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Telomerase activation cycles


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#1 VinceG

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Posted 24 September 2008 - 07:47 PM


I am interested in learning more about, first, the need for cycling the taking of telomerase activators with taking telomerase inhibitors like allicin, resveratrol and curcumin. And second, given that there is a need, what is the optimal periodicity of the cycle. As has been discussed on this Forum, TA Sciences suggests a 3-month on and 3-month off period between taking TA-65, while RevGenetics suggests a daily cycle wherein 3 or 4 hours should be elapsed after taking inhibiting supplements and Astral Fruit. Why not some other period like a week or month?

As to need for interrupting telomerase activation, presumably it is to clear out any incipient cancers since it is known that telomerase activation, while not by itself generating cancers, can throw any inactive malignancies into high metasticing gear. The telomerase inhibitors of concern are also known cancer inhibitors.
So, the off periods of telomerase activation are presumably to ward off any oncogenesis or spread of existing cancers. However I am not at all sure that the "telomerase inactivators" like resveratrol do so in normal non-cancerous cells, as at least one forum contributor has suggested. Any hard research references on this will be appreciated. So, is the need for de-activation a concern that the activator will exercise a more powerful effect than the inhibitors on any cancerous or pre-cancerous cells? Or is it that the inhibitors and activators will cancel each other out uinless there is cycling?

Second, what is the basis for selecting a short or long period for cycling? I am taking Astral Fruit. If it is true that the inhibitor substances affect telomerase expression only in malignant cells, then why should I worry about when in the day I take the supplement - presuming that a 24 hour cycle allows plenty of time for the activator activity to die out and be quiet. I would like to know more about the pharmakinetics of both the activators and the inhibitors. After taking them as a supplement, what is their active half-life in the body? It would seem that if that were known and is a simple answer for most tissues, it would provide an answer to the cycle length question.

Jim green's site http://greenwoodstor.../longevity.html has extensive discussion of and references to these questions but I have not been able to divine answers to them there.

Any light that can be shed on these questions will be appreciated.

Vince

#2 waldemar

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Posted 09 November 2008 - 11:29 AM

I'm very interested in this myself. Is cycling really neccessary? Probably the most important of the question here is if Resveratrol also inactivates Telomerase in healthy cells - which it probably doesn't because then it would be pro-aging, right?

Any new ideas/information?

#3 100YearsToGo

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Posted 09 November 2008 - 12:11 PM

I am interested in learning more about, first, the need for cycling the taking of telomerase activators with taking telomerase inhibitors like allicin, resveratrol and curcumin. And second, given that there is a need, what is the optimal periodicity of the cycle. As has been discussed on this Forum, TA Sciences suggests a 3-month on and 3-month off period between taking TA-65, while RevGenetics suggests a daily cycle wherein 3 or 4 hours should be elapsed after taking inhibiting supplements and Astral Fruit. Why not some other period like a week or month?

As to need for interrupting telomerase activation, presumably it is to clear out any incipient cancers since it is known that telomerase activation, while not by itself generating cancers, can throw any inactive malignancies into high metasticing gear. The telomerase inhibitors of concern are also known cancer inhibitors.
So, the off periods of telomerase activation are presumably to ward off any oncogenesis or spread of existing cancers. However I am not at all sure that the "telomerase inactivators" like resveratrol do so in normal non-cancerous cells, as at least one forum contributor has suggested. Any hard research references on this will be appreciated. So, is the need for de-activation a concern that the activator will exercise a more powerful effect than the inhibitors on any cancerous or pre-cancerous cells? Or is it that the inhibitors and activators will cancel each other out uinless there is cycling?

Second, what is the basis for selecting a short or long period for cycling? I am taking Astral Fruit. If it is true that the inhibitor substances affect telomerase expression only in malignant cells, then why should I worry about when in the day I take the supplement - presuming that a 24 hour cycle allows plenty of time for the activator activity to die out and be quiet. I would like to know more about the pharmakinetics of both the activators and the inhibitors. After taking them as a supplement, what is their active half-life in the body? It would seem that if that were known and is a simple answer for most tissues, it would provide an answer to the cycle length question.

Jim green's site http://greenwoodstor.../longevity.html has extensive discussion of and references to these questions but I have not been able to divine answers to them there.

Any light that can be shed on these questions will be appreciated.

