http://www.longecity.org/forum/topic/23865-investigating-the-copper-chelationcollagentendons-issue/
Stokestack posted :
So I was looking into the claims of collagen damage due to copper chelation, mainly because I experienced some odd Achilles pain and now have a raging case of plantar fasciitis after it had been dormant for a couple of years, without any explanatory increase or change in type of physical activity. This is after taking 500 mg Biotivia daily for two months. I noticed the Achilles problem before reading any marketing FUD about the copper/collagen issue. I do notice that a vendor of lower-dose resveratrol supplements has peppered the Web with the same propaganda on this issue, but I wanted to see whether there was any basis for it.
The scary part is the near absence of any studies on this exact problem, at least as far as I can find in a reasonable time. Apparently resveratrol is acknowledged to be a copper chelator, and there are lots of references to copper's role in collagen maintenance; for example, a study about how copper reduction can reduce the amount of collagen present in the case of diabetics with heart damage.
I find this relationship and my recent symptoms troubling enough to stop taking resveratrol altogether.
maxwatt posted :
It was only speculation on my part that resveratrol was a copper chelating agent. Aspirin is a copper chelator, and a Cox2 inhibitor. Resveratrol is a mild Cox2 inhibitor. Cox2 inhibition an copper chelation may or may not be linked but I begin to think not. Resveratrol does protect against oxidative damage in the presence of Copper according to some studies. At this time I can find no studies in pub med linking resveratrol to tendon or cartilage damage. I suspect the issue of resveratrol and tendon damage is an urban legend.
rhc124 posted :
Maxwatt, I have respected your opinion on many things but I do not agree with your "urban legend" comment. There has been too many people to report this issue. As with most drugs, some will have side effects and some will not,and resveratrol is no different. AS of to date I do not know of any long term human studies on resveratrol. I consider this forum as in the forefront of resveratrol users and thus it is our duty to report any side effects. I myself have spent over $1,000 on the product over the past year in my belief of its benifits. Yet I have experienced some side effects that I can guarantee that I have never experenced before. What we need to do is find out what is going on with this certain subset of users. If you have no problems with the product, then great for you, but some of us really do have side effects. Now we need all of the smart people on the board to tell us what is going on and I think it has to do something with copper.
elphaba posted :
I've also had a major problem with plantar fasciitis since taking resveratrol. I started with the 50% and am now taking 1 gram/day of 99% and problem still definitely present. I don't want to quit resveratrol because it has done amazing things for my blood pressure and cholesterol (and even minor benign cysts on my scalp that were marble size are decreasing in size to less than 25% of original size).
I've had chelation therapy before 6 or 7 years ago, can't remember how my copper was affected but I had 26 treatments and never had the plantar fasciitis. I also took a copper/zinc combo supplement recently for about a month hoping to eliminate the plantar fasciitis but no such luck.
Please post if anyone comes up with a solution to this problem. I am obese - 100 lbs overweight and I'm sure that doesn't help the situation but I didn't get the plantar fasciitis until after starting resveratrol and I was 100 lbs overweight the previous 5 years before starting resveratrol.
I'm taking glucosamine and MSM (sulfur) and Vitamin C and lots of other supplements. These seem to help relieve the aches and pains I have in my elbows and in the joints of my fingers and knees, mainly osteoarthritis, I think (prior to resveratrol) but hasn't prevented the plantar fasciitis from flaring up.
FunkOdyssey posted :
I am inclined to think any effects resveratrol has on tendons are mediated by the immune system, inflammation / repair signaling, and have nothing at all to do with copper. Copper chelation feels like an in-vitro red herring, since there is little/no free resveratrol and little/no free copper floating around in humans.
geddarkstorm posted :
I'm a molecular/cell biologist working on my Ph.D., so let's see if I can help any with trying to understand how resveratrol is functioning with these pains.
What FunkOdyssey suggested seems likely, for more reasons than one.
