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[FightAging] Tracing the Pathway Back for Resveratrol


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10 replies to this topic

#1 ImmInst

Posted 15 February 2012 - 01:49 PM


Resveratrol in and of itself is likely not terribly interesting for work on longevity - and certainly not worthy of the hype surrounding it. The same probably goes for sirtuins in general. This, however, is still a good example of work on tracing back the pathways of action of a metabolic change agent: "Research has previously suggested that resveratrol acts through activation of the sirtuin (SIR) gene family. This gene pathway, though controversial, has been implicated in life extension across several species. It has been reported that SIR extends lifespan in much the same way as caloric restriction which itself in turn may activate SIR. It has remained unclear however if resevertrol directly activates SIR or if it acts on SIR indirectly via another intermediary biochemical pathway. The current study successfully answered that question. Using several cell biology techniques the authors were able to demonstrate that resveratrol actually functions to activate SIR indirectly. They showed that resveratrol is really a phosphodiesterase inhibitor (PDE4). They demonstrated that reducing PDE4 allows cyclic AMP (cAMP) levels in the cells to rise. cAMP then increases the activity of AMPK which next increases NAD+ which finally increases SIR. This elegant study then went on to prove that the same life extending benefits of resveratrol could be achieved in rats by administering them the PDE4 inhibitor rolipram. ... inhibiting PDE4 with rolipram reproduces all of the metabolic beneļ¬ts of resveratrol, including prevention of diet-induced obesity and an increase in mitochondrial function, physical stamina, and glucose tolerance in mice. "

Link: http://extremelongevity.net/2012/02/13/resveratrol-study-finds-new-class-of-life-extension-molecules/


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#2 Mind Re: [FightAging] Tracing the Pathway Back for Resveratrol

  • Location:Wausau, WI
  • yes

Posted 15 February 2012 - 09:48 PM

Seems like an interesting result. Any comments from the resveratrol crowd? I suspect the resveratrol works (directly or indirectly) on some other metabolic pathways as well.

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#3 hamishm00 Re: [FightAging] Tracing the Pathway Back for Resveratrol

  • Location:United Arab Emirates

Posted 18 February 2012 - 06:39 AM

Bill Sardi was quick to pounce:

Rolipram would never be fit for human use. It causes uncontrollable vomiting, nausea and headaches. In 30 years pharmacologists have not been able to develop a phosphodiesterase inhibitor that does not cause these side effects. Resveratrol is still king. The National Institutes of Health is promoting a drug agenda.


Edited by hamishm00, 18 February 2012 - 06:39 AM.


#4 CaptainFuture Re: [FightAging] Tracing the Pathway Back for Resveratrol

  • Location:Europe

Posted 18 February 2012 - 08:26 AM

Does anyone ever verify what Bill Sardi says? I wonder where this guy has his information from. Maybe I made a mistake but when rolipram causes uncontrollable vomitting, nausea and headaches, then how could these studies be conducted and why didn't they report these problems?


PMID: 1475038

A multicenter randomized 4-week interindividual double-blind study was carried out in 58 hospitalized patients with major depressive disorder (DSM III 296.23, 296.22, 296.33, 296.32, 296.53 and 296.52) to test the dose-effect relationship of three different doses of the new cAMP-phosphodiesterase inhibitor rolipram: 3 x 0.25 mg, 3 x 0.50 mg and 3 x 1.00 mg rolipram/day. With respect to the desired effect, the 3 x 0.50 mg dosage stood out from the others in almost all relevant parameters. With respect to the response rate, the efficacy of the 3 x 0.25 mg dosage was about the same as that reported in the literature for placebo. The inferior performance of the 3 x 1.00 mg dosage compared to the 3 x 0.50 mg dosage might indicate a reverse U-shaped dose-effect relationship. There was good tolerance to all three dosages. There were no findings that might cast doubt on the safety of the dosages tested.


PMID: 6393150
The antidepressant effect of rolipram, believed to be based on a new mechanism of action, was investigated in an open phase II study in 10 depressive patients, most of whom had been refractory to previous antidepressant therapy. Five patients displayed a good to very good improvement of their depressive condition. Four patients failed to show any substantial improvement, and therapy had to be withdrawn in one case due to deterioration of the condition. In most cases, the antidepressant effect of the trial preparation became noticeable after 2-4 days of treatment only. Basing on the presented cases, the tolerance can be described as excellent compared to other antidepressants.

PMID: 2668980

"Rolipram improves signal transmission in central noradrenergic neurones at a pre- and postsynaptic level, and is thus a novel approach in antidepressant therapy. In order to prove efficacy, tolerance, and safety, several controlled studies are underway. Results of a randomized double-blind comparative trial versus imipramine involving 64 in-patients with Major Depressive Disorder (DSM III) in six independent centers will be presented and discussed. The chosen biometric model provided evidence that towards the end of the study imipramine was superior to Rolipram. The particular clinical relevance of this difference is discussed. As regards tolerance, nausea emerged as the typical side-effect of Rolipram, whereas imipramine precipitated mainly anticholinergic side-effects." [Nausea seems to be a normal side effect but far from uncontrollable.]


