28 replies to this topic

[lucid]

Are there studies that find a point of diminishing returns for resveratrol effectiveness, particularly in activating the sirituins? Particularly I wonder if it is possible to activate the sirituins to a higher degree than is done via CR?

[maxwatt]

I am only aware of a linear dose-response effect. Rats show toxic effects at a dose that is the human-scaled equivalent of something like over 7 grams a day,

[Anthony_Loera]

In the conclusions section of the paper entitled "Therapeutic potential of resveratrol: the in vivo evidence" written by Joseph A Baur and David Sinclair... Sinclair states the following...

"Conclusions
In mammals, there is growing evidence that resveratrol
can prevent or delay the onset of cancer, heart disease,
ischaemic and chemically induced injuries, diabetes,
pathological inflammation and viral infection. These
effects are observed despite extremely low bioavailability
and rapid clearance from the circulation. Administering
higher doses to improve efficacy might not be possible
as toxic effects have been observed at or above 1 g per kg
(body weight)147. Moreover, administering a daily dose
to a human weighing 75 kg with 100 mg per kg (body
weight) of resveratrol would require 2.7 kg of resveratrol
a year, at a current cost of about US$6,800. Therefore,
blocking the metabolism of resveratrol, developing
analogues with improved bioavailability, or finding
new, more potent compounds that mimic its effects will
become increasingly important."

The dosage he states is interesting. In my mind I believe he is stating that the cost of rsv at a dose of about 45mg for each pound of body weight may prevent folks from taking advantage of this.

What do you take from this?

Anthony Loera

[inawe]

Another question: If Sinclair thinks 100 mg/Kg is a good daily dose, why did he state somewhere else that he's taking 5mg/Kg a day?

[Anthony_Loera]

Price? I am not sure... I just read the paper published in Nature, and posted this piece here.

Why would he price it out in his paper like he did? Might have this been done to help investors who were considering Sirtris at the time?

not sure.

A

[inawe]

You are not suggesting that Sirtris finances are coloring his scientific advice, are you?

[Anthony_Loera]

No... I believe it was simply a message about resveratrol and the average person's access to it. (or rather how the resveratrol price may be a bit too high to add it to folks daily intake at 100mg a kilo of weight.)

I am not sure I usually see the economic side of it in a study, so it was interesting he would point this aspect out.

A

[niner]

In the pharmaceutical field, cost gets mentioned in some scientific papers. It's a legitimate concern, especially if the target population is poor. (Tropical medicine agents, AIDS drugs for the third world, etc) However, $6800/year is not that far out of line compared to a lot of common medicines where a patient cost near $3000/year is not particularly unusual. Considering that and the conflict of interest inherent in Sinclair being a principal at a drug startup whose sole product involves altering that price point, I agree with Anthony that the comment is a bit, um, fishy.

[lucid]

The dosage he states is interesting. In my mind I believe he is stating that the cost of rsv at a dose of about 45mg for each pound of body weight may prevent folks from taking advantage of this.

What do you take from this?

Anthony Loera

Well first of all he states that a 75kg human would require 2,700g of resveratrol a year. That is 7.4g per day, which is more than anyone on the forum takes that I am aware of and is at the toxic limit according to Maxwatt's post. (Which also makes me wonder what were the toxic symptoms displayed, tommorow when I'm not doing anything i may find which paper it is in to look it up.)

I am only aware of a linear dose-response effect. Rats show toxic effects at a dose that is the human-scaled equivalent of something like over 7 grams a day.

Well if we know the the best dose is under 7g then how close is it to 7g? I also wonder if dosage is taken in multiple times through out the day to maintain some 'optimium blood serum level', then what sort of sirtuin activation we can get. All of this begs the question whether more sirtuins yield more life-extension...? Perhaps even longer lifespan increases can be seen through pill induced sirtuin activation compared to CR alone... (even though data I have seen shows true CR to slightly better Resveratrol).

[maxwatt]

The 7 gram/day maximum dose I've mentioned allows a margin of error. It is based on the toxicology studies where 1000 mg/kg/day in rats caused kidney lesions, dehydration. At a five-to-one scaling factor (which is based on mass to surface ratios, not mass alone) that would be 200 mg/kg in a human. Cut that to 100 mg/kg for a safety factor. A 75 kg man could reasonably assume 7.5 grams a day is an upper limit to safe dosing.

Caveat: the study (referenced in the infinite resveratrol thread of 500 mg a day) studied rats at 1000 and 3000 mg/kg daily, and I think at 300 mg (not sure). No problems noted at lowest dose, 1000 mg showed mild kidney problems, 3000mg/kg daily more severe lesions and symptoms. All symptoms cleared up on cessation of dosing, except in the rodents that died (from other causes? Administration was by gavage.)

We know from the Auwerx's study that 400 mg/kg a day was safe for rats.

I believe Sinclair's $6800/kg cost refers to Sigma/Aldrich's catalog price for synthetic. An Indian manufacturer sells it for less than a third of that price. Plant extracts are cheaper still.

As far as I'm aware, the beneficial effects of resveratrol show a linear dose/response relationship up to the levels of toxicity. (I've never taken more than 2 grams a day personally.) A synthetic analog that was more effective at lower doses, with reduced toxicity, should show even more marked benefits than resveratrol

Lucid: (even though data I have seen shows true CR to slightly better Resveratrol).

Metformin shows better than resveratrol too. Combining metformin and resveratrol might switch on the CR genes that resveratrol misses. I think the reason more people are not using metformin is that is is a prescription drug.