Vince


Serum levels of curcumin peaks 1 to 2 hours after consumption and decline over a period of 12 hours. You can easily find this info. I suspect in the case of curcumin waiting 3 or 4 hours after ingestion to take astralogus won't be effective. You need to seperate them at least 14 hours. And even then curcumin crosses the blood brain barier and may be present in the brain even for a longer time. Maybe a better strategy would be to cycle them weekly? This is also a good idea for other reasons. Curcumin is known to inhibit P53 in colon cells and propably in other type of cells as well. Maybe not a good idea to inhibit P53 chronically.

With regards to the other inhibitors, its a long list. Maybe other board members can chip in. My wife is bugging me to take her out shopping. Longevity has to wait. Does having a wife shorten your lifespan?

Regards,

100YTG

Edited by 100YearsToGo, 09 November 2008 - 12:23 PM.


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#4 waldemar

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Posted 09 November 2008 - 01:40 PM

Does having a wife shorten your lifespan?


Don't think so. Most guys get a more regular sleep cycle when they are living with a gf/wife. When there are also kids the "perceived acceptable risk level" (when driving a car etc.) also drops. So I think having a wife should increase your lifespan. Of course it depends on the individual wife. ;-)

#5 100YearsToGo

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Posted 10 November 2008 - 02:58 AM

Does having a wife shorten your lifespan?


Don't think so. Most guys get a more regular sleep cycle when they are living with a gf/wife. When there are also kids the "perceived acceptable risk level" (when driving a car etc.) also drops. So I think having a wife should increase your lifespan. Of course it depends on the individual wife. ;-)



Thats great news. Any study to back that up? :) Just kidding.

#6 niner

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Posted 10 November 2008 - 06:17 AM

There are two issues to consider. One is the problem of cancers that would not be stopped by the lack of telomerase. That is the most crucial issue. The other problem is that of other supplements interfering with telomerase induction or action. To know how long of an "off" cycle you need, one needs to know how long the telomerase "lasts" after you stop taking the astragaloside. You also need to know how long it would take for a cancer cell line to "burn itself out" by using up its telomeres. Caution dictates a long "off" time in your cycling protocol. I lean toward following the Patton protocol, since there has been some experience with it, and as far as I know there have been no problems with runaway cancers.

The other question regarding supplements interfering with telomerase is of lesser importance in my opinion. To know what is a reasonable combining strategy, we need to know how the astragaloside works. Does it induce the expression of telomerase, leaving a telomerase complex active for a long time, or does it need to be present for the telomerase to function? If it's the former case, then there shouldn't be much interference trouble from other compounds. If a substance is a known inhibitor of telomerase, there may well be a short period of time when the telomerase is temporarily inactive. Unless it's a mechanism-based inhibitor, which is fairly unlikely, as soon as it washes out, the telomerase will be back in business again. If the astragaloside needs to be present for the telomerase complex to work, then you would probably want to maintain an adequate blood level of the astragaloside long enough for at least one telomere lengthening event. If the other supplements of interest are interfering with the action of the astragaloside itself, as opposed to interfering with plain telomerase, then you would need to cycle the interfering compounds "off" for a sufficient period of time before taking the astragaloside, determined by the pharmacokinetics of the interfering compound and its potency. For most of the compounds that we have been talking about, these time periods are likely to be on the order of hours rather than days, but you might need to avoid them for as long as a telomere lengthening event depending on mechanisms.

I've posed a lot of questions here. Without knowing the answers to those questions, I can't give any hard and fast advice regarding cycling. I can say that given what I know today, I would use the three month "off" period of the Patton protocol. If someone can point to mechanisms and potencies for the various compounds and activities of interest, that would be most helpful.

#7 maxwatt

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Posted 10 November 2008 - 11:33 AM

Does having a wife shorten your lifespan?


Don't think so. Most guys get a more regular sleep cycle when they are living with a gf/wife. When there are also kids the "perceived acceptable risk level" (when driving a car etc.) also drops. So I think having a wife should increase your lifespan. Of course it depends on the individual wife. ;-)



Thats great news. Any study to back that up? :) Just kidding.


Is your username, "100YearsToGo", a reference to your marriage? :)

#8 Anthony_Loera

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Posted 10 November 2008 - 01:41 PM

I have been looking through my information and comparing it to the other company that sells TA-65.

Here's the summary of the other company and the cycle:

1- 40mg of TA-41 = 5mg TA-65
2- People taking TA-65 take 5mg 2 times a day
3- There is a cycle break every 3 months, for 2 weeks. (meaning they stop TA-65 for 2 weeks every 3 months). It is not 3 months on, and 3 months off.

