Why did resveratrol not extend the lifespan of mice?

I think this may be important enough that it deserves its own topic. I noted this in a thread on resveratrol effects, but it is somewhat buried there.

When Sinclair released the second part of his study on resveratrol fed mice on a normal diet, the conclusion was that it did not extend their lifespan. But when the question was posed "what did the mice die of?" I carefully examined the paper and and found that the mice were infected with a retrovirus that caused lymphomas.

This is quote from the paper (Pearson et al., Resveratrol Delays Age-Related Deterioration and Mimics Transcriptional Aspects of Dietary Restriction without Extending Life Span, Cell Metabolism (2008), doi:10.1016/j.cmet.2008.06.011):

Blinded postmortem histopathology for disease or predisease
states was performed on visceral organs including the heart, kidneys,
liver, spleen, lungs, and pancreas (Table S3). Resveratrol
treatment did not significantly alter the distribution of pathologies
in SD groups. This included neoplasias, despite the potency
of resveratrol against implanted or chemically induced tumors,
recently reviewed elsewhere (Baur and Sinclair, 2006). This
may be related to the fact that the vast majority of these cases
were lymphomas, a tumor type for which the efficacy of resveratrol
has not been thoroughly assessed, and that is thought to be
triggered mainly by endogenous retroviruses in mice (Kaplan,
1967; Risser et al., 1983).

Apparently, the mice were dying of a disease against which resveratrol does not provide a defense: lymphomas caused by retroviruses. It would be interesting to repeat the study with mice that are not infected with this virus. It would be more than interesting.

Edited by maxwatt, 16 June 2009 - 12:46 PM.

Blinded postmortem histopathology for disease or predisease
states was performed on visceral organs including the heart, kidneys,
liver, spleen, lungs, and pancreas (Table S3). Resveratrol
treatment did not significantly alter the distribution of pathologies
in SD groups. This included neoplasias, despite the potency
of resveratrol against implanted or chemically induced tumors,
recently reviewed elsewhere (Baur and Sinclair, 2006). This
may be related to the fact that the vast majority of these cases
were lymphomas, a tumor type for which the efficacy of resveratrol
has not been thoroughly assessed, and that is thought to be
triggered mainly by endogenous retroviruses in mice (Kaplan,
1967; Risser et al., 1983).

Apparently, the mice were dying of a disease against which resveratrol does not provide a defense: lymphomas caused by retroviruses. It would be interesting to repeat the study with mice that are not infected with this virus.

Aren't endogenous retroviruses part of the genome? In that case they are not acquired by (new) infection.

Edited by seekonk, 16 June 2009 - 12:31 PM.

Resveratrol treatment did not significantly alter the distribution of pathologies in SD groups. This included neoplasias ... This may be related to the fact that the vast majority of these cases were lymphomas ... that is thought to be triggered mainly by endogenous retroviruses in mice (Kaplan, 1967; Risser et al., 1983).

Apparently, the mice were dying of a disease against which resveratrol does not provide a defense: lymphomas caused by retroviruses. It would be interesting to repeat the study with mice that are not infected with this virus. It would be more than interesting.

Thanks for the info here, maxwatt.

I googled forth the paper after you presented this paragraph, but, unfortunately, couldn't get any more detail as to the breakdown in causes of death than in this paragraph. It alludes to a Table S3, which, however, is not made available without some kind of subscription. It's not clear from its description in the paragraph whether that table contains more detail on the causes of death.

From reading the paragraph alone, it's not obvious just what proportion of the deaths were due to neoplasias, as opposed to other causes. Apparently the proportion for the resveratrol-fed mice is basically the same as with control mice.

Do you, or does anyone, have a sense of what those numbers might be for this population of mice?

Edited by Michael, 14 July 2009 - 10:37 AM.

Resveratrol kills TNF-alpha. TNF-alpha protects against lymphoma (blood cancer). The mice died because of a direct effect of resveratrol.

Resveratrol kills TNF-alpha. TNF-alpha protects against lymphoma (blood cancer). The mice died because of a direct effect of resveratrol.

edited: beat me to it by a minute..

it would be interesting to know if this dog was still alive:

http://www.imminst.o...showtopic=23986

Edited by prophets, 16 June 2009 - 01:58 PM.

Resveratrol kills TNF-alpha. TNF-alpha protects against lymphoma (blood cancer). The mice died because of a direct effect of resveratrol.