Firstly, resveratrol is metabolized into conjugates that have glucuronic acid or sulfate put onto its 3' hydroxyl group (which is located on the aromatic ring that has the two hydroxyls and thus is the site for chelation, see pdf here), making it impossible to chelate copper (PMID: 12523673). Almost no unconjugated resveratrol is ever secreted from the body, so if resveratrol chelated copper, it would be recovered during metabolism of said resveratrol.
Secondly, let's look at this paper
http://www.sciencedi...7885753766ad5df
Here we see the effects of resveratrol on copper is context dependent - that is, it doesn't interact as a chelator when either glutathione or vitamin C are around (and if you are alive, you've got at least glutathione).
Finally, it doesn't matter even if resveratrol acted as a copper chelator unless its Kd was somewhere around the range of copper using proteins and chaperons. For instance, zinc is the second most abundant metal in the body and crucial for proteins as diverse as heme synthesis, to zinc finger transcription factors. Now, citrate, or citric acid, which is part of the TCA cycle and critical for cellular metabolism, is a nice zinc chelator with a Kd of around 1.6X10-5 (or 16 micromolar). However, this does not affect the bioavailability of zinc in the cell as most zinc binding proteins have an even lower Kd. That is, the proteins that need zinc will always get the zinc first.
So, resveratrol could only harm copper metabolism if it could bind copper at a higher affinity than our normal proteins, and keep the copper bound till it was secreted, and this is apparently not the case. Even if it did have a higher Kd, you'd still need a significant ratio of resveratrol verses copper binding proteins to bind up enough of it to transiently pull it out of the body, and I seriously don't see that happening. And again, part of resveratrol being metabolised is the blockage of those hydroxyls needed for chelation, so copper would be released again. Resveratol also has a very short half life in the human body, so it'd be gone long before even its transient effects with metal chelation could cause problems, but not before it activates gene transcription of sirtuin genes from which its benefits are derived.
So then, my guess as to why resveratrol affects tendons might have to do with fluid, or electrolyte levels, and the joint bursa. Since resveratrol can block calcium efflux and influx channels in platelets, it may also in bursa cells and change the fluid levels. But, if that was the case, you'd have accompanied swelling if fluid increased, or joint grinding if it decreased. So, those who have pain, should also look to see if that's happening and that might give us a clue. Afterall, there's a lot of calcium action going on in the joint regions. Moreover, resveratrol could be considered an electrolyte itself, in that it'll change the osmotic conditions of the blood depending on how easily it is taken up into cells. All of this then may be abrogated by drinking a lot more fluid when taking resveratrol if high doses (over 500mg) are used, to try to keep electrolyte levels steady.
Another posibility, is resveratrol might be interacting with the material that makes up the joint and bursa fluids - glucosamino glycans, condroiton sulfates, and the like. I don't see why it would though, or if it'd even get in there. And one last posibility is it could be leading to calcium crystal formation in the joint area which can lead to psuedogrout. But, if that was so, the conditions would be far worst. So, again, it seems like an electrolyte misbalance from what I've read around this site.
@elphaba
Obviously it isn't copper, since increasing copper isn't doing anything. Plantar fasciitis can be caused by things as simple as changing activity levels (walking too much /or/ being idle can both cause it, go figure!), and bearing high amounts of weight over a long period of time - that is a primary cause, so it might have been simply a matter of time.Then again, it starting after taking up resveratrol is interesting. Definitely try taking more fluids and see what happens. There's also always quercetin which is a potent bioflavanoid against inflamation you can take too (also is an anti-viral, anti-cancer, anti-histamine, anti-oxident, and down regulates the innate immune system yet somehow boosts immune system effeciency), instead of things like glucosamine and MSM.
maxwatt posted :
@geddarkstorm -- A metabolite of quercetin is a Sirt1 inhibitor. Despite it's other benefits, it should perhaps not be used with resveratrol.
geddarkstorm posted :
Actually, I'm not all that convinced about that. There is only one paper, which I'll have to go to lab to get full access to, but they did not see inhibition of Sirt1 in vitro cells, only inhibition of their recombinant Sirt1 from the sound of it. Quercetin had no effect on the in vitro cells. That is, it's stated:
SIRT1 stimulation by polyphenols is affected by their stability and metabolism.
de Boer VC, de Goffau MC, Arts IC, Hollman PC, Keijer J. Mech Ageing Dev. 2006 Jul;127(7):618-27. Epub 2006 Apr 17.