Of course we don't sell or make TA-65, however I believe the TA-41 is Astragaloside IV as mentioned in another thread.

Cheers
A

#9 waldemar

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Posted 10 November 2008 - 02:38 PM

Well, these guys are talking about P16 expression all the time: http://www.imminst.o...showtopic=21166

It's mainly about GERON's "mysterious" TA-65, which is one (or more) of the compounds in astragalus. TA-65 inhibits P16, which is a tumor suppressor together with P53. The problem with P16 is that P16 increases with age and leads to the senescence of cells. So _theoretically_ P16 supression should increase cancer risk. The funny thing is that it doesn't. (1) and (2) mixed cells with H2O2 (an oxidant) and HDTIC (a P16 supressor). The cells should develop more cancer-like changes with P16 than without. But in the studies the damage was undone, and the control group without HDTIC was more damaged.

A different guy then mentions that Resveratrol, which expresses SIRT1, also reduces P16 expression: http://www.pubmedcen...ne-0001710-g003

Sorry for aidanpryde, karl_bednarik & co if i botched something in the translation. Feel free to correct me. :-)


(1)
Molofsky AV, Slutsky SG, Joseph NM, He S, Pardal R, Krishnamurthy J, Sharpless NE, Morrison SJ.
Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing.
Nature. 2006 Sep 28;443(7110):448-52. Epub 2006 Sep 6.

(2)
Wang P, Zhang Z, Ma X, Huang Y, Liu X, Tu P, Tong T.
HDTIC-1 and HDTIC-2, two compounds extracted from Astragali Radix, delay replicative senescence of human diploid fibroblasts.
Mech Ageing Dev. 2003 Dec;124(10-12):1025-34.



So what this basically says is that astragalus and resveratrol work synergistically doesn't it? ;-)

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#10 100YearsToGo

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Posted 10 November 2008 - 04:35 PM

Well, these guys are talking about P16 expression all the time: http://www.imminst.o...showtopic=21166

It's mainly about GERON's "mysterious" TA-65, which is one (or more) of the compounds in astragalus. TA-65 inhibits P16, which is a tumor suppressor together with P53. The problem with P16 is that P16 increases with age and leads to the senescence of cells. So _theoretically_ P16 supression should increase cancer risk. The funny thing is that it doesn't. (1) and (2) mixed cells with H2O2 (an oxidant) and HDTIC (a P16 supressor). The cells should develop more cancer-like changes with P16 than without. But in the studies the damage was undone, and the control group without HDTIC was more damaged.

A different guy then mentions that Resveratrol, which expresses SIRT1, also reduces P16 expression: http://www.pubmedcen...ne-0001710-g003

Sorry for aidanpryde, karl_bednarik & co if i botched something in the translation. Feel free to correct me. :-)


(1)
Molofsky AV, Slutsky SG, Joseph NM, He S, Pardal R, Krishnamurthy J, Sharpless NE, Morrison SJ.
Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing.
Nature. 2006 Sep 28;443(7110):448-52. Epub 2006 Sep 6.

(2)
Wang P, Zhang Z, Ma X, Huang Y, Liu X, Tu P, Tong T.
HDTIC-1 and HDTIC-2, two compounds extracted from Astragali Radix, delay replicative senescence of human diploid fibroblasts.
Mech Ageing Dev. 2003 Dec;124(10-12):1025-34.



So what this basically says is that astragalus and resveratrol work synergistically doesn't it? ;-)


The following study definitely shows that resv. activates telomerase:

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

"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."

It also shows some more worriesome stuff. Hope it doesn't keep resv users awake at night.

"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. "

The link to the study is courtesy of aidanpryde who sent it to me.

#11 Anthony_Loera

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Posted 10 November 2008 - 07:15 PM

Looks like dose dependant results... Low Dose vs High dose benefits anyone?

Our data support the pleiotropic
effects of resveratrol by showing nanomolar concentrations
of resveratrol initiate prosurvival effects by
upregulating or reactivating telomerase in progenitor
cells (Miloso et al., 1999; Bhat et al., 2001; Gusman
et al., 2001; Bhat and Pezzuto, 2002; Dong, 2003;
Signorelli and Ghidoni, 2005).
Micromolar concentrations of resveratrol in certain
cellular models may upregulate p53 by increasing
cellular content and inducing post-translational
modifications resulting in senescence and apoptosis


here is more:

Studies suggest that resveratrol has different effects
based on cell type, conditions and concentration
(Signorelli and Ghidoni, 2005; Lanzilli et al., 2006).
Higher concentrations are usually more effective on
highly proliferative cancer cells (Le Corre et al., 2005;
Signorelli and Ghidoni, 2005). We observed that low
concentrations of resveratrol activated telomerase in
slow growing mammary epithelial progenitors, as characterized
by cytokeratin markers, but only p53þ/ HME50cells immortalized. We did observe that both
luminal and myoepithelial (with possible basal cells)
lineage progenitors are telomerase competent and
capable of immortalization under conditions of mutant/
inactive p53 (Stingl et al., 2005). The observations
that only low concentrations of resveratrol produced
these effects in these cells, though surprising, were
highly reproducible.


