276 replies to this topic

[Nate-2004]

http://www.exeter.ac..._620529_en.html

 

A new way to rejuvenate old cells in the laboratory, making them not only look younger, but start to behave more like young cells, has been discovered by researchers at the Universities of Exeter and Brighton.

A  team led Professor Lorna Harries, Professor of Molecular Genetics at the University of Exeter, has discovered a new way to rejuvenate inactive senescent cells. Within hours of treatment the older cells started to divide, and had longer telomeres - the 'caps' on the chromosomes which shorten as we age.

This discovery, funded by the Dunhill Medical Trust, builds on earlier findings from the Exeter group that showed that a class of genes called splicing factors are progressively switched off as we age. The University of Exeter research team, working with Professor Richard Faragher and Dr Elizabeth Ostler from the University of Brighton, found that splicing factors can be switched back on with chemicals, making senescent cells not only look physically younger, but start to behave more like young cells and start dividing.

The researchers applied compounds called reversatrol analogues, chemicals based on a substance naturally found in red wine, dark chocolate, red grapes and blueberries, to cells in culture.  The chemicals caused splicing factors, which are progressively switched off as we age to be switched back on.  Within hours, the cells looked younger and started to rejuvenate, behaving like young cells and dividing. 

The research  Small molecule modulation of splicing factor expression is associated with rescue from cellular senescence, is published in the journal, BMC Cell Biology, https://bmccellbiol....2860-017-0147-7 .  

The discovery has the potential to lead to therapies which could help people age better, without experiencing some of the degenerative effects of getting old. Most people by the age of 85 have experienced some kind of chronic illness, and as people get older they are more prone to stroke, heart disease and cancer. 

Professor Harries said:  “This is a first step in trying to make people live normal lifespans, but with health for their entire life. Our data suggests that using chemicals to switch back on the major class of genes that are switched off as we age might provide a means to restore function to old cells.” 

Dr Eva Latorre, Research Associate at the University of Exeter, who carried out the experiments was surprised by the extent and rapidity of the changes in the cells. 

“When I saw some of the cells in the culture dish rejuvenating I couldn’t believe it. These old cells were looking like young cells. It was like magic,” she said. “I repeated the experiments several times and in each case the cells rejuvenated. I am very excited by the implications and potential for this research.”

As we age, our tissues accumulate senescent cells which are alive but do not grow or function as they should. These old cells lose the ability to correctly regulate the output of their genes. This is one reason why tissues and organs become susceptible to disease as we age. When activated, genes make a message that gives the instructions for the cell to behave in a certain way. Most genes can make more than one message, which determines how the cell acts.

Splicing factors are crucial in ensuring that genes can perform their full range of functions. One gene can send out several messages to the body to perform a function – such as the decision whether or not to grow new blood vessels – and the splicing factors make the decision about which message to make. As people age, the splicing factors tend to work less efficiently or not at all, restricting the ability of cells to respond to challenges in their environment. Senescent cells, which can be found in most organs from older people, also have fewer splicing factors.

 Professor Harries added: “This demonstrates that when you treat old cells with molecules that restore the levels of the splicing factors, the cells regain some features of youth.  They are able to grow, and their telomeres - the caps on the ends of the chromosomes that shorten as we age -  are now longer, as they are in young cells. Far more research is needed now to establish the true potential for these sort of approaches to address the degenerative effects of ageing. ” 

Professor Richard Faragher of the University of Brighton, will today argue for more research into the degenerative effects of ageing in a debate into whether science should be used to extend people’s lifespans. 

“At a time when our capacity to translate new knowledge about the mechanisms of ageing into medicines and lifestyle advice is limited only by a chronic shortage of funds, older people are ill-served by self-indulgent science fiction.  They need practical action to restore their health and they need it yesterday,” he said. 

Professor Faragher added:  “Our discovery of cell rejuvenation using these simple compounds shows the enormous potential of ageing research to improve the lives of older people” 

Date: 7 November 2017

[Mind]

Thanks for posting this Nate-2004.

