41 replies to this topic

[efosse]

What available herbs/drugs/supplements would or possibly might upregulate SIRT2? Seems as though it'd be the best way to lose fat (second to caloric restriction of course), and I have a pesky little bit of fat to lose...

Here's a review of the article in ScienceDaily:
http://www.scienceda...70815154329.htm

Here's the actual journal article abstract:
http://www.cellmetab...55041310700191X


********************************************************************
SIRT2 Regulates Adipocyte Differentiation through FoxO1 Acetylation/Deacetylation

Enxuan Jing,1 Stephane Gesta,1 and C. Ronald Kahn1,

1 Department of Cellular and Molecular Physiology, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA

Corresponding author
C. Ronald Kahn
c.ronald.kahn@joslin.harvard.edu

Summary

The family of mammalian Sirtuin proteins comprises seven members homologous to yeast Sir2. Here we show that SIRT2, a cytoplasmic sirtuin, is the most abundant sirtuin in adipocytes. Sirt2 expression is downregulated during preadipocyte differentiation in 3T3-L1 cells. Overexpression of SIRT2 inhibits differentiation, whereas reducing SIRT2 expression promotes adipogenesis. Both effects are accompanied by corresponding changes in the expression of PPARγ, C/EBPα, and genes marking terminal adipocyte differentiation, including Glut4, aP2, and fatty acid synthase. The mechanism underlying the effects of reduced SIRT2 in 3T3-L1 adipocytes includes increased acetylation of FOXO1, with direct interaction between SIRT2 and FOXO1. This interaction enhances insulin-stimulated phosphorylation of FOXO1, which in turn regulates FOXO1 nuclear and cytosolic localization. Thus, Sirt2 acts as an important regulator of adipocyte differentiation through modulation of FOXO1 acetylation/phosphorylation and activity and may play a role in controlling adipose tissue mass and function.

Edited by efosse, 16 August 2007 - 06:30 AM.

[edward]

Umm, can we say an entree of resveratrol and milk thistle (silymarin/silibin) in a Lecithin and oil infusion, perhaps with a quercetin appetizer and a Green Tea chaser followed by a healthy helping of Vitamin C... (I watched "Top Chef" tonight so ive got the cooking lingo stuck in my head)

[efosse]

Perhaps somebody who knows more about resveratrol can sort this out... but I thought resveratrol only upregulated SIRT1.

Here's a study:
****************************************************************
J. Biol. Chem, 10.1074
Accepted on January 31, 2005
Substrate specific activation fo sirtuins by resveratrol
Matt Kaeberlein, Thomas McDonagh, Birgit Heltweg, Jeffrey Hixon, Eric A. Westman, Seth Caldwell, Andrew Napper, Rory Curtis, Peter S. DiStefano, Stanley Fields, Antonio Bedalov, and Brian K. Kennedy

Biochemistry Dept., University of Washington, Seattle, WA 98195

Corresponding Author: bkenn@u.washington.edu

Resveratrol, a small molecule found in red wine, is reported to slow aging in simple eukaryotes and has been suggested as a potential calorie restriction mimetic. Resveratrol has also been reported to act as a Sirtuin activator, and this property has been proposed to account for its anti-aging effects. We show here that resveratrol is a substrate-specific activator of yeast Sir2 and human SirT1. In particular, we observe that, in vitro, resveratrol enhances binding and deacetylation of peptide substrates that contain Fluor de Lys, a non-physiological fluorescent moiety, but has no effect on binding and deacetylation of acetylated peptides lacking the fluorophore. Consistent with these biochemical data, we find that, in three different yeast strain backgrounds, resveratrol has no detectable effect on Sir2 activity in vivo, as measured by rDNA recombination, transcriptional silencing near telomeres, and life span. In light of these findings, the mechanism accounting for putative longevity effects of resveratrol should be reexamined.