I get the feeling that many people in this forum will be just fine.

A

#12 kai73

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Posted 10 November 2008 - 10:20 PM

well, what amazes me is that we keep talking as if there are independent human tests where TA-65 or Astragalus actually showed a telom activation.

As far as i know, none has any test Before and after on any of the 2 products so...

IMO TA-65 is a fake, it has been around for an year or more...if it was successful we would know now by people using it and showing real signs of age reversing...thing that we didn't see unfortunately :)

#13 100YearsToGo

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Posted 10 November 2008 - 10:51 PM

Looks like dose dependant results... Low Dose vs High dose benefits anyone?

Our data support the pleiotropic
effects of resveratrol by showing nanomolar concentrations
of resveratrol initiate prosurvival effects by
upregulating or reactivating telomerase in progenitor
cells (Miloso et al., 1999; Bhat et al., 2001; Gusman
et al., 2001; Bhat and Pezzuto, 2002; Dong, 2003;
Signorelli and Ghidoni, 2005).
Micromolar concentrations of resveratrol in certain
cellular models may upregulate p53 by increasing
cellular content and inducing post-translational
modifications resulting in senescence and apoptosis


here is more:

Studies suggest that resveratrol has different effects
based on cell type, conditions and concentration
(Signorelli and Ghidoni, 2005; Lanzilli et al., 2006).
Higher concentrations are usually more effective on
highly proliferative cancer cells (Le Corre et al., 2005;
Signorelli and Ghidoni, 2005). We observed that low
concentrations of resveratrol activated telomerase in
slow growing mammary epithelial progenitors, as characterized
by cytokeratin markers, but only p53þ/ HME50cells immortalized. We did observe that both
luminal and myoepithelial (with possible basal cells)
lineage progenitors are telomerase competent and
capable of immortalization under conditions of mutant/
inactive p53 (Stingl et al., 2005). The observations
that only low concentrations of resveratrol produced
these effects in these cells, though surprising, were
highly reproducible.


I get the feeling that many people in this forum will be just fine.

A


Indeed it is dose dependant:

" Our results demonstrate that 50 µM resveratrol decreases Rac and Cdc42 activity, whereas estrogen and 5 µM resveratrol increase Rac activity in breast cancer cells."

http://www.pubmedcen...i?artid=1813930

But who is to say how much uM a woman/man is getting to her/his breast cells? The above study is in Vitro. One would have to show that the concentration is constantly higher than 50 µM when taking resv. as a supplement.

Edited by 100YearsToGo, 10 November 2008 - 10:54 PM.


#14 niner

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Posted 11 November 2008 - 01:14 AM

Indeed it is dose dependant:

" Our results demonstrate that 50 µM resveratrol decreases Rac and Cdc42 activity, whereas estrogen and 5 µM resveratrol increase Rac activity in breast cancer cells."

http://www.pubmedcen...i?artid=1813930

But who is to say how much uM a woman/man is getting to her/his breast cells? The above study is in Vitro. One would have to show that the concentration is constantly higher than 50 µM when taking resv. as a supplement.

50 µM is a mammoth concentration of resveratrol by the standards of what is normally seen in blood following oral administration. A 5 gram oral dose of resveratrol led to a peak plasma level of 2.4 µM in a dose ranging study.

On the other hand, the report of nanomolar concentrations of resveratrol upregulating telomerase in progenitor cells is interesting, because that is a concentration that can easily be reached in plasma from oral dosing. However, a progenitor cell is not a normal somatic cell. It is a relatively rare cell that might just sit around doing nothing if it's not needed for tissue regeneration following an injury, for example. If the point of telomerase induction is to forestall senescence in somatic cells, it's not clear to me that the upregulation of telomerase in progenitors is necessarily what you need.

#15 waldemar

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Posted 11 November 2008 - 07:29 AM

So, to summarize this:

1) We have no idea if Astragalus works in humans, but perhaps it does.
2) We have to wait for Anthony's test results in February anyway to get a first impression.
3) There is no reason not to mix it with Resveratrol.