Since those mice who took resveratrol appear to have died from lymphoma at the same rate and in the same periods as control mice, don't you think your claim is a little hyperbolic?

It is not so simple. Though resveratrol inhibits TNF-alpha in some tissue, it apparently induces it in other tissue.

International Immunopharmacology
Volume 4, Issue 6, June 2004, Pages 713-720

Differential regulation of resveratrol on lipopolysacchride-stimulated human macrophages with or without IFN-γ pre-priming

Yong-Hong Feng, Yi-Na Zhu, Jin Liu, Yong-Xing Ren, Jian-Yi Xu, Yi-Fu Yang, Xiao-Yu Li and Jian-Ping Zou,

State Key Lab of Drug Research, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences., Shanghai 201203, PR China

Received 6 September 2003; Revised 29 October 2003; accepted 10 February 2004. Available online 5 March 2004.
Abstract

Resveratrol, a polyphenol compound found in grapes and red wines, is a prominent anti-cancer agent. In this study, we demonstrate that resveratrol enhanced TNF-α, IL-12 and IL-1β production from LPS activated phorbol myristate acetate (PMA) differentiated THP-1 human macrophages. Expression of CD86 on macrophages was enhanced by resveratrol alone and with LPS. When macrophages were primed with IFN-γ, resveratrol suppressed the expression of HLA-ABC, HLA-DR, CD80, CD86 and inhibited production of TNF-α, IL-12, IL-6 and IL-1β induced by LPS. The differential impact of resveratrol on expression of CD14 might be correlated with differential response of macrophages to LPS with or without IFN-γ priming.

it's clearly not all that simple. the epigenetic effects of compounds like resveratrol have wide ranging effects.


Resveratrol induces cerebral angiogenesis
http://www.ncbi.nlm....pubmed/17250973

Resveratrol inhibits angiogenesis in gliomas (brain tumors)
http://www.ncbi.nlm....pubmed/16619530

hopefully Sinclair will eventually elucidate all the pathways that resveratrol effects in the human body. the guy has been paid handsomely by GSK now, he should only be in it for the research at this point.


I remember reading a study from about 2 years ago called something like "NF-kB: innocent bystander or evil culprit?" reminds me of that paper a bit... maybe the tnf-a activity is an innocent bystander in this case. i guess we will only know over time.

Yeah, me three on this not being simple. The macrophages in the Feng et al. paper were treated with both LPS and phorbol esters, both of which are terrifically pro-inflammatory. While they are good tools for probing various aspects of the immune system, I don't know if it's relevant to normal in vivo states or not. I'm not an immunologist, so caveat emptor and all, but I thought I'd bring it up.

Resveratrol also failed to reduce body temperature and heart rate. Reduced body temperature by Calorie Restriction is an important part of its anti cancer effect and longevity effect.
Cool Mice Live Longer
http://www.livescien..._cool_mice.html

"Curiously, while experimental male mice lived 12 percent longer on average than normal males, experimental females had a 20 percent greater life expectancy. "Further studies will address the differences between males and females"

Resveratrol treatment in mice does not elicit the bradycardia and hypothermia associated with calorie restriction
http://www.fasebj.or...3/4/1032?ck=nck

Edited by Matt, 18 June 2009 - 05:58 PM.

Resveratrol also failed to reduce body temperature and heart rate. Reduced body temperature by Calorie Restriction is an important part of its anti cancer effect and longevity effect.
Cool Mice Live Longer
http://www.livescien..._cool_mice.html

Resveratrol treatment in mice does not elicit the bradycardia and hypothermia associated with calorie restriction
http://www.fasebj.or...3/4/1032?ck=nck

I agree. Resveratrol might stimulate SIRT1 to some degree, but it would appear that most of its positive effects are due to its SERM abilities and increased glucose management abilities (similar to Metformin). Increased energy typically means increased metabolic rate which is the exactly opposite of what calorie restriction is all about. Meaning, the failure of the calorie restriction models (in my opinion) is that they cannot ask the mice or worms how they feel. If you did, then they probably would tell you that the additional years were not worth the road that it takes to get there. Length is not everything when you feel like you are functioning at 50% for your entire life..

Tim Jones. CR is worth it, for me See my blog sometime, I've been doing it for a while now (just go to my profile for a link).

i'm somewhat in the tim jones camp. CR is effectively turning down the biological output of your body to conserve for a lower level of optimal performance/longevity. it's difficult to operate in a highly competitive environment (sports, work, etc.) on CR. if i was some academic/teacher sitting in a relaxed atmosphere, CR might be optimal.

