Old human cells rejuvenated in breakthrough discovery on ageing

I just posted a video you may want to watch on the  NAD subforums: a lecture by dr. Sinclair where states that he takes 1 gram of RSV (apparently orally) every morning.

A serum concentration of 2.4uM was not 'easily acheived'. It took a dose of 5 grams of resveratrol. And this is only half the concentration used in the in vitro study.

Unfortunately resveratrol just seems like a 'messy' molecule. As you said it generates large quantities of metabolites, which may or may not be good. In the study they generated a number of analogues, one of which had no SIRT activity, but still caused rejuvenation. So they clearly also think resveratrol needs tweaking to get at the good effects.

For information they have since been looking at H2S donor molecules, which have some but not all of the beneficial effects on old cells.

https://www.ncbi.nlm...ubmed/30026406/

Heres a link to the figure on plasma concentration vs dose.

http://cebp.aacrjour...=600&carousel=1

Notice how closely 2.5g gets to the peak and sustained levels in blood of a 5g dose?

Second as stated 4-9hour half life even for resveratrol itself on blood. Tripling or quadrupling by inhibiting enzymes and some people will be quite near the experimental dose in blood levels for like 10+hrs.

Resveratrol coadministration seems to more than double bioavailability of some other compounds. It seems that a few compounds competing for the same pathways could significantly boost the amount of unmetabolized resveratrol.

As stated there are 20x more metabolites which to me suggests blocking could keep a significant fraction of free resveratrol.

Third iirc some of the senescent cells were said to be exhibiting signs of mitosis at 17.5 hrs.

4th if it did indeed double telomere length restoring it to a more youthful level, this wouldnt have to be done on a daily basis. This would be something for once in a blue moon.

5th unless I missed it 24 hour 5micromole was what was used and again may not necessarily be the minimum time and dose for similar effects.

But future research is needed to develop optimal protocols

That is looking at rate of telomere loss it is said to be 35% to 40% per decade in some cells, iirc.

Doubling telomere length if true would be like more than 10 years off.

What would be interesting is if these megadoses affect telomeres in other cells.

Edited by Castiel, 12 August 2018 - 11:11 PM.

Regards senescent cells and regards the extracellular matrix and aging.

I've heard that as telomeres shorten detrimental epigenetic changes occur even long prior to senescence being reached. Second even a very small number of senescent cells can detrimentally affect a tissue.


Restoring telomeres reverses practically all changes and restores youthful gene expression, rejuvenating a cell, iirc. Cells taken from old humans create frail old skin in labs, while young cells create thick young skin. Reset the telomeres, and the old cells create thick young tissue just like the young cells. (research at geron, as commented on the book by Dr. Michael Fossel The telomerase revolution).

Note that in this thread resveratrol is shown to appear to lengthen telomeres and rejuvenate even senescent cells. It affects hundreds of genes and multiple sirtuins.

I think that Michael Fossel is probably right, and many of the effects of aging are not from fully senescent cells, but from the gradual shift in gene expression on a continuum from new to old, senescent cells.

So if we assume resveratrol and it's analogues can only extend telomeres in very old, senescent or near senescent cells (presumably because the telomere has to be short to permit access to the relevant histones, see http://journals.plos...al.pbio.2000016), then we'd need to repeat this protocol periodically to see results. We'd need to look at the turnover times for various tissues and hope to 'rescue' the old cells in that tissue at appropriate intervals. Or you could try dosing every day for a week. Then once a week, then once a month, etc to keep on top of it.

To demonstrate what I mean, here is my LifeLength telomere report histogram. If you can only 'rescue' the telomeres at the short end of the graph, then it would take a while to shift it all to the right.

Edited by QuestforLife, 13 August 2018 - 09:27 AM.

If it is indeed limited to extending only senescent and near senescent cell telomeres that could be a reason.  But I've only skimmed the previous articles, not sure it's been ruled out younger cells would also increase their telomeres upon exposure to resveratrol.   There exists alternate mechanisms for cells to keep good telomere length indefinitely as seen in for example germ line cells.   Resveratrol appears to have the ability to increase telomerase, will skim some of the relevant papers, but it may be that there are alternate mechanisms for it increasing telomerase activity even in younger cells.