#16 Anthony_Loera

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Posted 11 November 2008 - 01:50 PM

waldemar,

I have seen one study where res inhibits telomerase, and one that says the opposite.
I wouldn't consider that last one until I see another study and/or test with res and telomerase. I would feel more comfortable with at least a couple of tests that say res will not affect (inhibit) telomerase.

And yes... I am anxiously awaiting February as well.
It is certainly possible that we may gather a few volunteers/customers after the February test, if it comes back inconclusive (meaning no changes where found).

cheers
A

Edited by Anthony_Loera, 11 November 2008 - 01:55 PM.


#17 simon007

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Posted 11 November 2008 - 02:05 PM

Hi Waldemar,

I received the DVD from ta sciences about ta-65 and on this dvd somebody from ta sciences states that you should not use resveratrol in combination with ta-65.

I'll see if I can upload it.

Cheers,

Simon

#18 waldemar

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Posted 11 November 2008 - 06:52 PM

Ok, so the problem seems to be that we have really no idea if resv inhibits or activates telomerase. Perhaps someone from the resv-forum could drop by to enlighten us. :-)

#19 Guest_aidanpryde_*

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Posted 11 November 2008 - 07:22 PM

Waldemar the facts you have presented are fine translated. :) Only the statement that TA-65 inhibits P16 is not right, but it may be my failure if I have explained it in a not comprehensible way, that the substance HDTIC-1, which is isolated from astragalus inhibits P16, not TA-65. I thought that HDTIC could be the mysterious TA-65, but it is probably the cycloastragenol, nevertheless making the HDTIC not less interesting.

Resveratrol can activate telomerase. This function was shown in 2 papers. (1,2)
I have the full version of the second study somewhere, but unfortunately not as PDF, only the printed version. As I can remember they could exclude a possible estrogen-like activity of resveratrol as the telomerase activating pathway by administrating of an estrogen anatagonist and high dosage resveratrol. The telomerase activity in endothelial progenitor cells, in vitro, was still present. Estradiol on itself activates telomerase. With 50µM RSV the activity was highest, starting already with 10µM. Lesser concetrations were not included in their tests. 100µM were contraproductive and lead mostly to toxic effects but do not bother us, because of the small concentrations reached in vivo in humans.

Here are also 2 works which show telomerase inhibtion in cancer cells. (3,4)
Two actual paper say that resveratrol stimulated telomerase expression is pronounced enough, to delay senescence or even to immortalize cells without P53 by exposing the cells for 24h to resveratrol and so producing a continuous telomerase activity. In vivo it is probably an effect we can also not reach because of the fast degrading of RSV.

"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."

The two other say that RSV leads to downregulation of telomerase in two different cancer cell lines. Which of the statements is right? Probably both, because there may be several reasons for RSV toxicity in cancer cells. Especially some enzymes higher expressed in cancer cells like CYP1B1 could convert resveratrol for example to the more toxic piceatannol and explain different reactions in cancer and healthy cells. (5,6) It would perhaps also interesting if some more research would be done on effects of metabolites derived from resveratrol by degrading in liver. They may not be totaly uneffective and this could change some parts of our calculations.

To come back to the on topic and question: I also do not see a reason for cycling something like TA-65, if the use of this agent leads to formation of malignant cells for any reasons, a withdrawal won`t help because "real" cancer cells are not dependent of supplement caused telomerase activation. I also don`t see a real reason why RSV and some agents from Astragalus should not be used together. How useful and effective a combination of this 2 substances or the use of only one of them is for our longevity, remains not perfect clear for me. Although I am using resveratrol and hope for the best. :)
Somebody said once, that hope is just a lack of information.


(1)
Pearce VP, Sherrell J, Lou Z, Kopelovich L, Wright WE, Shay JW.
Immortalization of epithelial progenitor cells mediated by resveratrol.
Oncogene. 2008 Apr 10;27(17):2365-74. Epub 2007 Oct 29.

(2)
Xia L, Wang XX, Hu XS, Guo XG, Shang YP, Chen HJ, Zeng CL, Zhang FR, Chen JZ.
Resveratrol reduces endothelial progenitor cells senescence through augmentation of telomerase activity by Akt-dependent mechanisms.
Br J Pharmacol. 2008 Oct;155(3):387-94. Epub 2008 Jun 30.

