LONGECITY

The COMT Inhibitor Synergy thread is kind of getting old, and the point of it was not well established. I wanted to find a way to still get the benefits of herbs like Ginkgo and Astragulus while getting the benefit of a COMT Inhibitor. The trouble is that most herbs with catechols like tea (catechins) and coffee (caffeic acid) also inhibit a number of DNA enzymes like Telomerase and Topoisomerase.

We discussed some synergies with various other herbs, such as ones for MAO-B inhibition. I took some time to figure out exactly the purpose of the enzyme and determined that it only broke down molecules with the catechol ring (a phenyl ring plus an adjacent OH molecule). Eventually, I came to the conclusion that we'll need some type of larger molecule so that it won't get caught in the DNA enzymes... I remember reading somewhere that molecules within a certain diameter can penetrate the cell nucleus or get into DNA enzymes or something.

So I'm on the search for something like the following:

• Inhibits Catechol-O-Methyl-Transferase (COMT)
• Longer half life (6 to 10 hours as opposed to 2 or 3)
• Crosses the Blood Brain Barrier
• Does not inhibit DNA synthesis
  
  • No (or low) affinity in vitro for Telomerase, Topoisomerase, or DNA/RNA modifications.
  • OR too large in size to cross nuclear membrane.
• Easily bought (retail / wholesale only) in extract form.

As the thread went on, it became apparent that some catechols do not fit the criteria of DNA synthesis safety:

• EGCG
• Quercetin
• Catechin
• Epicatechin
• Fisetin
• Luteolin
• Resveratrol
• Caffeic Acid
• Chlorogenic Acid
• Caffeic Acid Phenethyl Ester

So far, I've got two great looking prospectives: rosmarinic acid and cichoric acid. Rosmarinic Acid is the best one so far, but unfortunately, it also raises GABA levels, so a need to take it with Ginkgo (high in Bilobalide) might arise if it's GABA-T inhibition is too strong. Cichoric acid seems better for cognition already low in anxiety and actually causes quite a cellular response, influencing an increase in acetylcholine receptor density. Unfortunately, it is not widely available in extract form apart from Echinacea, which fat people like me might want to veer away from the canabanoids.

Join me in this quest to find such a thing. Why? Because theoretically COMT inhibition will increase working capacity via slowing down Norepinephrine break-down in the Pre-Frontal Cortex. Theoretically great for ADHD, Dementia, Parkinsons, Depression, etc... Plus, I just want to. So there.
Edited by devinthayer, 27 October 2011 - 02:45 PM.

The trouble is that most herbs with catechols like tea (catechins) and coffee (caffeic acid) also inhibit a number of DNA enzymes like Telomerase and Topoisomerase.

Forgive my ignorance, as I am new to all this and still learning, but as a devoted green tea drinker (loose-leaf) I'd be interested to know what the effects are of this enzyme inhibition. Should my tea-drinking be a cause for worry? As far as I can tell it has only improved my mood, instilled a sense of calm, and sharpened my mind, no to mention the health benefits.

I also drink white tea and oolong regularly.

Is there some other effect I should be worried about?

Thanks.

The trouble is that most herbs with catechols like tea (catechins) and coffee (caffeic acid) also inhibit a number of DNA enzymes like Telomerase and Topoisomerase.

Forgive my ignorance, as I am new to all this and still learning, but as a devoted green tea drinker (loose-leaf) I'd be interested to know what the effects are of this enzyme inhibition. Should my tea-drinking be a cause for worry? As far as I can tell it has only improved my mood, instilled a sense of calm, and sharpened my mind, no to mention the health benefits.

I also drink white tea and oolong regularly.

Is there some other effect I should be worried about?

Thanks.

Not really. No, unless you are pregnant. The same mechanisms that make a great cancer fighter also make for one hell of a ride for your stem cells. Your DNA will age in a normal fashion, not at an accelerated rate. Assuming you are not a daily tea drinker, herbs like Ginkgo and Astragalus which help DNA function by reactivating telomerase (for about a 3 month period) will still have their effect on the second day after you do not drink your tea.