 

What's interesting is that some doses of resveratrol appear to inhibit telomerase activity in cancer cells.

 

The results of our investigation suggested that RSV effectively inhibited cell growth and caused cell death in dose-dependent (P < 0.05) and not in time-dependent manner (P > 0.05), in vitro. Interestingly, quantitative RT-PCR analysis demonstrated that at half inhibition concentration, RSV dramatically decreased mRNA expression of hTERT, the catalytic subunit of telomerase enzyme, which leads to prevention of cell division and tumor progression. -https://www.ncbi.nlm...les/PMC5501037/

 

 

 

Recently, resveratrol has been shown to affect the anti-aging process through activating human telomerase via a nicotinamide phosphoribosyltransferase (NAMPT) and sirtuin 4 (SIRT4)-dependent pathway in human aortic smooth muscle cells. Therefore, NAMPT-SIRT4-human telomerase reverse transcriptase (hTERT) axis may be a novel mechanism underlying reseveratrol’s beneficial effects on cardiovascular diseases-Effect of resveratrol and pterostilbene on aging and longevity

 

 

A critical role of nicotinamide phosphoribosyltransferase in human telomerase reverse transcriptase induction by resveratrol in aortic smooth muscle cells

 

Although resveratrol is widely consumed as a nutritional supplement, its mechanism of action remains to be elucidated fully. Here, we report that resveratrol activates human nicotinamide phosphoribosyltransferase (NAMPT), SIRT4 and telomerase reverse transcriptase (hTERT) in human aortic smooth muscle cells. Similar observations were obtained in resveratrol treated C57BL/6J mouse heart and liver tissues. Resverotrol can also augment telomerase activity in both human pulmonary microvascular endothelial cells and A549 cells. Blocking NAMPT and SIRT4 expression prevents induction of hTERT in human aortic smooth muscle cells while overexpression of NAMPT elevates the telomerase activity induced by resveratrol in A549 cells. Together, these results identify a NAMPT-SIRT4-hTERT axis as a novel mechanism by which resveratrol may affect the anti-aging process in human aortic smooth muscle cells, mouse hearts and other cells. These findings enrich our understanding of the positive effects of resveratrol in human cardiovascular diseases.-  https://www.ncbi.nlm...les/PMC4484421/

SIRT 4 dependent telomerase increase in multiple cell types

 

 

 

Furthermore and demonstrated for the first time in fibroblast cells, the extra SIRT-1 protein present in the cells caused specific RNA needed for telomerase protein to be made. In essence these authors conclude that the extra SIRT-1 protein induced by resveratrol (and by other methods) leads to more telomerase protein being made.-

https://www.revgenet...more-telomerase

SIRT1 prevents replicative senescence of normal human umbilical cord fibroblast through potentiating the transcription of human telomerase reverse transcriptase gene.

SIRT1, the mammalian homolog of sirtuins, has emerged as a mediator of the beneficial effects of calorie restriction. Among them, we focused on the SIRT1-induced prevention of cellular senescence, and tried to reveal the molecular mechanisms that define the effects of SIRT1. Firstly in this study, we observed that overexpression of SIRT1 resulted in the prevention of cellular senescence of normal human umbilical cord fibroblast HUC-F2 cells. Here, we focused on the human telomerase reverse transcriptase (hTERT) gene as a target of the SIRT1-induced prevention of cellular senescence. Results showed that SIRT1, SIRT1 activator, resveratrol, and SIRT1 activating condition, starved condition, increased the transcription of hTERT in HUC-F2 cells. Next, we found that SIRT1 increased hTERT transcription in a c-MYC-dependent manner, triggered the transcription of the c-MYC gene and increased the amount of c-MYC recruited to the hTERT promoter. Further, SIRT1 increased the transcriptional activation ability of c-MYC and correspondingly increased the amount of acetylated H4 histone at the hTERT promoter. All of these results indicated that SIRT1 activates hTERT transcription through the involvement of c-MYC, and suggested that this SIRT1-induced augmentation of hTERT transcription resulted in the extension of the cellular life span of HUC-F2 cells.