 

I found this little nugget rather funny "The discovery has the potential to lead to therapies which could help people age better"

 

Kind-of an oxy-moron. No such thing as "aging better" in my mind. There is only aging/pain/death or rejuvenation

[YOLF]

Still, I'd like to know what resveratrol analogues they're using and if I can get them

[mrkosh1]

Thanks for posting this Nate-2004.

 

I found this little nugget rather funny "The discovery has the potential to lead to therapies which could help people age better"

 

Kind-of an oxy-moron. No such thing as "aging better" in my mind. There is only aging/pain/death or rejuvenation

 

It's not an oxy-moron but an example of something far worse. As in some other controversial areas of research, there's a dogmatic stigma against claiming that anything could even have the potential to reverse aging. No, aging can't ever run backwards; people can't be made younger; we're all doomed to biologically degrade until we're sent away to a nursing home. As you have made clear, you can't age better, because aging equates to becoming more sickly, frailer, and weaker. If you are aging at all, you are already in the process of dying. 

 

When it comes to this method of cellular rejuvenation, I find it interesting. However, I'm concerned they may be looking over various forms of damage that is not being repaired. If they reverse the process of senescence and make sure there's not lingering unrepaired DNA damage or accumulations of Advanced Glycation Products, then they might really have something big. My guess is that a method like this would have to be combined with a cocktail of other therapies to reverse all the damage these cells have accumulated. I'd like for them to sequence the genome of both young cells (control), senescent cells, and the rejuvenated cells to see just how much genetic damage remains.

[Logic]

The Paper:
https://www.ncbi.nlm...les/PMC5645932/

I am waaaaaay out of practice at reading these papers and could not determine which of the analogues was best at rejuvenation from a quick scan, but believe there is enough info in the paper to synthesize these resveratrol analogues.
 

Synthesis of novel resveralogues

Resveratrol (Sigma Aldrich, UK; 1) was used to synthesise dihydroresveratrol 2 as reported previously [47]. (E)-N-(4-(3,5-Dimethoxystyryl)phenyl) methanesulfonamide 3 was synthesised from the previously reported nitro-substituted analogue 7 via an Fe/NH4Cl reduction to give amine 8 [26], followed by sulfonylation with methanesulfonyl chloride (Fig. 1b). The corresponding amide 9 was also prepared from 8, by acylation with acetylchloride. The product 9 was subjected to demethylation (BBr3, CH2Cl2) to give the target compound (E)-N-(4-(3,5-dihydroxystyryl)phenyl)acetamide 4. (E)-5-(4-(3,5-dimethoxystyryl)phenyl)-1H–tetrazole 5 and the isomeric 2-1H-tetrazole analogue 6 were prepared directly via acid-catalysed cycloaddition with azide ion from the 4- and 2-cyanostilbenes [26] (10 and 11 respectively). (Fig. 1b) Details of the synthesis, purification and characterisation of the resveralogues are given in Additional file 8.

Whether the analogue would have the same effect if ingested or injected is off course unknown and improbable?

[YOLF]

Acetylation generally improves absorption.

[Believer]

No, aging can't ever run backwards; people can't be made younger; we're all doomed to biologically degrade until we're sent away to a nursing home. As you have made clear, you can't age better, because aging equates to becoming more sickly, frailer, and weaker. If you are aging at all, you are already in the process of dying.

You are equivocating chronological aging with biological aging. Reversing chronological aging requires a time machine but reversing biological aging requires only a reversal of whatever causes it which is presumably a mix of dna damage and cell dysfunction due to other reasons.

 

[Nate-2004]

 

No, aging can't ever run backwards; people can't be made younger; we're all doomed to biologically degrade until we're sent away to a nursing home. As you have made clear, you can't age better, because aging equates to becoming more sickly, frailer, and weaker. If you are aging at all, you are already in the process of dying.