If you are not taking anti-aging nucleic acid herbs like Ginkgo and Astragalus AND you are not nursing or pregnant, you will have nothing to worry about. They do not cause cancer at normal concentrations, just inhibit overgrowth or fast growth like in cancer cells.

http://www.jneurosci...8.full.pdf html

In summary, these results strongly suggest that, in the context of attentional control, variation in dopamine signaling mediated by COMT is critical for processes that engage specific subregions of the prefrontal cortex (e.g., conflict management in the dorsal cingulate). These results add to evidence from pharmacological studies that dopaminergic modulation influences the efficiency of executive attention. Furthermore, they may represent a viable approach to understanding individual differences in attentional control and possibly neuropsychiatric disorders with complex genetic etiologies that show attentional deficits.

Neurobehavioral and genotoxic aspects of rosmarinic acid.

Rosmarinic acid is a naturally occurring hydroxylated compound. It is present in many plants, for example, it occurs in Artemisia capillaris, Calendulla officinalis, Melissa officinalis, Salvia officinalis and in other several plant families. It also shows a number of interesting biological activities, e.g. antiviral, antibacterial, antiinflammatory and antioxidant. The aim of the present study was to investigate the effect of the i.p. administration of rosmarinic acid (1, 2, 4 or 8 mg kg(-1)) on elevated plus-maze, step-down inhibitory avoidance and open field task in rats. In addition, we evaluated its genotoxic effect on brain tissue using the comet assay. Rosmarinic acid (2 and 4 mg kg(-1)) increased the number of entries in the open arms, suggesting an anxiolytic-like activity when used in lower doses, without affecting the short-term memory (STM) and long-term memory (LTM) retention on inhibitory avoidance task. Eight milligrams per kilograms of this acid was enough to increase the locomotion and motivation of the animals, but not 1, 2 or 4 mg kg(-1), suggesting that in lower doses, this compound can produce anxiolytic-like effect without exerting locomotor alterations or DNA damage in brain tissue.

Though Rosmarinic Acid does not meet the criteria causing DNA damage in the brain, cichoric acid only seems to inhibit DNA enzymes associated with the HIV virus, specifically the enzyme known as integrase. Integrase enables a virus to integrate its own DNA into the host cell, thereby permanently transforming the cell into a virus factory. This is what I call a vampire virus... it takes over your body at a cellular level. Cichoric acid prevents that from even happening. http://www.ncbi.nlm....choric acid DNA

Just adding a link. Might be of use to you . . .

http://www.anti-agin...-of-telomerase/

Just adding a link. Might be of use to you . . .

http://www.anti-agin...-of-telomerase/

Good find. It brings into question catechols effects on progenitor cells in vivo. In it, the following studies are quoted to support telomerase inhibition:

Resveratrol:
http://www.ncbi.nlm....pubmed/16465368 (breast cancer)
http://www.ncbi.nlm....pubmed/16918129 (colon cancer)

Curcumin:
http://www.ncbi.nlm....pubmed/16820928 (cancer)
http://www.ncbi.nlm....pubmed/17096185 (leukemia)
http://www.ncbi.nlm....pubmed/16445949 (K-562 cells: leukemia)
http://www.ncbi.nlm....pubmed/19191010 (human cervical carcinoma)

EGCG:
http://www.ncbi.nlm....pubmed/14767556 (breast cancer)
http://www.ncbi.nlm....pubmed/15975707 (carcinoma)
http://www.ncbi.nlm....pubmed/17570133 (breast cancer and leukemia)


The article then goes on to explain the hypocracy - how all these studies are done on cancerous or mutated cell lines, not healthy progenitor cells, which telomere lengthening is supposed to help. Thus, also included are the following renerences to support that at least resveratrol can lengthen telomeres in healthy cells and curcumin may only affect telomerase in unhealthy cell lines:


http://www.ncbi.nlm....pubmed/18587418

Resveratrol reduces endothelial progenitor cells senescence through augmentation of telomerase activity by Akt-dependent mechanisms.