"Using metabolically active HT29 cells we were able to show that quercetin (a stimulator of recombinant SIRT1) could not stimulate intracellular SIRT1. The major quercetin metabolite in humans, quercetin 3-O-glucuronide, slightly inhibited the recombinant SIRT1 activity which explains the lack of stimulatory action of quercetin in HT29 cells."
When I go into lab again tomorrow, I'll grab the full paper and tell you what they really saw. But notice, in the abstract, that quercetin activated the recombinant Sirt1 outside of a cell, but didn't the Sirt in the cells, and then its metabolite slightly inhibited recombinant Sirt1 which is part of their a-cellular assay from the sounds of it? (not sure, again have to get the paper), and in the end, there was no net effect of Sirt1 intracellularly from what it sounds like the abstract says. Furthermore, we know that recombinant Sirt1 assays are misleading as resveratrol is seen to directly interact with recombinant Sirt1 having a fluorophore, but not directly interact with native Sirt1 (that is, resveratrol's molecular mode of action doesn't appear to be direct binding and activation to Sirt1, or at least it doesn't seem clear from the studies I've read. There's intracellular pathways to activate Sirt1's various roles after all and resveratrol may activate an upstream effector that then turns on Sirt1). And even more, Sirt1 does have various rolls, so which roll would quercetin be inhibiting? This isn't even in vivo, which may change things yet again, and I've seen two papers so far that say quercetin activates Sirt1 in more complex systems (one I'll be referencing later). I really need that paper..
Still, even if quercetin's metabolite mildly inhibits Sirt1, the great increase in Sirt1 given by resveratrol while quercetin is being metabolized is probably all that's needed in theory, as activation of Sirt1 even transiently can lead to the deacylation of the PGC-1 gene, and it is that gene's transcription that gives all the beneficial effects of resveratrol seen to date. In other words, studies where the PGC-1 gene was modified so it could not be deacylated by Sirt1 resulted in resveratrol having no effect on cell metabolism and gene expression. Conversely, putting in PGC-1 which was always deacylated gave the same effects as seen by resveratrol (PMID: 17112576). So, resveratrol acts through the Sirt1 pathway to turn on PGC-1 and that is where we see our benefits. Sirt1 doesn't have to be on long, which is why even though resveratrol has a half life of ~14 minutes (3 hours with quercetin?), it is till long enough to activate Sirt1 to turn on PGC-1. That's why I'm a little skeptical that quercetin interferes with resveratrol to a significant extent till I see more evidence, especially in vivo.
On the other hand, quercetin affects other pathways, such as MAPK's. The effects you have when taking it may be due to its other functions, not interference with resveratrol, per ce. For instance, quercetin increases the expression of Bone sialoprotein which is implied to nucleate hydroxyapatite crystals in mineralized connective tissues (PMID: 17243115). Depending on the source of your joint pain, that could be a reason it increases it, by increasing calcium crystal formation. On the other hand, for other people, quercetin and its main metabolite (which is the sulfated version, not the glucuronidated form according to this paper) inhibits the inflammatory eicosanoid leukotriene B4 (PMID: 18096136), a powerful inflammatory mediator that may play a role in a lot of arthritis and other pains, along with other inflammatory eicosanoids. So, if that was the source, then quercetin would be expected to help. Nothing can be ruled out of course, and different cell lines and biochemistries may respond differently to the combination, and the two at once may have more effects than either alone. It would be interesting to know if quercetin by itself when not taking resveratrol affects your level of joint pain in any way, and maybe that will help tease this issue apart.