(3)
Lanzilli G, Fuggetta MP, Tricarico M, Cottarelli A, Serafino A, Falchetti R, Ravagnan G, Turriziani M, Adamo R, Franzese O, Bonmassar E.
Resveratrol down-regulates the growth and telomerase activity of breast cancer cells in vitro.
Int J Oncol. 2006 Mar;28(3):641-8.

(4)
Fuggetta MP, Lanzilli G, Tricarico M, Cottarelli A, Falchetti R, Ravagnan G, Bonmassar E.
Effect of resveratrol on proliferation and telomerase activity of human colon cancer cells in vitro.
J Exp Clin Cancer Res. 2006 Jun;25(2):189-93.

(5)
Piver B, Fer M, Vitrac X, Merillon JM, Dreano Y, Berthou F, Lucas D.
Involvement of cytochrome P450 1A2 in the biotransformation of trans-resveratrol in human liver microsomes.
Biochem Pharmacol. 2004 Aug 15;68(4):773-82.

(6)
Potter GA, Patterson LH, Wanogho E, Perry PJ, Butler PC, Ijaz T, Ruparelia KC, Lamb JH, Farmer PB, Stanley LA, Burke MD.
The cancer preventative agent resveratrol is converted to the anticancer agent piceatannol by the cytochrome P450 enzyme CYP1B1.
Br J Cancer. 2002 Mar 4;86(5):774-8.

Edited by aidanpryde, 11 November 2008 - 07:29 PM.


#20 waldemar

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Posted 11 November 2008 - 08:10 PM

Does having a wife shorten your lifespan?


Don't think so. Most guys get a more regular sleep cycle when they are living with a gf/wife. When there are also kids the "perceived acceptable risk level" (when driving a car etc.) also drops. So I think having a wife should increase your lifespan. Of course it depends on the individual wife. ;-)



Thats great news. Any study to back that up? :) Just kidding.


I'm not commenting about an U-shaped response curve or something. Must... not.... make...... joke.........

#21 waldemar

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Posted 11 November 2008 - 08:21 PM

aidanpryde, thanks, that was exactly the info I was looking for.

I think I'll hedge my bets by making a "hedging cap":
Micronized Resveratrol: 300 mg
Astragalus Extract: 300 mg
Chitosan: 10 mg
Ascorbic Acid: 10 mg
Polysorbat 80: 100 mg

3 times daily or so...

Astragalus an Resv as active compnents, and the rest for improving absorbation. If one of those turns out to have little effect in a few years - who cares? Still got the other one! :-)

Good or bad idea?
  • Agree x 1

#22 Guest_aidanpryde_*

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Posted 13 November 2008 - 08:33 PM

3 times daily or so...


Perhaps one time daily would be easier and would not produce a constant, continuous telomerase activation, if you know what I mean. :)
On the other side it remains questionable if resveratrol alone is enough to produce t. activation in vivo or even together with astragaloside IV. Does anybody has the exact information how high the plasma peaks were, that were reached with micronized RSV and polysorbate 80?

I would also consider something like carnosine for removing of glycated proteins/lipofuscin.

Edited by aidanpryde, 13 November 2008 - 08:34 PM.


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#23 waldemar

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Posted 13 November 2008 - 09:42 PM

aidanpryde, I still don't see the advantages of Carnosine over Meclofenoxate ;-)

Hm, so you think it would be better to take it once daily, instead of spreading the same amount out over the day in 3 portions?

#24 Guest_aidanpryde_*

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Posted 13 November 2008 - 10:52 PM

I would prefer one intake daily yes.

Carnosine:

Antiglycation action:

Alhamdani MS, Al-Kassir AH, Abbas FK, Jaleel NA, Al-Taee MF.
Antiglycation and antioxidant effect of carnosine against glucose degradation products in peritoneal mesothelial cells.
Nephron Clin Pract. 2007;107(1):c26-34. Epub 2007 Jul 24.

Hipkiss AR, Chana H.
Carnosine protects proteins against methylglyoxal-mediated modifications.
Biochem Biophys Res Commun. 1998 Jul 9;248(1):28-32.

Carnosine can react with already carbonylated (damaged, oxidized) proteins (AGEs, lipofuscin) stop their interaction with other proteins and perhaps mark them for destruction:

Hipkiss AR, Brownson C.
A possible new role for the anti-ageing peptide carnosine.
Cell Mol Life Sci. 2000 May;57(5):747-53.

Brownson C, Hipkiss AR.
Carnosine reacts with a glycated protein.
Free Radic Biol Med. 2000 May 15;28(10):1564-70.

