LONGECITY

Anticancer Agents Med Chem. 2010 Aug 10. [Epub ahead of print]
Updates of mTOR inhibitors.
Zhou H, Luo Y, Huang S.

Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932, USA.
Abstract
Mammalian target of rapamycin (mTOR) is a central controller of cell growth, proliferation, metabolism and angiogenesis. mTOR signaling is often dysregulated in various human diseases and thus attracts great interest in developing drugs that target mTOR. Currently it is known that mTOR functions as two complexes, mTOR complex 1/2 (mTORC1/2). Rapamycin and its analogs (all termed rapalogs) first form a complex with the intracellular receptor FK506 binding protein 12 (FKBP12) and then bind a domain separated from the catalytic site of mTOR, blocking mTOR function. Rapalogs are selective for mTORC1 and effective as anticancer agents in various preclinical models. In clinical trials, rapalogs have demonstrated efficacy against certain types of cancer. Recently, a new generation of mTOR inhibitors, which compete with ATP in the catalytic site of mTOR and inhibit both mTORC1 and mTORC2 with a high degree of selectivity, have been developed. Besides, some natural products, such as epigallocatechin gallate (EGCG), caffeine, curcumin and resveratrol, have been found to inhibit mTOR as well. Here, we summarize the current findings regarding mTOR signaling pathway and review the updated data about mTOR inhibitors as anticancer agents.

PMID: 20812900

PLoS One. 2010 Feb 15;5(2):e9199.
SIRT1 negatively regulates the mammalian target of rapamycin.
Ghosh HS, McBurney M, Robbins PD.

Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Abstract
The IGF/mTOR pathway, which is modulated by nutrients, growth factors, energy status and cellular stress regulates aging in various organisms. SIRT1 is a NAD+ dependent deacetylase that is known to regulate caloric restriction mediated longevity in model organisms, and has also been linked to the insulin/IGF signaling pathway. Here we investigated the potential regulation of mTOR signaling by SIRT1 in response to nutrients and cellular stress. We demonstrate that SIRT1 deficiency results in elevated mTOR signaling, which is not abolished by stress conditions. The SIRT1 activator resveratrol reduces, whereas SIRT1 inhibitor nicotinamide enhances mTOR activity in a SIRT1 dependent manner. Furthermore, we demonstrate that SIRT1 interacts with TSC2, a component of the mTOR inhibitory-complex upstream to mTORC1, and regulates mTOR signaling in a TSC2 dependent manner. These results demonstrate that SIRT1 negatively regulates mTOR signaling potentially through the TSC1/2 complex.

PMID: 20169165 [PubMed - in process]PMCID: PMC2821410 Free PMC Article

If rapamycin extends lifespan by inhibiting mTOR, one might expect the same from resveratol. Sinclair's study on normal diet mice did not find this to be the case, though they found resveratrol plus caloric restriction to extend mouse lifespan by more than CR alone did. They did use a genetically messed up mouse; I am awaiting the results of the NIA study on genetically heterologous mice.

Interesting thread, i'm not very familiar with the mTOR pathway, as weve seen with ketamine activating it induces rapid rapid synaptogenesis, could this be a big downside of mTOR inhibition?

mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists

Nanxin Li, Boyoung Lee, Rong-Jian Liu, Mounira Banasr, Jason M. Dwyer, Masaaki Iwata, Xiao-Yuan Li, George Aghajanian, Ronald S. Duman*
Science 20 August 2010; Vol. 329. no. 5994, pp. 959 - 964
DOI: 10.1126/science.1190287

Quote:
The rapid antidepressant response after ketamine administration in treatment-resistant depressed patients suggests a possible new approach for treating mood disorders compared to the weeks or months required for standard medications. However, the mechanisms underlying this action of ketamine [a glutamate N-methyl-D-aspartic acid (NMDA) receptor antagonist] have not been identified. We observed that ketamine rapidly activated the mammalian target of rapamycin (mTOR) pathway, leading to increased synaptic signaling proteins and increased number and function of new spine synapses in the prefrontal cortex of rats. Moreover, blockade of mTOR signaling completely blocked ketamine induction of synaptogenesis and behavioral responses in models of depression. Our results demonstrate that these effects of ketamine are opposite to the synaptic deficits that result from exposure to stress and could contribute to the fast antidepressant actions of ketamine.