Also, take a look at this paper:
Resveratrol protects dopaminergic neurons in midbrain slice culture from multiple insults.
Okawara M, Katsuki H, Kurimoto E, Shibata H, Kume T, Akaike A. Biochem Pharmacol. 2007 Feb 15;73(4):550-60. Epub 2006 Nov 9.
"Notably, resveratrol activates sirtuin family of NAD-dependent histone deacetylases implicated in regulation of various cellular processes including gene transcription, DNA repair and apoptosis. Here we examined neuroprotective effect of resveratrol on dopaminergic neurons in organotypic midbrain slice culture. Resveratrol and quercetin, another sirtuin-activating polyphenol, prevented the decrease of dopaminergic neurons and the increase of propidium iodide uptake into slices induced by a dopaminergic neurotoxin 1-methyl-4-phenyl pyridinium (MPP(+))."
Albeit, this isn't working with the metabolites of either, and I don't know if the neurons would metabolize them, so definitely take it with a grain of salt - the quercetin may not even have had its protective effects via Sirt1 but some other mechanism. It still paints a complex picture as here's a cell line that displays benefits from both resveratrol and quercetin. Everywhere I look, the story is painfully complex for all these compounds...
maxwatt posted :
I require about half as much resveratrol now as I did a year ago for the same level of pain relief in my joints. Using more causes an increase in pain. Other effects, such as better stamina, feeling of well being (mild, not extreme) decreased cold sensitivity, and perhaps lowered blood sugar, seem to be the same as with the higher dose.
Perhaps activating sirtuins has a cummulative effect; the genes stay activated (resulting in more P53 deacytlase and nf-KappaB inhibition). Or the changes induced mean natural sirtuin activation is returned to a more youthful state, so less exogenous stimulation is needed.
I still use 1.4 to 1.6 grams a day. I don't have any quercetin handy, or I might try that experiment. But I am not so curious as to go out and acquire any.
eddarkstorm posted :
You've been using resveratrol for about two years, based on your last post in the 1 year thread?
Taking into account the recent research about the role of Sirt1 distraction away from regulation and to DNA repair playing a part in aging, it's likely that long term stimulation of Sirt1 will reverse the accruement of Sirt1 gene regulation loss - that is, repackaging of heterochromatin and deactivated genes back to youthful levels, at which time keeping Sirt1 active will then mostly serve to keep PGC-1alpha on transcriptionally, and protect from DNA damage (specifically radiation, which causes double stranded breaks that Sirt1 is required for the repair of).
In that theoretical view, it makes perfect sense why you need less of it now. It's also likely then, if all this is correct, that you won't need to further decrease resveratrol intake much if at all once full Sirt1 gene pattern regulation is restored throughout your body, which it may now be.
qqqsimmons posted :
i wouldn't be at all surprised if resveratrol had an effect on copper levels. after a few weeks on Country Life Res+, i developed tinnitus.
after reading this thread, and remember my last case of tinnitus from zinc supplementation, i got a copper supplement.
a few hours after the first dose, the noise was pretty much gone. well, that was only about six hours ago, so i can't say for sure...
geddarkstorm posted :
That Country Life stuff is full of a lot more than resveratrol (only 50% resveratrol, who knows how much of that is trans, and only 100 mg is pretty much nothing). Also, I can't find anywhere where copper is associated with tinnitus what so ever, only zinc, which alleviates it. Copper is only taken with zinc as zinc can lead to copper deficiencies by impairing copper uptake from food. Tinnitus is associated with low levels of seratonin, which resveratrol may or may not affect if you're also taking a seratonin inhibitor thing. I doubt with the levels you're taking with that Country life stuff that resveratrol could do anything to your seratonin, and certainly not to copper.
https://www.longecity.org/forum/top...-copper-chelationcollagentendons-issue/page-2
Stokestack posted :
So I was looking into the claims of collagen damage due to copper chelation, mainly because I experienced some odd Achilles pain and now have a raging case of plantar fasciitis after it had been dormant for a couple of years, without any explanatory increase or change in type of physical activity. This is after taking 500 mg Biotivia daily for two months. I noticed the Achilles problem before reading any marketing FUD about the copper/collagen issue. I do notice that a vendor of lower-dose resveratrol supplements has peppered the Web with the same propaganda on this issue, but I wanted to see whether there was any basis for it.