 

 

SIRT 1 dependent telomerase increase

 

 

Edited by Castiel, 14 August 2018 - 05:40 PM.

Skimming the resveratrol  sirt4 article mentioned above this was interesting

 

As shown in Fig.​Fig.1B,1B, when we treated ASM cells with 50 μM of resveratrol over a period of 24 h, we determined that resveratrol induced hTERT expression which peaked at 6 h after treatment with a 3.6±0.3 fold increase compared to controls

 

https://www.ncbi.nlm...-10812-g001.jpg

 

Note on the graph that 25 micromole appears quite as effective as 50 micromole, only a very minor increase occurs(less than 5% increase iirc), and in this thread's paper even 5 micromole appears effective.  Assuming it is micromole per Liter as in the paper from this thread, the optimal dose needs to be found.

 

 

Another interesting finding from the same study:

 

 

It is generally accepted that resveratrol is a SIRT1 activator [12]. In this study, we explored SIRT1-7 using semi-quantitative RT-PCR, and our results showed resveratrol up-regulates SIRT1, SIRT3, SIRT4, and down-regulates SIRT6 in ASM cells (Fig. 5A and B). Of these four genes, SIRT4 was the most highly upregulated.

 

The following is also interesting

 

 

 

Because in 11-week aged mice, the telomerase activities were too high that most of bands appeared between 36 bp internal control and 50 bp bands in resveratrol treated mice (data not shown). In order to clearly show the effects of resveratrol, we then diluted the lysate 10 times in this group of miceand performed the telomerase activity assays again. Our data showed that resveratrol induced a noticeable increase in telomerase activity in 11-week aged mice (Fig. S3C).

Tert expression decreased with age in untreated mouse liver. Resveratrol induced Tert expression in both mice at age of 11-weeks. In 27-week aged mice, resveratrol failed to induce an increase in Tert expression as significantly as in the 11-week aged mice, which is in line with our results from the telomerase activity assay (Fig. S3B and C). Furthermore, resveratrol induced both Nampt and Sirt4 in the 27-week and 11-week aged mice (Fig. S3D).

Our data strongly suggests that resveratrol induced telomerase activity, along with Tert, Nampt, and Sirt4 expression in vivo.

 

It seems that it is able to induce more telomerase activity in younger vs older mice.    Not sure why.   It seems to me like this suggest it can induce telomerase activity in young cells.

 

 

NAD+ declines with age, and resveratrol works in part through sirtuins which need NAD+.   Some of the telomerase increasing effects of resveratrol, perhaps even those from this thread's original paper, may depend on sirtuin activity.

 

NAD+ decline, if sufficient could interfere with resveratrol's effects.

 

Some stuff from an article on NAD+ age related decline

https://www.ncbi.nlm...les/PMC5088772/

Mice lacking CD38 or treated with the CD38 inhibitor apigenin have elevated levels of NAD⁺ and are protected against deleterious effects of a high-fat diet

In this latest study, the authors show that protein levels of CD38, but not of SIRT1 or PARP1, increased in multiple tissues during aging, along with a corresponding increase in CD38 enzymatic activity (Camacho-Pereira et al., 2016). At 32 months, wild-type mice had about half the NAD⁺ of a young mouse, but the CD38 knockout showed no decrease

Interestingly, CD38 not only degrades NAD⁺ in vivo, but also NMN. When CD38 knockout mice were given injections of NAD⁺, NMN, or NR (which is converted to NMN), circulating levels of NAD metabolites remained stable after 150 min, long after they began to fall in the wild-type animals. Furthermore, when compared to the wild-type, CD38 knockout mice on a high-fat diet exhibited a much larger improvement in glucose tolerance when given NR. These findings suggest that the efficacy of NAD⁺ precursors may be enhanced by co-supplementation with CD38 inhibitors, which have been recently identified

This is a very interesting paper.

https://www.ncbi.nlm...ubmed/26456654/

Resveratrol prevents the skew in differentiation away from fat cells and towards bone cells that normally occurs with prolonged proliferation (aging) of mesenchymal stem cells. Even more interestingly resveratrol attenuates senescence of young MSCs, which express SIRT1, but accelerate the senecent of old MSCs that no longer express SIRT1.

