I posted this in the Inner Circle forum yesterday, I'll keep it going both places...

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This is the newest product from USP Labs, they've sent me some to test out on myself and a couple of clients.

Label:

Sir Plus
Calorie Restriction Mimetic
Extremely Potent Antioxidant
Extremely Potent Anti-Inflammatory

Youth Blend...............750mg
Tumeric (95% circuminoids)
Resveratrol (100mg trans-resveratrol)
Piperine

Here's a run-down:
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"In our quest to conquer our goals, we rarely come across a supplement, much less a supplement company, that innovates powerful, natural ANABOLIC supplements with healthy benefits that are as potent as Pro-hormones and Designer-Anabolics.

As bodybuilders and athletes, we are interested in health benefits, but our main concern is performance. Whether it’s increasing your vertical leap or bench press numbers, we understand performance is the name of the game.

At USP Labs, we are aware that your main concern is recuperation from exercise to rapidly increase muscular development and speed performance. We’re also aware that you consistently push your body to the limits and rely on us to bring you cutting edge formulas that allow you to do so.

In that push to reach new heights, our immunity (and ultimately health) is sacrificed. And inflammation, the biggest killer known to man, runs rampant throughout your body.

The biggest evil’s halting your goals and progress are the previously mentioned inflammation (think injury) and lowered immunosuppresion (think sickness).

After much demand we’ve finally developed the ultimate health, anti-estrogen and anti-inflammatory formula: SirPlus.

SirPlus combines two of the most remarkable anti-oxidants ever created into one super supplement.

Resveratrol and Curcuminoids are sickness’s kryptonite. If you want superhuman immunity then you need SirPlus.

SirPlus is the superman of antioxidant and anti inflammation that even has the potential to extend lifespan.

SirPlus is a potent antioxidant and anti-inflammatory that can extend your performance life. In fact, it will even do much more than that (which is quite amazing in itself).

In research SirPlus has been shown to:

1. May prevent muscle protein breakdown (anti-catabolic effect in skeletal muscle tissue) (1-4)
2. Increase testosterone levels and sperm production by anti-estrogenic activities, acting as a SERM, though not necessarily in the classical sense (5-11).
3. Analgesic effects (12).
4. Protect against hearing loss (12).
5. Reduce injury to kidneys, liver, lungs, spinal cord, lungs, intestine, colon, brain and heart (12). It's as close as you can come to an all around, all tissue protector.
6. Potent antioxidant and anti-inflammatory effects, much greater than that of common antioxidants (12).
7. A synergistic effects for anticancer activity (13).
8. Potent effects upon cardiovascular health (12).
9. Prevent immunosuppression and liver damage seen with ethanol
consumption (12).
10. Potential to extend lifespan (12).

Hmm… Potential to extend lifespan, please explain!

SIRT1 (sirtuin 1) is an important protein in humans that is a key mediator in calorie restriction and longevity. It is in fact considered the primary target of Resveratrol's beneficial metabolic effects.

In fact, activation of SIRT1 is tied to lipolysis and potentially, energy expenditure. Increased activity of SIRT1 is generally found when following a calorie restricted diet. In turn, potential benefits such as anti-aging and neurological benefits are realized, amongst many others. What can one do to reap the benefits of increasing SIRT1 activity without having to actually decrease calorie intake? Simple, we use a calorie restriction mimetic, such as Resveratrol, which will mimic that benefit of increased SIRT1 activity, without having to sacrifice calories from those hungry muscles.

A recent study found a strong correlation between the variation in the SIRT1 gene and energy expenditure. In other words, we might infer that or at least suppose that increasing SIRT1 activity can result in improve metabolic activity, one feature of which would be increased energy expenditure and lipolysis. This has in fact been supported by recent studies in mice


There are a few Misunderstandings that we would like to address about Resveratrol.