I'd really rather see something that inherently reduced MitROS. maybe methylene blue is a better answer. or maybe methylene blue + resveratrol... IDK.

Edited by prophets, 18 June 2009 - 08:12 PM.

i'm somewhat in the tim jones camp. CR is effectively turning down the biological output of your body to conserve for a lower level of optimal performance/longevity. it's difficult to operate in a highly competitive environment (sports, work, etc.) on CR. if i was some academic/teacher sitting in a relaxed atmosphere, CR might be optimal.

I'd really rather see something that inherently reduced MitROS. maybe methylene blue is a better answer. or maybe methylene blue + resveratrol... IDK.

I think it will take a combination of interventions. resveratrol does not according to gene-array profiling, reduce IGF-1, whereas luteolin does. Aerobic exercise will resultin brachycardia. Methylene blue might increase NAD/NADH ratio.... and so on.

Edited by maxwatt, 18 June 2009 - 11:06 PM.

Resveratrol does not decrease core temperature as I already mentioned above. Did Sinclair report this in the recent paper?

In Calorie Restriction studies when mice are raised in an increased ambient temperature the lymphoma protection isn't as great and lifespan is reduced in CR animals.. So maybe if body temperature were decreased by resveratrol, life extension would have been more significant. What do you think? Reduced body temperature in a few studies (can't find them right now) is crucial to CR's life extension effect it seems, and even by itself increases lifespan WITHOUT CR.

1. A tumor preventive effect of dietary restriction is antagonized by a high housing temperature through deprivation of torpor
Abstract

Energy restriction (ER) has proven to be the only effective means of retarding aging in mice. The mechanisms of multiplicity of effects of ER on aging remain, however, fragmentary. ER induces daily torpor, the induction of which is reduced by increasing the ambient temperature to 30°C. The effects of preventing hypothermia in ER animals were studied in terms of the expected consequences of ER on survival, disease pattern and a number of physiological parameters in autoimmune prone MRL/lpr mice and lymphoma prone C57BL/6 mice. The results demonstrate that torpor plays a crucial role in the prevention of lymphoma development but does not have an affect on other aspects of ER, such as prevention of autoimmune diseases.

Edited by Matt, 18 June 2009 - 11:36 PM.

Tim Jones. CR is worth it, for me See my blog sometime, I've been doing it for a while now (just go to my profile for a link).

Matt... I understand what you are trying to do, and I respect you for it...

This is only my opinion... You seem like a very bright and ambitious individual who is capable of great things. My suggestion would be instead of directing all of your attention to extend the length that you will be here why not instead put that sharp intellect towards other noble goals such as solving existing problems that currently have no solutions... Meaning, your focus (in my opinion) could be on advancing / helping our species instead of just individual goals.

Let me put it this way.... The first time I ever saw a small (and very special) child deteriorating rather quickly from an incurable condition that nothing could be done for, I would at that point giving anything to change places with that little girl and died for her no matter what my age was at the time. Meaning, there are things in life much more important than length and I think in time you will discover that.

Saying that, I am certainly not against looking at things that might be beneficial for increasing quality of life, which is why I monitor this and many other forums, but a normal life for me is perfectly fine. My goals differ from yours slightly, however. There are things out there (in my opinion) that are much more important than me personally living longer, and working towards those goals are what I feel are that most important. Meaning, what I think you might be searching for is purpose more than length, and the medical research community would love to have a bright and ambitious individual such as yourself to help make the future generations better. None of us could live the fulfilling lives we do today if it was not for the dedicated generations that came before us blazing the path we currently walk on. In my opinion, we must always remember this and do what we can while we are here to help return the favor to future generations... Me staying here too long would only hurt their time to "shine", so to speak...

Once again... This is only my opinion and is not intended to question your beliefs. As anyone who has missed breakfast can attest too, however, CR is not ideal for mental (or physical) performance...

Perhaps it would be nice to add Moringa Oleifera to try to prevent/kill the tumors, although I have no idea what dosages they used and what the type of the cancer was etc. See this article.
http://www.livinglakecountry.com/oconomowocfocus/news/41318722.html

Mice with the fatal cancers were treated with moringa, while other mice with cancer were left untreated as a control group; another group of healthy mice was treated with moringa as were the sick mice as a second control group.