[saxiephon]

MAX: You can get metformin from foreign suppliers without a prescription. I take 800mg each morning and get it from:

http://www.antiaging...z/metformin.htm

[Anthony_Loera]

Lucid,

the conclusions on the paper surprised me as well. I believe the conclusions that will be done using the latest Sirtris formulation on humans will likely lower the intake mentioned in this initial review by Sinclair.

I have not taken more than 2 grams a day as well. Having said that, I was told by our research consultant (PHD in experimental pathology from UCLA) who is looking through all the research papers that were quoted in David Sinclair's review. He mentioned that he is seeing research that leads him to believe that 'on the surface' it appears that different levels of resveratrol may work better for different diseases, he thinks that is throwing a wrench into finding the 'perfect' amount to take for the average person.

I asked about quality, and he said it was possible that the quality of rsv may have played a role in some of the studies, and the different levels of rsv. But that regardless of this unknown factor (rsv quality), the many positive outcomes in the research that has been done with resveratrol is amazing, as the molecule appears to work on many different systems of the body without many of our current pharmaceutical drug side effects.



Anthony

[maxwatt]

MAX: You can get metformin from foreign suppliers without a prescription. I take 800mg each morning and get it from:

http://www.antiaging...z/metformin.htm

Not the cheapest way to obtain it, but perhaps the most convenient. The terms and conditions require you to provide prescription information in the event customs detains the shipment, and you assume liability. Other vendors will reship if there is a problem.

I do think the barrier is not availability, but the prescription requirement puts many people off. FWIW, There is an herb that has the same effect as metformin, and contains a precursor as the active ingredient.

[health_nutty]

MAX: You can get metformin from foreign suppliers without a prescription. I take 800mg each morning and get it from:

http://www.antiaging...z/metformin.htm

Not the cheapest way to obtain it, but perhaps the most convenient. The terms and conditions require you to provide prescription information in the event customs detains the shipment, and you assume liability. Other vendors will reship if there is a problem.

I do think the barrier is not availability, but the prescription requirement puts many people off. FWIW, There is an herb that has the same effect as metformin, and contains a precursor as the active ingredient.

I don't take anything that requires a prescription. What is this herb you are talking about Max?

[DukeNukem]

>>> I do think the barrier is not availability, but the prescription requirement puts many people off.

I think this is true. Which is why, in my case, I had to do an extra amount of confidence building (through research and testimonials) before I starting taking Metformin (850mg daily) about 16 months ago. I buy mine through Anti-Aging Systems. Not sure if that's the cheapest, but so far I've never had problems ordering from that supplier, and I have bought quite a few things from them, including their Can-C eye drops (I use every night).

[niner]

I don't take anything that requires a prescription.

Health_Nutty, how far do you take this? I'd be dead now if it wasn't for some prescription drugs I had a while back. (Quite a load of them, at that...)

[maxwatt]

I don't take anything that requires a prescription.  What is this herb you are talking about Max?

The herb is Goats rue: the chopped leaf is available, and 12:1 liquid extracts which may be the best we can do. I'd be leery of what you'll find on the web, in that the dose will need to be titrated with every new batch you get. I'm looking for something standardized to the active ingredient, but drawing a blank so far. There is a lot of the herb available in Croatia and in North China; I can have a standardized extract made to order if I want a few hundred kilos. All told, metformin looks like a better bet for personal use. Importing is cheap, and only one shipment in ten gets stopped (if that many.) If you have a prescription, that wouldn't even be a problem.

[lucid]

Not the cheapest way to obtain it, but perhaps the most convenient. The terms and conditions require you to provide prescription information in the event customs detains the shipment, and you assume liability. Other vendors will reship if there is a problem.

I thought they would lock you up if customs searches your shipment and you don't have a prescription? I guess they just confiscate it?

[mike250]

i think they lock you up if its a controlled substance.

[maxwatt]

Not the cheapest way to obtain it, but perhaps the most convenient. The terms and conditions require you to provide prescription information in the event customs detains the shipment, and you assume liability. Other vendors will reship if there is a problem.

I thought they would lock you up if customs searches your shipment and you don't have a prescription? I guess they just confiscate it?

We're not a complete police state yet; just headed that way.

[Anthony_Loera]

I believe Mike is right,

it has to be on the FDA controlled substance list, if it's not, they will treat it like most other shipments, and send it back to the originator if it's not prescribed...

I think thats how that works...

A

[lucid]

I hate to continue off on this tangent, but some drugs sold on Antiaging-systems.com seem to be controlled substances, such as modafinil which is a Schedule IV controlled substance. Those would get you locked up though....

[mike250]

hmm so its not a prescription medicine?

[Anthony_Loera]

modafinil is a controlled substance, its on the FDA list.

A

[tintinet]

I'd be careful with Goat's Rue- check out the overdosage section.

[mike250]

modafinil is a controlled substance, its on the FDA list.

A

interesting. its a prescription medicine down here.

[Anthony_Loera]

there are different types of controlled substances... but its listed here:

http://www.usdoj.gov...scheduling.html

A

[health_nutty]

I don't take anything that requires a prescription.

Health_Nutty, how far do you take this? I'd be dead now if it wasn't for some prescription drugs I had a while back. (Quite a load of them, at that...)

I mis spoke. I don't take any prescription drugs I don't have a 'real' prescription for (which for me has luckily just been the occasional antibiotic and what not). I just don't need the hassle.

[Anthony_Loera]

since we are going off on a tanget...

I had to post this... it's a great cartoon of David:




ok... back to work..
A