LONGECITY

... (snip)

A 15% extension from two additions, that on their own, did not extend life.

To me, this outcome seems remarkable.

If it's for real, and not a statistical fluke or the result of letting the animals tolerate poor husbandry, it will be. As I said, I'd like to see further investigation.

-Michael
...(snip)

I quite agree. The paper was frustratingly inconclusive for many reasons. Further investigation is needed.

Krillin, I don't know how we missed this after all of our resveratrol bioavailability hacking, but glycerol is a good solvent for resveratrol, is pretty cheap and essentially nontoxic. It might be a terrific way to take resveratrol. In Sale's study, as you noted here and I noted here, they got the same Cmax/mg/kg with glycerol in mice as Marier's rats using cyclodextrin. Is glycerol the poor man's cyclodextrin? It should function as a solvent/antisolvent micronization scheme like ethanol, I'd think.

They actually used glycerol formal (product mixture from reaction of glycerol and formaldehyde). Straight glycerol is so sticky and viscous that I wouldn't enjoy trying to drink it, and diluting it might cause the resveratrol to drop out of solution. So I agree it might be a good ethanol substitute.

Well holy crap. I took "formal" to be a weird reference to concentration. British Journals and all... Oh well. Learn something new every day, don't you? So "glycerol formal" is available, but the tox properties of mixed polyethers undoubtedly contaminated with formaldehyde render it less interesting. Back to HPMC it is.

Niner,

Would you consider t-res in water with a small pinch of HPMC a "formulated" version or not?

Yes, it's a formulation. How well it works is going to depend on the particle size of the resveratrol, the smaller the better. Hedgehog advocated using only a small amount of HPMC, but I don't know if the exact ratio has been optimized or not. I would say that water/res/HPMC would perform somewhere between the high-end formulations like SRT501 and just plain resveratrol. Exactly where it falls on that continuum would depend on particle size. It should never be as bad as plain res or as good as SRT501.

Krillin, I don't know how we missed this after all of our resveratrol bioavailability hacking, but glycerol is a good solvent for resveratrol, is pretty cheap and essentially nontoxic. It might be a terrific way to take resveratrol. In Sale's study, as you noted here and I noted here, they got the same Cmax/mg/kg with glycerol in mice as Marier's rats using cyclodextrin. Is glycerol the poor man's cyclodextrin? It should function as a solvent/antisolvent micronization scheme like ethanol, I'd think.

They actually used glycerol formal (product mixture from reaction of glycerol and formaldehyde). Straight glycerol is so sticky and viscous that I wouldn't enjoy trying to drink it, and diluting it might cause the resveratrol to drop out of solution. So I agree it might be a good ethanol substitute.

Well holy crap. I took "formal" to be a weird reference to concentration. British Journals and all... Oh well. Learn something new every day, don't you? So "glycerol formal" is available, but the tox properties of mixed polyethers undoubtedly contaminated with formaldehyde render it less interesting. Back to HPMC it is.

Well I have looked @ glycerol just never bought it. Maybe it would unstack the resv molecules better than HPMC? Again you wouldn't use straight glycerol just a pinch like HPMC. Glycerol is typically used for lotions and I think can cause renal injuries? HPMC is prolly the safest for long term use.

Looking at the graph of net calories consumed by the SD, EOD, EOD High Resveratrol, and EOD Low Resveratrol, I'd have to estimate that the net calorie reduction for EOD Low Resveratrol group as compared to the SD group is, for most of the curve described, i.e., up to about 115 weeks, probably less than 10% on average. My impression is that such a very modest reduction would hardly be sufficient under ordinary calorie restriction to extend life (though I can be corrected on that point certainly). But if you look at the graph showing how many of the various groups survive up to 115 weeks, it's pretty clear that the EOD Low Resveratrol has already significantly differentiated itself from the SD group (only about 55% of the SD group survive at 115 weeks, but about 85% of the EOD Low resveratrol group survive). In fact, the survival rate of the EOD low res group at that stage also pretty well surpasses that of either the EOD or the EOD High res groups, according to the graph.