Edited by CaptainFuture, 18 February 2012 - 08:30 AM.

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#5 brunotto Re: [FightAging] Tracing the Pathway Back for Resveratrol

  • Location:Italy

Posted 27 April 2012 - 01:04 PM

Pentoxifylline is a PDE4 inhibitor... IMHO vomiting, nausea and headaches are part of the CAMP elevating effect of Pentoxifylline. If taken on totally empty stomach I do not have problems (even with 600 mg)...

http://en.wikipedia..../Pentoxifylline

#6 bixbyte Re: [FightAging] Tracing the Pathway Back for Resveratrol

  • Location:End of the Galaxy

Posted 30 April 2012 - 08:36 PM

Great a study to determine if Resveratrol activates Sirtuin directly or indirectly.
To me it well enough that Resveratrol might extend my lifetime. ;)
Also this study sites that Resveratrol spans a range of various phosphodiesterase (PDE) inhibitors.
Someone forget to mention?
The amounts of each PDE resveratrol inhibits in the study is a unique signature.
Have a Great Day!
____________________________________________________

Resveratrol in and of itself is likely not terribly interesting for work on longevity - and certainly not worthy of the hype surrounding it. The same probably goes for sirtuins in general. This, however, is still a good example of work on tracing back the pathways of action of a metabolic change agent: "Research has previously suggested that resveratrol acts through activation of the sirtuin (SIR) gene family. This gene pathway, though controversial, has been implicated in life extension across several species. It has been reported that SIR extends lifespan in much the same way as caloric restriction which itself in turn may activate SIR. It has remained unclear however if resevertrol directly activates SIR or if it acts on SIR indirectly via another intermediary biochemical pathway. The current study successfully answered that question. Using several cell biology techniques the authors were able to demonstrate that resveratrol actually functions to activate SIR indirectly. They showed that resveratrol is really a phosphodiesterase inhibitor (PDE4). They demonstrated that reducing PDE4 allows cyclic AMP (cAMP) levels in the cells to rise. cAMP then increases the activity of AMPK which next increases NAD+ which finally increases SIR. This elegant study then went on to prove that the same life extending benefits of resveratrol could be achieved in rats by administering them the PDE4 inhibitor rolipram. ... inhibiting PDE4 with rolipram reproduces all of the metabolic bene�ts of resveratrol, including prevention of diet-induced obesity and an increase in mitochondrial function, physical stamina, and glucose tolerance in mice. "
Link: http://extremelongev...sion-molecules/


View the full article



#7 brunotto Re: [FightAging] Tracing the Pathway Back for Resveratrol

  • Location:Italy

Posted 02 May 2012 - 07:07 AM

Then Apremilast (a specific Celegene's PDE4 inhibitor that is coming) will be very interesting... now on Phase 3

Psoriasis and psoriatic arthritis are common clinical conditions that negatively impact health-related quality of life and are linked to serious medical comorbidities. Disease mechanisms involve local and systemic chronic inflammatory processes. Available biologic therapies specifically target single inflammatory mediators, such as tumor necrosis factor-α (TNF-α), in the context of a larger inflammatory signaling cascade. To interrupt this pathological cascade earlier in the response or further upstream, and return pro-inflammatory and anti-inflammatory signaling to a homeostatic balance, the use of a phosphodiesterase4 (PDE4) inhibitor has been explored. PDE4 is the major enzyme class responsible for the hydrolysis of cyclic adenosine monophosphate (cAMP), an intracellular second messenger that controls a network of pro-inflammatory and anti-inflammatory mediators. With PDE4 inhibition, and the resulting increases in cAMP levels in immune and non-immune cell types, expression of a network of pro-inflammatory and anti-inflammatory mediators can be modulated. Apremilast is an orally available targeted PDE4 inhibitor that modulates a wide array of inflammatory mediators involved in psoriasis and psoriatic arthritis, including decreases in the expression of inducible nitric oxide synthase, TNF-α, and interleukin (IL)-23 and increases IL-10. In phase II studies of subjects with psoriasis and psoriatic arthritis, apremilast reversed features of the inflammatory pathophysiology in skin and joints and significantly reduces clinical symptoms. The use of an oral targeted PDE4 inhibitor for chronic inflammatory diseases, like psoriasis and psoriatic arthritis, represents a novel treatment approach that does not target any single mediator, but rather focuses on restoring a balance of pro-inflammatory and anti-inflammatory signals.

http://www.sciencedi...006295212000263

Edited by brunotto, 02 May 2012 - 07:10 AM.


