31 replies to this topic

[Yushua]

hi
yeah
Im wondering, what makes people talk about RSV so much over here? Been looking for supplements in general (health, exercise and nootropics) for a while, never came across it though (well, probably, but never specificly).
what makes it superior to others?

[unglued]

I think people are excited by the evidence that it made lab mice, among others, live 30% longer (Nature paper in November 2006). It would also fit with the observation that French people, who drink a lot of red wine, live longer than would be expected given the typical French diet.

There's been a lot of press coverage over the past two years; I'm surprised you didn't see any of it.

[nameless]

I think people are excited by the evidence that it made lab mice, among others, live 30% longer (Nature paper in November 2006). It would also fit with the observation that French people, who drink a lot of red wine, live longer than would be expected given the typical French diet.

There's been a lot of press coverage over the past two years; I'm surprised you didn't see any of it.

Except that mice fed a normal diet + resveratrol didn't live any longer than the control mice. And even the ones that were fed the poor diet, lived only 12% longer, not 30% (I think). And there is no evidence that it'll work on humans, and as of yet, not a single human study shows a real benefit.

Some would also say the reason for the French paradox is the fact there is no paradox -- the French diet could be considered healthier than the American diet.

I am surprised at the attention Resveratrol does get in these forums, compared to other supplements. It is possible that it will promote life extension or have some benefits in people, but as of yet, there is no real proof.

[Anthony_Loera]

I think the attention started after a few posts (see the pinned posts at the top of the forum) started getting a large amount of views.

The interest is there, and with the large amount of information that this forum has collected over time, it appears to be one of the few places to search for new information.

Resveratrol appears to have a large amount of effects on various systems, from possible cardio benefits, to increased endurance, and possible benefits regarding certain issues. I would say, do a search for a particular discussion. However, the information is getting a bit lost in the amount of posts that are compiled here.

A

[kai73]

There is no study on humans showing any benefit from taking resveratrol.
There is no study on animals fed with a normal diet showing any benefit from taking resveratrol.

There are some studies where animals fed with a shitty diet which were given (directly in blood) constantly huge amount of resveratrol lived 15-30% longer than rats just with shitty diet.
Note that in these studies:
- resveratrol was given directly in blood constantly (by eating it a human takes only 10% and even that 10% has a half-life of less than 1 hour)
- resveratrol in rats in these studies prevented them to become fat despite bad diet: in human taking resveratrol if they eat a lot they get fat anyway (so a clear proove that even the possible effect in rats with bad diet is not reproduced in men)

There are currently many studies on resveratrol so maybe in future we will know better if it's useful or not for life extension. Unfortunately, as now, there's no clear evidence :(

Edited by kai73, 05 January 2009 - 10:34 AM.

[maxwatt]

There is no study on humans showing any benefit from taking resveratrol.
There is no study on animals fed with a normal diet showing any benefit from taking resveratrol.

There are some studies where animals fed with a shitty diet which were given (directly in blood) constantly huge amount of resveratrol lived 15-30% longer than rats just with shitty diet.
Note that in these studies:
- resveratrol was given directly in blood constantly (by eating it a human takes only 10% and even that 10% has a half-life of less than 1 hour)
- resveratrol in rats in these studies prevented them to become fat despite bad diet: in human taking resveratrol if they eat a lot they get fat anyway (so a clear proove that even the possible effect in rats with bad diet is not reproduced in men)

There are currently many studies on resveratrol so maybe in future we will know better if it's useful or not for life extension. Unfortunately, as now, there's no clear evidence :(

There are many studies in animals showing life-extension and other benefits:

Curr Biol. 2006 Feb 7;16(3):296-300.
Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate.

Valenzano DR, Terzibasi E, Genade T, Cattaneo A, Domenici L, Cellerino A.
Scuola Normale Superiore, 56100 Pisa, Italy.
Resveratrol, a natural phytoalexin found in grapes and red wine, increases longevity in the short-lived invertebrates Caenorhabditis elegans and Drosophila and exerts a variety of biological effects in vertebrates, including protection from ischemia and neurotoxicity. Its effects on vertebrate lifespan were not yet known. The relatively long lifespan of mice, which live at least 2.5 years, is a hurdle for life-long pharmacological trials. Here, the authors used the short-lived seasonal fish Nothobranchius furzeri with a maximum recorded lifespan of 13 weeks in captivity. Short lifespan in this species is not the result of spontaneous or targeted genetic mutations, but a natural trait correlated with the necessity to breed in an ephemeral habitat and tied with accelerated development and expression of ageing biomarkers at a cellular level. Resveratrol was added to the food starting in early adulthood and caused a dose-dependent increase of median and maximum lifespan. In addition, resveratrol delays the age-dependent decay of locomotor activity and cognitive performances and reduces the expression of neurofibrillary degeneration in the brain. These results demonstrate that food supplementation with resveratrol prolongs lifespan and retards the expression of age-dependent traits in a short-lived vertebrate.
PMID: 16461283

Also studies in yeast, worms and flies show life extension.

The rodent studies did not administer resveratrol by gavage or by transfusion, it was in the food, and the "huge" amount was one that is feasible to attain. Your statement on human equivalence is unclear at best.

The rodents on a high fat diet with resveratrol did gain weight but not nearly as much as the high-fat control group. The anecdotal reports in humans have included some cases of weight gain, but not obesity; there are also anecdotal reports of weight loss.

[Crepulance]

Are there any current studies being done now regarding dosing by any labs, that we are currently waiting to hear results on?

Correct me if I'm wrong, but it seems that for many trials, there are people on these boards or elsewhere that dismiss the results due to innacuracies or irregularities with the environment or impurities with the way the tests were conducted, or state of the subjects being tested, etc. It would seem to me that a product with this much heat would have people running duplicate after duplicate after duplicate trials removing any and all negative or intrusive variables, to come up with conclusive, solid data regarding dosages. Is that happening?

Crep

There is no study on humans showing any benefit from taking resveratrol.
There is no study on animals fed with a normal diet showing any benefit from taking resveratrol.

There are some studies where animals fed with a shitty diet which were given (directly in blood) constantly huge amount of resveratrol lived 15-30% longer than rats just with shitty diet.
Note that in these studies:
- resveratrol was given directly in blood constantly (by eating it a human takes only 10% and even that 10% has a half-life of less than 1 hour)
- resveratrol in rats in these studies prevented them to become fat despite bad diet: in human taking resveratrol if they eat a lot they get fat anyway (so a clear proove that even the possible effect in rats with bad diet is not reproduced in men)

There are currently many studies on resveratrol so maybe in future we will know better if it's useful or not for life extension. Unfortunately, as now, there's no clear evidence :(

There are many studies in animals showing life-extension and other benefits:

Curr Biol. 2006 Feb 7;16(3):296-300.
Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate.