The scary part is the near absence of any studies on this exact problem, at least as far as I can find in a reasonable time. Apparently resveratrol is acknowledged to be a copper chelator, and there are lots of references to copper's role in collagen maintenance; for example, a study about how copper reduction can reduce the amount of collagen present in the case of diabetics with heart damage.
I find this relationship and my recent symptoms troubling enough to stop taking resveratrol altogether.
maxwatt posted :
It was only speculation on my part that resveratrol was a copper chelating agent. Aspirin is a copper chelator, and a Cox2 inhibitor. Resveratrol is a mild Cox2 inhibitor. Cox2 inhibition an copper chelation may or may not be linked but I begin to think not. Resveratrol does protect against oxidative damage in the presence of Copper according to some studies. At this time I can find no studies in pub med linking resveratrol to tendon or cartilage damage. I suspect the issue of resveratrol and tendon damage is an urban legend.
rhc124 posted :
Maxwatt, I have respected your opinion on many things but I do not agree with your "urban legend" comment. There has been too many people to report this issue. As with most drugs, some will have side effects and some will not,and resveratrol is no different. AS of to date I do not know of any long term human studies on resveratrol. I consider this forum as in the forefront of resveratrol users and thus it is our duty to report any side effects. I myself have spent over $1,000 on the product over the past year in my belief of its benifits. Yet I have experienced some side effects that I can guarantee that I have never experenced before. What we need to do is find out what is going on with this certain subset of users. If you have no problems with the product, then great for you, but some of us really do have side effects. Now we need all of the smart people on the board to tell us what is going on and I think it has to do something with copper.
elphaba posted :
I've also had a major problem with plantar fasciitis since taking resveratrol. I started with the 50% and am now taking 1 gram/day of 99% and problem still definitely present. I don't want to quit resveratrol because it has done amazing things for my blood pressure and cholesterol (and even minor benign cysts on my scalp that were marble size are decreasing in size to less than 25% of original size).
I've had chelation therapy before 6 or 7 years ago, can't remember how my copper was affected but I had 26 treatments and never had the plantar fasciitis. I also took a copper/zinc combo supplement recently for about a month hoping to eliminate the plantar fasciitis but no such luck.
Please post if anyone comes up with a solution to this problem. I am obese - 100 lbs overweight and I'm sure that doesn't help the situation but I didn't get the plantar fasciitis until after starting resveratrol and I was 100 lbs overweight the previous 5 years before starting resveratrol.
I'm taking glucosamine and MSM (sulfur) and Vitamin C and lots of other supplements. These seem to help relieve the aches and pains I have in my elbows and in the joints of my fingers and knees, mainly osteoarthritis, I think (prior to resveratrol) but hasn't prevented the plantar fasciitis from flaring up.
FunkOdyssey posted :
I am inclined to think any effects resveratrol has on tendons are mediated by the immune system, inflammation / repair signaling, and have nothing at all to do with copper. Copper chelation feels like an in-vitro red herring, since there is little/no free resveratrol and little/no free copper floating around in humans.
geddarkstorm posted :
I'm a molecular/cell biologist working on my Ph.D., so let's see if I can help any with trying to understand how resveratrol is functioning with these pains.
What FunkOdyssey suggested seems likely, for more reasons than one.