The mice treated with moringa survived and appeared to have lost their tumors.

"Within a month, they went from sickly looking to healthy looking with shiny coats. The mice not treated with the moringa died," Olander said.

The healthy mice who were administered moringa became more active, appeared younger as evidenced by the color of their fur and generally appeared even healthier, he said.

And Margaret's blog about it.
http://margaret.healthblogs.org/2009/05/18/moringa-oleifera-and-myeloma/

Or/and curcumin solved in oil. Since apparently even the small amount of curcumin in turmeric is already enough to prevent certain virus induced tumors in mice.
http://www.ncbi.nlm.nih.gov/pubmed/7526904

Administering 5% turmeric in the diet from 2 months of age showed suppression of mammary tumor virus-related reverse transcriptase activity and of preneoplastic changes in the mammary glands. Furthermore, feeding turmeric from 6 months of age resulted in a 100% inhibition of mammary tumors.

But for the lipofuscin removing and other anti aging effects of curcumin, I assume that high dosed curcumin and solved in oil would probably still be usefull.
http://www.ncbi.nlm.nih.gov/pubmed/16802111

Edited by DeadMeat, 19 June 2009 - 07:15 PM.

Cancer initiation pathways (below Ras) are different in MIce vs. Human:
http://www.nature.co...bs/nrc1235.html

Mice have telomere lengths several times longer than most mammals and are therefore more sensitive to many types of cancer: e.g.
http://www.springerl...xl9cf8qpg0trrl/

TERT-Knockout mice need 4-6 generations for their offspring to show severe premature aging, which strongly indicates that cancer progression in mice may not even require telomerase activation.

Suppressing COX-2 and the Ras oncogene can prevent cancer initiation, this might be interesting on high long-term doses of resveratrol:
e.g. http://www.medscape....le/563831_print

Edited by mixter, 04 July 2009 - 12:48 PM.

TERT-Knockout mice need 4-6 generations for their offspring to show severe premature aging, which strongly indicates that cancer progression in mice may not even require telomerase activation.

Yeah, I think they can die from telomerase negative cancers because they're so tiny. That makes testing WILT hypotheses somewhat more challanging I guess.

Edited by kismet, 04 July 2009 - 01:55 PM.

This thread seems to have gone off on a few tangents. I think what Maxwatt was saying is too improtant to go off track. If the results are effectivly skewed by an added intervention, then for life extension purposes, they are invalid. If that is the case, then the book may still be open on whether Resveratrol can increase maximum lifespan. Resveratrol does not necessarily have to exactly mimic CR, the method by which it works may be different and not yet understood.

Is there any valid experiment that definitivly proves that Resveratrol does not extend maximum lifespan? If not, it certainly seems worth getting one underway.

... As we know from the Sinclair/de Cabo report (3), high-dose resveratrol does help to partially normalize the lives of such animals -- but it doesn't do much -- and, in terms of mortality, doesn't do anything -- for normally-fed. normal-weight mice. ...

What did the mice die of? "...the vast majority of these cases were lymphomas, a tumor type for which the efficacy of resveratrol has not been thoroughly assessed, and that is thought to be triggered mainly by endogenous retroviruses in mice..." The C57B mice used in de Cabos study are infected with an endogenous retrovirus. If the lab had burned down in a fire, one could as well declare resveratrol did not extend life-span because the mice all died in the fire.

Max, did you read the full paragraph from which you're quoting?

Histopathology Blinded postmortem histopathology for disease or predisease states was performed on visceral organs including the heart, kidneys, liver, spleen, lungs, and pancreas (Table S3). Resveratrol treatment did not significantly alter the distribution of pathologies in SD groups. This included neoplasias, despite the potency of resveratrol against implanted or chemically induced tumors, recently reviewed elsewhere (Baur and Sinclair, 2006). This may be related to the fact that the vast majority of these cases were lymphomas, a tumor type for which the efficacy of resveratrol has not been thoroughly assessed, and that is thought to be triggered mainly by endogenous retroviruses in mice (Kaplan, 1967; Risser et al., 1983). ((1); my emphasis)

Above, you seem to be mistaking them to mean that .the vast majority of deaths in C57Bl/6 mice are caused by lymphomas, which if you read that quote in context, it's clear that they aren't saying (and in any case isn't true). Rather, "these cases" refers to neoplasia. They're saying that the majority of the cancers in their study were lymphomas, of which the majority in turn are thought to be caused by ERVs. If you look at their Table S3, you'll see that "only" about half of the mice died from any form of cancer, which isn't much lower than the rate in humans (and remember that mice don't naturally get heart disease) -- and some proportion of these in turn are lymphomas (they don't break this down).