BACKGROUND AND PURPOSE:
Recent studies have shown that resveratrol increased endothelial progenitor cells (EPCs) numbers and functional activity. However, the mechanisms remain to be determined. Previous studies have demonstrated that increased EPC numbers and activity were associated with the inhibition of EPC senescence, which involves activation of telomerase. Therefore, we investigated whether resveratrol inhibits the onset of EPC senescence through telomerase activation, leading to potentiation of cellular activity.

EXPERIMENTAL APPROACH:
After prolonged in vitro cultivation, EPCs were incubated with or without resveratrol. The senescence of EPCs were determined by acidic beta-galactosidase staining. The bromo-deoxyuridine incorporation assay or a modified Boyden chamber assay were employed to assess proliferative or migratory capacity, respectively. To further examine the underlying mechanisms of these effects, we measured telomerase activity and the phosphorylation of Akt by western blotting.

KEY RESULTS:
Resveratrol dose dependently prevented the onset of EPCs senescence and increased the proliferation and migration of EPCs. The effect of resveratrol on senescence could not be abolished by eNOS inhibitor or by an oestrogenic receptor antagonist. Resveratrol significantly increased telomerase activity and Akt phosphorylation. Pre-treatment with the PI3K inhibitor, LY294002, significantly attenuated resveratrol-induced telomerase activity.

CONCLUSIONS AND IMPLICATIONS:
Resveratrol delayed the onset of EPC senescence and this effect was accompanied by activation of telomerase through the PI3K-Akt signalling pathway. The inhibition of EPCs senescence by resveratrol might protect EPCs against dysfunction induced by pathological factors in vivo and improve EPC functional activities in a way that may be important for cell therapy.

And also this one...

http://www.ncbi.nlm....pubmed/17968319

Immortalization of epithelial progenitor cells mediated by resveratrol.

Within the hierarchy of epithelial stem cells, normal progenitor cells may express regulated telomerase during renewal cycles of proliferation and differentiation. Discontinuous telomerase activity may promote increased renewal capacity of progenitor cells, while deregulated/continuous telomerase activity may promote immortalization when differentiation and/or senescent pathways are compromised. In the present work, we show that resveratrol activates, while progesterone inactivates, continuous telomerase activity within 24 h in subpopulations of human Li-Fraumeni syndrome-derived breast epithelial cells. Resveratrol results in immortalization of mixed progenitor cells with mutant p53, but not human epithelial cells with wild type p53. Our results demonstrate the potential for renewing progenitor cells with mutant p53 to immortalize after continuous telomerase expression when exposed to certain environmental compounds. Understanding the effects of telomerase modulators on endogenous telomerase activity in progenitor cells is relevant to the role of immortalization in the initiation and progression of cancer subtypes.

Though this one is not as convincing...

http://www.ncbi.nlm....pubmed/17569215

Cell growth regulation.

Curcumin, the active ingredient of turmeric (Curcuma longa) used in culinary and medical practices in Asia, has immense potential for being used in cancer chemotherapy because of its control over the cell growth regulatory mechanisms. The present chapter throws light on the role of curcumin in modulating the various phases of the cell cycle and its apoptosis-inducing effects. This is followed by a discussion on the implications of these effects of curcumin for its use as a chemotherapeutic agent in cancer. Curcumin affects various cell cycle proteins and checkpoints involving downregulation of some of the cyclins and cyclin-dependent kinases, upregulation of cdk inhibitors, and inhibition of DNA synthesis. In addition, curcumin also exerts indirect control over cell division such as inhibition of telomerase activity. Remarkably, some studies point toward a selective growth-inhibitory effect of curcumin on transformed cell lines compared to nontransformed cell lines. Curcumin has also been demonstrated to have proapoptotic effects in several in vitro studies, mostly through the mitochondria-mediated pathway of apoptosis. Curcumin-mediated regulation of apoptosis involves caspases, Bcl2 family members, inhibitors of apoptosis proteins, and heat shock proteins. The accumulating data on the in vitro and in vivo actions of curcumin together with the ongoing human clinical trials will provide a better understanding of curcumin-mediated cell growth regulation, ultimately catering to the needs of human welfare.

