281 replies to this topic

[VP.]

So even if you count Longevinex's increase to 100 mg. per capsule, you'd still be looking at around 320 capsules per day to get the same amount in an adult human... And even if you could swallow that many (and assuming unlimited production by Longevinex), it would cost about $80,000 per year.

Pro cyclists will most likely be the first athletes to experiment using Resveratrol at high doses. Cycling is a sport that has very high rewards for gifted aerobic mutants.(Armstrong) Past history shows that health concerns are not a priority for cyclists who want to win. Resveratrol's side effects at 400mg/kg are probably minor compared to blood doping and high doses of EPO. In the 90's a number of cyclists died in their sleep from overdosing on EPO. Recent cycling drug busts in Spain showed that some top pros are/were spending over $50,000 a year for doping. $80,000 a year is not much for riders making over 2 million a year. Resveratrol is not a banned drug in sports (yet). If future studies back up it's long term health benefits can it ever be banned?

[VP.]

Chris Patil from the excellent aging research blog Ouroboros had this to say about the recent Resveratrol research:

I heard this story at the Cold Spring Harbor Laboratory meeting on the Molecular Genetics of Aging about a month ago, and since then itfs been published online at Nature. The data were impressive at the conference and continue to be in the manuscript: Resveratrol extends life in mice, and appears to protect them from the health harms of a high-calorie diet. Baur et al.:

Resveratrol (3,5,4Œ-trihydroxystilbene) extends the lifespan of diverse species including Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. In these organisms, lifespan extension is dependent on Sir2, a conserved deacetylase proposed to underlie the beneficial effects of caloric restriction. Here we show that resveratrol shifts the physiology of middle-aged mice on a high-calorie diet towards that of mice on a standard diet and significantly increases their survival. Resveratrol produces changes associated with longer lifespan, including increased insulin sensitivity, reduced insulin-like growth factor-1 (IGF-I) levels, increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1alpha) activity, increased mitochondrial number, and improved motor function. Parametric analysis of gene set enrichment revealed that resveratrol opposed the effects of the high-calorie diet in 144 out of 153 significantly altered pathways. These data show that improving general health in mammals using small molecules is an attainable goal, and point to new approaches for treating obesity-related disorders and diseases of ageing.

This paper is just the beginning, as the study is still underway: David Sinclairs group is also following cohorts of mice that are being fed either lab-standard or calorie-restricted diets, so we can expect another report in a few months time when those mice are expected to be expiring.

As of the CSHL conference, the CR and standard groups werenft old enough to see any difference between their lifespans yet; consequently, there was no way to tell whether resveratrol was having a life-extending effect. The effect of resveratrol on the high-calorie animals was quite striking, however: their lifespan curves were essentially indistinguishable from the animals eating the less caloric diets.

Given that the high-calorie ad libitum diet is thought to be a good model of what we humans are doing to ourselves in the West, these results have convinced me to start investigating source of commercially available resveratrol. In the meantime, of course, I will continue drinking red wine ad libitum.

http://ouroboros.wordpress.com/

[VP.]

Here's a shocking video of the mice on a treadmill. PETA is not going to like this.

http://www.brightcov...hannel=86240652

Edited by velopismo, 18 November 2006 - 05:54 AM.

[Brian]

When trying to convert mice doses to humans, you can't just do a simple mg/kg straight conversion. There is a metabolic rate issue, which generally means humans only need around an order of magnitude less mg/kg compared to mice to get the same effects.

[VP.]

When trying to convert mice doses to humans, you can't just do a simple mg/kg straight conversion. There is a metabolic rate issue, which generally means humans only need around an order of magnitude less mg/kg compared to mice to get the same effects.

This has been discussed. The number mentioned was 7.5:1

[olderbutwiser]

I'm curious about the claims of 100mg Resveratrol in Longevinex brand caps.
The way I read the package label, there can be no more than 15mg - and only if the polyphenol content is pure Resveratrol.
Am I reading something wrong? (wouldn't be the first time [glasses] )

OBW - lurking through

[doug123]

Olderbutwiser: that is specifying the difference between resveratrol from wine (they say at least 15mg) and the Giant knotweed content 100-15 = 85mg -- for a total of 100mg resveratrol.

[olderbutwiser]

That certainly is the best case interpretation of the label - but it isn't the industry standard one.

What the label says is that it contains (as one ingredient) - 100mg of a proprietary blend that is guaranteed to provide not less than 15mg of "stabilized red wine polyphenols". There is absolutely nothing on the label that states any quantity of resveratrol content at all. By industry standard labelling nomenclature, in order for there to be 100mg of resveratrol per capsule, "Longvinex proprietary blend" would have to be pure resveratrol.

