87 replies to this topic

[Brainbox]

Regarding autoimmunity, it also depends on ones genetic constitution. So an individual prone to developing autoimmune reactions might benefit from certain targeted and specific immune system manipulations while someone who is less prone to it might not.

Along the same line, the question about efficacy in humans of rapamycin will certainly also depend on ones genes. It's my feeling that developing and using medication in a crude way to ward off crude health issues, like dealing with rejection of transplanted tissue, is something completely different as compared to optimising biological processes to enhance health and lifespan in otherwise healthy individuals.

The fact that the rapamycin studies seem to be of high scientific standard is very promising, but at the same time the methodology in this phase of research that ensures repeatability and comparability through standardisation does not deal with real-life genetic variation at all.

Edited by Brainbox, 12 July 2009 - 04:29 PM.

[AgeVivo]

So the ITP showed that rapamycin extends lifespan of lab mice. Many here are talking about curcumin, because it also inhibits mTOR, and is a priori less dangerous for humans. Curcumin is on the list of things to be tested by the ITP: http://www.nia.nih.g...dsInTesting.htm

[AgeVivo]

So the immunosuppressant rapamycin extends mouse lifespan under quasi sterile conditions.
What do you think of testing rapamycin on mouse lifespan under normal conditions, i.e. MPrize @ home ?

(http://www.imminst.o...showtopic=21310) If one has to choose, would you prefer smthg else to be tested by MPrize at home first? (methylene blue, benagene, curcumin, other)

[kismet]

Just to clarify some points...

Not sure why you say rapamycin "causes" cancer in mice, if as Michael's post suggests, the basic breakdown in the number of deaths caused by cancer in the mice fed rapamycin is essentially equivalent to the number of such deaths in the controls (with possibly some greater proportion of lymphoma cancers among the dead mice).

First you are confusing incidence and mortality. Number of deaths != number of animals suffering from cancer. But why am I saying that?
Rapamycin is suspected (if not definitely known) to cause cancer in humans. Mechanistically it's easy to argue that immunosuppression causes cancer. It's also safe to assume that such an effect was observed in mice considering that overall cancer incidence was 50% higher and lymphoma incidence was also 50% higher; it's all in the data I provided. Then again they did not do any statistical tests on those numbers so it's possible that rapamycin did not increase incidence and it's merely an exponential increase in age-related cancers or some other issue.

I assume that there's something non-trivial the authors are trying to assert here, when they raise the possibility that the effects of rapamycin may, consistent with the evidence, be accounted for by assuming rapamycin is merely "postponing death from cancer". I assume that they may be asserting that there's a possibility that for some period of time rapamycin may protect from cancer (or at least death from cancer -- presumably the idea would be that the mice initially contract cancer at the same times as their peers in the control group, but don't so quickly succumb from it), and that the outcome might be fully explained under that assumption.

Yes. But they're talking about mortality. I simply tried to explain the difference between incidence and mortality which you seem to confuse. There's no proof that rapamycin protected from cancer, i.e. that it prevents carcinogenesis. Considering that the incidence was higher, but the mice lived longer still, one could speculate that - as expected from a chemotherapeutic treatment - it slowed progression. However, the data they provide is not enough to jump to too many conclusions (it could very well protect from carcinogensis depending on the age-relatd incidence of cancers, but it's highly unlikely).

How does one make that determination definitively? (Is it the case, for example, that the oldest mice even in the classic CR experiments, when they do finally die, don't do so from cancer but from some other cause? I assume there's some reason researchers conclude that it isn't simply putting off death from cancer that gives CR a legitimate claim to extending life. What should we be looking for from rapamycin that, apparently, the researchers here don't yet claim to have observed?)

This is a good point. The answer: histopathology and more experiments e.g. to show a dose-response curve like with CR; and an initiation-age response-curve like with CR [the younger you start the better the outcomes]; and an exact break-down of cancer incidence to answer the questions Michael raises. 

And of course all this relates back to human beings, who don't seem so much to die from cancer (or at least I gather they don't), and certainly not from lymphoma in particular.

Most old people die with, but many people also die from cancer. It is not to be taken lightly and protection from any cancer(s) would be a dream.

If, say, resveratrol is a better protective against the causes that kill human beings (such as frail bones and muscles, cardiovascular weakness, etc.) it's still possible that human beings would respond better to resveratrol than to an mTOR inhibitor, if that mTOR inhibitor only forestalls cancer or retards death from cancer.