Firstly, resveratrol is metabolized into conjugates that have glucuronic acid or sulfate put onto its 3' hydroxyl group (which is located on the aromatic ring that has the two hydroxyls and thus is the site for chelation, see pdf here), making it impossible to chelate copper (PMID: 12523673). Almost no unconjugated resveratrol is ever secreted from the body, so if resveratrol chelated copper, it would be recovered during metabolism of said resveratrol.
Secondly, let's look at this paper
http://www.sciencedi...7885753766ad5df
Here we see the effects of resveratrol on copper is context dependent - that is, it doesn't interact as a chelator when either glutathione or vitamin C are around (and if you are alive, you've got at least glutathione).
Finally, it doesn't matter even if resveratrol acted as a copper chelator unless its Kd was somewhere around the range of copper using proteins and chaperons. For instance, zinc is the second most abundant metal in the body and crucial for proteins as diverse as heme synthesis, to zinc finger transcription factors. Now, citrate, or citric acid, which is part of the TCA cycle and critical for cellular metabolism, is a nice zinc chelator with a Kd of around 1.6X10-5 (or 16 micromolar). However, this does not affect the bioavailability of zinc in the cell as most zinc binding proteins have an even lower Kd. That is, the proteins that need zinc will always get the zinc first.
So, resveratrol could only harm copper metabolism if it could bind copper at a higher affinity than our normal proteins, and keep the copper bound till it was secreted, and this is apparently not the case. Even if it did have a higher Kd, you'd still need a significant ratio of resveratrol verses copper binding proteins to bind up enough of it to transiently pull it out of the body, and I seriously don't see that happening. And again, part of resveratrol being metabolised is the blockage of those hydroxyls needed for chelation, so copper would be released again. Resveratol also has a very short half life in the human body, so it'd be gone long before even its transient effects with metal chelation could cause problems, but not before it activates gene transcription of sirtuin genes from which its benefits are derived.
So then, my guess as to why resveratrol affects tendons might have to do with fluid, or electrolyte levels, and the joint bursa. Since resveratrol can block calcium efflux and influx channels in platelets, it may also in bursa cells and change the fluid levels. But, if that was the case, you'd have accompanied swelling if fluid increased, or joint grinding if it decreased. So, those who have pain, should also look to see if that's happening and that might give us a clue. Afterall, there's a lot of calcium action going on in the joint regions. Moreover, resveratrol could be considered an electrolyte itself, in that it'll change the osmotic conditions of the blood depending on how easily it is taken up into cells. All of this then may be abrogated by drinking a lot more fluid when taking resveratrol if high doses (over 500mg) are used, to try to keep electrolyte levels steady.
Another posibility, is resveratrol might be interacting with the material that makes up the joint and bursa fluids - glucosamino glycans, condroiton sulfates, and the like. I don't see why it would though, or if it'd even get in there. And one last posibility is it could be leading to calcium crystal formation in the joint area which can lead to psuedogrout. But, if that was so, the conditions would be far worst. So, again, it seems like an electrolyte misbalance from what I've read around this site.
@elphaba
Obviously it isn't copper, since increasing copper isn't doing anything. Plantar fasciitis can be caused by things as simple as changing activity levels (walking too much /or/ being idle can both cause it, go figure!), and bearing high amounts of weight over a long period of time - that is a primary cause, so it might have been simply a matter of time.Then again, it starting after taking up resveratrol is interesting. Definitely try taking more fluids and see what happens. There's also always quercetin which is a potent bioflavanoid against inflamation you can take too (also is an anti-viral, anti-cancer, anti-histamine, anti-oxident, and down regulates the innate immune system yet somehow boosts immune system effeciency), instead of things like glucosamine and MSM.
maxwatt posted :
@geddarkstorm -- A metabolite of quercetin is a Sirt1 inhibitor. Despite it's other benefits, it should perhaps not be used with resveratrol.
geddarkstorm posted :
Actually, I'm not all that convinced about that. There is only one paper, which I'll have to go to lab to get full access to, but they did not see inhibition of Sirt1 in vitro cells, only inhibition of their recombinant Sirt1 from the sound of it. Quercetin had no effect on the in vitro cells. That is, it's stated:
SIRT1 stimulation by polyphenols is affected by their stability and metabolism.
de Boer VC, de Goffau MC, Arts IC, Hollman PC, Keijer J. Mech Ageing Dev. 2006 Jul;127(7):618-27. Epub 2006 Apr 17.