The labelling requirements are the only stringent requirements on supplement producers. They can get away with alluding to pretty much anything they want to in their literature and advertising. Reading the content label cuts through the chaff.

I'm not arguing that there is not 100mg of resveratrol per cap of Longevinex. If there is at least 100mg of resveratrol per capsule, it certainly would be advantageous for Longevinex to clearly label it as such.

OBW

[xanadu]

Very good point, OBW. I have been cheated too many times and then found weasel wording in the literature that let them get away with it. Now, when I see weasel words I automatically assume I'm getting hosed and am probably right. What's wrong with just taking a lot of caps of giant knotweed or it's extract?

[kenj]

olderbutwiser, I don't think the label is updated.

[cesium]

Removed post after reviewing Longevinex website info.

Edited by cesium, 19 November 2006 - 01:04 AM.

[VP.]

The folks at Fight Ageing ( http://www.fightaging.org/) found a link to the entire French resveratrol study. Take the time to read it. The press for once are not exaggerating the results. Resveratrol is without a doubt a very potent chemical. It's just stunning. If you had told me a few years ago that we would have a orally available supplement that could produce results like these I would have called it total B.S. It's so potent that I have to wonder what are the possible adverse effects. After all there are no free lunches, are there?

http://images.cell.c...ell/lagouge.pdf

[syr_]

http://images.cell.c...ell/lagouge.pdf

OK, I'm sold.

[jlgibbons]

Maybe Mind wouldn't mind emailing Dr. Sinclair again to see why he uses Longevinex. I'd also be interested to know if his parents and the half of his lab that is taking resveratrol supplements also use Longevinex. For that matter, maybe he could ask what Dr. Sinclair would look for in a resveratrol supplement should he ever be able to recommend that people take it.

[doug123]

Good work!

You might want to remove as much private information as you can as this is a public website and I understand that is a private email.

[mitkat]

Well...let's all hop on that train *sells everything, buys lots of resveratol*

[syr_]

Well, if someone plans to buy in bulk, I'd take a share of 50-100gms.

[opales]

Hmmm, my friend did a little investigation, and did not find evidence that resveratrol metabolism between mice and humans are all that different, in fact, he found evidence of the opposite.

Below picture from (1) describes the pharmacokinetics of resveratrol in mice, and it appears (as I read it) that the resveratrol is converted to sulfate and glucuronide conjugates immediately after absorbtion, which is the same phenomenon as seen in humans, and which has been the reason for skepticism whether the mice results are applicaple to humans.

So if it works in mice, and the metabolism is very similar humans, then logically it should...

(1) Human, Rat, and Mouse Metabolism of Resveratrol

http://www.springerl...p1w8x132042r55/

Attached Files

•  clip_image001.gif   57.53KB   50 downloads

[health_nutty]

Hmmm, my friend did a little investigation, and did not find evidence that resveratrol metabolism between mice and humans are all that different, in fact, he found evidence of the opposite.

You lost me with the number of negations, are you saying he found evidence that they are the same?

[wtjewell]

Thanks for the advice, personal info removed.....

Good work! 

You might want to remove as much private information as you can as this is a public website and I understand that is a private email.

[doug123]

Thanks for the advice, personal info removed.....

Yeah, remind me not to tell you anything about my private life...ha ha.

No, but seriously, there should be a certain degree of privacy implied in communications such as a private email...the least you can do is ask the individual if they care that their private communication is posted to the "public" web. Not everyone wants to be "indexed" by Google and other search engines.

[opales]

Hmmm, my friend did a little investigation, and did not find evidence that resveratrol metabolism between mice and humans are all that different, in fact, he found evidence of the opposite.

You lost me with the number of negations, are you saying he found evidence that they are the same?

LOL, I was wondering if I was overdoing the negations, sorry. Yes, the picture I showed appears to tell that resveratrol metabolism in mice and men are very similar.

That would of course imply that theoretical worries about lack of bioavailability in humans are not relevant because the same phenomenon is seen in mice yet it still works. Someone at M&M implied a while back that there is drastic difference in resveratrol metabolism between mice and humans ("mice have 30% bioavailability while humans have 0%"), I really don't know where that comes from.

FYI, I have understood Sinclair has concomitantly tested resveratrol on normal mice too (the previous tests were on obese mice), those results should probably be ready in couple or at maximum 6 months I guess.

[jlgibbons]

Sincalir is one of the scientists who has signed on with the Methuselah Prize and has been signed on for a while. I suspect he laready knows whether the mice in that study have lived longer than a normal lifespan.