The mice died of all kinds of things, IOW (notably, other cancers, kidney disease, and (in the obese, high-sucrose-high-saturated-fat-fed mice (the ones that first raised the hype factor on resverarol) fatty liver), not just lymphomas -- it's just that lymphoma is the single biggest cause of cancer, which latter is the single biggest cause of death.

Note also that resveratrol didn't just fail to protect them from lymphomas, but that "Resveratrol treatment did not significantly alter the distribution of " "histopathology for disease or predisease states ... [in] visceral organs including the heart, kidneys, liver, spleen, lungs, and pancreas (Table S3)" in the animals fed a normal diet.

The C57B mice used in de Cabos study are infected with an endogenous retrovirus. If the lab had burned down in a fire, one could as well declare resveratrol did not extend life-span because the mice all died in the fire.

Do remember that every mammal on the planet is infected with an endogenous retrovirus . "Endogenous retroviruses (ERVs) constitute approximately 8-10% of the human and mouse genome." (2)

So many substances have been tested for life-extension using C57B mice, and have come up short. It looks to me the reason is that unless the substance protects against lymphoma, the mice will die of that before other life-extending effects are manifest. We have a flawed model for testing life-extension.

Well, I do agree with this to a point -- but anything short of human testing is always flawed in some sense. The question isn't whether these mice die of something more often than something else (this is true of any model!): the question is whether they die early in some artificial way. The C57Bl/6 is used so often in large part because for a mouse it is very long-lived: C57Bl/6 live longer than other strains precisely because they don't die earlier of other causes. You've gotta die of something ...

While (6) wasn't a lifespan study, it used the more genetically-diverse hybrid of C57BL/6Å~C3H/HeF1, and still found "no decrease in spontaneous tumors at the time of sacrifice (Supplemental Table S2). In particular, spontaneous liver tumors were abundant in mice fed the control diet or resveratrol, but rare in CR mice."

All that said:

N.B. CR (including EOD feeding) is known to protect against lymphomas. Resveratrol does not. De Cabo found EOD feeding plus resveratrol mice lived longer than the EOD alone group. It is possible that EOD protected against lymphoma in these groups, and the addition of resveratrol extended life-span beyond what EOD alone did by other mechanisms.

Yup, an entirely plausible hypothesis -- although it's worth noting that nominally, at least, more of the EOD-fed animals died of cancer than AL animals did (though the difference (60% vs 50%) wasn't significantly different, and again, we don't have the breakdown on lymphomas specifically). The major reductions in death were in kidney disease and in "other." The EOD-plus-lower-dose-resveratrol group had about the cancer incidence of AL animals -- it's just that they took longer to develop it.

Again, you've gotta die of something.

Despite what I say above and elsewhere, I am still following the resveratrol story, and am glad to know that NIA's ITP is also testing the stuff, and doing so in a more genetically-heterogeneous stock. This has its pros and cons, but these mice do have a nice, long life and a diversity of causes of death. (Unfortunately, AFAICS, they aren't repeating the combined EOD-plus-res part of (1), nor, as would IMO be better yet, combining it with a higher, but submaximal, level of CR).

But to those taking more supplemental resveratrol than is present a moderate intake of wine a day right now, before such studies are completed, I ask: where is the better evidence on which you're gambling your long-term health? We have no evidence of extension of life in any mammal -- just the near-normalization of premature mortality in animals rendered obese and diabetic because of a life gorging on a high-sucrose, high-saturated-fat diet. Of note, (8) found (similarly to Auwerx and de Cabo) that resveratrol gave significant protection to obese, high-fat-diet fed Wistar rats (not mice, let alone C57Bl/6) against "hyperglycaemia, dyslipidemia, increased serum oxidized-LDL (ox-LDL) and hepatic oxidative stress," it gave no such benefits to normal-weight, normal-diet rats: in fact, resveratrol supplementation of "standard-fed-rats reduced glutathione-antioxidant defense system and enhanced hepatic lipid hydroperoxide [my emphasis]." Above, remember, just such a diabetic, obese, junkfood-died rodent model study (Auwerx) was favorably referenced as evidence of the safety of resveratrol!