[jackm]

It turned out some new findings actually showed resveratrol activate both Sirt1 and Sirt2, and more evidence showed they have overlapping targets. But unfortunately, if Sirt2 can keep us lean, it would give you Parkinson's, tough choice


Suzuki K, Koike T.
Related Articles, Links
Abstract Resveratrol abolishes resistance to axonal degeneration in slow Wallerian degeneration (WldS) mice: activation of SIRT2, an NAD-dependent tubulin deacetylase.
Biochem Biophys Res Commun. 2007 Aug 3;359(3):665-71. Epub 2007 Jun 4.



Outeiro TF, Kontopoulos E, Altmann SM, Kufareva I, Strathearn KE, Amore AM, Volk CB, Maxwell MM, Rochet JC, McLean PJ, Young AB, Abagyan R, Feany MB, Hyman BT, Kazantsev AG.
Related Articles, Links
Abstract Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson's disease.
Science. 2007 Jul 27;317(5837):516-9. Epub 2007 Jun 21.

[efosse]

jackm,

Argh! But perhaps resveratrol's other mechanisms of action prevent the SIRT2 and Parkinson's effect? Who knows...

thanks for the cites, though!

cheers,
efosse

[efosse]

Actually -- one other point. The Outeiro et al article showing that sirt2 inhibition prevents Parkinson's dosen't show that sirt2 overexpression CAUSES Parkinson's, does it? While resveratrol may not prevent Parkinson's it may not increase the risk of Parkinson's.

Thoughts/comments?

[maxwatt]

There are seven SirT genes, 1-3 inthe nucleus, 7 I think is in the mitochondria, one is in the nucleolus..... And different sirtuins activate them to different and separate degrees. I can't begin to sort it out.

[jackm]

It may or may not, anyone want to be the first for the testimony?

Actually -- one other point. The Outeiro et al article showing that sirt2 inhibition prevents Parkinson's dosen't show that sirt2 overexpression CAUSES Parkinson's, does it? While resveratrol may not prevent Parkinson's it may not increase the risk of Parkinson's.

Thoughts/comments?

[efosse]

Do you take resveratrol, maxwatt?

[maxwatt]

Do you take resveratrol, maxwatt?

Between twoand three grams a day.

[marcopolo]

Here is another interesting article, even if it doesn't directly extend lifespan it sounds like it may at least make a good diet pill, perhaps-

http://www.scienceda...70626115338.htm

[neogenic]

Given that article, have some of the members using higher doses, or any doses or resveratrol seen body composition changes?

[suspire]

No: Been on 2.3 grams of resveratrol for a couple of months now(multiple sources of resveratrol) for a couple of months now and have seen no changes in body weight/composition, amount of grey hairs, etc.

[marcopolo]

But are you overweight to begin with? I imagine if you are fit or thin there would not be much of a noticeable change.

[suspire]

Yeah, I am 6'3" and 230 lbs. While I do work out and some of that is muscle, enough of that is fat to put me into the overweight category. I haven't seen any of the usual indicators that supposedly come with resveratrol: more hair/less grey hair(I'm 32 and just beginning to grey), increased endurance, change in body weight/composition, etc.

At the high doses, I thought I'd see something. That isn't to say it isn't doing something--I am just not observing any effects.

[saxiephon]

SUSPIRE QUOTE:
"Been on 2.3 grams of resveratrol for a couple of months now(multiple sources of resveratrol) for a couple of months now and have seen no changes in body weight/composition, amount of grey hairs, etc."



The effect may be time dependent! I've been on 2.5 grams 98-99% TR for 4 months and have lost 10 LBS mostly in the belly. I'm 6'2" and now weigh 165 LBS.

Better than that my stamina is much improved!

[neogenic]

How much does that cost? Pure Trans-ResV @ 2.5grams (a whopping dose)...that's got to be expensive. I'd be a bit concerned at dosing that high as well. What's the impetus or thought process behind that dose as well? Is that based on research using a conversion factor? Just wondering. Clearly the results are fascinating and I'd love to have more people sound off on this. Maybe a poll or a whole new thread is called for. A small scale study of:

Ht., Wt., Age, Dose of TR, type of TR (source), length of time used/duration/frequency, and lastly body composition changes or performance differences.

