6 replies to this topic

[opales]

http://www.ncbi.nlm....pubmed/23874150

PLoS Biol. 2013 Jul;11(7):e1001603. doi: 10.1371/journal.pbio.1001603. Epub 2013 Jul 9.
Effects of resveratrol and SIRT1 on PGC-1α activity and mitochondrial biogenesis: a reevaluation.

Higashida K, Kim SH, Jung SR, Asaka M, Holloszy JO, Han DH.

Source

Division of Geriatrics and Nutritional Sciences, Department of Medicine, Washington University School of Medicine in St. Louis, Missouri, United States of America.

Abstract

It has been reported that feeding mice resveratrol activates AMPK and SIRT1 in skeletal muscle leading to deacetylation and activation of PGC-1α, increased mitochondrial biogenesis, and improved running endurance. This study was done to further evaluate the effects of resveratrol, SIRT1, and PGC-1α deacetylation on mitochondrial biogenesis in muscle. Feeding rats or mice a diet containing 4 g resveratrol/kg diet had no effect on mitochondrial protein levels in muscle. High concentrations of resveratrol lowered ATP concentration and activated AMPK in C₂C₁₂ myotubes, resulting in an increase in mitochondrial proteins. Knockdown of SIRT1, or suppression of SIRT1 activity with a dominant-negative (DN) SIRT1 construct, increased PGC-1α acetylation, PGC-1α coactivator activity, and mitochondrial proteins in C₂C₁₂ cells. Expression of a DN SIRT1 in rat triceps muscle also induced an increase in mitochondrial proteins. Overexpression of SIRT1 decreased PGC-1α acetylation, PGC-1α coactivator activity, and mitochondrial proteins in C₂C₁₂ myotubes. Overexpression of SIRT1 also resulted in a decrease in mitochondrial proteins in rat triceps muscle. We conclude that, contrary to some previous reports, the mechanism by which SIRT1 regulates mitochondrial biogenesis is by inhibiting PGC-1α coactivator activity, resulting in a decrease in mitochondria. We also conclude that feeding rodents resveratrol has no effect on mitochondrial biogenesis in muscle.

[hav]

The newer study seems to be questioning the conclusions of this older study, which they cite:

Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha.

Diminished mitochondrial oxidative phosphorylation and aerobic capacity are associated with reduced longevity. We tested whether resveratrol (RSV), which is known to extend lifespan, impacts mitochondrial function and metabolic homeostasis. Treatment of mice with RSV significantly increased their aerobic capacity, as evidenced by their increased running time and consumption of oxygen in muscle fibers. RSV's effects were associated with an induction of genes for oxidative phosphorylation and mitochondrial biogenesis and were largely explained by an RSV-mediated decrease in PGC-1alpha acetylation and an increase in PGC-1alpha activity. This mechanism is consistent with RSV being a known activator of the protein deacetylase, SIRT1, and by the lack of effect of RSV in SIRT1(-/-) MEFs. Importantly, RSV treatment protected mice against diet-induced-obesity and insulin resistance. These pharmacological effects of RSV combined with the association of three Sirt1 SNPs and energy homeostasis in Finnish subjects implicates SIRT1 as a key regulator of energy and metabolic homeostasis.

I don't have the full-text of the older study but I bolded a few sentences in the abstract that suggest its methods included not only feeding the mice resveratrol, but having them to do aerobic exercise consisting of running.

It's not clear that this newer study made any effort to duplicate the exercise methods of the older study. I read and searched through the full-text of the newer study a few times and couldn't find any mention of any kind of aerobic exercise in their methods or results. Although they expressed an interest in exercise performance studies, they seemed to have expressed their strongest interest as follows:

Because it is difficult to motivate people to exercise, an effective, nontoxic exercise mimetic—that is, an “exercise pill”—could have great public health value. Therefore, the reports that, in addition to protecting against obesity and insulin resistance, resveratrol feeding mimics not only the adaptive response to endurance exercise but also the adaptations to strength training and motor skill exercise training were of great interest to us. The present study was undertaken to further evaluate the adaptive response of skeletal muscle mitochondria to resveratrol treatment.