1. Oral bioavailability isn't sufficient.

In Reality:

The extensive conjugation (sulfation and glucuronidation) doesn't mean that the compound has no oral bioavailability in humans. The question from those researching resveratrol has been how is resveratrol allowing for all of these beneficial effects despite having what they thought to be low oral bioavailability. One answer has been that perhaps, contrary
to the generalized rule of thumb that conjugation leads to inactivation, those conjugated resveratrol metabolites were still somewhat active in serum. The most recent answer with mounting evidence is that these conjugation products are acting as reservoirs or endogenous/biologic pro-drugs in the body, allowing for the release of free resveratrol locally and/or systemically after the conjugation moieties (sulfate and Beta-glucuronic acid) are cleaved by sulfatase and Beta-glucuronidase respectively (14-16). With this in mind, it explains why a much lower amount of resveratrol than calculated (i.e., if we assume conjugated products as permanently inactive metabolites) would need to be administered in order to achieve necessary serum concentrations of the free compound. A most recent study has in fact provided direct evidence to support this hypothesis (17).

The fact that many who are actually providing original research are taking regular trans-resveratrol provides some testament to the fact that oral bioavailability isn't the issue it was once thought to be.

2. Insufficient stability and degradation of product.

In Reality:

The stability of resveratrol has only been shown to be an issue when one is dealing with a reference standard of pure trans-resveratrol, not an extract
(18).

Sirplus Is A Must Have In Your Supplement Arsenal!

We did a very small first run of Sirplus. We only have 126 bottles of SirPlus in stock and they will be sold at a first come, first serve basis. Limit is 10 bottles per order."

References

1. Wyke SM, Tisdale MJ. “Induction of protein degradation in skeletal muscle by a phorbol ester involves upregulation of the ubiquitin-proteasome proteolytic pathway.� 2006 May;78(25):2898-2910
2. Thaloor D, et al. “Systemic administration of the NF-kappaB inhibitor curcumin stimulates muscle regeneration after traumatic injury.� Am J Physiol. 1999 Aug;277(2 Pt 1):C320-9
3. Tisdale MJ. “The ubiquitin-proteasome pathway as a therapeutic target for muscle wasting.� J Support Oncol. 2005 May-Jun;3(3):209-17.
4. Wyke SM, Russell ST, Tisdale MJ. “Induction of proteasome expression in skeletal muscle is attenuated by inhibitors of NF-kappaB activation.� Br J Cancer. 2004 Nov 1;91(9):1742-50.
5. Juan ME, et al. “trans-Resveratrol, a natural antioxidant from grapes, increases sperm output in healthy rats.� J Nutr. 2005 Apr;135(4):757-60.
6. Bowers JL, et al. “Resveratrol acts as a mixed agonist/antagonist for estrogen receptors alpha and beta.� Endocrinology. 2000 Oct;141(10):3657-67.
7. Wang Y, et al. “The Red Wine Polyphenol Resveratrol Displays BI-Level Inhibition on Aromatase in Breast Cancer Cells.� Toxicol Sci. 2006 Apr 11; E-Published Ahead of Print
8. Turner RT, et al. “Is resveratrol an estrogen agonist in growing rats?� Endocrinology. 1999 Jan;140(1):50-4.
9. Lu R, Serrero G. “Resveratrol, a natural product derived from grape, exhibits antiestrogenic activity and inhibits the growth of human breast cancer cells.� J Cell Physiol. 1999 Jun;179(3):297-304.
10. Bhat KP, Pezzuto JM. “Resveratrol exhibits cytostatic and antiestrogenic properties with human endometrial adenocarcinoma (Ishikawa) cells.� Cancer Res. 2001 Aug 15;61(16):6137-44.
11. Wu F, Safe S. "Differential activation of wild-type estrogen receptor
alpha and C-terminal deletion mutants by estrogens, antiestrogens and
xenoestrogens in breast cancer cells." J Steroid Biochem Mol Biol. 2007 Jan;103(1):1-9
12. Baur JA, Sinclair DA. “Therapeutic potential of resveratrol: the in
vivo evidence.� Nat Rev Drug Discov. 2006 Jun;5(6):493-506.
13. HemaIswarya S, Doble M. “Potential synergism of natural products in the treatment of cancer.� Phytother Res. 2006 Apr;20(4):239-49.
14. Walle T, Hsieh F, DeLegge MH, Oatis JE Jr, Walle UK 2004 High
absorption but very low bioavailability of oral resveratrol in humans. Drug Metab Dispos 32: 1377-1382
15. Wang LX, Heredia A, Song H, Zhang Z, Yu B, Davis C, Redfield R 2004 Resveratrol glucuronides as the metabolites of resveratrol in humans: characterization, synthesis, and anti-HIV activity. J Pharm Sci 93:2448-2457.
16. Maier-Salamon A, Hagenauer B, Wirth M, Gabor F, Szekeres T, Jager W 2006 Increased Transport of Resveratrol Across Monolayers of the Human Intestinal Caco-2 Cells is Mediated by Inhibition and Saturation of Metabolites. Pharm Res 23:2107-2115
17. Abd El-Mohsen M, Bayele H, Kuhnle G, Gibson G, Debnam E, Kaila Srai S, Rice-Evans C, Spencer JP 2006 Distribution of [3H]trans-resveratrol in rat tissues following oral administration. Br J Nutr 96:62-70
18. Soleas GJ, Angelini M, Grass L, Diamandis EP, Goldberg DM 2001 Absorption of trans-resveratrol in rats. Methods Enzymol 335:145-154
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I plan to check out some of the cited research to learn more about the potential benefits of this product, as I'll admit to having only a general knowledge of the ingredients.