Sorry, but right now that's unnecessary wishful thinking (not even speculation, because those two substances have nothing in common; could very well work in "synergy" and evidence in favour of resveratrol is quite weak IAC). Let's wait for firm data showing whether rapamycin postpones aging. If it doesn't, then we can compare it to resveratrol and speculate whether resveratrol or mTORC1/TOR inhibition is superior -- does anyone notice that I'm not even mentioning rapamycin in this sentence? That substance is toxic at the doses used and it will never ever find its way into the clinic as a treatmet for aging (so it's pretty strange to already start arguing which of those two completely different approaches/substances is "better"). At this very moment this looks so much bigger than resv.

Edited by kismet, 12 July 2009 - 07:55 PM.

[niner]

It might be worthwhile to revisit the excellent Autophagy thread we had not too long ago. Lots of interesting information there. One thing that occurred to me that was discussed here is Ron Mignery's Protein Cycling dietary scheme. (Monograph) I don't know if there's any real evidence that it works, but the concept is interesting: Eat no protein on some days, and replace the calories with carbs and fats. The lack of a new supply of amino acids should induce autophagy, assuming that it would be triggered by amino acid deficiency and not solely by an energy deficit.

I stumbled upon a commercial website that provides a nice overview of mTOR in the context of cancer, containing some good general info. It's by Novartis Oncology, and if you click around on the site, you can get to an area "for non-US residents" (US residents not allowed?) that contains details about the Novartis pipeline. Must be skirting some sort of US regulation there. An oddity...

[VidX]

I consider doing Intermittent Fasting a few days a month (one being 24h), doing physical activities on these days (to use primary energy sources) and then some cardio at the end of it to induce the lack of oxygen (what induces autophagy).

[Michael]

All:

First, a lot of folks are speculating that the immunosuppressive effects of rapamycin are distinct from its suppression of mTOR. In fact, the two are directly mechanistically linked, through mTOR's effects on the proliferation of T-cells and the proliferation and activation of B-cells (6). So don't imagine that you can get one without the other, or that rapamycin's effects are simple antiinflammatory ones (as if the catch-all "antiinflammatory" were simple ...). Moreover, it causes hypercholesterolemia: that may be an entirely acceptable tradeoff in a cancer patient or transplant recipient (or in a mouse, who doesn't face the risk of heart disease), but it's a lousy bet for an otherwise-healthy human, for whom CHD remains the number one killer.

Speaking of which:

And of course all this relates back to human beings, who don't seem so much to die from cancer (or at least I gather they don't), and certainly not from lymphoma in particular.

Don't know where you got that impression: cancer remains the number two cause of death in American men and women, and as the tables linked on those pages show, it's actually the number one cause for several decades in midlife and early seniority in both genders -- ie, right around the sixty-year mark extrapolated from the rodent study.

Now:

There is a large group of multiple myeloma patients taking as much as 8 grams of turmeric daily, for over four years. It seems to be a viable treatment for the condition. Some side effects are reported HERE .

There are thirty people in that trial, and we're hearing only the self-reported anecdotes from the minority of patients taking part in an online discussion forum after just a couple of years of taking the stuff, likely including at least a few folks on placebo; I wouldn't exactly call that a reliable data source. And, of course, people with a devastating disease like multiple myeloma are not exactly the best people in whom to test for subtle, slow-acting effects. Remember how long it took to definitively establish the problems with Rezulin and Vioxx; remember that this was after being used by literally thousands of patients, under rigorous monitoring, for many years, in relatively healthy people. It was only after they got out into even wider use that the problems began to be clear.

“Do Not Use for Seven Years After FDA Approval” Drugs

For many years, we have warned patients not to use newly approved drugs unless they are one of the decided minority of new drugs with evidence that they provide a breakthrough beyond existing treatments. A study, involving Dr. Sidney Wolfe as one of the authors, provides clear evidence why this caution of waiting seven years is well founded. A total of 548 new chemical entities (drugs marketed for the first time in the United States) were approved in 1975–1999. By 1999, 45 drugs (8.2%) acquired one or more black-box warnings and 16 (2.9%) were withdrawn from the market. The estimated probability of acquiring a new black-box warning or being withdrawn from the market over a period of 25 years was 20%. Half of these black-box warning changes occurred within 7 years of drug introduction; half of the withdrawals occurred within 2 years. The article concluded that serious adverse drug reactions commonly emerge after FDA approval. The safety of new agents cannot be known with certainty until a drug has been on the market for many years.2 This study provides the basis for our “Seven-Year Rule” concerning newly marketed drugs that are not therapeutic breakthroughs.