So this might explain the different effects on normal and cancer cells that resveratrol appears to have, where it increases HTERT in many normal cell lines, but decreases it in cancer cells.

So there might be some synergy in boosting SIRT1 with other supplements before using resveratrol.

But the counter to this argument is that in the paper that started this thread SIRT1 was not required to rejuvenate cells, implying that for senescent fibroblasts atleast, there must be a SIRT independent mechanism.

This is a very interesting paper.

https://www.ncbi.nlm...ubmed/26456654/

Resveratrol prevents the skew in differentiation away from fat cells and towards bone cells that normally occurs with prolonged proliferation (aging) of mesenchymal stem cells. Even more interestingly resveratrol attenuates senescence of young MSCs, which express SIRT1, but accelerate the senecent of old MSCs that no longer express SIRT1.

So this might explain the different effects on normal and cancer cells that resveratrol appears to have, where it increases HTERT in many normal cell lines, but decreases it in cancer cells.

So there might be some synergy in boosting SIRT1 with other supplements before using resveratrol.

But the counter to this argument is that in the paper that started this thread SIRT1 was not required to rejuvenate cells, implying that for senescent fibroblasts atleast, there must be a SIRT independent mechanism.

 

 

Note that in one of the papers I linked, it indicates that in addition to sirt1, resveratrol affects sirt3, and sirt4.  And that its effects is strongest in sirt4 sirtuin.  Also it indicates that sirt4 is also able to increase telomerase activity.

So I'm on another 5 day water fast next week, what do you suppose I'd get from resveratrol as far as bioavailability in a completely fasted state?

So I'm on another 5 day water fast next week, what do you suppose I'd get from resveratrol as far as bioavailability in a completely fasted state?

I’m a anti-growth purist in terms of fasting. That means zero digestion, even with the gelatin caps.

So I’ll take pterostilbene and resveratrol with a cup of black coffee with my last meal before the fast.

I’m a anti-growth purist in terms of fasting. That means zero digestion, even with the gelatin caps.

So I’ll take pterostilbene and resveratrol with a cup of black coffee with my last meal before the fast.

 

Well, that doesn't answer my question but... technically, I think, according to Valter Longo, that level of purity is entirely unnecessary and only results in additional suffering.

 

If what you're trying to achieve is ketosis and autophagy, the main thing to avoid is carbs and protein. The gelatin caps aren't going to have any effect on mTORC1.  I'd go nuts if I couldn't have coffee or add cocoa to the coffee or take green tea extract, all those things curb the hunger and make the whole thing bearable. I got to 7.0 in terms of blood ketones by the 96th hour, so I was definitely not hurting anything. I don't know where I was in terms of autophagy but if Longo is at all knowledgeable about this, I should have been experiencing a lot of it by that point, especially considering his FMD has a lot more eating involved yet still accomplishes the same thing.

 

My main concern here is whether resveratrol would have any different effect in terms of bioavailability, if you're 72 hours into a fast.

Edited by Nate-2004, 15 August 2018 - 02:42 PM.

Note that in one of the papers I linked, it indicates that in addition to sirt1, resveratrol affects sirt3, and sirt4. And that its effects is strongest in sirt4 sirtuin. Also it indicates that sirt4 is also able to increase telomerase activity.

You're quite right, they only checked SIRT1 activity in the resveratrol analogues so maybe SIRT4 was mediating the HTERT activation..