#8 bixbyte Re: [FightAging] Tracing the Pathway Back for Resveratrol

  • Location:End of the Galaxy

Posted 02 May 2012 - 03:27 PM

Then Apremilast (a specific Celegene's PDE4 inhibitor that is coming) will be very interesting... now on Phase 3

Psoriasis and psoriatic arthritis are common clinical conditions that negatively impact health-related quality of life and are linked to serious medical comorbidities. Disease mechanisms involve local and systemic chronic inflammatory processes. Available biologic therapies specifically target single inflammatory mediators, such as tumor necrosis factor-α (TNF-α), in the context of a larger inflammatory signaling cascade. To interrupt this pathological cascade earlier in the response or further upstream, and return pro-inflammatory and anti-inflammatory signaling to a homeostatic balance, the use of a phosphodiesterase4 (PDE4) inhibitor has been explored. PDE4 is the major enzyme class responsible for the hydrolysis of cyclic adenosine monophosphate (cAMP), an intracellular second messenger that controls a network of pro-inflammatory and anti-inflammatory mediators. With PDE4 inhibition, and the resulting increases in cAMP levels in immune and non-immune cell types, expression of a network of pro-inflammatory and anti-inflammatory mediators can be modulated. Apremilast is an orally available targeted PDE4 inhibitor that modulates a wide array of inflammatory mediators involved in psoriasis and psoriatic arthritis, including decreases in the expression of inducible nitric oxide synthase, TNF-α, and interleukin (IL)-23 and increases IL-10. In phase II studies of subjects with psoriasis and psoriatic arthritis, apremilast reversed features of the inflammatory pathophysiology in skin and joints and significantly reduces clinical symptoms. The use of an oral targeted PDE4 inhibitor for chronic inflammatory diseases, like psoriasis and psoriatic arthritis, represents a novel treatment approach that does not target any single mediator, but rather focuses on restoring a balance of pro-inflammatory and anti-inflammatory signals.

http://www.sciencedi...006295212000263

__________________________________________________

The PDE superfamily is comprised of 11 types of PDEs
(PDE1–11) of which multiple isoforms exist. PDEs have different
substrate specificities: PDEs 4, 7, and 8 are cAMP-selective
hydrolases, PDEs 5, 6, and 9 are cGMP-selective hydrolases,
and PDEs 1, 2, 3, 10, and 11 can hydrolyze both cAMP and
cGMP to varying degrees. Multiple members of the PDE superfamily
are usually expressed in each cell. We measured the activities
of recombinant PDEs 1, 2, 3, 4, and 5 in the presence
of resveratrol. We found that resveratrol inhibited PDE1
(IC50 6 mM), PDE3 (IC50 10 mM), and PDE4 (IC50 14 mM)
but did not affect the activity of PDEs 2 or 5 (Figure 4A).

Therefore: Resveratrol is a Nonselective phosphodiesterase inhibitors.

source: http://www.scienceda...20202151133.htm

#9 brunotto Re: [FightAging] Tracing the Pathway Back for Resveratrol

  • Location:Italy

Posted 03 May 2012 - 05:59 AM

Therefore: Resveratrol is a Nonselective phosphodiesterase inhibitors.
source: http://www.scienceda...20202151133.htm


Quite similar to Pentoxyphilline that I use...

#10 CaptainFuture Re: [FightAging] Tracing the Pathway Back for Resveratrol

  • Location:Europe

Posted 03 May 2012 - 03:28 PM

Great a study to determine if Resveratrol activates Sirtuin directly or indirectly.
To me it well enough that Resveratrol might extend my lifetime. ;)
Also this study sites that Resveratrol spans a range of various phosphodiesterase (PDE) inhibitors.
Someone forget to mention?
The amounts of each PDE resveratrol inhibits in the study is a unique signature.
Have a Great Day!



Hi bixbyte,

Rolipram is a potent PDE4 inhibitor. Do we know how strong the influence of PDE4 on live extension is? Would Resveratrol and its bigger range be a better choice?

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#11 niner Re: [FightAging] Tracing the Pathway Back for Resveratrol

  • Location:Philadelphia

Posted 03 May 2012 - 06:20 PM

The PDE superfamily is comprised of 11 types of PDEs
(PDE1–11) of which multiple isoforms exist. PDEs have different
substrate specificities: PDEs 4, 7, and 8 are cAMP-selective
hydrolases, PDEs 5, 6, and 9 are cGMP-selective hydrolases,
and PDEs 1, 2, 3, 10, and 11 can hydrolyze both cAMP and
cGMP to varying degrees. Multiple members of the PDE superfamily
are usually expressed in each cell. We measured the activities
of recombinant PDEs 1, 2, 3, 4, and 5 in the presence
of resveratrol. We found that resveratrol inhibited PDE1
(IC50 6 mM), PDE3 (IC50 10 mM), and PDE4 (IC50 14 mM)
but did not affect the activity of PDEs 2 or 5 (Figure 4A).


Before anyone gets too carried away with this data, note the IC50s involved. (They are actually micromolar values, not millimolar as quoted.) These are the concentrations that would be required to inhibit the various PDEs to 50% of their normal activity. Even the lowest of these, 6 uM for PDE1, is a resveratrol concentration that no one is likely to see in vivo. If you look at the paper, you will see them dosing their mice at crazy levels like 400 mg/kg. Unless you guys are dosing 30 grams of resveratrol, you might want to rethink this.




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