Therefore, one way of protecting yourself without being deprived of new, breakthrough drugs, is to say no to using newly approved drugs unless they are in the small minority of such drugs with a significant therapeutic benefit.

On balance, it seems to me the risks from curcumin supplementation are low enough to outweigh the possible unknown negatives. Especially if one is over sixty.

The risks aren't low -- they're unknown. And the benefits are unknown, too: we have yet to see a lifespan study with curcumin in normal, healthy rodents, and two-year toxicity and carcinogenicity studies at multiple doses in mice and rats showed no consistent or significant benefits. (1)



Let's remind ourselves of the slippery slope we're skating down, folks.

Rapamycin, a toxic immunosuppressant, has been shown in a rodent study to extend lifespan when administered to old (not yet young) mice.

One of the things that rapamycin does is inhibit mTOR.

Curcumin, in a test tube and in mutant mice with cancer, has been found to inhibit mTOR at high dose.

We are assuming that rapamycin will slow aging in humans the way that it appears to do in mice; on that assumption, we are assuming that it will not kill us by toxic immunosuppression first; on those assumptions, we we are assuming that it does so through mTOR, and not one of the other off-target effects of rapamycin; on those assumptions, we we are assuming that the effects of curcumin on mTOR under highly abnormal conditions will also do occur in normal, healthy organisms; on those assumptions, we we are assuming that this will all occur in humans; on those assumptions, we we are assuming that the benefits of mTOR inhibition by rapamycin will also be exhibited by curcumin's (still uncertain!) effects on mTOR, even tho' we've already seen from the paper Niner posted (3) and in more detail from a recent review on efforts to come up with new 'tweaked' rapamycin analogs (4) that there are multiple ways to regulate the two enzyme isoforms and their up- and downstream targets, so that mTOR inhibition from rapamycin may not have hte same effects as the possible "mTOR inhibition" by curcumin; and we are also assuming that none of curcumin's zillion off-target effects ("including cell proliferation pathway (cyclin D1, c-myc), cell survival pathway (Bcl-2, Bcl-xL, cFLIP, XIAP, c-IAP1), caspase activation pathway (caspase-8, 3, 9), tumor suppressor pathway (p53, p21) death receptor pathway (DR4, DR5), mitochondrial pathways, and protein kinase pathway (JNK, Akt, and AMPK)", a wide variety of inflammatory markers, and the "GST enzyme activity [that] has been shown to be up- or down-regulated in rat tissues after oral consumption of curcumin, depending on the dose and route of administration" (2) -- ie, the fact that it's a very 'dirty' agent) won't outweigh these purported benefits ...

Even though (again!) the 2-year toxicology studies on curcumin show no clear benefits in normal mice or rats at all, at all.

Now, look. The people on Imminst are, with very few exceptions, relatively young, very healthy folks, with good lifestyles, relatively high socioeconomic status, etc. If you're an average (let alone an unusually-health-conscious) 60-year-old, you have about thirty years of life expectancy left -- and if you're thirty, of course, you have many more. You'd be taking this stuff for decades. I put it to you that there is no good reason to gamble your existing good health on what is at the moment an hypothesis-piled-on-hypothesis house of cards whose analog in Biblical scholarship is The Holy Blood and the Holy Grail.

some good points by MR. I do agree with Maxwatt, however. There are a billion people in India eating curcumin in droves, which has only helped the country to show a lower level of alzheimers.

Hoo, boy. Prophets, I fear that your usually good instincts for the evidence were momentarily on vacation, here .

First, "traditional use" is an extremely unreliable basis for making safety or efficacy decisions. Imagine if the West had not latched upon tobacco, and it were just being latched upon by the supplement industry today. "Tobacco has been used in traditional Native American medicine for millennia before Columbus. Used in healing ceremonies, tobacco is treasured for its ability to energize, motivate, and lend a sense of clarity and focus to users. While an initial irritation can develop on first use, users quickly adjust to this healing crisis. No side-effects have been reported."