Any thoughts?

A friend of mine is finishing her PhD in Nutritional Biochemistry, and always has the inside scoop on things like resveratrol before they're published, I'm going to talk to her this weekend and see if she has any new info.

The Piperine makes me a bit nervous. Wasn't there some talk a while back about how this stuff can boost bioavailability of environmental toxins as well?

The name sucks. I like what I've read about resveratrol though.

I read the same thing about Phytic Acid (IP6) when it came out, but that apparantly was a misguided concern. I need to look in to Piperine, I usually to quite a bit more research before I start popping pills...been too damn busy lately to catch up on these things.




Agreed. As ShuffleUp pointed out, the name looks to be derived from SIRT1, as in a Surplus of SIRT1.

Or maybe whoever was in charge of naming it had a SirPlus of Vodka in their bloodstream at the time.

So, as far as feedback here, I suppose I won't be running this log long enough to comment on life extension capabilities, but I'll surely report back if I hit the century mark.

I'm looking for the anti-inflammation effects as far as short term tangible results. I'm aching lately after large strength gains from a Havoc cycle and some hard training of late...so this should be a good time to test that aspect.

This might go over well at imminst.org forums. Some of those guys are doing 500mg+/day of resv.

I think the name is brilliant if you have an understanding of the resveratrol.

I suppose this is a supplement that is directed towards a more educated consumer, it's not a get huge/get ripped supp that attracts the average monosyllabic meathead.

So you might have something there...although it is still fairly obscure, maybe I'm distracted lately but I sure didn't know what the hell it meant at first.

While the piperine may increase the BA of curcumin is there any evidence it will do the same to resveratrol? I haven't followed the threads on imminst but I believe the idea of 500mg dose was to overwhelm the enzyme responsible for metabolization and allow some to make into the bloostream.

1. Oral bioavailability isn't sufficient.

In Reality:

The extensive conjugation (sulfation and glucuronidation) doesn't mean that the compound has no oral bioavailability in humans. The question from those researching resveratrol has been how is resveratrol allowing for all of these beneficial effects despite having what they thought to be low oral bioavailability. One answer has been that perhaps, contrary
to the generalized rule of thumb that conjugation leads to inactivation, those conjugated resveratrol metabolites were still somewhat active in serum. The most recent answer with mounting evidence is that these conjugation products are acting as reservoirs or endogenous/biologic pro-drugs in the body, allowing for the release of free resveratrol locally and/or systemically after the conjugation moieties (sulfate and Beta-glucuronic acid) are cleaved by sulfatase and Beta-glucuronidase respectively (14-16). With this in mind, it explains why a much lower amount of resveratrol than calculated (i.e., if we assume conjugated products as permanently inactive metabolites) would need to be administered in order to achieve necessary serum concentrations of the free compound. A most recent study has in fact provided direct evidence to support this hypothesis (17).

The fact that many who are actually providing original research are taking regular trans-resveratrol provides some testament to the fact that oral bioavailability isn't the issue it was once thought to be

Since cessation of my Havoc cycle, my joints have gone from bad to worse...but I think I know why.

I've been taking 600mg (6 caps) of 60X0 a night, just recently dropped down to 300mg due to morning fatigue and this joint pain. I think the combo of the AI with the SERM-like capabilities of the SirPlus have had to much of an estrogen clearing effect on my body. That and since the Havoc itself has anti estrogen capabilities, I think I'm doing some damage here.