Valenzano DR, Terzibasi E, Genade T, Cattaneo A, Domenici L, Cellerino A.
Scuola Normale Superiore, 56100 Pisa, Italy.
Resveratrol, a natural phytoalexin found in grapes and red wine, increases longevity in the short-lived invertebrates Caenorhabditis elegans and Drosophila and exerts a variety of biological effects in vertebrates, including protection from ischemia and neurotoxicity. Its effects on vertebrate lifespan were not yet known. The relatively long lifespan of mice, which live at least 2.5 years, is a hurdle for life-long pharmacological trials. Here, the authors used the short-lived seasonal fish Nothobranchius furzeri with a maximum recorded lifespan of 13 weeks in captivity. Short lifespan in this species is not the result of spontaneous or targeted genetic mutations, but a natural trait correlated with the necessity to breed in an ephemeral habitat and tied with accelerated development and expression of ageing biomarkers at a cellular level. Resveratrol was added to the food starting in early adulthood and caused a dose-dependent increase of median and maximum lifespan. In addition, resveratrol delays the age-dependent decay of locomotor activity and cognitive performances and reduces the expression of neurofibrillary degeneration in the brain. These results demonstrate that food supplementation with resveratrol prolongs lifespan and retards the expression of age-dependent traits in a short-lived vertebrate.
PMID: 16461283

Also studies in yeast, worms and flies show life extension.

The rodent studies did not administer resveratrol by gavage or by transfusion, it was in the food, and the "huge" amount was one that is feasible to attain. Your statement on human equivalence is unclear at best.

The rodents on a high fat diet with resveratrol did gain weight but not nearly as much as the high-fat control group. The anecdotal reports in humans have included some cases of weight gain, but not obesity; there are also anecdotal reports of weight loss.

[Anthony_Loera]

See these trials:
http://clinicaltrial...r="Resveratrol"



A

[kismet]

Maxwatt, thanks to the NIA we will get definitive proof in the coming years but resveratrol still failed in the most important test so far (the only study in healthy rodents!), maybe it was because of the study design as you imply or maybe not. Interestingly the intermittent feeding (IF) + low dose resveratrol group showed mild life extension,  what is your current take on it? Was this a result of chance?

The NIA, though, will also give the resv in food, up to 1200 ppm. What is your opinion? Are such tests bound to fail? I don't see why, it should be stable in the food and the animal's consumption can be easily tracked, no?

Edited by kismet, 05 January 2009 - 07:19 PM.

[Ringostarr]

What other supplement in the history of mankind can produce these results (see below)? Step back a momement and THINK about it.

From the NIH website:
"A major finding of the study reported today is that resveratrol prevented age-related and obesity-related cardiovascular functional decline in the mice as determined by several parameters. Total cholesterol was significantly reduced in 22-month-old non-obese mice after 10 months of resveratrol treatment, although triglyceride levels had only a slight, non-significant trend toward a decrease. Further, the aortas of 18-month-old obese and non-obese mice treated with resveratrol functioned significantly better than untreated mice. Resveratrol also moderated inflammation in the heart.

In addition to cardiovascular function, the scientists found resveratrol to have a variety of positive effects on other age-related problems in mice:

• Treated mice tended to have better bone health, as measured by thickness, volume, mineral content and density, and bending stiffness compared to the non-treated control group.
• At 30 months of age, resveratrol-treated mice were found to have reduced cataract formation, a condition found to increase with age in control-group mice.
• Resveratrol enhanced balance and motor coordination in aged animals. Scientists found significant improvement in performance at 21 and 24 months versus 15 months in the resveratrol-treated mice but not in the untreated mice.
• Resveratrol partially mimicked the effects of dietary restriction on the gene expression profiles of liver, skeletal muscle and adipose (fatty) tissue in mice."

[nameless]

The problem with saying resveratrol is responsible for so many health benefits is: the human studies are still ongoing. We don't know anything for sure yet. And although it is very tempting to extrapolate rodent health benefits to humans, we really shouldn't do that. And as for life extension, there is no evidence it will do much at all for rodents (or people) eating a healthy diet.

As for the health benefits listed above, Vitamin D + K2 may have much greater benefits (especially in regard to heart and bone health), than resveratrol will. At least there are human studies on D + K2.

But we shall see. Again, what I find strange is how much attention resveratrol has gotten, and how many people here take it in large doses, without any human studies to back it up. This is a fantastic site full of people who usually rely on scientific evidence for any supplements they take, but many seem to be gambling based on several rodent studies with so-so results. I hope resveratrol does show health benefits in people, and if it's does, I'll take it too. But it's premature to think otherwise at this point.

[kismet]

The problem with saying resveratrol is responsible for so many health benefits is: the human studies are still ongoing. We don't know anything for sure yet. And although it is very tempting to extrapolate rodent health benefits to humans, we really shouldn't do that. And as for life extension, there is no evidence it will do much at all for rodents (or people) eating a healthy diet.

What I really hate is that it was marketed and hailed as the next big thing, a CR-mimetic, a true life-extension drug, but so far failed in rigorous tests. So I want you guys to chime in on the NIA's intervention testing program and tell me what you think about their dosing regimens in mice:
Resveratrol 300 ppm 12 months (Age at treatment initiation)
Resveratrol 1200 ppm 12 months
Resveratrol 300 ppm 4 months

As for the health benefits listed above, Vitamin D + K2 may have much greater benefits (especially in regard to heart and bone health), than resveratrol will. At least there are human studies on D + K2.

Or green tea and cocoa, optimal nutrition + blood testing and CR just to name a few interventions I believe to produce much more or equally impressive results (so far).  I am not disputing the many positive effects of resveratrol, though.

But we shall see. Again, what I find strange is how much attention resveratrol has gotten, and how many people here take it in large doses, without any human studies to back it up. This is a fantastic site full of people who usually rely on scientific evidence for any supplements they take, but many seem to be gambling based on several rodent studies with so-so results. I hope resveratrol does show health benefits in people, and if it's does, I'll take it too. But it's premature to think otherwise at this point.

But megadosing is cool! That is the name of the game on imminst anyway. Although someone needs to play guinea pig one day, so depending on your assessment of the risks you may volunteer to be the first even as a life extensionist.

Edited by kismet, 05 January 2009 - 07:23 PM.

[Ringostarr]

The problem with saying resveratrol is responsible for so many health benefits is: the human studies are still ongoing. We don't know anything for sure yet. And although it is very tempting to extrapolate rodent health benefits to humans, we really shouldn't do that. And as for life extension, there is no evidence it will do much at all for rodents (or people) eating a healthy diet.

As for the health benefits listed above, Vitamin D + K2 may have much greater benefits (especially in regard to heart and bone health), than resveratrol will. At least there are human studies on D + K2.

But we shall see. Again, what I find strange is how much attention resveratrol has gotten, and how many people here take it in large doses, without any human studies to back it up. This is a fantastic site full of people who usually rely on scientific evidence for any supplements they take, but many seem to be gambling based on several rodent studies with so-so results. I hope resveratrol does show health benefits in people, and if it's does, I'll take it too. But it's premature to think otherwise at this point.