Second: turmeric is 5% curcuminoids. Suppose that an average Indian consumes one whole tablespoon of the stuff a day (a typical curry-type recipe might contain a teaspoon of the stuff) -- that's 6.8 g turmeric, wich is 340 mg curcuminoids. It takes multi-gram doses of curcumin a day before it even starts to show up in your blood -- and even then, almost entirely as glucuronidated and sulfated liver-enzyme metabolites! I put it to you that there is really no analogy from its presence in the Indian diet, even if that were relevant data -- which it's not:

Third, to jump from "this entire nation eats a lot of X and gets less disease Y compared to this other entire nation" is cross-cultural junk science.

And fourth, even if cross-cultural comparisons were a reasonable source of health information (and they're not!), the belief that Indians (and people in many other developing nations) have lower incidence of dementia is actually outdated, based in large part in the lack of adaptation of the DSM-IV criteria to the local culture: using a system designed for international use, the standardized prevalence adjusted for age, sex, and education is 8.2-8.7% (similar to Western Europe), not the 0.8-2.7% previously reported.(5)

Given that both CR and Rapamycin seem to work through inhibiting mTor, I don't see the harm in speculating on the mechanism involved.

Speculating about the mechanism is harmless; indeed, it's a necessary part of the scientific process. The next step from speculation is testing that speculation out -- in rodents, not in yourself! -- and with (at least initially) highly-controlled conditions, including highly-specific agents, not a molecular 'shotgun' like curcumin.

What I consider an "inflammatory response" is basically anything that involves the body responding to ROS, not necessarily a persistent condition of arthritis treated with aspirin. Running outside produces ROS and the body responds to it. If CR reduces MitROS output, such that the body sustains less damage. If Rapamycin retards protein synthesis and the body's response to ROS (even if it occurs), then there are some mechanistic parallels here, at the very least.

These are really very different phenomena. The principle problem with mtROS is (most likely) that they cause large deletion mutations in mitochondrial DNA, not their direct effects on the rest of cells and tissues. Those other effects -- or the body's inflammatory responses to them -- are quite another matter. And chronically modulating inflammatory responses with rapamycin or curcumin would be very closely analogous to doing so with chronic inflammation, since mtROS are being puked out all the time, and at rising rates with age

So the ITP showed that rapamycin extends lifespan of lab mice. Many here are talking about curcumin, because it also inhibits mTOR, and is a priori less dangerous for humans. Curcumin is on the list of things to be tested by the ITP: http://www.nia.nih.g...dsInTesting.htm

Yes. So let's at least wait a few years for the ITP to give us some lifespan studies before self-experimenting, OK? Remember the null effects and occasional disasters already encountered with innocent-looking essential nutrients like folic acid, selenium, and sundry "antioxidants."

Look, folks: we have decades -- and we're in this game for millennia. We have time on our side. We are working toward an ageless future of unlimited youthful lifespans, with life expectancies in the multiples of centuries -- let's start thinking like the kinds of people we must become. For starters, let's learn some freakin' patience, for crying out loud !

-Michael

1: Ravindran J, Prasad S, Aggarwal BB. Curcumin and Cancer Cells: How Many Ways Can Curry Kill Tumor Cells Selectively? AAPS J. 2009 Jul 10. [Epub ahead of print] PubMed PMID: 19590964.

3. Thoreen CC, Kang SA, Chang JW, Liu Q, Zhang J, Gao Y, Reichling LJ, Sim T, Sabatini DM, Gray NS. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem. 2009 Mar 20;284(12):8023-32. Epub 2009 Jan 15. PubMed PMID: 19150980; PubMed Central PMCID: PMC2658096.

3. National Toxicology Program. NTP Toxicology and Carcinogenesis Studies of Turmeric Oleoresin (CAS No. 8024-37-1) (Major Component 79%-85% Curcumin, CAS No. 458-37-7) in F344/N Rats and B6C3F1 Mice (Feed Studies). Natl Toxicol Program Tech Rep Ser. 1993 Aug;427:1-275. PubMed PMID: 12616304.

4. Abraham RT, Gibbons JJ. The mammalian target of rapamycin signaling pathway: twists and turns in the road to cancer therapy. Clin Cancer Res. 2007 Jun 1;13(11):3109-14. Review. PubMed PMID: 17545512.

5. Llibre Rodriguez JJ, Ferri CP, Acosta D, Guerra M, Huang Y, Jacob KS, Krishnamoorthy ES, Salas A, Sosa AL, Acosta I, Dewey ME, Gaona C, Jotheeswaran AT, Li S, Rodriguez D, Rodriguez G, Kumar PS, Valhuerdi A, Prince M; 10/66 Dementia Research Group. Prevalence of dementia in Latin America, India, and China: a population-based cross-sectional survey. Lancet. 2008 Aug 9;372(9637):464-74. Epub 2008 Jul 25. PubMed PMID: 18657855.