The SIRT4 paper is interesting in that after 6 hours the cells in 50uM of resveratrol had as high levels of telomerase as the telomerase positive test cells! But on the downside the effect fades by 24 hours, so this looks like a NAD mediated, temporary anti-stress effect.

Still it might be possible to develop an effective cycled dose strategy when telomerase is upregulated every so many days, once the system has reset back to baseline.

You're quite right, they only checked SIRT1 activity in the resveratrol analogues so maybe SIRT4 was mediating the HTERT activation..

The SIRT4 paper is interesting in that after 6 hours the cells in 50uM of resveratrol had as high levels of telomerase as the telomerase positive test cells! But on the downside the effect fades by 24 hours, so this looks like a NAD mediated, temporary anti-stress effect.

Still it might be possible to develop an effective cycled dose strategy when telomerase is upregulated every so many days, once the system has reset back to baseline.

 

 

What is also nice is that as mentioned 25uM had almost the same effect, less than 5% difference in increase in activity.   Further research is needed but it may be that a dose of 10uM or less may also be highly effective.  In the other paper 5uM was effective at increasing telomerase though it may or may not be through sirt4.   And again even a dose lower than 5uM might be effective, but that should hopefully be tested, and optimal dose found.

Edited by Castiel, 18 August 2018 - 10:06 AM.

So in the SIRT4 paper you posted Castiel, Resveratrol very impressively unregulated telomerase expression, but only for a few hours - and it had practically returned to baseline at 24hours.  This increase was dependent on NAMPT, abolishing NAMPT also stopped telomerase. I note however that HTERT was upregulated at lower levels of resveratrol than NAMPT (25uM Fig 1c rather than 50uM Fig 2a), so perhaps the already present NAMPT enzyme can be used up - but for a sustainable rise more NAMPT is required (which as we've already discussed acts via SIRT4).

 

So if HTERT is falling back to baseline because NAMPT is falling back to baseline, perhaps all we need to do is find a better way of raising NAMPT (or NAD) sustainably.

 

https://www.ncbi.nlm...one.0164710.pdf

 

For example H2S appears to have many health benefits. According to the above paper, only 1uM of a Sulphide donor is required is boost NAMPT. It is able to boost the NAD/NADH ratio very significantly ( from 4:1 to 10:1 after 7 days of treatment, See Fig 4G). It also activates HTERT, though much less than resveratrol (See Fig 2C),probably because it acts through SIRT1 not SIRT4. So perhaps a combination therapy of resveratrol and a suitable H2S donor would be synergistic?

 

The best H2S donor in my opinion is Allicin Max, which is stablised allicin - you get 180mg per tablet, guaranteed.

 

https://www.allimax.us/

 

And of course there is the usual NAD boosters, such as NR, NMN or methylene blue.

 

Perhaps David Sinclair is on to something!

 

I still think we will have bioavailability issues with resveratrol - so I'm going to try and make some liposomal resveratrol, so I can get to that magical 25uM figure.

 

 

Edited by QuestforLife, 21 August 2018 - 10:10 AM.

 

So if HTERT is falling back to baseline because NAMPT is falling back to baseline, perhaps all we need to do is find a better way of raising NAMPT (or NAD) sustainably. 

 

Not sure it is necessary to keep it above baseline for long.   The senescent cells were already showing signs of replication at 17~hours. The 24 hours 5uM (was it?) basically doubled telomere length, as mentioned, might be through sirt4 affecting the splicing factors, might not, more research needed.

 

But the NAD dependence could point to why resveratrol is less effective at restoring telomeres the older the animal.

 

It also seemed to have very high telomere increase rate in younger cells, significantly higher than in older cells, if I'm not misreading.   So if cells rejuvenate it could potentially be even more potent on second or subsequent treatments.