"Using metabolically active HT29 cells we were able to show that quercetin (a stimulator of recombinant SIRT1) could not stimulate intracellular SIRT1. The major quercetin metabolite in humans, quercetin 3-O-glucuronide, slightly inhibited the recombinant SIRT1 activity which explains the lack of stimulatory action of quercetin in HT29 cells."
When I go into lab again tomorrow, I'll grab the full paper and tell you what they really saw. But notice, in the abstract, that quercetin activated the recombinant Sirt1 outside of a cell, but didn't the Sirt in the cells, and then its metabolite slightly inhibited recombinant Sirt1 which is part of their a-cellular assay from the sounds of it? (not sure, again have to get the paper), and in the end, there was no net effect of Sirt1 intracellularly from what it sounds like the abstract says. Furthermore, we know that recombinant Sirt1 assays are misleading as resveratrol is seen to directly interact with recombinant Sirt1 having a fluorophore, but not directly interact with native Sirt1 (that is, resveratrol's molecular mode of action doesn't appear to be direct binding and activation to Sirt1, or at least it doesn't seem clear from the studies I've read. There's intracellular pathways to activate Sirt1's various roles after all and resveratrol may activate an upstream effector that then turns on Sirt1). And even more, Sirt1 does have various rolls, so which roll would quercetin be inhibiting? This isn't even in vivo, which may change things yet again, and I've seen two papers so far that say quercetin activates Sirt1 in more complex systems (one I'll be referencing later). I really need that paper..
Still, even if quercetin's metabolite mildly inhibits Sirt1, the great increase in Sirt1 given by resveratrol while quercetin is being metabolized is probably all that's needed in theory, as activation of Sirt1 even transiently can lead to the deacylation of the PGC-1 gene, and it is that gene's transcription that gives all the beneficial effects of resveratrol seen to date. In other words, studies where the PGC-1 gene was modified so it could not be deacylated by Sirt1 resulted in resveratrol having no effect on cell metabolism and gene expression. Conversely, putting in PGC-1 which was always deacylated gave the same effects as seen by resveratrol (PMID: 17112576). So, resveratrol acts through the Sirt1 pathway to turn on PGC-1 and that is where we see our benefits. Sirt1 doesn't have to be on long, which is why even though resveratrol has a half life of ~14 minutes (3 hours with quercetin?), it is till long enough to activate Sirt1 to turn on PGC-1. That's why I'm a little skeptical that quercetin interferes with resveratrol to a significant extent till I see more evidence, especially in vivo.
On the other hand, quercetin affects other pathways, such as MAPK's. The effects you have when taking it may be due to its other functions, not interference with resveratrol, per ce. For instance, quercetin increases the expression of Bone sialoprotein which is implied to nucleate hydroxyapatite crystals in mineralized connective tissues (PMID: 17243115). Depending on the source of your joint pain, that could be a reason it increases it, by increasing calcium crystal formation. On the other hand, for other people, quercetin and its main metabolite (which is the sulfated version, not the glucuronidated form according to this paper) inhibits the inflammatory eicosanoid leukotriene B4 (PMID: 18096136), a powerful inflammatory mediator that may play a role in a lot of arthritis and other pains, along with other inflammatory eicosanoids. So, if that was the source, then quercetin would be expected to help. Nothing can be ruled out of course, and different cell lines and biochemistries may respond differently to the combination, and the two at once may have more effects than either alone. It would be interesting to know if quercetin by itself when not taking resveratrol affects your level of joint pain in any way, and maybe that will help tease this issue apart.