In mice, resveratrol doesn't fully replicate CR-induced gene expression changes (6) nor induce some demonstrably important CR-induced metabolic changes (7). Heck, it's not even clear that the stuff does any good in yeast (where the whole hype got started) (3); nor in Drosophila elegans (note that Partridge's group is possibly the most experienced lab in the world in doing lifespan studies in Drosophila) (4); nor in another (tephritid) species of fruit flies ((5): there may have been a marginal effect in flies fed 1 of the 24 different diet combinations, but I'm skeptical of that result, and IAC there was no effect in the other 23 diets); nor in C. elegans (4) -- and in mammals, again, the evidence to date is against it, except as a complementary intervention in animals also on mild EOD CR.

There are no studies on the safety of resveratrol in humans lasting even a few months, and there what appear to me to be a disturbing number of independent reports of joint pain. These are anecdotal, of course, and could be coincidental, but they aren't the standard headaches-and-upset-tummies stuff, and there seem to be an awful lot of them. Even if you aren't getting this pain, if it's real, the unknown mechanism leaves open the question of unknown other, more subtle or long-term effects in humans.

Again, I challenge you folks to seriously ask: on what evidential basis are you gambling your health on this stuff?

-Michael

1. Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, Labinskyy N, Swindell WR, Kamara D, Minor RK, Perez E, Jamieson HA, Zhang Y, Dunn SR, Sharma K, Pleshko N, Woollett LA, Csiszar A, Ikeno Y, Le Couteur D, Elliott PJ, Becker KG, Navas P, Ingram DK, Wolf NS, Ungvari Z, Sinclair DA, de Cabo R.
Resveratrol Delays Age-Related Deterioration and Mimics Transcriptional Aspects of Dietary Restriction without Extending Life Span.
Cell Metab. 2008 Aug;8(2):157-68.
PMID: 18599363 [PubMed - as supplied by publisher]

2. Lee YK, Chew A, Phan H, Greenhalgh DG, Cho K. Genome-wide expression profiles of endogenous retroviruses in lymphoid tissues and their biological properties. Virology. 2008 Apr 10;373(2):263-73. Epub 2008 Jan 9. PubMed PMID: 18187179; PubMed Central PMCID: PMC2427371.

3. Kaeberlein M, McDonagh T, Heltweg B, Hixon J, Westman EA, Caldwell S, Napper A, Curtis R, Distefano PS, Fields S, Bedalov A, Kennedy BK.
Substrate specific activation fo sirtuins by resveratrol.
J Biol Chem. 2005 Jan 31; [Epub ahead of print]
PMID: 15684413

4. Bass TM, Weinkove D, Houthoofd K, Gems D, Partridge L.
Effects of resveratrol on lifespan in Drosophila melanogaster and Caenorhabditis elegans.
Mech Ageing Dev. 2007 Aug 14; [Epub ahead of print]
PMID: 17875315 [PubMed - as supplied by publisher]

5. The Prolongevity Effect of Resveratrol Depends on Dietary Composition and Calorie Intake in a Tephritid Fruit Fly.
Zou S, Carey JR, Liedo P, Ingram DK, Müller HG, Wang JL, Yao F, Yu B, Zhou A.
Exp Gerontol. 2009 Mar 2. [Epub ahead of print]
PMID: 19264118

6. Barger JL, Kayo T, Vann JM, Arias EB, Wang J, Hacker TA, Wang Y, Raederstorff D, Morrow JD, Leeuwenburgh C, Allison DB, Saupe KW, Cartee GD, Weindruch R, Prolla TA.
A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice.
PLoS ONE. 2008 Jun 4;3(6):e2264.
PMID: 18523577 [PubMed - in process]

7. Resveratrol treatment in mice does not elicit the bradycardia and hypothermia associated with calorie restriction.
Mayers JR, Iliff BW, Swoap SJ.
FASEB J. 2008 Dec 4. [Epub ahead of print]
PMID: 19056839

8. Resveratrol toxicity: effects on risk factors for atherosclerosis and hepatic oxidative stress in standard and high-fat diets.
Rocha KK, Souza GA, Ebaid GX, Seiva FR, Cataneo AC, Novelli EL.
Food Chem Toxicol. 2009 Mar 16. [Epub ahead of print]
PMID: 19298841

Again, I challenge you folks to seriously ask: on what evidential basis are you gambling your health on this stuff?