Interesting thread, i'm not very familiar with the mTOR pathway, as weve seen with ketamine activating it induces rapid rapid synaptogenesis, could this be a big downside of mTOR inhibition?

mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists

Nanxin Li, Boyoung Lee, Rong-Jian Liu, Mounira Banasr, Jason M. Dwyer, Masaaki Iwata, Xiao-Yuan Li, George Aghajanian, Ronald S. Duman*
Science 20 August 2010; Vol. 329. no. 5994, pp. 959 - 964
DOI: 10.1126/science.1190287

This is an interesting question...might reseveratrol negatively affect synaptogenesis and neurogenesis? If so, this would have important implications on cognition, learning and mood. I'd be interested to hear opinions on this.
Edited by Michael, 27 October 2010 - 05:52 PM.
Trim quote

I used resveratrol on my patients for a while, but have never encountered any problems with cognition or memory. It could be the case however that if it has a negative effect, this may take some time to appear clinically

....
This is an interesting question...might reseveratrol negatively affect synaptogenesis and neurogenesis? If so, this would have important implications on cognition, learning and mood. I'd be interested to hear opinions on this.

Apparently it is not a problem, at least in mice. Quite the opposite, apparently.

Front Aging Neurosci. 2009 Dec 9;1:4.
Resveratrol preserves cerebrovascular density and cognitive function in aging mice.
Oomen CA, Farkas E, Roman V, van der Beek EM, Luiten PG, Meerlo P.

Department of Molecular Neurobiology, Center for Behavior and Neuroscience, University of Groningen Groningen, The Netherlands.
Abstract
Resveratrol, a natural polyphenol abundant in grapes and red wine, has been reported to exert numerous beneficial health effects. Among others, acute neuroprotective effects of resveratrol have been described in several models of neurodegeneration, both in vitro and in vivo. In the present study we examined the neuroprotective effects of long-term dietary supplementation with resveratrol in mice on behavioral, neurochemical and cerebrovascular level. We report a preserved cognitive function in resveratrol-treated aging mice, as shown by an enhanced acquisition of a spatial Y-maze task. This was paralleled by a higher microvascular density and a lower number of microvascular abnormalities in comparison to aging non-treated control animals. We found no effects of resveratrol supplementation on cholinergic cell number or fiber density. The present findings support the hypothesis that resveratrol exerts beneficial effects on the brain by maintaining cerebrovascular health. Via this mechanism resveratrol can contribute to the preservation of cognitive function during aging.

PMID: 20552055

Also some more to look into:

Resveratrol protects spatial learning in middle-aged C57BL/6 mice from effects of ethanol.
Ranney A, Petro MS.
Behav Pharmacol. 2009 Jul;20(4):330-6.
PMID: 1957174

Consuming a diet supplemented with resveratrol reduced infection-related neuroinflammation and deficits in working memory in aged mice.
Abraham J, Johnson RW.
Rejuvenation Res. 2009 Dec;12(6):445-53.
PMID: 20041738

Resveratrol prevents memory deficits and the increase in acetylcholinesterase activity in streptozotocin-induced diabetic rats.
Schmatz R, Mazzanti CM, Spanevello R, Stefanello N, Gutierres J, Corrêa M, da Rosa MM, Rubin MA, Chitolina Schetinger MR, Morsch VM.
Eur J Pharmacol. 2009 May 21;610(1-3):42-8. Epub 2009 Mar 19.
PMID: 19303406


However, resveratrol's effect on mTOR may not be all that strong:

Cell Cycle. 2009 Jun 15;8(12):1901-4. Epub 2009 Jun 21.
At concentrations that inhibit mTOR, resveratrol suppresses cellular senescence.
Demidenko ZN, Blagosklonny MV.

