.

 

 

That is awesome news if we can get own hands on it and if its effective in all tissues down to our tendons and cardiovascular! If we can also reliably (soon) kill off senescent cells without making ourselves sick, and rejuvenate the others with this resveratrol / analogue therapy old age might be much different for us than it was for our parents and grandparents.


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#43 greenwich

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Posted 12 December 2017 - 02:32 AM

Our next experiment has to be mainlining. Right?



#44 YOLF

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Posted 12 December 2017 - 06:20 PM

 

You should try to apply to scars and things like that which would noticable faster

 

Scars form from excess collagen and generally grows only in one direction. Collagen doesn't get replaced or removed with skin cell turnover. There's no reason why it would affect scars that I can imagine at the moment.

 

@Rocket I'm pretty sure you're right:

  

Actually, you just have to raise collagenase by taking way too much collagen and it'll age you horribly, thus destroying all of your collagen. With the new age breakers, you can then begin to fix the rest slowly.


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#45 RWhigham

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Posted 13 December 2017 - 03:22 AM

Liposomal resveratrol should bypass intestinal metabolism and immediate liver metabolism. (Most lipids are transported by the lymph system and enter the bloodstream up around the neck in contrast to proteins, carbohydrates, and short-chain fatty acids which are transported via the portal vein (draining the intestines) directly to capillary beds in the liver.

 

Probably a high speed blender with lecithin and resveratrol is all it takes..


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#46 Kirito

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Posted 13 December 2017 - 09:00 AM

I just remembered this paper from a while back - http://www.tandfonli...35100009X466131

 

Very interesting how resveratrol (and probably many other things) could have such opposite effects at different times of day. Night time seems like the way to go.

 

Thread with discussion on it: http://www.longecity...tion-pro-oxida/


Edited by Kirito, 13 December 2017 - 09:04 AM.


#47 Rocket

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Posted 13 December 2017 - 02:33 PM

Liposomal resveratrol should bypass intestinal metabolism and immediate liver metabolism. (Most lipids are transported by the lymph system and enter the bloodstream up around the neck in contrast to proteins, carbohydrates, and short-chain fatty acids which are transported via the portal vein (draining the intestines) directly to capillary beds in the liver.

 

Probably a high speed blender with lecithin and resveratrol is all it takes..

 

That's all it takes to what? bypass the "gut" and get directly into the bloodstream and cells to replicate the cellular rejuvenation event?



#48 Oakman

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Posted 13 December 2017 - 04:47 PM

 

Liposomalresveratrol should bypass intestinal metabolism and immediate liver metabolism. (Most lipids are transported by the lymph system and enter the bloodstream up around the neck in contrast to proteins, carbohydrates, and short-chain fatty acids which are transported via the portal vein (draining the intestines) directly to capillary beds in the liver.

 

Probably a high speed blender with lecithin and resveratrol is all it takes..

 

That's all it takes to what? bypass the "gut" and get directly into the bloodstream and cells to replicate the cellular rejuvenation event?

 

 

Nice thought, but no, not so fast.

 

"Because resveratrol is so extensively metabolized in the gut before it even has a chance to reach the bloodstream (see the other sidebar), it’s tempting to think that one might improve its bioavailability by bypassing the digestive tract in favor of a more direct route to the blood. Indeed, such a route is available through the use of PEGylated liposomes, which are manmade cells that encapsulate drugs or nutritional supplements so that they can be delivered to the blood without interference from agents that might alter them.

...

Because this technique promises good delivery of free (unmetabolized) resveratrol to the blood, it can produce higher blood levels of resveratrol—briefly. The problem here, though, is that the liver will still rapidly metabolize the resveratrol as soon as it’s released by the liposomes, as indicated by a study that compared oral and intravenous delivery of resveratrol to human subjects.1 With oral delivery, no free resveratrol was detectable in the blood at any time (its metabolites were readily detectable, however); with IV delivery, there were measurable levels initially, but they dropped quickly and were gone after half an hour.

 

It seems that, for whatever reasons, nature may not want free resveratrol to be in our blood, despite its potentially outstanding health benefits. Only time and further research will indicate the best course of action for capitalizing on this potential."

 

The study of rejuvenation indicated multiple hours of resveratrol were needed. Our liver is just too efficient in disposing of 'foreign' substances, regardless of our puny efforts to subvert its actions. So maybe a combination of these work-arounds may help, at least somewhat, but it looks like we are fighting an uphill battle here. Get past one defense (intestinal breakdown), face another - liver detox. Perhaps we can slow this process with liver enzyme inhibition, but that is likely short lived as well, it seems.


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#49 Rocket

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Posted 13 December 2017 - 05:15 PM

Hypothetically, if we can prevent the R from being metabolized by the gut/liver, how much R would be required for an average human?