"so so results"? These results are fantastic. Granted they are in mice but keep in mind that from an evolutionay standpoint mice and humans are extremely close. Also keep in mind that resveratrol did extend the life of rodents on a poor diet and Many westerners eat a poor diet - and that is not changing anytime soon. Also keep in mind that mice typically do not die of heart disease, alzheimers disease, diabetes complications, or the normal types of cancers found in humans (i.e. the type of diseases that resveratrol combats). The poor diet induced these diseases in the rats and resveratrol did in fact work. I agree the jury is still out for humans and as such I do not take more than a gram per day but, from a big picture perspective, I can connect the dots - there is something vey beneficial to sirtuin activiation and resveratrol activiates at least sirtuins one and seven.

[maxwatt]

Maxwatt, thanks to the NIA we will get definitive proof in the coming years but resveratrol still failed in the most important test so far (the only study in healthy rodents!), maybe it was because of the study design as you imply or maybe not. Interestingly the intermittent feeding (IF) + low dose resveratrol group showed mild life extension,  what is your current take on it? Was this a result of chance?

The NIA, though, will also give the resv in food, up to 1200 ppm. What is your opinion? Are such tests bound to fail? I don't see why, it should be stable in the food and the animal's consumption can be easily tracked, no?

You are welcome. The rodent study you are referring to, in my opinion is inconclusive one way or another due perhaps to poor lab conditions: sanitation, feed quality or lighting schedule, possible urban air pollution, or many other possible factors as compared to other labs work with similar mice. The strain of mouse used typically lives longer than any did in this study.

I do not have an opinion on the NIA studies without studying the protocols. I hope we can gain some useful knowledge from these studies. I wouldn't say resveratrol failed it's most rigorous test in a scientific sense, only that the results were inconclusive, as they so often are in science

nameless, you asked why do people jump on this with only evidence in mice? It is not without precedent. The same thing happened with r-alpha lipoic acid and acetyl-l-carnatine; many supplement based on a few mice studies and no human studies. At least if it works in mice it is more likely to work in humans than something that works in worms, or some herbs that folk medicine calls a longevity potion. I suppose thatwhen a legitimate life extending supplement comes along, there will be two phases: too soon to tell, then to late for it to do any good for most of us. Some people are cautious, others are willing to take what they see as a slight but acceptable risk. There is plenty of evidence resveratrol improves the health of rodents even on a standard diet even if in the lab conditions it did not translate into an increased life span. If I can die at 95 in vigorous health versus dying at 95 after 10 years incoherent and incontinent in a nursing home, the choice is clear. Sinclair's rodent study in standard diet mice implied such a choice may be possible.

It is obvious resveratrol has received a lot of hype, but mostly deserved IMO, at least compared to other things. Other supplements no doubt are beneficial too. EGCG is one of my favorites. Like resveratrol it shows a SIRT activation. There is some epidemiological evidence in its favor, too. I remember seeing a study showing that Chinese who drank five or more small cups of green tea a day lived on average 10 years longer than those who did not. Silymarin (milk thistle) is another supplement I'd like to see studied. Like resveratrol it shows P53 and SIRT activation, and is the only thing known to restore liver function in cases of Amanita poisoning. Its potential for life extension is completely unexplored.

[Dmitri]

I think people are excited by the evidence that it made lab mice, among others, live 30% longer (Nature paper in November 2006). It would also fit with the observation that French people, who drink a lot of red wine, live longer than would be expected given the typical French diet.

There's been a lot of press coverage over the past two years; I'm surprised you didn't see any of it.

Some scientists believe it might be all the compounds in red wine working synergistically together which produces the health benefits not resveratrol alone. It’s happened with other supplements such as Fiber? People thought fiber alone would prevent disease, but recent studies showed no improvements or reduction levels which lead some to believe it was the fiber and other antioxidants in vegetables, Legumes and whole grains working together to produce the benefits rather than the fiber itself. Do you think the same thing will result from Rsv if disappointing results continue?

[Crepulance]

Anthony, I was meaning more about mouse/longevity trials. Do you have a link to any trials ongoing relating to that?


Crep

See these trials:
http://clinicaltrial...r="Resveratrol"



A

[geddarkstorm]

Wow, I certainly missed all the fun.

Being a scientist, a biologist, myself, it is actually kinda sad to see the misconceptions that go around about studies. You have to understand, for every result that they say is "significant" is because, statistically compared to an identical paired control group, the group on the drug or special condition were two standards of deviation removed in their mean from the mean of the control. The key here is identically paired control group. When you control all other factors, the only factor that you are varying must account for the majority of any significant effects seen, since they are outside of the normal variation range possible for the control. Notice, normal variation range is also a vital key point; natural variation is already accounted for in these studies.

So, what does resveratrol do in mice fed a standard diet? Oh, only doubles the endurance of said mice when fed 400mg/kg, significantly increases artery health, bone density, motor control, motor coordination, metabolic gene transcription and chromosome stability, strength, and a host of other parameters. When feeding only 100mg/kg to mice on an every other day feeding diet, you also get a significant increase in life span. Hmm, there we are on the opposite side of the spectrum from high fat. Even minimal doses of 22mg/kg increase health, life span, and abilities of high fat diet mice to that of standard fed mice. Resveratrol's effects are noticed far more so in the high fat diet mice because there's more to fix in them; you can't get much healthier when you are already healthy!

The French Paradox is a real paradox. Comparing actual values of what's consumed bears that out, and the fact the paradox is reproducible in a western diet by the inclusion of moderate levels of red wine. There's been plenty of studies about that. What is in red wine that could synergistically associate with resveratrol and increase its effect? Quercetin, which has been shown, in vivo, to protect resveratrol from metabolization by the liver, keeping it effective longer. Why do people think scientists narrowed down the good effects of red wine to resveratrol? There was a reason, you know, not random guessing. And quercetin does a lot of stuff too, a lot which synergizes with resveratrol, including stopping adipogenesis, cancer, and acting as anti-virals (anti-biotic in the case of quercetin at least).

About vitamin D: did you know, resveratrol upregulates the vitamin D receptor, increasing its effectiveness? Vitamin D is not magical, heck, it isn't even a vitamin in the strictest sense as our bodies make it. But it is highly important, and it showing wonderful effects could easily be attributed to the fact that in our society now we are probably very likely to have low levels of vitamin D deficiency due to our lack of being in the sun. Not just because we stay inside working, eating, and playing, but because we also wear clothes which blocks our ability to get those wonderful UV rays that are needed for vitamin D production by our bodies (and here we thought UV was all bad). Heck, and we love sun screen too (cause we think UV is all bad). All of these developments are highly new from nature's historical perspective and we are certainly not biologically adjusted for them yet. Still, if someone thinks vitamin D is the most wonderful thing ever, then resveratrol's ability to synergize with it should rise an eyebrow.