 

Because in 11-week aged mice, the telomerase activities were too high that most of bands appeared between 36 bp internal control and 50 bp bands in resveratrol treated mice (data not shown). In order to clearly show the effects of resveratrol, we then diluted the lysate 10 times in this group of miceand performed the telomerase activity assays again. Our data showed that resveratrol induced a noticeable increase in telomerase activity in 11-week aged mice

Tert expression decreased with age in untreated mouse liver. Resveratrol induced Tert expression in both mice at age of 11-weeks. In 27-week aged mice, resveratrol failed to induce an increase in Tert expression as significantly as in the 11-week aged mice,

-source linked above earlier in this thread

 

 

As I mentioned a rough reading of telomere loss rate would suggest that if 24Hr 5uM doubles telomere length it turns back clock by over 10 years at least in some cell types in terms of telomere length.   Since the same treatment on younger animals is even more potent, again if I'm not misreading, it does seem like it is not necessary to maintain high telomerase activity for long, a few hours is enough, as I don't think it likely that telomere loss rate would increase above baseline following telomere lengthening.   It could potentially take like 10 years to lose the restored telomere length.   

 

One might hypothesize that two or more high dose treatments with accompanying inhibitors NAD+ boosters etc, even if spaced a few years apart would basically turn the clock all the way back, at least in terms of telomere length.   This would require a proper protocol to be developed and tested, as  well as the optimal dose obtained.

Edited by Castiel, 01 September 2018 - 08:47 PM.

 

 

http://cebp.aacrjour...=600&carousel=1

 

Rechecked the graph of 2.5g vs 5g resveratrol, and while close in graph failed to notice the side bar is in multiples of 10 so even small differences would still be significant.

 

5g gave a peak of around 2.4uM iirc.  EDIT  But there is a several fold variation between individuals some achieving substantially higher.

 

Peak plasma levels of resveratrol at the highest dose were 539 +/- 384 ng/mL (2.4 micromol/L), which
occurred 1.5 h post-dose. https://www.zhion.co...rol_Dosage.html

Graph suggests some individuals managed to sustain over 1000ng/ml at 5g resveratrol, which should be near 5~micromol/L(5uM) if 539ng is 2.4micromol/L

http://cebp.aacrjour...=600&carousel=1

 

But as we saw a drop from 50uM to 25uM only resulted in less than 5% drop, even at a drop to 5uM it still doubled telomeres, one would have to see how much telomere lengthening dropped between 25uM and 5uM, might or might not be a significant drop.   Even lower levels might still see decent levels of telomerase activity, research is needed to find what the minimal dose required for decent activity is.   Perhaps I missed it, but unless reasoning was given somewhere to suggest 5uM is the lowest effective dose, there may be a lower dose that has effectiveness.

Edited by Castiel, 01 September 2018 - 11:00 PM.

 

Resveratrol's insolubility in water makes liposomal encapsulation quite difficult. I suspect that the commercial products advertised as liposomal resveratrol are actually emulsions.

 

A more accessible approach to improve the bioavailability could be to make a phytosomal form of reserveratrol.

 

“RESVERATROL-PHOSPHOLIPID COMPLEXES (PHYTOSOMES) WITH IMPROVED PHYSICOCHEMICAL PROPERTIES FAVORABLE FOR DRUG DELIVERY VIA SKIN” (2015)

https://www.research...LIVERY_VIA_SKIN

 

“Bioavailability and activity of phytosome complexes from botanical polyphenols: the silymarin, curcumin, green tea, and grape seed extracts” (2009) 

https://www.slidesha...and-application

 

“Phospholipid Complex Technique for Superior Bioavailability of Phytoconstituents” (2017) https://www.ncbi.nlm...es/PMC5426732/ 

 

“Nano Phytosomes of Quercetin: A Promising Formulation for Fortification of Food Products with Antioxidants” (2014) http://journals.tbzm...PHARM-20-96.pdf

 

“Phytosome as a Novel Biomedicine: A Microencapsulated Drug Delivery System” (2015) https://www.omicsonl...3X.1000116.pdf 

 

“Preparation and Evaluation of Phytosomes Containing Methanolic Extract of Leaves of Aegle Marmelos (Bael)” (2015) http://sphinxsai.com...-240)V8N6PT.pdf

 

 

So how is a phytosomal form different to a liposomal one?