You are equivocating chronological aging with biological aging. Reversing chronological aging requires a time machine but reversing biological aging requires only a reversal of whatever causes it which is presumably a mix of dna damage and cell dysfunction due to other reasons.

 

 

I think you missed the greater context of what he was trying to convey about stigmas and taboos in scientific circles.

[marcobjj]

so the obvious question is, how can we get a  hold of such resveratrol analogues? as it was with C60 OO, let the "rat" race begin!

Edited by marcobjj, 12 November 2017 - 04:45 AM.

[HaplogroupW]

so the obvious question is, how can we get a  hold of such resveratrol analogues?
 

 

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.

 

To put a finer point on it, look at figure 1a: it lists the 6 resverlogues, and #1 is resveratrol. When they show results, they usually show result for each of the 6. E.g. figure 5c Telomere length, #1 had the best effect (longest relative telomeres).

Edited by HaplogroupW, 12 November 2017 - 10:01 AM.

[Rocket]

So what's better? Removing senescent cells? Or turning them back on? Seems like you can't have it both ways. And so it looks like once again resveratrol is a miracle chemical until its used in a living human being... I took resveratrol for a long time and deemed it a bust. 2 years ago it was glycine in the news, now its resveratrol again.

Edited by Rocket, 13 November 2017 - 02:06 AM.

[Nate-2004]

These are analogues not regular resveratrol.

[HaplogroupW]

These are analogues not regular resveratrol.

 

 

I didn't make up a baseless assertion. I described exactly where to look in the paper. Here is a quote from the caption of figure 1:

 

Synthesis and characterisation of novel resveralogues. a Structures of resveralogues 1–6. Compounds are: 1 resveratrol, 2 resveratrol’s primary metabolite, dihydroresveratrol, 3 (E)-N-(4-(3,5-dimethoxystyryl) phenyl)methanesulfonamide, 4 (E)-N-(4-(3,5-dihydroxystyryl)phenyl)acetamide, 5 (E)-5-(4-(3,5-dimethoxystyryl)phenyl)-1H–tetrazole and 6 (E)-5-(2-(3,5-dimethoxystyryl)phenyl)-1H–tetrazole.

 

[RWhigham]

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

Edited by RWhigham, 13 November 2017 - 04:08 AM.

[Nate-2004]

Interesting. The inhibitors for CYP1A2 are two specific antibiotics and an SSRI I've never taken. I can't take SSRIs because of tremor, but not sure if one day matters or if one day is effective for inhibiting this enzyme. The last one is a relatively safe blood pressure medication, verapamil. That may be our best bet here. Combine this with ingesting resveratrol sublingually or via IM injection and it may be a win.

 

If resveratrol is lipid based it'll probably absorb easily under the tongue or into the skin via DMSO at that molecular weight.

Edited by Nate-2004, 13 November 2017 - 03:19 PM.

[Rocket]

 

#1 of 6 was resveratrol itself, and it had roughly similar effects as all the other resveralogues

 

 

Exactly! Resveratrol once again to the supposed "rescue". And these other analogues are just as effective as resveratrol according to the publication.

 

Hasn't even Sinclair himself said that resveratrol hasn't worked out as planned..?? I am fairly certain he did say that. Another publication about an effect in a test tube that will not correlate to human rejuvenation. People have been mega-dosing resveratrol and I am fairly confident no one has been rejuvenated.

 

2 years ago glycine was the new wonder chemical. 3 years ago it was NR. Now the pendulum is back to resveratrol.

Edited by Rocket, 13 November 2017 - 04:01 PM.

[RWhigham]

If we keep CYP1A2  inhibited for 24 hrs while dosing with 5 umol/L of resveratrol, in theory we can clear our senescent cells

 

I should have said rejuvenate our stem cells - much better than killing them.

 

 Combine this with ingesting resveratrol sublingually or via IM injection and it may be a win.

 

The problem is not absorption from the gut,  but that it's immediately destroyed by CYP1A2 in the liver.