Why else do we think resveratrol is so great... because we actually know what it's doing: The activation of Sirt1 in humans. And we know what Sirt1 does, and we now believe that loss of Sirt1 function is a conserved primary mechanism of aging from yeast to humans. It's resveratrol's ability to restore and activate Sirt1 function that gives it the majority of its benefits, which has been shown by making Sirt1 knock out cell lines and lines that lacked the ability for Sirt1 to regulate the PGCalpha promotor, which is the gene specifically that Sirt1 is turning on, once resveratrol turns Sirt1 protein on, which goes on to cause the down stream phenotypical effects associated with resveratrol, and even CR. That's why resveratrol is such a good CR mimic, without all the nasty side effects of starving ones body and cells.

There are no other known chemicals or molecules that can do this (at least that I know of, other than some synthetics based of off resveratrol that are currently being tested, but who knows if they'll work out). Resveratrol effects a fundamental aspect of cellular biology in all eukaryotic organisms so far tested, that's why plants make it to protect themselves in times of stress. It's also what stands it apart from any other supplement out there. It isn't some metabolite or hormone mimic, it isn't unbalancing metabolic pathways, it isn't causing desensitization of the body in the long run, or side effects associated with cellular sensors monitoring pathways strangely out of balance due to supplement affecting metabolic processes and then upregulating the counter processes leading to bad effects in the long term. Resveratrol instead is hitting something so upstream, and so fundamental to the eukaryotic domain of life that has a conserved roll to activate survival pathways, increase mitochondria, cellular health, keep proper gene expression profiles right, and so forth. Why this is important, why cells even need such a boost is due to damage accrued over time which inactivates Sirt1's functions to keep proper gene transcription going - see, resveratrol is, through Sirt1, restoring gene transcription back to what it should be. That's what's so special about it. Instead of artificially boosting something your body already should have enough of, resveratrol is restoring the cells to what they should be, which aging and bad diet have robbed them of. Sirt1 is awesome.

But, at the same time, resveratrol isn't some all wonder drug. Even though it's repairing a major pathway, we are still limited by our genetics. Turning genes back on correctly isn't going to help too much if the genes are improperly mutated, though it's still better than having them misfire. The more complex the multicellular organism, the more one pathway alone isn't going to rid all problems from said organism. Because we have hundreds of cell types, verses worms or yeast, resveratrol shouldn't, it shouldn't, be able to boost our life span as much as in them, based on what Sirt1 does. It's so sad to me that people look at it not boosting mice life expectancy as much as in yeast, and then throwing their hands up and saying it isn't doing anything. Oh no, it's doing a heck of a lot, and gives a lot of other supplements, like vitamin D, a chance to do a lot more than they could otherwise. But we have two other, primary methods of aging to consider that expound heavily when you increase complexity - mitochondrial dysfunction from whence most aging starts, and telomere length. Heck, the length of telomeres may even, some evidence suggests, act like a literal clock in our cells telling them when to start aging on purpose.

In that vein, resveratrol is only part, a major, important part, I think, but still just one part of a whole. It fixes a lot of aging and diet associated declines in health, but it can't fix everything such as mitochondria breaking down, or, especially, telomeres degrading to nothing. And it can't fix your genes.

And of course too much of resveratrol would be bad - it's a physical molecule, and like everything in life, from water to oxygen to fat, too much of it means it'll start interacting with things it wouldn't normally and cause weird reactions, or cause other things to come out of balance, that equals bad.

Well, that's my obligatory 3am rant - and only just my opinions founded on the current facts known to science and known to me, as much as possible.

Edited by geddarkstorm, 06 January 2009 - 09:30 AM.

[maxwatt]

. . .What is in red wine that could synergistically associate with resveratrol and increase its effect? Quercetin, which has been shown, in vivo, to protect resveratrol from metabolization by the liver, keeping it effective longer. Why do people think scientists narrowed down the good effects of red wine to resveratrol? There was a reason, you know, not random guessing. . . .

...also polydatin, to name another

[kismet]

Maxwatt, I have addressed your response (unfortunately I have net yet read the references I provided), read below.

Resveratrol's effects are noticed far more so in the high fat diet mice because there's more to fix in them; you can't get much healthier when you are already healthy!

That is the same way drugs work. They cure or maintain the sick. Unfortunately this is not how true life extension works, because it must either slow down damage accumulation (gerontological approach) or reverse enough of the important damage that accumulated (the elegant engineer's approach). Resveratrol may do neither, but as Maxwatt pointed out we really don't know because of the inconclusive data by Sinclair.
To me absence of evidence is close to evidence of absence in the case of life extension, because I prefer the err on the side of caution and am young enough to wait it out, so I don't have to gamble (that's why I said resveratrol "failed" so far). And I appreciate Michael's arguments, supplements are not harmless so many of them are likely to be a failure in humans as long as they have not been distinctively proven to robustly extend life span in rodents. Yes, mere disease prevention is a failure strictly speaking, because heaps of different supplements can help to square the curve a little.
We will find out very soon to which group resveratrol belongs.

Anthony, I was meaning more about mouse/longevity trials. Do you have a link to any trials ongoing relating to that?

Crep

See these trials:
http://clinicaltrial...r="Resveratrol"


A

I have. The NIA's ITP as I am going to point out the third time - which you have probably missed, Crep - will spend quite a lot of their resources to test resveratrol. See here for more information on the compounds in testing.

 ....
....

I do not have an opinion on the NIA studies without studying the protocols. I hope we can gain some useful knowledge from these studies. I wouldn't say resveratrol failed it's most rigorous test in a scientific sense, only that the results were inconclusive, as they so often are in science

The NIA's protocol is well documented, somwhere, I'll try to find and assemble the important information. So that you or other interested people can give me or more importantly them (the NIA researchers) feedback if you do not want resveratrol to fail yet again because of methodological flaws. Even though personally I'd really want them to exchange one of the three resveratrol groups for metformin..
It seems they are successively testing the cohorts, cohort 1 already finished and was a big failure, Michael provided a very good summary of the program, the substances used and mentions their protocols. You may want to read his post to get an overview of how they treat the animals, I will quote the important parts and papers:
"They are being tested at 3 independent academic and industry centers -- one each at the Jackson Laboratories (TJL -- a nonprofit business which breeds, sells, and studies laboratory mice and related equipment), the University of Michigan (UM -- Richard Miller's biogerontology lab), and one at the University of Texas Health Sciences Center at San Antonio (UT -- the Barshop Institute for Longevity and Aging Services, headed by Arlan Richardson).

Agents are administered, usually in the food or water, to groups of specific pathogen-free male and female ... UM-HET3 mice[,] the progeny of CB6F1 females and C3D2F1 males and are genetically heterogeneous, the equivalent of a large sibship. Each mouse is observed until its natural death or until it becomes so severely ill that survival for more than an additional week seems very unlikely. The design includes sufficient numbers of mice (80 in each treatment group and 170 in the control group) to provide 80 percent power to detect a 10 percent increase in average lifespan.