#50 RWhigham

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Posted 13 December 2017 - 06:30 PM

link  The in vitro experiment had 5 umol concentration (per liter is understood)  

Molar weight of resveratrol = 228 g/mol.  (5 umol/L)(228 g/mol) = 1.14 g/L. = 5.6 g/5 L of blood = 44.8 g/40 L of body fluid

 

15% of the cells were rejuvenated after 24 hrs at 5 umol.  Also see   link

 

The experimenters waited until a cell culture passed it's replication limit and appeared mostly senescent. Likely the 15% that rejuvenated were not quite senescent  Senescent cells may not have rejuvenated per comments 

So what is happening here is that the treatment is restoring proliferative capacity in cells that have lost that ability 

because of the signaling from nearby senescent cells.

 

Rejuvenating that 15% from near senescence all the way back to youthfulness was impressive, 

 

 


Edited by RWhigham, 13 December 2017 - 06:46 PM.


#51 HaplogroupW

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Posted 13 December 2017 - 07:14 PM


Nice thought, but no, not so fast.

 

[...deleted...]

 With oral delivery, no free resveratrol was detectable in the blood at any time (its metabolites were readily detectable, however); with IV delivery, there were measurable levels initially, but they dropped quickly and were gone after half an hour.

 

 

One of the resveralogues, #2 of 6, tested in the the Harries et al paper is "resveratrol’s primary metabolite, dihydroresveratrol". With the exception of inflammatory protein expression (figure 2), this metabolity had roughly similar benefits as resveratrol and others. So perhaps we might expect some benefit even from merely the metabolite.
 


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#52 Rocket

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Posted 13 December 2017 - 07:22 PM

link  The in vitro experiment had 5 umol concentration (per liter is understood)  

Molar weight of resveratrol = 228 g/mol.  (5 umol/L)(228 g/mol) = 1.14 g/L. = 5.6 g/5 L of blood = 44.8 g/40 L of body fluid

 

15% of the cells were rejuvenated after 24 hrs at 5 umol.  Also see   link

 

The experimenters waited until a cell culture passed it's replication limit and appeared mostly senescent. Likely the 15% that rejuvenated were not quite senescent  Senescent cells may not have rejuvenated per comments 

So what is happening here is that the treatment is restoring proliferative capacity in cells that have lost that ability 

because of the signaling from nearby senescent cells.

 

Rejuvenating that 15% from near senescence all the way back to youthfulness was impressive, 

 

45g for 15%

Then roughly 300g for 100%.

Yikes.

 



#53 RWhigham

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Posted 13 December 2017 - 08:32 PM

Math error 

 

Molar weight of resveratrol = 228 g/mol.  (5 umol/L)(228 g/mol) = 1.14 g/L. = 5.6 g/5 L of blood = 44.8 g/40 L of body fluid

Off by a factor of 1000. Should have been mg not g

 5 umol/L)(228 g/mol) = 1.14 mg/L = 5.6 mg/5L = 44.8 mg/40 L fo body fluid.

 

Double checking 5 umol from the original article Small molecule modulation of splicing factor expression is associated with rescue from cellular senescence

"Remarkably, treatment with even very low doses (5 μM) of the resveralogues led to significant increases (up to 0.6 population doublings) in total cell numbers over only 24 h of drug exposure, while vehicle-only controls remained proliferation-arrested (Fig. 5a)."


Edited by RWhigham, 13 December 2017 - 08:34 PM.

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#54 Oakman

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Posted 13 December 2017 - 09:17 PM

 


Nice thought, but no, not so fast.

 

[...deleted...]

 With oral delivery, no free resveratrol was detectable in the blood at any time (its metabolites were readily detectable, however); with IV delivery, there were measurable levels initially, but they dropped quickly and were gone after half an hour.

 

 

One of the resveralogues, #2 of 6, tested in the the Harries et al paper is "resveratrol’s primary metabolite, dihydroresveratrol". With the exception of inflammatory protein expression (figure 2), this metabolity had roughly similar benefits as resveratrol and others. So perhaps we might expect some benefit even from merely the metabolite.
 

 

 

Wondering how long R's metabolites hang around? If dihydro-R remains, even if it only a few hours, multi-timed doses could prolong dosing do what we're talking about ~24hrs.


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#55 greenwich

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Posted 14 December 2017 - 01:37 AM

This idea has intuitive appeal to me. If sulfation tears down R via the intestines, and glucuronidation via CYP1A2 in the liver, and we keep dosing R throughout the day, maybe we can exhaust the sulfur supply and CYP1A2 substrates. Then more and more R makes it through to the body. And because it's just a 24 hour protocol, we don't have to worry overmuch about the R toxicity. Just a single day of abuse. Or even 36. 12 hours of substrate tear-down, and 24 hours of R slip-through.