 

The oral bioavailability of resveratrol is almost zero due to rapid and extensive metabolism and the consequent formation of various metabolites 

 

That's a bit misleading. The oral availability is 100% except it's all turned into metabolites. 

 

Hasn't even Sinclair himself said that resveratrol hasn't worked out as planned..?? I am fairly certain he did say that. Another publication about an effect in a test tube that will not correlate to human rejuvenation. People have been mega-dosing resveratrol and I am fairly confident no one has been rejuvenated.

 

Show me the study with CYP1A2 completely inhibited for 24 hours while taking 5-40 g of resveratrol. Oh, no one's done that?

 

Skepticism is warranted, but the prospect of rejuvenating senescent cells instead of killing them is attractive, and is likely safer than killing them, although there could be a cancer risk.  On the other hand, the risky part may be finding a way to safely inhibit CYP1A2 100% for 24 hours.

Edited by RWhigham, 13 November 2017 - 05:25 PM.

[Nate-2004]

 

 On the other hand, the risky part may be finding a way to safely inhibit CYP1A2 100% for 24 hours.

 

 

Verapamil is considered safe. The problem is gaining access to it since it is prescription only. 

[RWhigham]

There is an informative discussion of this paper by Josh Mitteldorf  Scroll down to item "4. Splicing Factors rescue senescent cells"  The comments are also interesting.

Edited by RWhigham, 13 November 2017 - 09:09 PM.

[Nate-2004]

There is an informative discussion of this paper by Josh Mitteldorf  Scroll down to item "4. Splicing Factors rescue senescent cells"  The comments are also interesting.

 

 

Resveratrol was identified about 15 years ago as a compound that extends lifespan in many species (but perhaps not in mammals).  Resveratrol has many effects, but the primary mode of action has been thought to be through SIR2 (or SIRT1) or related compounds called sirtuins that are selective gene silencers.  But the LaTorre group set out to show that the anti-aging benefit was through splicing factors rather than sirtuins.  They synthesized variations on the resveratrol molecule and tested them until they found one that promotes slicing factors but has no effect on sirtuins.  

Using this resveratrol analog, they were able to turn senescent cells back into fully functioning cells, with restored telomeres and other epigenetic changes.  They demonstrated that this was accomplished through splicing factors, and without sirtuins.

All this was done in (human) cell cultures, and it the horizons are now open to see what effect such rejuvenation has at the whole body level.

[maxwatt]

WRT resveratrol rejuvenating senescent cells:  resveratrol "kills" defective mitochondria.  Assuming the cell has other, functioning mitochondria, it is rejuvenated.  And resveratrol in high concentration induces apoptosis of cells that lack functioning mitochondria.  

 

 

[Nate-2004]

 

 

The problem is not absorption from the gut,  but that it's immediately destroyed by CYP1A2 in the liver. 

 

 

 

Is it just this enzyme though? I thought it was P450 enzymes that metabolized it.

[Logic]

NB that this was an in-vitro study.
Any oral resveratrol you take, just like Quercetin et-al, will be metabolised by the liver into more or less benign molecules.
ie:  In-Vitro does NOT = In-Vivo! 

Look at the the metabolites of R to get an idea of any in-vivo results you might experience. (In normal healthy cells..?  See below)  

There are some R metabolites that show very interesting positive effects.

 

It should be noted, once again, that Pterostilbene is pretty much R, but less prone to the above mentioned metabolism and more prone to be absorbed by cells.

ie:  In-vitro R results = in-vivo P results..........!  (More or less)

Here is a writeup I did on P years ago:  (It was edited by Tom Andre F. (French...))
http://www.pterostilbene.com
The draft original, with clickable links:
https://drive.google...H8WGk7uOvTl7PlA

 

That said:

As we have evolved alongside/eating plants, so the body has some neat tricks to turn these benign, liver metabolised,  molecules back into active forms at the locations where said active molecules are required.
ie:  There is evidence that the benign, metabolised molecules flowing in the bloodstream remain so until they encounter cells/areas where their more active forms are required.  These areas seem to have the correct ...'biology' to modify the molecule to what is required.

ie:  More of the required form of R may be reaching the cells that require it than previously thought.
(I will post more on this in the Dasatinib group buy thread shortly, time allowing)

Edited by Logic, 28 November 2017 - 11:25 AM.