Each mouse also is evaluated for a small set of age-sensitive traits, such as changes in the immune system, spontaneous activity, and lens turbidity. Mice not enrolled in the longevity study are exposed to each intervention to permit assessment of blood and tissue levels of the agents and to help determine if each agent is having its expected metabolic or physiological effect."

"Their diets, housing, and other laboratory protocols have been very carefully considered, as outlined in the new report (8), and implemented uniformly across the 3 sites.
...
8. Richard A. Miller, David E. Harrison, Clinton M. Astle, Robert A. Floyd, Kevin Flurkey, Kenneth L. Hensley, Martin A. Javors, Christiaan Leeuwenburgh, James F. Nelson, Ennio Ongini, Nancy L. Nadon, Huber R. Warner, Randy Strong.
An Aging Interventions Testing Program: Study Design and Interim Report
Aging Cell (OnlineAccepted Articles)."

To see how the tested substances fared and how they actually handled their mice you may want to read the study I posted in the same thread, which may provide some additional hints.
Aging Cell. 2008 Jul 9. [Epub ahead of print]
Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice.
”a log-rank test showed that both NDGA (p = 0.0006) and aspirin (p = 0.01) led to increased lifespan of male mice. Comparison of the proportion of live mice at the age of 90% mortality was used as a surrogate for measurement of maximum lifespan; neither NDGA (p = 0.12) nor aspirin (p = 0.16) had a significant effect in this test.”

Edited by kismet, 06 January 2009 - 03:47 PM.

[geddarkstorm]

Maxwatt, I have addressed your response (unfortunately I have net yet read the references I provided), read below.

Resveratrol's effects are noticed far more so in the high fat diet mice because there's more to fix in them; you can't get much healthier when you are already healthy!

That is the same way drugs work. They cure or maintain the sick. Unfortunately this is not how true life extension works, because it must either slow down damage accumulation (gerontological approach) or reverse enough of the important damage that accumulated (the elegant engineer's approach). Resveratrol may do neither, but as Maxwatt pointed out we really don't know because of the inconclusive data by Sinclair.
To me absence of evidence is close to evidence of absence in the case of life extension, because I prefer the err on the side of caution and am young enough to wait it out, so I don't have to gamble (that's why I said resveratrol "failed" so far). And I appreciate Michael's arguments, supplements are not harmless so many of them are likely to be a failure in humans as long as they have not been distinctively proven to robustly extend life span in rodents. Yes, mere disease prevention is a failure strictly speaking, because heaps of different supplements can help to square the curve a little.
We will find out very soon to which group resveratrol belongs.

I think you missed some important information. It's known that Sirt1 activation does indeed repair DNA damage. In fact, without Sirt1, you cannot repair double stranded DNA breaks, making an organism absolutely sensitive to radiation. Also, the fact Sirt1 activation by resveratrol has been shown to reverse and resist many degenerative effects again shows its use in life span enhancement. Therefore, Sirt1 activation by resveratrol both resists damage, and reverses damaging genetic regulation changes. So, it does do both approaches. And again, it has significantly increased maximal healthy life span of mice, not just those on high fat diets, but those on every other day feedings too - and increases standard fed mice life spans at some doses, just not significantly (the P value was 0.09 if I remember right, had to be 0.05 to be termed significant). And it increases the absolute life span of yeast, worms, drosophila, and fish.

My point is that no one factor, what so ever, is likely to ever increase maximal life span absolutely, aging is a controlled process by many factors. Resveratrol could certainly add 20 years to your healthy, normal life, but instead of you dying at 70, you die at 90, you're still within the standard population deviations - one cannot know how you would have lived without it. And there's certainly globs of evidence to say you'll live a lot healthier when you're at your end at 90 with it, than you would have been at 70 without. Also, without activating Sirt1 function, it's likely no other potential life span maximum improving drug may work, you need to address all the aging pathways when in such complex organisms as us.

Again, we know the science behind all this, that's where this differs from things like asprin where the method of action is not completely known. Resveratrol, via Sirt1, has been proven and born out in in vivo studies, and so far in human studies inadvertently here, though not well controlled in any sense, there's quite a correlation. Resveratrol has not failed, it's quite remarkable.

[unglued]

Outriderx's one post seems to have spurred a lively discussion. It's interesting how threads mutate somewhat. There are a lot of topics in the Resveratrol forum, and I guess it's very easy to create a new one, so I wonder why, if there was all this pent-up desire for a topic on Contravening Evidence Against Resveratrol and Rebuttals Thereof, someone didn't just start one by that name so it would be easier to find. Strictly speaking, the question was "Why is there so much interest in this one particular supplement?", which is slightly different than "Why is this interest misguided?"

I took Outriderx's question literally and figured someone ought to reply to it, if only as a summary of the 1000-post topics not everyone wants to read through.

Anthony's post #4 raises an interesting point. His theory is that people are interested in resveratrol because of possible cardio benefits, increased endurance, and other positive effects. That may be true of some people, but my sense is that those are more like markers for a lot of us, because it would take decades to do a study on whether it makes humans live longer. Hypothetically, if they found a drug that made mice live much longer and also turned them green, I think people would be looking in the mirror every day and posting excitedly on how green they were turning. Of course, it helps that the markers are ones that are already conventionally accepted as being associated with health and longer life.

Also in response to #4: while some of the activity on the Resveratrol forum may have fed itself because the activity level attracted the attention of existing ImmInst readers, it was the other way around for me. I had never heard of ImmInst before (though I have some interest in life extension), and found the "500 club" topic by doing a Google search on "resveratrol dosage" because I wanted to know the latest thinking on how much I should take. So I discovered ImmInst through the resveratrol forum, not the other way around. I'm probably not the only one.

[kismet]

Unglued, I am not going to address much of your post at the moment, sorry. The data on life span and quality of life may or may not be good or even great for that matter, I am not in a position to judge. However, I've seen significant increases of average life span and/or health span with so many supplements, starting from creatine over to cocoa and no one hails them as a great break-through.
It's just that strictly speaking the jury is out on its ability to extend maximum life span in the healthy (which it was supposed to do), no one would jump straight to releasing a drug or phase III trials from "promising" and "almost significant" results in rodents. However, extension of maximum life span is the very essence of any real anti-aging treatment.
We are taking step by step already, let's not jump to conclusions (early human trials of resveratrol for cancer and NIA's testing is under way).
I am only trying to dampen the hype a little, until we have robust, unbiased results. If you are convinced and don't feel you have enough time to wait it out, go ahead play guinea pig, it's totally fine.

No one factor increases maximal life span? Actually methionine restriction does, calorie restriction (ok this is not really one) and AGE restriction probably do (restriction of one single nutrient/variable). Many mutations do (most importantly those of growth hormone signalling), low GH/IGF-1 levels in rodents work the same way. Mitochondria targeted catalase. So this does not seem to be a valid counter-argument.