Now what that says to me is that the life extending benefits of EOD combined with low res have little or nothing to do with any actual change in net consumption of calories, which is minimally different. My expectation is that scientifically that is an important point. I can imagine that there might be models of aging that directly have to do with what happens to the cells and the body when calories are consumed, and not so much to do with genes being activated or inactivated. I'd expect that this experimental result shows pretty well that aging must involve something other than the direct effects of consuming x number of calories.

All of which suggests to me that CR mimetics should be quite possible. And the hope that such mimetics might induce the good effects of CR without the various downsides -- perhaps even leading to longer, healthier lives -- seems a more reasonable hope after this experiment.

Just to elaborate a bit on what I said in my last post, I think what we can say is that if EOD without any appreciable net reduction in calories were to extend life, then we might say EOD itself is a "CR-mimetic": it's fooling the body into thinking that it has fewer calories, but not actually reducing the net number of calories. This is likewise true if one says that about EOD plus low resveratrol.

And if EOD can so fool the body, there's no obvious reason to believe that other techniques -- quite possibly including some kind of supplement -- might not do so as well.

Glycerol + Vital Prime resveratrol doesn't work at all. First I tried 500 mg res with a tablespoon of USP glycerol (tried it years ago for hyperhydration). The res didn't want to get wet. So brought the glycerol up to 1/4 cup and eventually got the res trapped inside the glycerol. I wouldn't call it mixed. Then I poured it into about 8 ounces of water and got a lot of resveratrol floaters on the top. It looked a lot worse than HPMC, which doesn't work well with Vital Prime. (My HPMC is amazing with milk thistle, so I know it can work if the particle size is small enough.)

Well its looks like resveratrol is a dud from these studies! Thats unfortunate!

Well its looks like resveratrol is a dud from these studies! Thats unfortunate!

Read the thread again. Some of us think the lab conditions were so poor that none of the mice lived as long as the same strain of mice lived in other studies, even on a standard diet. So poor animal husbandry may have confounded the results, and you can't judge from this single study. But the resverarol group were healthier and more vigorous in age than the non-resveratrol mice on a standard diet. So resveratrol may at least alleviate the rigors of aging, o, as seems more likely to me, may result in some degree of life extension, though it was masked by the poor lab environment in this study.

Does resvertrol decrease the body temperature in rodents? There was one study the other year showed that just loweing the body temperature of mice by half a degree and they lived longer. I don't actually have the study but only seen the news reports. Apparently when you increase a rodents body temperature when they're on CR, they have less protection against cancer and don't live as long.
http://www.livescien..._cool_mice.html

Does resvertrol decrease the body temperature in rodents? There was one study the other year showed that just loweing the body temperature of mice by half a degree and they lived longer. I don't actually have the study but only seen the news reports. Apparently when you increase a rodents body temperature when they're on CR, they have less protection against cancer and don't live as long.
http://www.livescien..._cool_mice.html

My recollection is that it hasn't been shown to do so. I've not noticed a drop in my body temperature since supplementing with it, but then I've not been looking for it.

You cannot translate results regarding resveratrol or CR alone to this strain of mice, nor extrapolate to humans. But the two together did extend lifespan, somehow overcoming the genetic defect in this strain that prevents CR from working. And there was an increase in health.

When a compound is a failure in mice during pharmacuetical testing, typically that compound is dropped and not brought to human trials. The reaon mice are used by everyone from Glaxo Smith Kline to the M Prize is because their biology reacts similiarly enough to humans that they have become the gold standard. Now maybe, there is a more promising effect in humans, but because our biology is more complex I certainly wouldn't bet on it.

The statements you have listed indicate that CR plus resveratrol equals some life extension, but resveratrol has been touted precisely because it was suppose to be an alternative to CR, not an addendum.

Why don't they use Chimpanzees? They're the closest living evolutionary relatives to humans; wouldn't we get better results from them?
Edited by Michael, 05 December 2009 - 12:36 PM.
Trim quotes

Why don't they use Chimpanzees? They're the closest living evolutionary relatives to humans; wouldn't we get better results from them?

Chimps are very expensive, for one thing. For another, they live a long time, so looking at survival is much harder.