6.Maria Z. Siemionow. Tissue surgery. ISBN 1852339705. Springer, 2006. Pg 18.

Edited by Michael, 13 July 2009 - 05:59 PM.

[pmachin]

It's becoming official, rapamycin works - http://news.bbc.co.u...lth/8139816.stm

Is there any evidence that this increase could be translated to humans percentage-wise? For all we know it was only a constant increase and humans will only get a few months more as well. They should at least try it on a longer-living vertebrate like a dog to get two data points to extrapolate from.

[Mind]

Past discussion about curcumin (skeptical about megadosing).

Some other topics at Imminst about curcumin

Seems the balance of epidemiological studies are in favor of curcumin as a net health benefit, however I am quite wary of megadosing. I figure the amount I get in curry flavored dishes would not be harmful.

[kismet]

All:

First, a lot of folks are speculating that the immunosuppressive effects of rapamycin are distinct from its suppression of mTOR. In fact, the two are directly mechanistically linked, through mTOR's effects on the proliferation of T-cells and the proliferation and activation of B-cells (6). So don't imagine that you can get one without the other, or that rapamycin's effects are simple antiinflammatory ones (as if the catch-all "antiinflammatory" were simple ...).

Wow, that's kind of a deal-breaker. That's even more problematic than I thought; but I hope that the immuno-suppressive effects are just a - currently unavoidable side-effect - of systemic mTOR inhibition and not the driver behind the life-extending effect, because that would be really bad. Maybe people should really see this paper for what it is: a proof of concept. And it's not even definite yet.

Is there any evidence that this increase could be translated to humans percentage-wise? For all we know it was only a constant increase and humans will only get a few months more as well. They should at least try it on a longer-living vertebrate like a dog to get two data points to extrapolate from.

Just wait, it's all happening. But first they need to reproduce the result in rodents, using other doses and find some non-toxic derivative, which may or may not happen.

Edited by kismet, 13 July 2009 - 06:44 PM.

[100YearsToGo]

Here is a nice picture showing what happens upstreams and downstreams of mtor. Note that the increase in longetivity could be because of any of the downstream factors. Some were mentioned in this thread some were not. Educated guesses are welcome. As long as everyone is aware that they are just educated guesses I don't see harm in it.

Edited by 100YearsToGo, 13 July 2009 - 07:43 PM.

[100YearsToGo]

some good points by MR. I do agree with Maxwatt, however. There are a billion people in India eating curcumin in droves, which has only helped the country to show a lower level of alzheimers. Several studies which show it is well tolerated. I don't see the harm.

Given that both CR and Rapamycin seem to work through inhibiting mTor, I don't see the harm in speculating on the mechanism involved. What I consider an "inflammatory response" is basically anything that involves the body responding to ROS, not necessarily a persistent condition of arthritis treated with aspirin. Running outside produces ROS and the body responds to it. If CR reduces MitROS output, such that the body sustains less damage. If Rapamycin retards protein synthesis and the body's response to ROS (even if it occurs), then there are some mechanistic parallels here, at the very least.

ill try to respond later more in depth.

Nice guess. Rapamycin does have the effect of lowering mitochondria membrane potential and consumption of oxygen. That can lead to life extension at least in lower organism. See also http://www.nature.co...ature06322.html

Edited by 100YearsToGo, 13 July 2009 - 08:23 PM.

[youandme]

Lovin this thread...!

I will jump back out..but one quick question on Rodents/Rapamycin Testing...
A lot of posts about further Rodent Testing...

How sure can we be of the results from Rodent testing with Rapamycin...?

Or further..directed towards the knowing ...could we say that the mTOR mechanism and Rampamycin's actions can be the same between Rodent's and Human's..

What confidence can we impart on these and any further Rodent/Rapamycin Testing and Result's.

Perhaps one day we will be able to feed our complete unique genome into a computers human model...then input the drug/dosage we would like to try and the computer model will give us an accurate complete expected result of the drug interactions on our body...

[AgeVivo]

Would anyone know where to find preclinical (=animal) long-term (= typically 2 years) toxicity data concerning rapamycin?

For instance the curcumin lifespan curves posted above from Michael come from the NTP website, that displays such data. Rapamycin has not been tested by the NTP.