[VP.]

opales said

Hmmm, my friend did a little investigation, and did not find evidence that resveratrol metabolism between mice and humans are all that different, in fact, he found evidence of the opposite.

Hmmm, did this study show that resveratrol dosing in humans and mice have the same effects for the same dose/kg? I'm not sure if that's what they are saying.
Someone has done some recent cleanup on the resveratrol wikipedia entry and this is one of the new entries:

The amounts used in the mouse study were approximately 22.4 mg/kg body weight per day. Scaling this amount to human body weights would imply an "equivalent human dose" of 1.5 to 2.0 grams/day. Compensating for the fact that humans have slower metabolic rates than mice would change the equivalent human dose to the range of 150 to 200 mg/day, but given that many red wines contain 3-4 milligrams of resveratrol per liter, a comparable intake would require roughly 50 bottles of wine per day. The truth is that many differences exist between mouse and human metabolism, and the effects of any given oral dose in humans remain unknown. As of November 2006 there is only one published human trial in the scientific literature and that was for safety, not efficacy. Single (one day only) oral doses of 1.0, 2.5 and 5.0 grams were given to 29 volunteers. No serious adverse events were noted. [18]. There is no human evidence yet that quantities found in red wine or in standard supplements are sufficient for any health effect.

This was posted at Future Pundit in response to the above Wiki entry by Dr. Kurt Miller:

BW (body weight) in Kg to the 3/4 power is a suprisingly good first estimate, and a starting point for dosage studies across mammalian species, per the late great Herr Doktor Professor Max Klieber, an expert in animal energetics. Critically, this is an estimate of metabolic rate, which in turn gives a good estimate of caloric need. His work might directly apply, as pointed out by rsilvetz, as this appears to be an energy related issue. I think Kleiber did this work about 75 years ago. Some drugs (not nutrients) have dosages which seem wholly independent of this rule of thumb regarding energy, as they are not metabolic rate/energy related.

So, if you had a giant mouse at 50 grams and he daily recieved revasterol 20 mg / kg of body weight (not 20 mg / kg of diet; interestingly and obviously, nutrient density of foods is about the same across species, in that afterall we are eating mostly the same things) his daily dose would be a single milligram. This is in the range of many vitamins and some minerals for a mouse. [the calculation being 50g/1000g x 20 mg, where 50g is the mouse weight times the quantity 20mg/1000g; grams cancel out, 50 x 20 is 1000, and 1000/1000 = 1; leaving 1 mg]. So, if the mouse was given 200 mg / kg, then the dose would be 10 mg per day and 400 mg/kg would be 20 mg.

20 mg to the 3/4 power in kg would be [2 X 10(neg 5 power)3/4 power... sorry no calculator available to do the math. Anyway, I hope this helps.

This comment was added by rsilvetz:

OK. Reviewed the state of the art. (Couldn't sleep.) Randall please blow away previous posts as they are grossly incorrect mathwise. Moral of the story: Don't take cold medicine and try to do math.

Have better numbers. Avg mouse is 35 gr or 0.035 kg. We'll use 70 kg for a human. Even though energetics vary to the tune of 3/4th power, it's sitting in the denominator, thus (70 kg/0.035 kg)^(1-3/4)= 2000^(1/4)=6.69 scaling factor.

This puts the human dosage based on the mouse studies at:

(Wiki) 22.4/6.69= 3.35 mg/kg/day = 234 mg/day

200/6.69= 29.9 mg/kg/day = 2093 mg/day = 2.093 gr/day

400/6.69= 59.8 mg/kg/day = 4186 mg/day = 4.186 gr/day

So it appears we can do this by supplementation. Dosage adjusts downward because our physiologic clock is slower than a mouses, even though our total energy requirements are much higher. Eg if you compare heart rates, mouse ~ 700, humans ~72

http://hep.ucsb.edu/...i-scaling.1.GIF

http://www.futurepun...i?entry_id=3896

Do you think the study opaoles brought up refutes rsilvetz's calculations?

[opales]

No my reference was a counterargument to the claim that humans and mice have completely different metabolism so any mice studies are irrelevant from human point of view. More importantly argument has been that while mice preserve 30% of absorbed trans-reseveratrol in circulation, humans preserve 0%, while the rest is converted in to trans-resveratrol conjugates. This would most likely mean that humans would not gain any benefits from ingested resveratrol.

The study I provided (IMO) shows that in mice too almost all resveratrol is converted into conjugates, YET IT STILL WORKS (implying that either conjugates are themselves biologically active or are converted back to trans-reseveratrol in cells).

Trouble in scaling from mice to men is a rather minor detail compared to the lack of any effect.

Edited by opales, 23 November 2006 - 12:02 PM.