Why don't they use Chimpanzees? They're the closest living evolutionary relatives to humans; wouldn't we get better results from them?

Chimps are very expensive, for one thing. For another, they live a long time, so looking at survival is much harder.

Even though they live long we could still see what effects resveratrol has on their biology. Scientists have been using rhesus monkeys for almost 20 years for CR experiments they could have done the same with resveratrol; but now that you mention they're very expensive I can see why they haven't been used.

I had a premonition that we're not going to see anymore spectacular lab results from Sirtris's SRT501 now that it belongs to GlaxoSmithKline. No surprise to me the lab results from Sinclair's SRT501 shows no improvement in healthy middle age mice survival. Sirtris initially had a good idea like the rest of us, that's to cure everybody of all their ailment. Woundn't that be great? If living longer and healthier is the side effect of SRT501 then that would be the added bonus for all of us!

All those spectacular press releases from Sinclair about Resvertrol extending live from all species before the Glaxo buy out. Now after the buy out, you hear well it doesn't seems to extend live for healthy mice after all. It makes you wonder why did Sinclair do his earlier research base on fat mice instead of normal mice?

Sinclair was idealistic but now he and the rest of Sirtris are getting a lesson from Glaxo on pharma business 101. Producing one single drug to "manage or treat never cure" multiple problems will kill your other markets. Not to mention it will be competing with some of its own existing pipline. What better way for Galxo to get rid of their competitor then to buy them out.

What will end up happening is SRT501 will be used for treating not curing 1 or 2 diseases while other spin off new drugs developed from this technology will treat other specific diseases.

Drug patents only last for 20 years before generic are allow to copy and made it worthless and cheap like aspirin.

Does resvertrol decrease the body temperature in rodents? There was one study the other year showed that just loweing the body temperature of mice by half a degree and they lived longer. I don't actually have the study but only seen the news reports. Apparently when you increase a rodents body temperature when they're on CR, they have less protection against cancer and don't live as long.
http://www.livescien..._cool_mice.html

My recollection is that it hasn't been shown to do so. I've not noticed a drop in my body temperature since supplementing with it, but then I've not been looking for it.

I have not taken my temperature to compare either, but for some reason, now that the cold has set in (Minnesota), I have noticed that I seem a bit more susceptible to it this year. I started resveratrol early in the summer. It could just be my imagination, or it could just be due to a nice, long, moderate fall and then a quick change to cold weather and I haven't adjusted yet.

I would be interested in whether any of the human/rat studies monitored temperature, however.

David

I have not taken my temperature to compare either, but for some reason, now that the cold has set in (Minnesota), I have noticed that I seem a bit more susceptible to it this year. I started resveratrol early in the summer. It could just be my imagination, or it could just be due to a nice, long, moderate fall and then a quick change to cold weather and I haven't adjusted yet.

I would be interested in whether any of the human/rat studies monitored temperature, however.

David

Actually, according to this paper PMID: 17112576 , resveratrol made mice significantly resistant to cold, but that was on a 400mg/kg dosage. Different dosage levels might have slightly different effects.

Heres a new study below. It's interesting that when you raise the temperature of calorie restricted mice they are less resistant to cancer. Could this be one the reasons as I mentioned a few months ago of resveratrol failure to extend lifespan significantly?

FASEB J. 2008 Dec 4.
Resveratrol treatment in mice does not elicit the bradycardia and hypothermia associated with calorie restriction.
Mayers JR, Iliff BW, Swoap SJ.

*Department of Biology, Williams College, Williamstown, Massachusetts, USA.