Interesting, effect on old cells:

Holliday R, McFarland GA.
A role for carnosine in cellular maintenance.
Biochemistry (Mosc). 2000 Jul;65(7):843-8.

Perhaps a little bit far catched from this work:
"Late passage cells in normal medium are rejuvenated when transferred to medium containing carnosine, and become senescent when carnosine is removed."

Also nice:

Shao L, Li QH, Tan Z.
L-carnosine reduces telomere damage and shortening rate in cultured normal fibroblasts.
Biochem Biophys Res Commun. 2004 Nov 12;324(2):931-6.

"Cells continuously grown in 20 mM carnosine exhibited a slower telomere shortening rate and extended lifespan in population doublings."

Review:
http://protein.bio.m...l/65070907.html

#25 waldemar

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Posted 13 November 2008 - 11:46 PM

aidanpryde, That looks very interesting. Thanks for the information!

#26 jamesagreen

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Posted 23 June 2010 - 06:49 PM

I am interested in learning more about, first, the need for cycling the taking of telomerase activators with taking telomerase inhibitors like allicin, resveratrol and curcumin. And second, given that there is a need, what is the optimal periodicity of the cycle. As has been discussed on this Forum, TA Sciences suggests a 3-month on and 3-month off period between taking TA-65, while RevGenetics suggests a daily cycle wherein 3 or 4 hours should be elapsed after taking inhibiting supplements and Astral Fruit. Why not some other period like a week or month?

As to need for interrupting telomerase activation, presumably it is to clear out any incipient cancers since it is known that telomerase activation, while not by itself generating cancers, can throw any inactive malignancies into high metasticing gear. The telomerase inhibitors of concern are also known cancer inhibitors.
So, the off periods of telomerase activation are presumably to ward off any oncogenesis or spread of existing cancers. However I am not at all sure that the "telomerase inactivators" like resveratrol do so in normal non-cancerous cells, as at least one forum contributor has suggested. Any hard research references on this will be appreciated. So, is the need for de-activation a concern that the activator will exercise a more powerful effect than the inhibitors on any cancerous or pre-cancerous cells? Or is it that the inhibitors and activators will cancel each other out uinless there is cycling?

Second, what is the basis for selecting a short or long period for cycling? I am taking Astral Fruit. If it is true that the inhibitor substances affect telomerase expression only in malignant cells, then why should I worry about when in the day I take the supplement - presuming that a 24 hour cycle allows plenty of time for the activator activity to die out and be quiet. I would like to know more about the pharmakinetics of both the activators and the inhibitors. After taking them as a supplement, what is their active half-life in the body? It would seem that if that were known and is a simple answer for most tissues, it would provide an answer to the cycle length question.

Jim green's site http://greenwoodstor.../longevity.html has extensive discussion of and references to these questions but I have not been able to divine answers to them there.

Any light that can be shed on these questions will be appreciated.

Vince


Dear Vince,
(1) Optimal Perodicity of Cycle
I get the impression that the half-cycle time may actually be less than 24 hours for
most drugs. Then a full cycle could run in two days, telomerase up-regulated on day 1,
telomerase inhibited on day 2. This certainly applies, for instance, to all the drugs
used in bodybuilding. The charm of leaving the thing telomerase up-regulated for 3 months
is that hopefully some results will be measurable after just 3 months, I mean, after just
3 months one sees longer telomeres, we hope and pray. Otherwise, we get measurable results
half as fast, not as good for customer confidence when the telomere growth phenomenon is
barely measurable.
(2) Telomerase as a Telomerase Activator
Note that since resveratrol is a SIRT1 activator involved in gene silencing,
it seems strange that resveratrol would be used at all to activate telomerase.
One expects behavior analogous to a histone deacetylase, with chromatin condensation
and a quieting down of transcription. That is why I suspect that resveratrol had better
be confined to a telomerase inhibition time cell distinct from the telomerase activation
time cell. On the other hand, diligent experiment could prove otherwise. Resveratrol
is inexpensive and may be taken up to 2000 mg/dose.
- Jim Green http://greenwdks.hos.../longevity.html

that

Edited by jamesagreen, 23 June 2010 - 06:51 PM.

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#27 chrono

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Posted 24 June 2010 - 09:17 AM

So to be clear, what do we think about resveratrol use during a telomerase activation cycle? Might it be ok to take it on the opposite end of the day from the activator, maybe every other day+, or should it be avoided entirely?