 

I've had some success dissolving resveratrol in 95% alcohol before making a lipsomal mix. I expect some is actually in the liposomes and some is just in emulsion, as you suggest.

 

Castiel - to get even 2.4uM you needed 5g, and when I've tried this it's not been pleasant for my digestion! Some form of liposomal resveratrol is the way to go IMO.

 

I've had some very promising results using liposomal resveratrol from Actinovo in combination with some other supplements. I intend to make some of my own lipsomal resveratrol and then report back when I have more to say.

Edited by QuestforLife, 03 September 2018 - 08:41 AM.

You guys seem to be very well up in matters of Resveratrol. So I hope one or two you can form an opinion about Sardi's claim that his product Longevinex outperforms plain RSV because the RSV is protected in the liver by quercetin and bioperine.

Also:  it is micronized though it is not the only RSV supplement in that respect.

Here he states his claim:

http://www.resveratr...sveratrol/1635/

Unlike many I've actually got some time for Bill Sardi, I think he knows what he's talking about.

 

But I don't think he's demonstrated greater bioavailability with Longevinex than plain resveratrol. If he has, and someone can point to a study, I'd be grateful.

 

 

Pioneers like Sardi, Sinclair, Guarente and Brenner draw a lot of flak, as they say in the UK. They are used to it.

 

Asking Sardi about this is a good idea, but I asked knowledgeable people from this thread for their take on this. Meanwhile we can assume that Sardi builds on research like this:

https://www.ncbi.nlm...pubmed/11055264

So how is a phytosomal form different to a liposomal one?

 

 

This illustration should help clarify the difference between liposomes and phytosomes.  https://www.research..._fig1_230727931

 

Briefly, liposomes encapsulate water soluble drug. With phytosomes, the drug is bound to phospholipids.

 

It should be possible to dissolve resveratrol with phospholipids in alcohol and stir for a week or so, then evaporate the alcohol and redissolve in water. Resveratrol that is not bound to phospholipids should precipitate out since it is insoluble in water. The precipitate could be collected and weighted, thus determining the concentration of bound resveratrol in the solution.  Sonification of the solution would then produce stable lipid spheres. At least, that's my theory. I haven't tried to make this yet and intend to do so before year end when I can work it into my schedule.

Edited by Fafner55, 03 September 2018 - 02:45 PM.

This illustration should help clarify the difference between liposomes and phytosomes.  https://www.research..._fig1_230727931

 

Briefly, liposomes encapsulate water soluble drug. With phytosomes, the drug is bound to phospholipids.

 

It should be possible to dissolve resveratrol with phospholipids in alcohol and stir for a week or so, then evaporate the alcohol and redissolve in water. Resveratrol that is not bound to phospholipids should precipitate out since it is insoluble in water. The precipitate could be collected and weighted, thus determining the concentration of bound resveratrol in the solution.  Sonification of the solution would then produce stable lipid spheres. At least, that's my theory. I haven't tried to make this yet and intend to do so before year end when I can work it into my schedule.

 

Thanks Fafner - that's an interesting idea, I may try it (especially as it allows you to measure your success in encapsulation).

 

I don't know that it's necessary however. I suspect you can drop the resveratrol and water straight into a alcohol-lecithin solution and smash it up in a blender. That's what this patent seems to suggest, anyways, at least for lipoic acid, which is not water soluble.

 

https://patents.goog...0120171280A1/en

 

I've only really used water soluble supplements making DIY liposomes, so I might be well off however.

To my knowledge, the dramatic in vitro successes of resveratrol have not been replicated in vivo in humans. Part of the problem is poor bio-availability, and with the proper delivery system (whether phytosome or liposome or another approach) that problem should be solvable. After that, it appears that in older people resveratrol might not be effective, and may do more harm than good by accelerating cellular senescence. Figure 1 of the following paper illustrates that point.