Oncotarget, Albany, NY, USA.
Abstract
Here we demonstrated that, at cytostatic, near-toxic concentrations, resveratrol inhibited S6 phosphorylation and prevented the senescence morphology in human cells. Using a sensitive functional assay, we found that resveratrol partially prevented loss of the proliferative potential associated with cellular senescence. Resveratrol was less effective than rapamycin, because aging-suppression by resveratrol was limited by its toxicity at high concentrations. We discuss whether concentrations of resveratrol that inhibit mTOR (target of rapamycin) and suppress cellular senescence are clinically achievable and whether partial inhibition of mTOR by resveratrol might be sufficient to affect organismal aging.

PMID: 19471118

Edited by maxwatt, 10 October 2010 - 01:59 PM.

....
This is an interesting question...might reseveratrol negatively affect synaptogenesis and neurogenesis? If so, this would have important implications on cognition, learning and mood. I'd be interested to hear opinions on this.

Apparently it is not a problem, at least in mice. Quite the opposite, apparently.

But while resveratrol better preserves existing neural nets, ketamine helps create them, if I'm reading the studies correctly and their conclusions are human-extensible. This would suggest the hypothesis that people on resveratrol should actually be less creative and learn more slowly than those who don't consume it. It's just that the former group would maintain their level of functionality for longer. The tradeoff justifies some careful analysis.

very interesting indeed

metformin also decrease the Mtor pathway trough indirect mechanism and if think to a higher extent than resveratrol, plus it has also some other added benefits(apetite supresant, glucose regulation, grwoth hormone cascade inhibition).

I will try to find the links to this claim, when I have some time though.

very interesting though

thank you for posting

But while resveratrol better preserves existing neural nets, ketamine helps create them, if I'm reading the studies correctly and their conclusions are human-extensible. This would suggest the hypothesis that people on resveratrol should actually be less creative and learn more slowly than those who don't consume it. It's just that the former group would maintain their level of functionality for longer. The tradeoff justifies some careful analysis.

Since ketamine works as a "shock" therapy, it may be ideal to combine them, a few days off resveratrol, then use the dose in the antidepressant study's to rapidly induce synaptogenesis and then return to resveratrol.
Edited by Michael, 27 October 2010 - 05:54 PM.
Trim quotes

....
This is an interesting question...might reseveratrol negatively affect synaptogenesis and neurogenesis? If so, this would have important implications on cognition, learning and mood. I'd be interested to hear opinions on this.

Apparently it is not a problem, at least in mice. Quite the opposite, apparently.

But while resveratrol better preserves existing neural nets, ketamine helps create them, if I'm reading the studies correctly and their conclusions are human-extensible. This would suggest the hypothesis that people on resveratrol should actually be less creative and learn more slowly than those who don't consume it. It's just that the former group would maintain their level of functionality for longer. The tradeoff justifies some careful analysis.

I do know ketamine disrupts working memory, and the effect of high doses persists long after cessation. It also prevents memory consolidation. I am having a hard time understanding your basis for suggesting this hypothesis. Ketamine seems like a good way of messing yourself up except at low doses, or to correct very specific deficits or chemical insults.


Neuroscience. 2010 Jun 2;167(4):969-73. Epub 2010 Mar 22.
Ketamine impairs recognition memory consolidation and prevents learning-induced increase in hippocampal brain-derived neurotrophic factor levels.
Goulart BK, de Lima MN, de Farias CB, Reolon GK, Almeida VR, Quevedo J, Kapczinski F, Schröder N, Roesler R.

Laboratory of Molecular Neuropharmacology, Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
Abstract
The non-competitive N-methyl-d-aspartate (NMDA) glutamate receptor antagonist ketamine has been shown to produce cognitive deficits. However, the effects of ketamine on the consolidation phase of memory remain poorly characterized. Here we show that systemic administration of ketamine immediately after training dose-dependently impairs long-term retention of memory for a novel object recognition (NOR) task in rats. Control experiments showed that the impairing effects of ketamine could not be attributed to an influence on memory retrieval or sensorimotor effects. In addition, ketamine prevented the increase in hippocampal brain-derived neurotrophic factor (BDNF) levels induced by NOR learning. Our results show for the first time that ketamine disrupts the consolidation phase of long-term recognition memory. In addition, the findings suggest that the amnestic effects of ketamine might be at least partially mediated by an influence on BDNF signaling in the hippocampus.