Dietary supplementation with resveratrol may produce calorie restriction-like effects on metabolic and longevity endpoints in mice. In this study, we sought to determine whether resveratrol treatment elicited other hallmark changes associated with calorie restriction, namely bradycardia and decreased body temperature. We found that during short-term treatment, wild-type mice on a calorie-restricted diet experienced significant decreases in both heart rate and body temperature after only 1 day whereas those receiving resveratrol exhibited no such change after 1 wk. We also used ob/ob mice to study the effects of long-term treatment because previous studies had indicated the therapeutic value of resveratrol against the linked morbidities of obesity and diabetes. After 12 wk, resveratrol treatment had produced no changes in either heart rate or body temperature. Strikingly, and in contrast to previous findings, we found that resveratrol-treated mice had significantly reduced endurance in a treadmill test. Quantitative reverse transcriptase-polymerase chain reaction suggested that a proposed target of resveratrol, Sirt1, was activated in resveratrol-treated ob/ob mice. Thus, we conclude that the bradycardia and hypothermia associated with calorie restriction occur through mechanisms unaffected by the actions of resveratrol and that further studies are needed to examine the differential effects of resveratrol in a leptin-deficient background.-Mayers, J. R., Iliff, B. W., Swoap, S. J. Resveratrol treatment in mice does not elicit the bradycardia and hypothermia associated with calorie restriction.
Edited by Matt, 07 December 2008 - 04:56 PM.

I saw this abstract as well. Unfortunately, until the whole study is published, we won't know any of the details like the doseage they used, etc......

Heres a new study below. It's interesting that when you raise the temperature of calorie restricted mice they are less resistant to cancer. Could this be one the reasons as I mentioned a few months ago of resveratrol failure to extend lifespan significantly?

FASEB J. 2008 Dec 4.
Resveratrol treatment in mice does not elicit the bradycardia and hypothermia associated with calorie restriction.
Mayers JR, Iliff BW, Swoap SJ.

Edited by Michael, 25 November 2009 - 11:09 PM.
Trim quote

Yeah, those ob/ob mice are genetically altered to have impaired metabolism so they are obese. This is different from mice that are simply over fed till they are fat. So the results are not for a wildtype, typical mouse - if the systems resveratrol activated Sirt1 is trying to upregulate are completely shot to heck or missing, it isn't going to do much.

You don't want to have to lower your temperature to increase life span if you can help it. Lower temperature means slower chemical reactions, including slower rate of heart pace maker cells, hence the bradycardia. But, it also can mean slower cognition and reaction times, lower energy, etc etc. Sure, you might increase your natural life span, but at a potentially great cost to quality of life.

Resveratrol affects mainly just one part of the aging system, a very big part, but still only one. The more complex the organism, the less likely mitigating only one aging pathway is going to greatly increase life span, hence why yeast gain the greatest life span boost from resveratrol and mice much less (though span boost has been seen in several studies in normal mice). Telomeres and defunct mitochondria also have to be repaired, and cancer warded off, if you want to significantly increase life span in a higher vertebrate.

Heres a new study below. It's interesting that when you raise the temperature of calorie restricted mice they are less resistant to cancer. Could this be one the reasons as I mentioned a few months ago of resveratrol failure to extend lifespan significantly?

FASEB J. 2008 Dec 4.
Resveratrol treatment in mice does not elicit the bradycardia and hypothermia associated with calorie restriction.
Mayers JR, Iliff BW, Swoap SJ.

... Strikingly, and in contrast to previous findings, we found that resveratrol-treated mice had significantly reduced endurance in a treadmill test. ...

I wonder if these mice were having trouble with their tendons?
Edited by Michael, 25 November 2009 - 11:11 PM.
Trim quote

I saw this abstract as well. Unfortunately, until the whole study is published, we won't know any of the details like the doseage they used, etc......

FASEB J. 2008 Dec 4.
Resveratrol treatment in mice does not elicit the bradycardia and hypothermia associated with calorie restriction.
Mayers JR, Iliff BW, Swoap SJ.

... We found that during short-term treatment, wild-type mice on a calorie-restricted diet experienced significant decreases in both heart rate and body temperature after only 1 day whereas those receiving resveratrol exhibited no such change after 1 wk. We also used ob/ob mice to study the effects of long-term treatment ... After 12 wk, resveratrol treatment had produced no changes in either heart rate or body temperature. Strikingly, and in contrast to previous findings, we found that resveratrol-treated mice had significantly reduced endurance in a treadmill test. ...

cut&paste from the study. A late reaction, but found your remark just now while re-reading some posts.