Also, take a look at this paper:
Resveratrol protects dopaminergic neurons in midbrain slice culture from multiple insults.
Okawara M, Katsuki H, Kurimoto E, Shibata H, Kume T, Akaike A. Biochem Pharmacol. 2007 Feb 15;73(4):550-60. Epub 2006 Nov 9.
"Notably, resveratrol activates sirtuin family of NAD-dependent histone deacetylases implicated in regulation of various cellular processes including gene transcription, DNA repair and apoptosis. Here we examined neuroprotective effect of resveratrol on dopaminergic neurons in organotypic midbrain slice culture. Resveratrol and quercetin, another sirtuin-activating polyphenol, prevented the decrease of dopaminergic neurons and the increase of propidium iodide uptake into slices induced by a dopaminergic neurotoxin 1-methyl-4-phenyl pyridinium (MPP(+))."
Albeit, this isn't working with the metabolites of either, and I don't know if the neurons would metabolize them, so definitely take it with a grain of salt - the quercetin may not even have had its protective effects via Sirt1 but some other mechanism. It still paints a complex picture as here's a cell line that displays benefits from both resveratrol and quercetin. Everywhere I look, the story is painfully complex for all these compounds...
maxwatt posted :
I require about half as much resveratrol now as I did a year ago for the same level of pain relief in my joints. Using more causes an increase in pain. Other effects, such as better stamina, feeling of well being (mild, not extreme) decreased cold sensitivity, and perhaps lowered blood sugar, seem to be the same as with the higher dose.
Perhaps activating sirtuins has a cummulative effect; the genes stay activated (resulting in more P53 deacytlase and nf-KappaB inhibition). Or the changes induced mean natural sirtuin activation is returned to a more youthful state, so less exogenous stimulation is needed.
I still use 1.4 to 1.6 grams a day. I don't have any quercetin handy, or I might try that experiment. But I am not so curious as to go out and acquire any.
eddarkstorm posted :
You've been using resveratrol for about two years, based on your last post in the 1 year thread?
Taking into account the recent research about the role of Sirt1 distraction away from regulation and to DNA repair playing a part in aging, it's likely that long term stimulation of Sirt1 will reverse the accruement of Sirt1 gene regulation loss - that is, repackaging of heterochromatin and deactivated genes back to youthful levels, at which time keeping Sirt1 active will then mostly serve to keep PGC-1alpha on transcriptionally, and protect from DNA damage (specifically radiation, which causes double stranded breaks that Sirt1 is required for the repair of).
In that theoretical view, it makes perfect sense why you need less of it now. It's also likely then, if all this is correct, that you won't need to further decrease resveratrol intake much if at all once full Sirt1 gene pattern regulation is restored throughout your body, which it may now be.
qqqsimmons posted :
i wouldn't be at all surprised if resveratrol had an effect on copper levels. after a few weeks on Country Life Res+, i developed tinnitus.
after reading this thread, and remember my last case of tinnitus from zinc supplementation, i got a copper supplement.
a few hours after the first dose, the noise was pretty much gone. well, that was only about six hours ago, so i can't say for sure...
geddarkstorm posted :
That Country Life stuff is full of a lot more than resveratrol (only 50% resveratrol, who knows how much of that is trans, and only 100 mg is pretty much nothing). Also, I can't find anywhere where copper is associated with tinnitus what so ever, only zinc, which alleviates it. Copper is only taken with zinc as zinc can lead to copper deficiencies by impairing copper uptake from food. Tinnitus is associated with low levels of seratonin, which resveratrol may or may not affect if you're also taking a seratonin inhibitor thing. I doubt with the levels you're taking with that Country life stuff that resveratrol could do anything to your seratonin, and certainly not to copper.
https://www.longecity.org/forum/top...-copper-chelationcollagentendons-issue/page-2