PMID: 20338225

On a side note, and I would never have thought that Ketamine would ever be mentioned in relation to Resveratrol, it was rumored that astronauts were being trained to tolerate periods of weightlessness and zero gravity with Ketamine, underwater.

Talk about truly floating.

[SNIP: Studies showing that Resveratrol inhibits mTOR -- in vitro].

If rapamycin extends lifespan by inhibiting mTOR, one might expect the same from resveratol. Sinclair's study on normal diet mice did not find this to be the case, though they found resveratrol plus caloric restriction to extend mouse lifespan by more than CR alone did. They did use a genetically messed up mouse; I am awaiting the results of the NIA study on genetically heterologous mice.

Wait no more. NIA's ITP Confirms: Resveratrol Does Not Extend Lifespan in Normal, Healthy Mice; Confirms Limited Benefit to Rapamycin.
Edited by Michael, 28 October 2010 - 01:06 AM.

[SNIP: Studies showing that Resveratrol inhibits mTOR -- in vitro].

If rapamycin extends lifespan by inhibiting mTOR, one might expect the same from resveratol. Sinclair's study on normal diet mice did not find this to be the case, though they found resveratrol plus caloric restriction to extend mouse lifespan by more than CR alone did. They did use a genetically messed up mouse; I am awaiting the results of the NIA study on genetically heterologous mice.

Wait no more. NIA's ITP Confirms: Resveratrol Does Not Extend Lifespan in Normal, Healthy Mice; Confirms Limited Benefit to Rapamycin.

Did you mean to post this link here or in the thread started by you linking to the article you wrote over at SENS? Perhaps, keep it in one thread so its easier to follow.

My question is that, on the chart ...it appears the resveratrol had 'some' effect in males at least as evident by the graph. Of course I can't expand it big enough to actually tell.

With that said, despite the finding of no significant life expansion increase in 'mice', what were the findings, if any, on 'healthy' life extension. Even if the supplement doesn't increase span, does it increase overall health of the subjects during that span? If so, it would still be a worthy supplement.

Again ...maybe consolidate into a single thread rather than cross posting so its easier to follow.

Thanks

But while resveratrol better preserves existing neural nets, ketamine helps create them, if I'm reading the studies correctly and their conclusions are human-extensible. This would suggest the hypothesis that people on resveratrol should actually be less creative and learn more slowly than those who don't consume it. It's just that the former group would maintain their level of functionality for longer. The tradeoff justifies some careful analysis.

Since ketamine works as a "shock" therapy, it may be ideal to combine them, a few days off resveratrol, then use the dose in the antidepressant study's to rapidly induce synaptogenesis and then return to resveratrol.

NMDA receptor currents are requisite for synaptogenesis, so a blockade with a nasty drug like ketamine would have the opposite effect. Ketamine has been used, however, with some effect for treating some categories of depression, but the results are very preliminary.
Edited by Rol82, 04 November 2010 - 12:29 PM.

But while resveratrol better preserves existing neural nets, ketamine helps create them, if I'm reading the studies correctly and their conclusions are human-extensible. This would suggest the hypothesis that people on resveratrol should actually be less creative and learn more slowly than those who don't consume it. It's just that the former group would maintain their level of functionality for longer. The tradeoff justifies some careful analysis.

Since ketamine works as a "shock" therapy, it may be ideal to combine them, a few days off resveratrol, then use the dose in the antidepressant study's to rapidly induce synaptogenesis and then return to resveratrol.

NMDA receptor currents are requisite for synaptogenesis, so a blockade with a nasty drug like ketamine would have the opposite effect.