Edited by kismet, 06 January 2009 - 09:57 PM.

[maxwatt]

Unglued, I am not going to address much of your post at the moment, sorry. The data on life span and quality of life may or may not be good or even great for that matter, I am not in a position to judge. However, I've seen significant increases of average life span and/or health span with so many supplements, starting from creatine over to cocoa and no one hails them as a great break-through.
It's just that strictly speaking the jury is out on its ability to extend maximum life span in the healthy (which it was supposed to do), no one would jump straight to releasing a drug or phase III trials from "promising" and "almost significant" results in rodents. However, extension of maximum life span is the very essence of any real anti-aging treatment.
We are taking step by step already, let's not jump to conclusions (early human trials of resveratrol for cancer and NIA's testing is under way).
I am only trying to dampen the hype a little, until we have robust, unbiased results. If you are convinced and don't feel you have enough time to wait it out, go ahead play guinea pig, it's totally fine.

No one factor increases maximal life span? Actually methionine restriction does, calorie restriction (ok this is not really one) and AGE restriction probably do (restriction of one single nutrient/variable). Many mutations do (most importantly those of growth hormone signalling), low GH/IGF-1 levels in rodents work the same way. Mitochondria targeted catalase. So this does not seem to be a valid counter-argument.

Calorie restriction did not extend life span in a genetically wild-strain of mouse. So far the data on calorie restriction in humans indicates improved heath, but there is no hard evidence of life-extension in humans for CR at this point, and even mouse data is questionable. Much was made of the revelation by gene array studies that resveratrol does not affect IGF-1 expression, as CR does in rodents, but a recent study found that humans practicing CR also did not show any effect on IGF-1.

AGE restriction would most likely improve health, but I would not expect it to increase maximum life span. Our genetic program for aging probably evolved before we began cooking our food.

It's like doing a jigsaw puzzle, but one where the pieces' shapes are constantly changing.

The most interesting proposal I've heard of is to transfect one's cells with avian mitochondria, but modification of the nucleus would also be needed; mammalian nuclei and avian nuclei interact differently with their respective mitochondria (the nucleus synthesizes different proteins for the mitochondria in birds than in mammals) and the mismatch would prevent avian mitochondria from reproducing in mammalian cells. I suppose it could be packaged as a supplement. Anthony? A German team was actually working on this.

The more I learn, the less I find I truly know.

[geddarkstorm]

Unglued, I am not going to address much of your post at the moment, sorry. The data on life span and quality of life may or may not be good or even great for that matter, I am not in a position to judge. However, I've seen significant increases of average life span and/or health span with so many supplements, starting from creatine over to cocoa and no one hails them as a great break-through.
It's just that strictly speaking the jury is out on its ability to extend maximum life span in the healthy (which it was supposed to do), no one would jump straight to releasing a drug or phase III trials from "promising" and "almost significant" results in rodents. However, extension of maximum life span is the very essence of any real anti-aging treatment.
We are taking step by step already, let's not jump to conclusions (early human trials of resveratrol for cancer and NIA's testing is under way).
I am only trying to dampen the hype a little, until we have robust, unbiased results. If you are convinced and don't feel you have enough time to wait it out, go ahead play guinea pig, it's totally fine.

No one factor increases maximal life span? Actually methionine restriction does, calorie restriction (ok this is not really one) and AGE restriction probably do (restriction of one single nutrient/variable). Many mutations do (most importantly those of growth hormone signalling), low GH/IGF-1 levels in rodents work the same way. Mitochondria targeted catalase. So this does not seem to be a valid counter-argument.

Actually, none of those things are true in the sense we are talking about. See this for the methionine restriction, the only example I could find, and this on calorie restriction in the same model organism.

In both instances we find the same conclusion: the restrictions cause a decrease in growth of the organism, so that these aren't actual restrictions - the amount the rats are taking in per gram of body weight is the same as controls get on the unrestricted diet. The reason they live longer is because they are in a sort of stasis: cells aren't dividing as much, pathways are sluggish, it's as if time has been slowed for them, but this is a bad thing. Impairing growth to prolong life span is unacceptable, and is hardly going to work in a non laboratory setting where diseases and other natural hardships will be able to take advantage of the hampered systems, lowered energy and strength. If you can't ward off pathologies, you can't extend life. So no, starving is not a "single factor that increases [maximal] life span", and it's unlikely to work in the real world or in humans due to the detrimental consequences, though a little bit of restriction can be beneficial by activating, you guessed it, Sirt1.

Catalase overexpression, as you were referring to (see here), requires genetic manipulation, which is not something we can do in ourselves, and cannot be included in all this. I was specifically leaving out genetics, as that plays the biggest role, but is not a "compound" or something you can take, so you cannot use that as a counter. In any case, mitochondrial targeting of catalase or SOD again targets one aspect of the aging model - mitochonrial dysfunction by fighting ROS; though, outside of the laboratory, again, these compounds might actually damage the organism as ROS production is important for immunology - hence why antioxidants have never increased maximal life span in humans, and there's some evidence from meta studies that suggests high levels of antioxidants increase mortality[see here and here]. A better way to go is to upregulate UCPs, which respond only once ROS rises to damaging levels to uncouple mitochondria and attenuate ROS production - Sirt1 activation significantly upregulates UCP3.

Moreover, repairing mitochondria alone isn't likely to increase maximal life span in a complex organism like humans. After all, telomeres are the definite measure of the maximum life span, as once they get low enough, no matter the other conditions in the cell, senescence will ensue from the loss of replicative ability. But even if you elongate telomeres but lose Sirt1, you will age and die as genes become disregulated. Even if you keep telomeres and Sirt1 but lose mitochondria, again aging and death are soon to follow as damage accrues from adherent ROS production. Creatine and cocoa (which has low amounts of resveratrol), obviously do not significantly increase maximal life span, because again, only one pathway at best is being addressed (that isn't to say they aren't good to take though ). So, I'm sorry, but the conclusion still stands as far as I can see, and I could always be wrong about many things , that there is no one factor you can take out there that will increase true maximal life span and health at the same time that we know of. Resveratrol is as close as it gets in a single compound so far as found because of its action to turn on Sirt1, yes for the healthy, and especially those on a bad diet, that's why there's hype about it - not to mention its health boosting effects are profound and are not relying on screwing up or mimicking metabolite levels, or starving yourself. But why not take it in combination with other compounds?

Edited by geddarkstorm, 07 January 2009 - 03:17 AM.