Edited by greenwich, 14 December 2017 - 01:38 AM.

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#56 Rocket

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Posted 14 December 2017 - 01:42 AM

This idea has intuitive appeal to me. If sulfation tears down R via the intestines, and glucuronidation via CYP1A2 in the liver, and we keep dosing R throughout the day, maybe we can exhaust the sulfur supply and CYP1A2 substrates. Then more and more R makes it through to the body. And because it's just a 24 hour protocol, we don't have to worry overmuch about the R toxicity. Just a single day of abuse. Or even 36. 12 hours of substrate tear-down, and 24 hours of R slip-through.


Isn't grapefruit juice an inhibitor of cyp1a2? Then its just sulfation to contend with.
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#57 greenwich

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Posted 14 December 2017 - 02:00 AM

Grapefruit is just one of many CYP1A2 inhibitors. Curcumin and Cimetidine also do this. See wikipedia. Note: I have experienced sudden caffeine intolerance via massive curcumin and alcohol for 2-3 weeks. Recovered my ability to drink coffee after 2 weeks dry and no supplements. CYP1A2 is responsible for 87% of liver metabolism of caffeine. So when you get caffeine intolerance, I suspect, you have probably fried your CYP1A2.


Edited by greenwich, 14 December 2017 - 02:02 AM.

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#58 greenwich

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Posted 14 December 2017 - 02:26 AM

We've already established, earlier in this thread, that the Wikipedia article is wrong about St. John's Wort (https://en.wikipedia.org/wiki/CYP1A2). Also, I think the 'cumin' reference is erroneous -- at least, I can't find any articles that corroborate it. But on the other hand, there are copious NIH articles attesting to curcumin and cimetidine's diminishment of the CYP1A2.


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#59 Nate-2004

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Posted 14 December 2017 - 03:59 PM

Probably a high speed blender with lecithin and resveratrol is all it takes..

 

Wait, explain this?



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#60 Nate-2004

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Posted 14 December 2017 - 04:07 PM

 

 

Liposomalresveratrol should bypass intestinal metabolism and immediate liver metabolism. (Most lipids are transported by the lymph system and enter the bloodstream up around the neck in contrast to proteins, carbohydrates, and short-chain fatty acids which are transported via the portal vein (draining the intestines) directly to capillary beds in the liver.

 

Probably a high speed blender with lecithin and resveratrol is all it takes..

 

That's all it takes to what? bypass the "gut" and get directly into the bloodstream and cells to replicate the cellular rejuvenation event?

 

 

Nice thought, but no, not so fast.

 

"Because resveratrol is so extensively metabolized in the gut before it even has a chance to reach the bloodstream (see the other sidebar), it’s tempting to think that one might improve its bioavailability by bypassing the digestive tract in favor of a more direct route to the blood. Indeed, such a route is available through the use of PEGylated liposomes, which are manmade cells that encapsulate drugs or nutritional supplements so that they can be delivered to the blood without interference from agents that might alter them.

...

Because this technique promises good delivery of free (unmetabolized) resveratrol to the blood, it can produce higher blood levels of resveratrol—briefly. The problem here, though, is that the liver will still rapidly metabolize the resveratrol as soon as it’s released by the liposomes, as indicated by a study that compared oral and intravenous delivery of resveratrol to human subjects.1 With oral delivery, no free resveratrol was detectable in the blood at any time (its metabolites were readily detectable, however); with IV delivery, there were measurable levels initially, but they dropped quickly and were gone after half an hour.

 

It seems that, for whatever reasons, nature may not want free resveratrol to be in our blood, despite its potentially outstanding health benefits. Only time and further research will indicate the best course of action for capitalizing on this potential."

 

The study of rejuvenation indicated multiple hours of resveratrol were needed. Our liver is just too efficient in disposing of 'foreign' substances, regardless of our puny efforts to subvert its actions. So maybe a combination of these work-arounds may help, at least somewhat, but it looks like we are fighting an uphill battle here. Get past one defense (intestinal breakdown), face another - liver detox. Perhaps we can slow this process with liver enzyme inhibition, but that is likely short lived as well, it seems.

 

 

This is why I'm doing my protocol of one day a week with multiple angles of attack on CYP1A2 in addition to 600mg trans-resveratrol every 3 hrs with a solution of 70% DMSO with ~1200mg Quercetin (sublingually before swallowing). I am still, however, not entirely convinced that CYP1A2 is the target. I have yet to find any research indicating that as the enzyme that metabolizes resveratrol.

 

I also have the problem of being naturally high in CYP1A2 according to my genotype on 23 and Me. That's definitely an additional challenge if this is indeed the enzyme.


Edited by Nate-2004, 14 December 2017 - 04:10 PM.






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