So I'm going to drop to 2 caps of 60X0 for 2 days, then down to 1 cap for 2 days, then go off.

I'll report back.

USP- aside from the anti-inflammation capabilities, anything else you'd like me to report back on with this product?

Here's what my good friend had to say (finishing her PhD at Tufts, masters in Nutritional Biochemistry, really smart girl, as well as a former fitness competitor, so she's in the game):

soooo....the res story. let me start by saying that res is great, and has
been shown in animals and cells to do a lot of the things that you
mentioned. one thing i would argue is that it is absolutely not stable in
vivo. however, the metabolites may very well mediate some of the effects
that are seen (so i agree with the bioavailability thing). but the dose
needed in mice to see some of the effects, even assuming that some unknown
metabolite(s) of res may actually mediate some of the effects, is still
extremely high. what kind of a dose is in this product? i know that you
could never get enough from red wine, and res probably has little to do with
the french paradox actually.

the sirtuin story is interesting actually. it's definitely true that
sirtuins mediate the effects of caloric restriction on lifespan. there's no
doubt about that. and res was discovered as a caloric restriction mimetic,
yes, based on it's ability to bind SIRT1. but i guess the debate in the
field right now comes down to the biological assays used to show that
binding! when the researchers "tagged" the protein to be able to see it,
that in of itself may have caused it to be able to bind sirtuins. anyways, i
don't know where the research on that is right now, but i imagine the
experiments will be re-done (if not already) and show more definitively that
it does indeed bind SIRT1 (though it is almost surely not the "primary"
target of res as it was once thought). the question is what the heck does a
little SIRT binding mean to a human? no one knows.

the lipolysis thing is probably true. although we believe the guy who showed
lipolysis (a close collaborator of our lab), we were never able to repeat
it, which was kind of disconcerting. but increasing lipolysis in humans
doesn't mean all that much anyways, unless your increasing expenditure as
well. and on that note, it is too early to conclude that res has effects on
energy expenditure. david sinclair's paper should be coming out soon and at
least based on his presentation last year, he has been able to show that in
mice. but at HIGH doses. so who knows. and mice. that means nothing for
humans.

that was a lot of info, but i guess at the end of the day, it may not a bad thing to take.
there don't seem to be any real negatives to res, at least yet. and turmeric is
sure a hot commodity in research these days!! i was just helping a girl on
my floor a few months ago who wanted to show that it activates AMPK in fat
cells. it did.

Double post

That last note regarding turmeric is intriguing.

The sulfation of resveratrol is purportedly responsbile for its anti-estrogenic effects. So would competitive sulfatase inhibitors like quercetin, daidzein, naringenin, etc increase BA of reseveratrol?

This might sound simple, but if Reservatrol's main issue appears to be stability in vivo, should we not be hunting down precursors?

Why, do you believe precursors would survive the GI tract and then react with some enzyme forming resveratrol? If sulfation and glucuronidation are repsonsible for the "stability in vivo" then it would make sense to focus on inhibitors like phytoestrogens and piperine.

I'm way out of my depth here, chemistry-wise. I was just thinking logically with regards to PHs etc that deliver the desired hormone vs metabolism of precursors.

This certainly seems to be what ergo are trying to achieve with the new 6OXO Extreme - Trans-Res with quercetin and piperine.

Ironically, i was looking into quercetin as a means to stabilize T-Res a week or two back.

I can understand the inclusion of quercetin and piperine to prevent conjugation but I don't see the reason for the Trans-Res. It has purported anti-estrogenic activity but through the same mechanism as quercetin, so it seems a bit redundant.

Because the trans-res is what effects SIRT1.

That's my reason for using it but in a test booster type product category that effect might be lsot on most people. Hence why I was assuming it was for it's anti-estrogenic effect.

I wonder why he chose quercetin as opposed to other alternatives. I know GXR has quercetin analogs Q3D Q4D and that it potentiated some stim and nootropic products. So was
it due to their sulfatase inhibition?

try this

sirplus (turmeric, trans resveratrol, piperine), quercetin and lecithin

Sulfatase was not considered. Quercetin is used because its one of the best CYP450 inhibitors found naturally, plus the analogs have glucose-slowing properties from the intestines. IIRC there are some effects on COMT also.