I'd love to see the members post that and maybe we can see what's what here. Especially with the uniqueness of so many using pure TR here.

[marcopolo]

I just ordered my first bottle of 99% resveratrol and will start taking 600mg or more per day as soon as it gets here. Cost me $66.00 plus shipping and would be a months supply at 600mg per day. It may be worth it if I can eat anything I want over the holidays, not have to spend hours at the gym, and still not get fat LOL.

[neogenic]

Hmm. That's not 99% TRANS-resveratrol though, so half of that is a throwaway and may even negate some of the benefit of the Trans isomer.

[marcopolo]

here is what they say-

Amount per serving:
Polygonum cuspidatum extract: 307 mg * [standardized to 98% purity, providing 300 mg transresveratrol (Glycon)].

It is Relentless Improvements brand, mostly because they were the only low emodin content product that will even be in stock in the next couple of weeks that I could find.
BTW I have a question for the Resveratrol distributors that frequent this board. Why is it that I cannot find high quality large dose resveratrol capsules at the local health food store? I have to order them online. The highest dosage I could find in the store(Sacramento area) is Nature's Way 37.5mg resveratrol, and that is with high emodin which I don't do well with.

[ilanso]

Speaking of fat burners (marcopolo's Science article). Seems R100 (is that 100% trans-res?) actually kills the fat cells, whereas R50 (50%?) only weakens them:

(The FASEB Journal. 2007;21:550.32)
© 2007 FASEB

550.32
Resveratrol Inhibits Adipogenesis and Induces Apoptosis in 3T3-L1 Adipocytes
Srujana Rayalam1, Jeong-Yeh Yang1, Mary Anne Della-Fera1, Hea Jin Park1, Suresh Ambati1 and Clifton A Baile1,2

1 University of Georgia, Department of Animal and Dairy Science, Athens, GA, 30602,
2 University of Georgia, Department of Foods and Nutrition, Athens, GA, 30602

ABSTRACT

Adipose tissue mass can be decreased by inhibiting adipogenesis and by removal of both preadipocytes and mature adipocytes by apoptosis. We investigated the effects of resveratrol, a flavonoid, on adipogenesis and apoptosis using 3T3-L1 cells. Preadipocytes and mature adipocytes were treated with resveratrol ® at 50 and 100 (M. Viability was measured by MTS assay; apoptosis was measured by single strand DNA ELISA. In preadipocytes, R50 and R100 decreased cell viability by 15.2 ± 3.6 and 24 ± 1.7 % (p<0.001) of control respectively after 48 hours. In mature adipocytes R50 and R100 decreased cell viability by 11.9 ± 2.1 and 21 ± 3 % (p<0.001) of control respectively after 48 hours. However, R50 did not induce apoptosis in either preadipocytes or mature adipocytes, whereas R100 increased apoptosis in mature adipocytes by 46 ± 8.7% (p<0.001) more than control after 48 hours. The effect on apoptosis in mature adipocytes was also confirmed with Hoechst staining. Resveratrol’s effect on adipogenesis was examined by AdipoRedTM assay and Oil red O staining after treatment during differentiation. Resveratrol at 25 and 50 (M concentration significantly decreased lipid accumulation by 44±1.2% and 96.3±0.3% of control respectively (p<0.001). These results show that resveratrol acts directly on adipocytes to reduce cell viability and adipogenesis and induce apoptosis and thus may have applications in the treatment of obesity.

[niner]

Preadipocytes and mature adipocytes were treated with resveratrol ® at 50 and 100 (M.

I think what you are seeing here is a mistranslation of a Greek "mu", the symbol for micro (10**(-6)). The capital "M" stands for molar, which means moles of resveratrol per litre of solution. Even 50 micromolar is an order of magnitude higher than any blood level of resveratrol that I've heard of in a human.