Edited by AgeVivo, 14 July 2009 - 10:54 AM.

[maxwatt]

Would anyone know where to find preclinical (=animal) long-term (= typically 2 years) toxicity data concerning rapamycin?

For instance the curcumin lifespan curves posted above from Michael come from the NTP website, that displays such data. Rapamycin has not been tested by the NTP.

Because it's such an effective immuno-suppressant, rapamycin is not likely to show up in pre-clinical tests.
PKA knock-out mice have shown extended life span in females.; I wonder it this is a downstream effect of mTOR inhibition, perhaps via PPAR pathways?

metformin is also an mTOR inhibitor, is an approved treatment for diabetes, and has been studied vis a vis lifespan. Results positive, but equivocal for generalization even in mice. Toxicity is such it should be monitored, main undesirable side effect is lactic-acidosis which can be fatal. If you have mild diabetes type II, and are prescribed metformin, I've no doubt it will extend your life-span.

I do know a few non-diabetic individuals are using metformin in life-extension hope, but I would be hesitant to go that route. Still, I think metformin is promising for NIA life-span trials.

Edited by maxwatt, 14 July 2009 - 02:04 PM.

[kismet]

metformin is also an mTOR inhibitor, is an approved treatment for diabetes, and has been studied vis a vis lifespan. Results positive, but equivocal for generalization even in mice. Toxicity is such it should be monitored, main undesirable side effect is lactic-acidosis which can be fatal.

Why doesn't metformin lead to immunosuppression if it effectively suppresses mTOR? According to MR those two are mechanistically linked (via mTOR activity of B-/T-Cell) Low activity on mTOR? Different activity on mTOR? Selectivity?

How sure can we be of the results from Rodent testing with Rapamycin...?

Surer than from Drosophila, which is surer than C. elegans which is probably surer than... Ok, but that's not sure enough. I fully expect to see some primate data and phase I, II and III trials from future mTOR-modulators before they go mainstream (and, no, rapamycin will never be used by healthy people).

Perhaps one day we will be able to feed our complete unique genome into a computers human model...then input the drug/dosage we would like to try and the computer model will give us an accurate complete expected result of the drug interactions on our body...

We're far away from being able to simulate simple single-celled organisms in much of detail. But it's also effectively impossible to simulate an organism's response based on genetic make-up alone. There are 3-4 splice variants per gene. Methylation status & gene expression. Dozens of post-translational modifications. Phenotype != genotype.

Edited by kismet, 14 July 2009 - 04:48 PM.

[maxwatt]

Why doesn't metformin lead to immunosuppression if it effectively suppresses mTOR? According to MR those two are mechanistically linked (via mTOR activity of B-/T-Cell) Low activity on mTOR? Different activity on mTOR? Selectivity?
......

This may offer a clue:

Cancer Res. 2007 Nov 15;67(22):10804-12.
Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells.

Dowling RJ, Zakikhani M, Fantus IG, Pollak M, Sonenberg N.
Department of Biochemistry, McGill Cancer Centre, Montreal, Quebec, Canada.
Metformin is used for the treatment of type 2 diabetes because of its ability to lower blood glucose. The effects of metformin are explained by the activation of AMP-activated protein kinase (AMPK), which regulates cellular energy metabolism. Recently, we showed that metformin inhibits the growth of breast cancer cells through the activation of AMPK. Here, we show that metformin inhibits translation initiation. In MCF-7 breast cancer cells, metformin treatment led to a 30% decrease in global protein synthesis. Metformin caused a dose-dependent specific decrease in cap-dependent translation, with a maximal inhibition of 40%. Polysome profile analysis showed an inhibition of translation initiation as metformin treatment of MCF-7 cells led to a shift of mRNAs from heavy to light polysomes and a concomitant increase in the amount of 80S ribosomes. The decrease in translation caused by metformin was associated with mammalian target of rapamycin (mTOR) inhibition, and a decrease in the phosphorylation of S6 kinase, ribosomal protein S6, and eIF4E-binding protein 1. The effects of metformin on translation were mediated by AMPK, as treatment of cells with the AMPK inhibitor compound C prevented the inhibition of translation. Furthermore, translation in MDA-MB-231 cells, which lack the AMPK kinase LKB1, and in tuberous sclerosis complex 2 null (TSC2(-/-)) mouse embryonic fibroblasts was unaffected by metformin, indicating that LKB1 and TSC2 are involved in the mechanism of action of metformin. These results show that metformin-mediated AMPK activation leads to inhibition of mTOR and a reduction in translation initiation, thus providing a possible mechanism of action of metformin in the inhibition of cancer cell growth.
PMID: 18006825

Metformin seems to affect mTOR by activating AMPK, where rapamycin according to OneHundredYearsToGo's diagram, works via FKBP12. Why this makes a difference I can't even guess.