[Nate-2004]

I marked this as unsure because there is not nearly enough in-vivo human study on Pterostilbene at this time. We have no idea how it behaves in humans compared to Resveratrol.  I read your article though, interesting but just not convincing.

 

See this thread here where we discuss ways of getting around the liver enzymes. 

Edited by Nate-2004, 28 November 2017 - 02:19 PM.

[Rocket]

So why doesn't someone engineer injectible resveratrol and bypass the digestive system? If this is the closest thing to a holy grail, there doesn't seem to be any interest here. Bodybuilders have been injecting resveratrol from what I think are store bought supplements, some guys reporting weight loss from it.

Edited by Rocket, 09 December 2017 - 02:49 AM.

[Nate-2004]

From what I gather it's not about absorption it's about enzymes metabolizing it too fast. So injecting it would do nothing to change how fast it's metabolized would it? I've been focused on inhibiting these enzymes with a combination of various approaches throughout a single day, mostly competitive inhibitors like caffeine, grapefruit, dandelion and chamomile tea, curcumin and quercetin. All things which have apparently been shown in humans specifically to inhibit CYP1A2. Nobody's really discussed this approach nor intermittent bursts of use. I'm trying it in an n=1 and will report back when I've gone through a few cycles.

Edited by Nate-2004, 09 December 2017 - 02:52 PM.

[YOLF]

 

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...

[Rocket]

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?

[YOLF]

Well, I've never been fond of using DMSO, I've even steered away from MSM as a supplement in favor of other sulfur sources.

[Oakman]

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?

 

I'm become more and more excited about the possibilities of resolving senescence with Resveratrol, but the problem of reaching and maintaining high serum levels pretty much nixes results we want and need to potentially get the job done. Juicing, teas, pills, all the work just seems like a witches brew to get some possible tangible results.

 

Sublingual seems to be the best path to success. Much better to completely bypass the hazards of the digestive system, and far quicker too, than trying to navigate the digestion process to stop natural processes of digestion and liver detoxification.  This brand says it has a multitude of sublingual formulations, resveratrol being one, but I can't find it anywhere, although many of their others are on Amazon. Otherwise, this is the only sublingual formulation I've found actually for sale.

 

Beyond that, and potentially in the DIY realm, this forum thread was started by a fellow who did research on a ribose-resveratrol buccal formulation. The resultant patent. This .pdf of results he got, which were very impressive (both for Cmax x13 and UTC for buccal administration. The method he used fairly easy to duplicate, basically mixing ribose and minute amounts of resveratrol to obtain serum levels greatly exceeding normal oral doses up to 2.5grams.

 

"• tRes Solubility: Ribose Solubility was measured by adding 1.3mg of resveratrol to 1mL water or 1M ribose. Tubes were sonicated to dissolve tRes in both water and 1M ribose. Samples were tested by UV, MS, and tandem MS detection methods. Lozenge Analysis: tRes lozenges containing 50% Ribose by weight with sucrose and fructose were produced. Resveratrol content was confirmed to be 73.0μg/mg by HPLC by Martin Javors, PhD and Gregory Friesenhahn at the Biological Psychiatry Analytical Laboratory at UTHSC-SA."

 

Apparently nothing came of the work, likely due to the problems that were discussed in the thread about companies being investment-shy. Nevertheless, given the potential senescence treatment possibilities we're discussing here, it looks worth trying to duplicate his formulations towards senescence, or, at a minimum, trying the one commercial sublingual product would be worth investigation.