[maestro949]

What we need to do is find markers that indicate that resveratrol is active in mice and then do human trial looking for the same markers. Another idea would be to see if the resveratrol has any affect on the premature aging diseases like progeria. Perhaps give it a go on senescence-accelerated mice first though.

[luminous]

I think I've been assimilated. Last week, I ordered and received a supply of Ortho-Core, Piracetam and Phenibut. This week, I ordered Resveratrol. I didn't realize that ImmInst is like the Hotel California ("You can check out any time you like, but you can never leave.")

[xanadu]

More importantly argument has been that while mice preserve 30% of absorbed trans-reseveratrol in circulation, humans preserve 0%, while the rest is converted in to trans-resveratrol conjugates. This would most likely mean that humans would not gain any benefits from ingested resveratrol.

And yet the fact remains that this substance has shown remarkable effects in humans and they did not need 50 glasses or 50 gallons or whatever of wine per day to realise these effects. I know everyone is tired of me saying that but it is a fact. Theories are good but we need to touch in to reality now and then. There is no evidence I'm aware of that shows smaller amounts of resveratrol do not have these same benefits and that you need the huge amounts used in the mice trials. Everyone assumes that since they used a large amount that this is the minimum you should shoot for rather than perhaps a maximum. You could look at it from the point of view that this amount is safe but any more may not be.

We also do not fully understand how it works in the body. We assume that high serum levels are needed but that may not be the case. It may bind to other substances or change form in some way before it does it's work. I'm more pragmatic, I look at whether it works or not and not look so much at whether it fits my preconceptions about how it should work. It may be that any more than a few milligrams a day is simply excreted into the urine because it isn't needed. We will know more about that later on.

[FunkOdyssey]

The effects demonstrated by resveratrol in the mice studies are far beyond the "remarkable" effects of red wine consumption. We have not proven that humans can reproduce the benefits enjoyed by the test mice, but if it is possible, it will require higher doses of resveratrol than you can obtain from red wine. Unless you know any red wine drinkers that doubled their running endurance and look like trained athletes without exercise?

As far as your assertion that there is no evidence that smaller amounts of resveratrol do not produce the same benefits, I'm fairly certain such evidence does exist. For example, in the infamous fish study, resveratrol extended lifespan in a dose-dependent manner. Hopefully someone with more intimate knowledge of the research will chime in with details and citations.

[VP.]

xanadu says

There is no evidence I'm aware of that shows smaller amounts of resveratrol do not have these same benefits and that you need the huge amounts used in the mice trials

The first vertebrate study shows dose does matter, a great deal. http://www.life-enha...int.asp?ID=1685

Using 157 turquoise killifish bred by an Italian drug development company, Lay Line Genomics (which funded the study and which holds the rights for commercial exploitation of this aging model), the researchers conducted experiments on the antiaging effects of resveratrol.3 Beginning when the fish reached sexual maturity at 4 weeks of age, the researchers gave them food (bloodworm larvae—yum!) that was supplemented with resveratrol at three different concentrations: 24, 120, and 600 micrograms of resveratrol per gram of food.* (A fourth group, the controls, received no resveratrol.) The fish were given defined amounts of food twice daily so that their resveratrol intake could be accurately known.
*One microgram per gram of food is equal to one milligram per kilogram of food. Thus, assuming an average daily intake of 0.5 kg (1.1 lb) of food for humans, these fish doses would correspond to daily resveratrol intakes of 12, 60, and 300 mg, respectively, for humans.
The results were astonishing: whereas all the control fish died by 12 weeks of age (as did the fish receiving the lowest dose of resveratrol), the fish receiving the two higher doses of resveratrol lived much longer. In the fish receiving 120 mcg/g of food, the median lifespan increased by 33%, and the maximum lifespan increased by 27%. In the fish receiving 600 mcg/g of food, the median and maximum lifespans increased by 56% and 59%, respectively.
Life extension occurred equally in both sexes and was not linked to a loss of fertility: at 12 weeks of age, when all the controls were dead, the resveratrol-fed females continued to lay eggs, and the resveratrol-fed males were still able to fertilize them. Furthermore, the eggs hatched normally, and the fry developed into normal adults.

From the N. Wade article in the NYT: http://www.imminst.o...=6&t=13062&st=0

One person who is not following this prudent advice, however, is Dr. Sinclair, the chief author of the study. He has long been taking resveratrol, though at a dose of only five milligrams per kilogram. Mice given that amount in a second feeding trial have shown similar, but less pronounced, results as those on the 24-milligram-a-day dose, he said.

For mice at least, 24 mg/kg is better than 5 mg/kg. How much better? We will find out sometime next year.