Suggesting they may have intentionally deprived their subjects of exercise. If that's the case, all they may have proved is that resveratrol is not an “exercise pill” but only in regard to the few things they measured, namely SIRT1 and PGC-1α activity. They didn't measure the more obvious markers of sedentary life-style, however, which they do acknowledge such as "obesity, insulin resistance, type 2 diabetes, atherosclerosis, and frailty" so they don't completely prove even that point.

Howard

[Darryl]

I haven't really bought into resveratrol, which appears to act as a poorly bioavailable polyphenol Nrf2 activator and weak mitochondrial respiratory chain poison/AMPK activator, rather than as a direct Sirt1 activator. It seems likely menaquinones (K2 Mk8 & Mk9) from certain cheeses offer better explanations for the "French paradox".

Beher, Dirk, et al. "Resveratrol is not a direct activator of SIRT1 enzyme activity." Chemical biology & drug design 74.6 (2009): 619-624.
Pacholec, Michelle, et al. "SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1." Journal of Biological Chemistry 285.11 (2010): 8340-8351.
Hu, Yi, et al. "The controversial links among calorie restriction, SIRT1, and resveratrol." Free Radical Biology and Medicine 51.2 (2011): 250-256.

I will note there have been wildly varying results of resveratrol on autophagy induction (one of the pillars of my personal supplement regimen):

Armour, Sean M., et al. "Inhibition of mammalian S6 kinase by resveratrol suppresses autophagy." Aging 1.6 (2009): 515.
Pietrocola, Federico, et al. "Pro-autophagic polyphenols reduce the acetylation of cytoplasmic proteins." Cell Cycle 11.20 (2012): 3851-3860.

Edited by Darryl, 10 December 2013 - 08:46 PM.

[timar]

I absolutely agree with Darryl. I think resveratrol is overhyped due to both commercial interests and the impact of David A. Sinclair and a few other vocal researchers. SInclair made a fortune by selling his company Sirtris to GSK, which may have had an impact on his impartiality. Dipak Das, who contributed much to the resveratrol hype, has been convicted of having fabricated much of his work regarding resveratrol. Most of his papers on resveratrol have been retracted since.

I think the french paradox can be explained by a combination of red wine polyphenols other than resveratrol, e.g (pro)anthocyanidines, some elements of the Mediterranean diet, compounds from cheese (menaquinones, peptides, polyamines and bioactive compounds from fungi, e.g. statins) and last but not least the fact that saturated fat doesn't seem to be quite as much an offender as previously thought. Wikipedia has a surprisingly good article on this subject.

Edited by timar, 10 December 2013 - 10:30 PM.

[hav]

... Dipak Das, who contributed much to the resveratrol hype, has been convicted of having fabricated much of his work regarding resveratrol. Most of his papers on resveratrol have been retracted since.
...

Fwtw, UCONN apparently withdrew its 60,000 page report from its web site some time ago. I think the only "conviction" was before the college Board of Trustees which allegedly denied him the opportunity to defend. A court of law has not passed on the report yet. And might not ever if the college settles his defamation lawsuit. Dr Das died on Sept 19, 2013, btw. I assume his estate will probably amend and continue the federal court lawsuit.

I don't know that Dr Das fueled the resveratrol hype as much as suggested. My sense is that his conclusions about low dosages being effective were the most controversial. I personally never accepted that, but there is other research that supports it. Here's an article that contains numerous study cites, with none from Dr. Das...

http://www.lef.org/m...veratrol_04.htm

But I still go with around 1.5 grams a day myself in reliance on studies using higher dosages.

Howard

[itz4you2]

As a person that has used this supplement daily for a couple of years, The concept of it as "snake oil" is not feasible. While I no longer use it (the quality brands are quite expensive) I did notice benefits that were distinctly not "placebo". Similar to some other supplements, you can only go so far with this. As far as Sirt1, well, could be wishful thinking in some instances. It definately reduces body fat, along those lines of thinking it should act in a positive manner on arterial health as well. That does not mean I recommend it. People with HCV should be careful with it.

[xEva]

People with HCV should be careful with it.

Could you elaborate on this please?