[AgeVivo]

Being a scientist, a biologist, myself, it is actually kinda sad to see the misconceptions

me too, but more about the following misconceptions:

for every result that they say is "significant" is because, statistically compared to an identical paired control group the group on the drug or special condition were two standards of deviation removed in their mean from the mean of the control. The key here is identically paired control group. When you control all other factors

if you are really a scientist you should know that details count in experiments and if conditions are bad (eg MHV virus in the control group but not in the resveratrol group) then interpretations are bad/irrelevant. Appearently they didn't "control all other factors"

Why else do we think resveratrol is so great... because we actually know what it's doing: The activation of Sirt1 in humans. (...) But, at the same time, resveratrol isn't some all wonder drug. (...) In that vein, resveratrol is only part, a major, important part, I think, but still just one part of a whole. It fixes a lot of aging and diet associated declines in health, but it can't fix everything (...) And of course too much of resveratrol would be bad - it's a physical molecule

A mixture of quite not established results with sound moderate thoughts... well, so far i'm not convinced.

[kismet]

In both instances we find the same conclusion: the restrictions cause a decrease in growth of the organism, so that these aren't actual restrictions - the amount the rats are taking in per gram of body weight is the same as controls get on the unrestricted diet. The reason they live longer is because they are in a sort of stasis: cells aren't dividing as much, pathways are sluggish, it's as if time has been slowed for them, but this is a bad thing. Impairing growth to prolong life span is unacceptable, and is hardly going to work in a non laboratory setting where diseases and other natural hardships will be able to take advantage of the hampered systems, lowered energy and strength. If you can't ward off pathologies, you can't extend life. So no, starving is not a "single factor that increases [maximal] life span", and it's unlikely to work in the real world or in humans due to the detrimental consequences, though a little bit of restriction can be beneficial by activating, you guessed it, Sirt1.

In my opinion your rebuttal of methionine restriction is based on semantics. Yes, it is unacceptable for many - because it leads to growth arrest similar to CR, it may or may not be responsible for the many benefits from CR - but methionine most certainly is a single factor necessary for growth (being the start codon of every amino acid it may be an ultimate single regulator of growth and cancer), I feel like it's a perfect example.

Catalase overexpression, as you were referring to (see here), requires genetic manipulation, which is not something we can do in ourselves, and cannot be included in all this. I was specifically leaving out genetics, as that plays the biggest role, but is not a "compound" or something you can take, so you cannot use that as a counter. In any case, mitochondrial targeting of catalase or SOD again targets one aspect of the aging model - mitochonrial dysfunction by fighting ROS; though, outside of the laboratory, again, these compounds might actually damage the organism as ROS production is important for immunology - hence why antioxidants have never increased maximal life span in humans, and there's some evidence from meta studies that suggests high levels of antioxidants increase mortality[see here and here]. A better way to go is to upregulate UCPs, which respond only once ROS rises to damaging levels to uncouple mitochondria and attenuate ROS production - Sirt1 activation significantly upregulates UCP3.

Yes, unfortunately it is a genetic intervention, but I merely used it as an example of a single factor responsible for aging or its prevention. There are so many "single factors" that will (in my opinion at least) most certainly affect maximum life span, because of their countless downstream effects. Mitochondrial aging is one of those. I'm pretty sure the immune system was not affected much or even at all, because the catalase was targeted to mitochondria. Surprisingly you left the biggest weakness of this intervention unattacked: Will it work in humans? Humans are known to have superb antioxidant systems already (longest lived primate, 20 times the life span of mus musculus aka mice...)
Antioxidants as we know them are completely useless in treating human aging.

Moreover, repairing mitochondria alone isn't likely to increase maximal life span in a complex organism like humans. After all, telomeres are the definite measure of the maximum life span, as once they get low enough, no matter the other conditions in the cell, senescence will ensue from the loss of replicative ability. But even if you elongate telomeres but lose Sirt1, you will age and die as genes become disregulated. Even if you keep telomeres and Sirt1 but lose mitochondria, again aging and death are soon to follow as damage accrues from adherent ROS production. Creatine and cocoa (which has low amounts of resveratrol), obviously do not significantly increase maximal life span, because again, only one pathway at best is being addressed (that isn't to say they aren't good to take though ). So, I'm sorry, but the conclusion still stands as far as I can see, and I could always be wrong about many things , that there is no one factor you can take out there that will increase true maximal life span and health at the same time that we know of. Resveratrol is as close as it gets in a single compound so far as found because of its action to turn on Sirt1, yes for the healthy, and especially those on a bad diet, that's why there's hype about it - not to mention its health boosting effects are profound and are not relying on screwing up or mimicking metabolite levels, or starving yourself. But why not take it in combination with other compounds?

I guess you accept that many "single factors/pathways" have downstream effects, but you are of the opinion it still won't be enough if we fix them - and therefeore the downstream problems - in the grand scheme of things?
Telomeres are not yet a big contributor to aging, because they last quite long in vivo. If we can't get our own stemcells to replace the tissue damage, telomeres may be a longterm death-sentence, but we don't need to worry about it now (and there are solutions on the horizon).
Creatine and cocoa do not increase maximum life span? Yes, that is correct, but neither has resveratrol been proven to robustly extend life span in healthy rodents. That is my whole argument. Obviously resveratrol could extend maximum life span, but so far we have no information either way (some positive and some negative so far). Creatine and cocoa were examples of supplements that regularly extend health span and provide a multitude of benefits, which is the only claim that can be backed up for resveratrol so far. I will repeat it once again, we do not have seen robust life extension (max life span) from resveratrol, so we do not know if works!
I've never tried to argue resveratrol's (non life extension) benefits.
I think your argument about "knowing how resveratrol works" is either wrong (I believe our knowledge is quite limited), a red herring (in fact it is never important to understand how a compound works to effectively use it) or at the very least only a weak mechanistic argument in favor of resveratrol. The numbers do not lie: and the numbers tell us we don't know if it extends max. life span.

Even though I still don't buy the resveratrol hype you are trying to sell me, I'm getting more and more interested in it. Maybe the compound merits much more research than I've been willing to spend after the last major study.

You forgot to refute or try to refute AGE-restriction as a single factor, but maxwatt adressed some other interesting points (including AGE restriction):

Calorie restriction did not extend life span in a genetically wild-strain of mouse. So far the data on calorie restriction in humans indicates improved heath, but there is no hard evidence of life-extension in humans for CR at this point, and even mouse data is questionable. Much was made of the revelation by gene array studies that resveratrol does not affect IGF-1 expression, as CR does in rodents, but a recent study found that humans practicing CR also did not show any effect on IGF-1.

Yes, I'm well aware of the data, let me review what I information I've gathered about the wild mice study, but I cannot guarantee it is all correct, since it has been a long time when I looked at the issue (I think some of it is from the paper, a blog and MR - it's always a joy to read his rebuttals), that was my synthesis:
A recent study in wild mice (Idaho mice) by Harper et al found conflicting results (2006). There was no increase in mean longevity, most probably due to increased mortality in early life and a decrease later on, but ‘a maximum likelihood fitted Gompertz mortality model’ indicated a shallower death rate in the CR group. The longest-lived 8.1% (n=6) of the animals were from the CR group and a strong anti-cancer effect was noted. Cr animals weighed 47.6% (!!) of AL animals, among the CR animals those with even lower weight died earlier. Corticosterone was higher, T was lower. Mean and average life span did not differ significantly. Yet the maximum life span was increased by 14% (1403 vs 1601d)
Explanations include that Idaho wild mice have already low IGF-1 levels and growth hormone receptor mice do not exhibit increased life spans due to CR (ok, this is not entirely true).
That wild mice eat already 20% less on a weight-adjusted AL basis than inbred lab mice and thus the imposed CR regimen was too severe (0.8*0.6 [0.6 amount of food] = 0.48% calories, similar to the weight they achieved).