Wrong

But while resveratrol better preserves existing neural nets, ketamine helps create them, if I'm reading the studies correctly and their conclusions are human-extensible. This would suggest the hypothesis that people on resveratrol should actually be less creative and learn more slowly than those who don't consume it. It's just that the former group would maintain their level of functionality for longer. The tradeoff justifies some careful analysis.

Since ketamine works as a "shock" therapy, it may be ideal to combine them, a few days off resveratrol, then use the dose in the antidepressant study's to rapidly induce synaptogenesis and then return to resveratrol.

NMDA receptor currents are requisite for synaptogenesis, so a blockade with a nasty drug like ketamine would have the opposite effect.

Wrong

Okay, I must be imagining things to support my ostensible prejudice.

NMDA agonists block synaptogenesis in rodents, specifically research into Huntington's disease using rodent models.

NMDA agonists block synaptogenesis in rodents, specifically research into Huntington's disease using rodent models.

Yes, but I thought this finding was confined to disease models where this group of receptors is hyperactive. Are the receptors completely knocked out in research experiments that you make reference to?

NMDA agonists block synaptogenesis in rodents, specifically research into Huntington's disease using rodent models.

Yes, but I thought this finding was confined to disease models where this group of receptors is hyperactive. Are the receptors completely knocked out in research experiments that you make reference to?

My understanding is NMDA is but weakly inhibited my memantine, which is possibly useful in Huntington's where extra-synaptic NMDA receptors are a problem; they get hyperactive and kill the neurons; these would be more affected by a weak inhibitor than the synaptic receptors, which you don't want to knock out or the neuron would be non-functional. So a weak NMDA inhibitor in theory would only block the extra-synaptic receptors, preventing neuronal death, whilst sparing the synaptic receptors which allow the neuron to function. At least that's the theory, but I don't think it's worked out so well in the lab, at least so far. The dose is everything.
Edited by maxwatt, 06 November 2010 - 12:04 AM.

Okay, I must be imagining things to support my ostensible prejudice.

A quick search for ketamine can turn up alot of stuff on this board

Wait no more. NIA's ITP Confirms: Resveratrol Does Not Extend Lifespan in Normal, Healthy Mice; Confirms Limited Benefit to Rapamycin.

So either

• Resveratrol does not inhibit mTOR enough, or
• Rapamycin does not extend lifespan by inhibiting mTOR, but through some other mechanism, or
• Resveratrol does something else that cancels the life-extending effect of inhibiting mTOR.

It seems paradoxical that resveratrol-fed mice seemed healthier, but died at about the same age none-the-less. Whatever kills mice in general, is not inhibited by resveratrol though other effects of aging seem to be.
Edited by maxwatt, 07 November 2010 - 01:18 AM.

It seems paradoxical that resveratrol-fed mice seemed healthier, but died at about the same age none-the-less. Whatever kills mice in general, is not inhibited by resveratrol though other effects of aging seem to be.

Reading all this.
Perhaps the study was flawed?

Resveratrol does not protect against a certain form of cancer from which that strain of mice in the study often die. But if you are a human (or mouse) and you eat a western diet - and consequently are prone to diabetes, heart disease, and certain forms of cancer such as colon cancer - resveratrol very well might help you live longer. The problem, all of this is speculation because most of the research money is coming from big pharma and big pharma does not want natural compounds to outperform its offerings.

It seems paradoxical that resveratrol-fed mice seemed healthier, but died at about the same age none-the-less. Whatever kills mice in general, is not inhibited by resveratrol though other effects of aging seem to be.

Reading all this.
Perhaps the study was flawed?

The problem, all of this is speculation because most of the research money is coming from big pharma and big pharma does not want natural compounds to outperform its offerings.

THis.

How did ketamine get into this? =/ NMDA receptor activity is necessary for memory formation - NMDA antagonists like ketamine block that from happening.

Anywyas, I talked with Matt Kaeberlein some time ago and he said that resveratrol was definitively negative (only one lab has managed to produce positive results from it - and it wasn't even from normal-strain mice, but rather, diseased mice).