The heart rate, body temperature, and activity levels of wild-type mice were analyzed over a 1 wk period of CR treatment (CR group), resveratrol treatment (RSV group), and ad libitum feeding of standard chow (control group). The diet supplemented with 0.1% resveratrol resulted in an average dose of 87 mg resveratrol kg bw 1 day 1.

The distance run by the resveratrol-treated animals, however, decreased. The actual difference in the distance run by the groups was dramatic, with the ObC (standard diet) group running more than 5 as far as the ObR (resveratrol diet) group (Fig. 3C).

In addition, a treadmill test revealed that resveratrol negatively affected the endurance of ob/ob mice over a 12-wk course of treatment.

Given previous reports describing the beneficial effect of resveratrol on endurance in mice fed a high-fat diet (30), we were surprised to find that the ObR mice performed more than 5-fold worse than ObC mice in a treadmill endurance test

Edited by Michael, 25 November 2009 - 11:14 PM.

The paper in the above post does appear to contradict the reported endurance gains seen in Sinclair's and Auwerx' studies. However Auwerx paper noted that the mice exhiited less spontaneous activity, and their activity level was lower than the controls. In the video I've seen of Sinclair's mice, it appeared the mice were forced to exercise to exhaustion; perhaps the treadmill setup in Mayers' study permitted the mice to poop out without penalty, so it appeared they had less endurance?

Reports by our athletic human rodents indicates greater stamina. Has anyone who is not motivated to exercise noticed a decrease in the desire to workout or engage is strenuous activity?

The paper in the above post does appear to contradict the reported endurance gains seen in Sinclair's and Auwerx' studies. However Auwerx paper noted that the mice exhiited less spontaneous activity, and their activity level was lower than the controls. In the video I've seen of Sinclair's mice, it appeared the mice were forced to exercise to exhaustion; perhaps the treadmill setup in Mayers' study permitted the mice to poop out without penalty, so it appeared they had less endurance?

Reports by our athletic human rodents indicates greater stamina. Has anyone who is not motivated to exercise noticed a decrease in the desire to workout or engage is strenuous activity?

How did they force the mice to exhaustion? I cannot find the method in "Resveratrol Improves Mitochondrial Function and Protects against Metabolic Disease by Activating SIRT1 and PGC-1α" and the "Resveratrol improves health and survival of mice on a high-calorie diet" has the following in the method paragarph:

Results shown are the average of three trials per mouse, measuring time to fall from an accelerating rotarod (4–40 r.p.m. over 5 min). Data from animals that survived to 24 months are shown.

There was no treadmill test in there.Maybe the second study is not the one you're refering to?

in the "Resveratrol treatment in mice does not elicit the bradycardia and hypothermia associated with calorie restriction" study the following method was used:

For all trials, the open-ended back of the treadmill was blocked with cardboard. When mice touched the cardboard block, they were prodded with a second piece of cardboard; this served to encourage them to move to the front of the treadmill. For each trial, mice were run until exhausted, with exhaustion being defined as a failure to respond to repeated, firm prodding as well as a reliance on the cardboard support to continue at the set pace. Time to exhaustion and top speed were recorded, and from these numbers total distance was calculated.

[For the rotarod]:

Resveratrol treatment did not affect activity in either the dark or light cycle. As a measure of agility, the mice were subjected to a rotarod test on a gradually accelerating rotarod before resveratrol treatment, and after 3, 6, and 11 wk into the trial. Both ob/ob groups performed significantly inferior to the WTC mice (Fig. 3B). In addition, the average time to fall for the WTC group remained stable over the course of the study—there was no significant change in average fall time between wk 0 and 11. Performance on the rotarod in both ObC and ObR groups significantly diminished over the 12 wk of the study (paired t test, P < 0.05 for both the ObC and ObR groups). This finding is likely the result of the weight gain in these animals (Fig. 2A)

Edited by Michael, 05 December 2009 - 12:40 PM.
Cleanup

see above

I was referring to a video from Dr. Sincair, on U-tube, of two mice on parallel treadmills; I wrongly inferred or implied this was a video from those papers. Perhaps if we attach the treadmills and roto-rods to computer keyboards, and test resveratrol fed mice a million times, they will somehow key in the complete works of Shakespeare amid the random noise? Maybe we should hurry to take resveratrol while it still works? Did a janitor switch cages before the testing? Seriously, contradictory studies occur frequently; eventually they may converge on a repeatable result.