In fact I'm of the opinion that the igf-1 issue with human CR may be much more of a problem.

AGE restriction would most likely improve health, but I would not expect it to increase maximum life span. Our genetic program for aging probably evolved before we began cooking our food.
AGE restriction to me is yet another "single factor" modulating many or even most downstream effects of aging.

So you think restriction of exogenous AGEs won't be enough, contrary to the mouse data presented? Glycation damage certainly is a great problem of aging, just how much we can influence it by diet is another question. I have always assumed mild extension of maximum life span should be possible with AGE restriction.

....
The more I learn, the less I find I truly know.

I concur.

Edited by kismet, 08 January 2009 - 12:08 AM.

[maxwatt]

. . . .

AGE restriction would most likely improve health, but I would not expect it to increase maximum life span. Our genetic program for aging probably evolved before we began cooking our food.
AGE restriction to me is yet another "single factor" modulating many or even most downstream effects of aging.

So you think restriction of exogenous AGEs won't be enough, contrary to the mouse data presented? Glycation damage certainly is a great problem of aging, just how much we can influence it by diet is another question. I have always assumed mild extension of maximum life span should be possible with AGE restriction.
....

I suspect restriction of exogenous AGEs will be analogous to eliminating a disease state, rather than extending an organism's natural maximal life-span. Use of exogenous age-breakers to reverse glycation might improve health, but except where AGE accumulation leads to diseases, such as possibly congestive heart failure or some forms of brain dysfunction, it looks to be palliative to me. The longest lived humans seem to have been relatively unaffected by AGE accumulation, due to good genetics or other forms of luck. Getting a substantial cohort to live past 120 I consider to be human life extension under the strictest definition. The strategies we are discussing potentially can make 80 and 90 year-olds healthy and more vigorous, but I do not think it will extend the life-spans of those outliers who are going to make it past 110 without such intervention.

Lengthening telomeres to extend live span sounds good in theory, but does anyone have examples of human tissue that stops functioning because of shortened telomeres before death occurs from other causes?

[geddarkstorm]

Kismet, I've been arguing this entire time that resveratrol does not extend maximal life span, and that it should never be expected to in humans by itself; time and again I've said that. And again, we see that there is no one single molecule you can take that will increase your maximal human life span, not a single one - my point stands. You'd have to live over 108 years to be two standards of deviation away from the mean life span of a human, and thus significant. We've seen that nothing aside from genetics (i.e. telomeres) can get a person there so far, and genetics isn't some compound you can take. None of your examples are single factors that increase maximal life, not a single one. They may increase relative life span, by correcting issues that will shorten life span, and that's the difference. Resveratrol can certainly, from its mode of action, and multitudes of in vivo experiments, increase life span by correcting the Sirt1 loss issue that will shorten life span. See what I mean now? But, again, this entire time I've been saying resveratrol will not increase maximal life span - you have to fix every pathway of aging - mitochondrial dysfunction, Sirt1 dysfunction, and telomere loss - to fix aging and increase maximal life span. Also, we know from people who do live to and around 108 years that they have longer telomeres in their cells (this likely isn't the only reason they lived so long). Telomeres don't have to completely run out for their shortening length to kill a cell, and stem cells will not be able to make up the difference over the long run, as the fact of life and death proves; even stem cells are finite age wise in in vivo conditions (one problem of aging is impaired healing, thus stem cell function), only cancer is truly immortal age wise.

Back to methionine restriction, and the CR, we see two other overlooked facts. One, for methionine restriction they had to start the rats on it from early age after weening. Two, once the rats had grown a little older, putting them on the restriction did not increase life span. That's telling. It would never work in me or you, or anyone else on these boards. Do you know what other, more common term we have for the lack of a single nutrient in the diet leading to stunted growth and incomplete development? Oh yes, we call it malnutrition, or deficiency. There's a whole open "laboratory" (a horrible way to put it, I know) in our world where humans are experimented on every day when it comes to restricted diets and lacking certain nutrients. We call that "lab" the Third World, and the majority of humanity is in that terrible condition. But who lives longer, them or people in first world countries? Why? Because if you are deficient in anything, real world hardships will finish you off, so none of these factors can extend life span. Methionine restriction does not extend life span. CR does not extend maximal life span, but keeps life span from being shortened even more away from the maximal, through activation of Sirt1 (I see a common theme here) and other pathways (i.e. autophagy) that clean up cells and prevent pathologies, which are what ultimately shorten the life span.

I didn't bother with AGE because Maxwatt had that covered. AGE is a factor that shortens life span, getting rid of it in consequence, just like getting rid of bacterial infections in consequence, lengthens life span but does not lengthen maximal life span, sorry to say. Of course, AGE is only a symptom of an ailing metabolism, likely paired to mitochondrial and Sirt1 dysfunction. After all, it doesn't happen in younger up to middle age, and what are the factors that actually change from there to when AGE starts causing problems? Those two dysfunctions. Of course, there could be even more dysfunctions, but which ones are mere manifestations of true sources?

Edited by geddarkstorm, 08 January 2009 - 04:34 PM.

[geddarkstorm]

Oh, and about catalase, actually it would likely effect immunology negatively. We know this because of UCP2 and 3 knock out mice. UCPs are inner mitochondrial transmembrane proteins. They respond to a host of peroxidation and super oxide factors to cause mild uncoupling of the proton motive force from ATP synthesis in the mitochondria, which consequently decreases the amount of ROS produced (wastes some energy as well). When these proteins are knocked out of mice, the mice show increased ROS production in their mitochondria, but also show a significant increase in macrophage function and ability to kill phagocytosed organisms. That is, mitochondria produced ROS plays a roll in pathogen elimination, so mitochondrial targeted catalase, which would lower ROS, would also be expected to decrease immune system efficiency.

ROS management is a balancing act between pros and cons - you want the best immune function while keeping ROS from damaging mitochondria or cellular components, that's partly what UCPs are for.

Edited by geddarkstorm, 08 January 2009 - 05:27 PM.

[stephen_b]

Lengthening telomeres to extend live span sounds good in theory, but does anyone have examples of human tissue that stops functioning because of shortened telomeres before death occurs from other causes?

My (perhaps incorrect) understanding was that a cell's vitality doesn't just drop off when telomeres run out, but that vitality declines in some measure as telomere's shorten, perhaps due to some program activating. Does anyone know of there is evidence for this?

StephenB