Good question. It applies to every supplement that has gone into to or out of fashion through the years. People want extra healthy years and are willing to take some risks.

Again, I challenge you folks to seriously ask: on what evidential basis are you gambling your health on this stuff?

Good question. It applies to every supplement that has gone into to or out of fashion through the years. People want extra healthy years and are willing to take some risks.

They want extra years, but they won't get any if they screw up themselves like that (as recently discussed). If those fad supplements come and go this should make us think. Most importantly, supplementation is not a game where you stand nothing to lose (you can harm yourself). If your standards of evidence are that low, you'd have jumped on the antioxidant bandwagon in the 90s after promising evidence from epidemiology and animal experiments (and we know how that turned out). How many times do people need to get burned?

Edited by kismet, 31 August 2009 - 02:57 PM.

I have been and I remain enthusiastic about resveratrol. I have not been trying to recommend it to anyone, I suppose it might seem that way. I have on occasion cautioned that it is an untested self-experiment if one does choose to try it. Though the actual risk may be unknown or unquantifiable, I do have a sense that it is low. In mice it has never been shown to shorten life-span in any reasonably attainable dose, and if mice were merely little people metabolically, I would say it is safe. But mice are not completely like people, though similar enough to be used as models for many human diseases.

Resveratrol does inhibit nfKappa-B inflamation, and is more effective for me than any inflammatory my rheumatologist suggested. Resveratrol does induce mitochondrial biogenesis, and mitochondrial myopathy (e.g. sarcopenia) is one of the more annoying aspects of aging. Sinclair's normal-diet mouse study did find the resveratrol group more vigorous and apparently healthy than the controls as they aged, even though hey found no life-extension. Yet the calorie restricted mice who took resveratrol outlived both the controls and the resveratrol-alone group. One can posit that some beneficial effect was at work.

In one's sixties the possible improvement in quality of life might be judged to outweigh any risk. If one is thirty, perhaps not. But I would not an adult who is intelligently informed and risk-aware not to use this or most other supplements. (If asked I will give a list of things I would not use.)

While most organisms' DNA harbors endogenous retroviruses, the I do not think the majority of these are inevitably lethal. Mice seem particularly unlucky this way.

Tim Jones. CR is worth it, for me See my blog sometime, I've been doing it for a while now (just go to my profile for a link).

Matt... I understand what you are trying to do, and I respect you for it...

This is only my opinion... You seem like a very bright and ambitious individual who is capable of great things. My suggestion would be instead of directing all of your attention to extend the length that you will be here why not instead put that sharp intellect towards other noble goals such as solving existing problems that currently have no solutions... Meaning, your focus (in my opinion) could be on advancing / helping our species instead of just individual goals.

Let me put it this way.... The first time I ever saw a small (and very special) child deteriorating rather quickly from an incurable condition that nothing could be done for, I would at that point giving anything to change places with that little girl and died for her no matter what my age was at the time. Meaning, there are things in life much more important than length and I think in time you will discover that.

Saying that, I am certainly not against looking at things that might be beneficial for increasing quality of life, which is why I monitor this and many other forums, but a normal life for me is perfectly fine. My goals differ from yours slightly, however. There are things out there (in my opinion) that are much more important than me personally living longer, and working towards those goals are what I feel are that most important. Meaning, what I think you might be searching for is purpose more than length, and the medical research community would love to have a bright and ambitious individual such as yourself to help make the future generations better. None of us could live the fulfilling lives we do today if it was not for the dedicated generations that came before us blazing the path we currently walk on. In my opinion, we must always remember this and do what we can while we are here to help return the favor to future generations... Me staying here too long would only hurt their time to "shine", so to speak...

Once again... This is only my opinion and is not intended to question your beliefs. As anyone who has missed breakfast can attest too, however, CR is not ideal for mental (or physical) performance...

Tim, I think you may present a false choice regarding research topics. If you assume that somebody wants to work in medicine, almost every medical advance that helps a specific condition will also expand lifespans, either directly by addressing a certain cause of death, or indirectly by contributing to understanding of the human body.

It is not a zero-sum game. In fact, most of the time, it is closer to the opposite of that. Especially since despite all the bravado on the Imminst forums, understanding of the human body is currently very limited, and more impressive medical advances will require us to advance the baseline level of science first.

Edited by imm1288, 05 October 2009 - 06:38 AM.