[ilanso]

The capital "M" stands for molar, which means moles of resveratrol per litre of solution. Even 50 micromolar is an order of magnitude higher than any blood level of resveratrol that I've heard of in a human.

If the above is achieved (by unspecified means) res blood concentration, then, given the blood volume in the average person (5.6l), R50 would translate into approx. 64mg per full body, which doesn't seem excessive. Even the R100 (128mg) is pretty reasonable, given that I take 1.5g/d. Of course, I have no idea what percentage is bioavailable, even when taken in a PEG suspension. Still, 1500mg yielding 128mg worth of blood-circulating res molecules doesn't seem like such an impressive feat.
(I guess I optimistically assumed the conjugates to not be completely inert)

Edited by ilanso, 16 September 2007 - 08:05 AM.

[maxwatt]

It desn't look like even a five gram dose will achieve these levels.

Phase I dose escalation pharmacokinetic study in healthy volunteers of resveratrol, a potential cancer chemopreventive agent.Boocock DJ, Faust GE, Patel KR, Schinas AM, Brown VA, Ducharme MP, Booth TD, Crowell JA, Perloff M, Gescher AJ, Steward WP, Brenner DE.
Cancer Biomakers and Prevention Group, Department of Cancer Studies and Molecular Medicine, Leicester Royal Infirmary, Leicester University, Leicester LE2 7LX, United Kingdom.

The red grape constituent resveratrol possesses cancer chemopreventive properties in rodents. The hypothesis was tested that, in healthy humans, p.o. administration of resveratrol is safe and results in measurable plasma levels of resveratrol. A phase I study of oral resveratrol (single doses of 0.5, 1, 2.5, or 5 g) was conducted in 10 healthy volunteers per dose level. Resveratrol and its metabolites were identified in plasma and urine by high-performance liquid chromatography-tandem mass spectrometry and quantitated by high-performance liquid chromatography-UV. Consumption of resveratrol did not cause serious adverse events. Resveratrol and six metabolites were recovered from plasma and urine. Peak plasma levels of resveratrol at the highest dose were 539 +/- 384 ng/mL (2.4 micromol/L, mean +/- SD; n = 10), which occurred 1.5 h post-dose. Peak levels of two monoglucuronides and resveratrol-3-sulfate were 3- to 8-fold higher. The area under the plasma concentration curve (AUC) values for resveratrol-3-sulfate and resveratrol monoglucuronides were up to 23 times greater than those of resveratrol. Urinary excretion of resveratrol and its metabolites was rapid, with 77% of all urinary agent-derived species excreted within 4 h after the lowest dose. Cancer chemopreventive effects of resveratrol in cells in vitro require levels of at least 5 micromol/L. The results presented here intimate that consumption of high-dose resveratrol might be insufficient to elicit systemic levels commensurate with cancer chemopreventive efficacy. However, the high systemic levels of resveratrol conjugate metabolites suggest that their cancer chemopreventive properties warrant investigation.

PMID: 17548692

[neogenic]

Maybe we'll start seeing IV resveratrol with the IV Vitamin C by extensionists. What is the highest dose of Trans-ResV anyone is doing on the board?

[roex]

RevGenetics.com

[dannov]

I'm doing 4 grams 98.2% trans-rev in a 2g Miralax solution with 20mg of BioPerine neogenic, so hopefully my absorption levels will be considerably better than in that study! >.<

[neogenic]

So are you seeing any body composition changes at that dosing?

[dannov]

Too early to tell since it's only been a few days thus far, and I'm in pretty good shape as it is. Time will tell though, and I'm hoping for the best.

[my8086]

dannov, any appetite suppression, "sense of well being" or energy at that dose so far? I have not noticed any appetite suppression. Sense of well being, mood elevation, yes, energy, eh, maybe. Fewer gray hairs for sure. After taking varying amounts (500mg - 1000mg/day) for 3 months or so, I don't feel that res is living up to it's claim as an AI, at least in my case.