The paper in the above post does appear to contradict the reported endurance gains seen in Sinclair's and Auwerx' studies. However Auwerx paper noted that the mice exhiited less spontaneous activity, and their activity level was lower than the controls. In the video I've seen of Sinclair's mice, it appeared the mice were forced to exercise to exhaustion; perhaps the treadmill setup in Mayers' study permitted the mice to poop out without penalty, so it appeared they had less endurance?

Reports by our athletic human rodents indicates greater stamina. Has anyone who is not motivated to exercise noticed a decrease in the desire to workout or engage is strenuous activity?

There was an electric shock at the end of the treadmill. If they slowed down (therefore reaching the end of the treadmill) their tails were shocked.

The paper in the above post does appear to contradict the reported endurance gains seen in Sinclair's and Auwerx' studies. However Auwerx paper noted that the mice exhiited less spontaneous activity, and their activity level was lower than the controls. In the video I've seen of Sinclair's mice, it appeared the mice were forced to exercise to exhaustion; perhaps the treadmill setup in Mayers' study permitted the mice to poop out without penalty, so it appeared they had less endurance?

Reports by our athletic human rodents indicates greater stamina. Has anyone who is not motivated to exercise noticed a decrease in the desire to workout or engage is strenuous activity?

There was an electric shock at the end of the treadmill. If they slowed down (therefore reaching the end of the treadmill) their tails were shocked.

Was that in the Mayers study? Or something Sinclair or his disciples did?

The paper in the above post does appear to contradict the reported endurance gains seen in Sinclair's and Auwerx' studies. However Auwerx paper noted that the mice exhiited less spontaneous activity, and their activity level was lower than the controls. In the video I've seen of Sinclair's mice, it appeared the mice were forced to exercise to exhaustion; perhaps the treadmill setup in Mayers' study permitted the mice to poop out without penalty, so it appeared they had less endurance?

Reports by our athletic human rodents indicates greater stamina. Has anyone who is not motivated to exercise noticed a decrease in the desire to workout or engage is strenuous activity?

Resveratrol enhances the desire and ablity to exercise in my case. On workout days I time my ingestion to coincide with peak levels (approx 1 hour) and the onset of an hour long workout, hopefully this enhances Resveratrols action and absorption into cells. Resveratrol and exercise are very compatible in that stamina, as well as muscle tonus is markedly increased. I wouldnt go so far as to say that it b uilds muscle, but I would say that it helps maintain what a regular weight-lifter has built already, it does seem to increase vascularity, enhanced blood flow to muscles encourages tissue maintenence.

see above

I was referring to a video from Dr. Sincair, on U-tube, of two mice on parallel treadmills; I wrongly inferred or implied this was a video from those papers. Perhaps if we attach the treadmills and roto-rods to computer keyboards, and test resveratrol fed mice a million times, they will somehow key in the complete works of Shakespeare amid the random noise? Maybe we should hurry to take resveratrol while it still works? Did a janitor switch cages before the testing? Seriously, contradictory studies occur frequently; eventually they may converge on a repeatable result.

I know the video. I'm just curious in which study they used this method. I cannot find it in the method paragraph so that's strange.

see above

I was referring to a video from Dr. Sincair, on U-tube, of two mice on parallel treadmills; I wrongly inferred or implied this was a video from those papers. Perhaps if we attach the treadmills and roto-rods to computer keyboards, and test resveratrol fed mice a million times, they will somehow key in the complete works of Shakespeare amid the random noise? Maybe we should hurry to take resveratrol while it still works? Did a janitor switch cages before the testing? Seriously, contradictory studies occur frequently; eventually they may converge on a repeatable result.

I know the video. I'm just curious in which study they used this method. I cannot find it in the method paragraph so that's strange.

Is this the video? They refernce the electrical shock:
http://link.brightco...bctid=317939070