“Different effects of resveratrol on early and late passage mesenchymal stem cells through β-catenin regulation” (2015) https://www.scienced...30721X?via=ihub

 

Co-dosing resveratrol with an NAD+ booster is probably essential for older people.

 

 

To my knowledge, the dramatic in vitro successes of resveratrol have not been replicated in vivo in humans. Part of the problem is poor bio-availability, and with the proper delivery system (whether phytosome or liposome or another approach) that problem should be solvable. After that, it appears that in older people resveratrol might not be effective, and may do more harm than good by accelerating cellular senescence. Figure 1 of the following paper illustrates that point.
“Different effects of resveratrol on early and late passage mesenchymal stem cells through β-catenin regulation” (2015) https://www.scienced...30721X?via=ihub

Co-dosing resveratrol with an NAD+ booster is probably essential for older people.

Yes that is exactly what we've been discussing above (see Post #226) and I've previously referenced that paper. You need to combine NAD uplift and the consequent SIRT activation with resveratrol. Indeed resveratrol accelarates the senescence of non-SIRT expressing mesenchymal stem cells. I see this as a good thing however, as resveratrol also probably uses this mechanism to destroy cancer cells.

So has Sinclair et al. already got this sussed? I think a limitation of his regime is that 1 gram of resveratrol is unlikely to do much in Vivo. Not nothing. Just not significant enough levels resveratrol to make use of the elevated NAD to make SIRT4 and telomerase. Hence why we need to solve the liposomal/phytosomal problem.

I also think we need a variety of NAD and or NAMPT precursors to get the best bang for our buck. I've been experimenting with allicin and methylene blue, but that's a subject for another day and possibly thread.

Edited by QuestforLife, 03 September 2018 - 07:14 PM.

So how is a phytosomal form different to a liposomal one?

 

I've had some success dissolving resveratrol in 95% alcohol before making a lipsomal mix. I expect some is actually in the liposomes and some is just in emulsion, as you suggest.

 

Castiel - to get even 2.4uM you needed 5g, and when I've tried this it's not been pleasant for my digestion! Some form of liposomal resveratrol is the way to go IMO.

 

I've had some very promising results using liposomal resveratrol from Actinovo in combination with some other supplements. I intend to make some of my own lipsomal resveratrol and then report back when I have more to say.

2.4uM in some individuals, others seem to reach 5uM at same 5g dose and sustain it for nearly 10 hours, unless graph is inaccurate.

 

There are substances that compete for clearance with resveratrol and could potentially be coadministered.  There is also the mentioned coadministration with NAD+ boosters which may also lower required dose, as well as substances like Apigenin that have been hypothesized would keep the effect of an NAD+ booster high.

 

At least at 98+% purity does not seem to badly affect digestion at a high dose.  Though perhaps some people could be affected.   Liposomal might be an interesting choice.

Edited by Castiel, 04 September 2018 - 04:52 PM.

I've put all my thoughts on resveratrol, NAD/NAMPT/AMPK, SIRTUINS and telomeres in one place, here:

https://www.longecit...on/#entry857309

Some of the research links I've posted here are there too with more besides as well as my personal experiences with the protocol so far.

I will continue to contribute to this thread where appropriate however.

Edited by QuestforLife, 04 September 2018 - 06:02 PM.

So how is a phytosomal form different to a liposomal one?

 

I've had some success dissolving resveratrol in 95% alcohol before making a lipsomal mix. I expect some is actually in the liposomes and some is just in emulsion, as you suggest.

 

Castiel - to get even 2.4uM you needed 5g, and when I've tried this it's not been pleasant for my digestion! Some form of liposomal resveratrol is the way to go IMO.

 

I've had some very promising results using liposomal resveratrol from Actinovo in combination with some other supplements. I intend to make some of my own lipsomal resveratrol and then report back when I have more to say.

 

There are new products of resveratrol which are emodin free, which may ease digestion.   They utilize genetically engineered yeast rather than japanese knotweed for resveratrol production, ensuring 0% emodin.