Edited by devinthayer, 31 October 2011 - 04:53 PM.

I was looking for a link between Methylfolate and COMT. There seems to be some sort of transcription factor involved, but I fail to see any direct correlation beyond the scope of genetic factors of schizophrenia and bipolar. Does anyone know if Methylfolate increases COMT activity or inhibits COMT activity?
Edited by devinthayer, 15 December 2011 - 05:37 PM.

I just became very interested in this topic. I have the val/val polymorphism so I have a high COMT activity. That explains why I have low dopamine associated problems and my estrogen levels were so low. Any updates? Personal experiences ? I responded very well to Rhodiola in the past, mind you, with a little anxiety, so I think this is the route I'll take. I figure Uridine will help take the edge off any anxiety.

Another thing to consider is that COMT uses up a lot of SAMe and magnesium. It also makes you less responsive to green tea, so larger doses are probably needed. Shame..
Edited by Lufega, 15 April 2012 - 12:20 AM.

In response to this topic, I would like to find a good source of cichoric acid to try. Most Echinacea supplements are standardized to a measly 2%.

Has anyone had any success?

I found 98% extract, but it's over $10/mg.

Join me in this quest to find such a thing. Why? Because theoretically COMT inhibition will increase working capacity via slowing down Norepinephrine break-down in the Pre-Frontal Cortex. Theoretically great for ADHD, Dementia, Parkinsons, Depression, etc... Plus, I just want to. So there.

I'd just go with gunafacine being a adreno agonist in the prefrontal cortex. Otherwise, you can go down to the Amazon rain-forest and look for undiscovered plants that act as potent COMT inhibitors... :D
Edited by redan, 01 June 2012 - 05:55 PM.

Here's an unexpected COMT inhibitor. No idea what doses are needed though.

Comparative study of mechanical responses of hepatic arteries strips to adrenalin in presence of pyridoxine and pyridoxal-5'-phosphate.

Bettini V, Martino R, Munari L, Mayellaro F, Ton P.

Abstract

Since it is known that PLP inhibits "in vitro" the COMT much more than pyridoxine; the influence of pyridoxine to the response of hepatic arteries isolated to AD has been compared to the influence of PLP to the same arteries. As for as the increase in percent is concerned, the result is that PLP gives rise to a greater answer to AD than pyridoxine. Such effects lacked when pyrogallol, a powerful COMT inhibitor, was present. Taking such results as a basis, it has been concluded that the mechanism of action of pyridoxine and of PLP was metabolic and that it was based on the COMT inhibition, even for the hepatic arteries. It was been also deduced that the higher efficiency of PLP compared to the pyridoxine's was due to its greater capacity to inhibit the COMT.

didn't realize that Quercetin was in that list that it inhibits the DNA Enzyme. What is the purpose fo the DNA Enzyme and why not inhibit it? Im trying to understand the posts but it is so far unfamiliar territory.

didn't realize that Quercetin was in that list that it inhibits the DNA Enzyme. What is the purpose fo the DNA Enzyme and why not inhibit it? Im trying to understand the posts but it is so far unfamiliar territory.

I just googled this:

DNA-manipulation enzymes - There are specialized enzymes that move along DNA strands and repair them. There are other enzymes that can untwist DNA strands to reproduce them (DNA polymerase). Still others can find small patterns on DNA and attach to them, blocking access to that section of DNA (DNA-binding proteins).

So is that a good thing or a bad thing. Doesn't sound good.

So is that a good thing or a bad thing. Doesn't sound good.

No. I am not too happy about it, but I'm not worried enough at this point to give up the CILTEP routine.