The same question applies to many other compounds that may inhibit telomerase. I would really like to keep taking fish oil consistently for a number of reasons. Can we speculate about how detrimental inhibitors might be—completely negating activators, or maybe (as suggested by niner) creating a timeframe in which lengthening events are less likely to occur?

#28 Logan

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Posted 09 September 2010 - 03:56 PM

So to be clear, what do we think about resveratrol use during a telomerase activation cycle? Might it be ok to take it on the opposite end of the day from the activator, maybe every other day+, or should it be avoided entirely?

The same question applies to many other compounds that may inhibit telomerase. I would really like to keep taking fish oil consistently for a number of reasons. Can we speculate about how detrimental inhibitors might be—completely negating activators, or maybe (as suggested by niner) creating a timeframe in which lengthening events are less likely to occur?


I'm also interested in this, anyone have anything to offer?

#29 Brian Augustyniak

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Posted 11 September 2010 - 12:50 AM

Here's a wrinkle to consider...given that I'm an amateur maybe I'm missing the obvious:

What if resveratrol et al reduces telomere activity only in abberant cells, and not in healthy cells? It seems all the counter-points assume resveratrol inhibits telomeres in all cells, and the same with P53.

Aren't there hundreds of studies indicating resveratrol, curcumin, green tea, etc. inhibit cancer? If they inhibit cancer partly due to telomere inhibition, does this necessarily mean they also inhibit telomere lenthening in healthy cells? That seems to be an ssumption with zero studies done in this regard.

All the discussions make sense on the surface with respect to cycling, timing, etc. But is biochemistry that simple? I think not. We're all assuming, logically or not.

The question remains...what to do? How to hedge one's bet based on sound logic (which may not ultimately be true).

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#30 DorianGrey

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Posted 24 May 2013 - 02:04 AM

I hope I can re-open this old thread. I am currently thinking about the best protocol and compounds. I want to establish a baseline telomer length measurement before I start the journey, so I take the time to do a thorough research.

@James: I really love the list you've put together, I wish I had the time to read through all the articles, but it gave me very interesting leads. I try to filter for substances with good availability from pricing/supply perspective, established safety profile and high impact, at least shown in vitro.

Here are my considerations for the dosing schedule:
- cancer cells can divide as fast as every 4 days or just every 500 days. Worst case, every 4 days means after two weeks you have already 8 cells to fight instead of one. After 3 months its 4.2 Mio. This is of course a worst case scenario. Just, the cell division happens also without inducers.
- Telomerase has a stability in the 24h range, so a daily on-off cycle isn't a great idea at all. It also seems that the stability of the corresponding RNA and substrate is in the days range. Then, how long are the telomers accessible for telomerase, and what is the half-life time of telomerase activators like Cyclo and Silymarin, or phyto-estrogens. So how long does it take to get back to insignificant levels, and that level is meant in the cells, not just in blood plasma!
- what's the best time of day to take telomerase inducers for best bioavailability? I am tempted to think after a light meal before bedtime, but might be totally wrong and twice a day or before a meal may be better.
- why would I take special telomerase blocking substances in the off-period, in the end I am trying hard enough to get things started? Another aspect is that I don't want to sacrifice the fish oil completely. Any cancer cell either has telomerase on, then I probably need a really long off time on strong inhibitors to get rid off it. I am not so sure a short time suppression with nutraceuticals is really doing much, despite many studies showing there is some efficacy on some tumor types. If telomerase in the malign tumor is "off", then cells divide until reaching the Hayflick limit. So adding lets say 0.5 kb via mild telomerase induction to the average 6kb or 7kb doesn't make a huge difference in my opinion.

My conclusions:

Inducers should be used long enough to allow for an effect, at least a few days. Cycling inducers and inhibitors the same day or every other day looks nonsensical to me.

Induction could in theory have a greater effect in cells that are dividing fast, so you don't want to assist that too much. One longer off-time may be the right thing to add a safety margin, especially when phyto-estrogens are used. On the other end, probably it makes sense to have induction over a longer period instead of trying to get everything accomplished quickly, cell division in adults is quite slow in most tissues (bone marrow being an exemption).

=> I like the idea of two weeks on, two weeks off cycles when you can take all supplements regardless of slightly inhibiting effects. I would add a 4 months downtime during the year so the body has lots of time to desensitize and re-balance side-effects, if any. Basically I'd stretch a 4 months regimen over 8 months. I could also see 2 weeks on vs. 3 weeks off being an option if the induction effect wears off slowly (matter of days).

Please feel free to critique my outline.




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