[AgeVivo]

Because it's such an effective immuno-suppressant, rapamycin is not likely to show up in pre-clinical tests.

No, no: all drugs are preclinically tested.

I eventually found some information : Wyeth commercializes rapamune, whose active ingredient is sirolimus = rapamycin, and some information is at http://www.wyeth.com...ling.asp?id=139 , in particular the NONCLINICAL TOXICOLOGY section:

Carcinogenicity studies were conducted in mice and rats. In an 86-week female mouse study at sirolimus doses 30 to 120 times higher than the 2 mg daily clinical dose (adjusted for body surface area), there was a statistically significant increase in malignant lymphoma at all dose levels compared with controls. In a second mouse study at dosages that were approximately 3 to 16 times the clinical dose (adjusted for body surface area), hepatocellular adenoma and carcinoma in males were considered sirolimus-related. In the 104-week rat study at dosages equal to or lower than the clinical dose of 2 mg daily (adjusted for body surface area), there were no significant findings.

Sirolimus was not genotoxic in the in vitro bacterial reverse mutation assay, the Chinese hamster ovary cell chromosomal aberration assay, the mouse lymphoma cell forward mutation assay, or the in vivo mouse micronucleus assay. Fertility was diminished slightly in both male and female rats following oral administration of sirolimus at doses approximately 10 times or 2 times, respectively, the clinical dose of 2 mg daily (adjusted for body surface area). In male rats, atrophy of testes, epididymides, prostate, seminiferous tubules and/or reduction in sperm counts were observed. In female rats, reduced size of ovaries and uteri was observed. Reduction of sperm count in male rats was reversible upon cessation of dosing in one study. Testicular tubular degeneration was also seen in a 4-week intravenous study of sirolimus in monkeys at doses that were approximately equal to the clinical dose (adjusted for body surface area).

104-week: hey that's enough to see effects on lifespan! too bad they don't publicly show lifespan curves when they do such studies... anyone working at Wyeth?

Lobby for lifespan tests when toxicity tests are performed!
http://www.imminst.org/forum/index.php?showtopic=31164

Edited by AgeVivo, 14 July 2009 - 11:10 PM.

[maxwatt]

No, no: all drugs are preclinically tested.
.....

(blush) I meant pre-clinical trials for human or even primate life-extension.

[Doc Eight or DE]

[Edit by MR: DE wants to know: Would taking zoledronic acid w/ Rapamycin be ideal for life extention?]

Edited by Michael, 24 July 2009 - 11:17 AM.
Identifying uncharcterized link

[wiserd]

Regarding turmeric, salicylicates interfere with vitamin K1. Without stacking K2 on top of turmeric in any long term therapy, we open the door for calcification of soft tissue and increased heart attack risk. (Yes, blood thinners like warfarin that work by interfering with vitamin K1 decrease heart attack risk short term. But they increase it in the long run.)

K2 comes from bacteria, incidentally. The most notable source outside the human gut is Japanese natto.

[fatboy]

I wonder, though each of these may require prohibitively large doses or have undesired side effects, if instead a combination would might have an additive effect without side effects? For instance, curcumin plus caffeine plus metformin? I am speculating, not recommending.

Hmmm ... I am already on curcumin + caffeine + metformin + reseveratrol + testosterone + HCG. Guess I'll see what happens. Only thing me and my doc are still on the fence about is HGH.

[VidX]

I wonder, though each of these may require prohibitively large doses or have undesired side effects, if instead a combination would might have an additive effect without side effects? For instance, curcumin plus caffeine plus metformin? I am speculating, not recommending.

Hmmm ... I am already on curcumin + caffeine + metformin + reseveratrol + testosterone + HCG. Guess I'll see what happens. Only thing me and my doc are still on the fence about is HGH.

Tasty combo :D... I'd go for physiological dose of GH, but I'm not a doc, so...
How old r you?

[fatboy]

Tasty combo :D... I'd go for physiological dose of GH, but I'm not a doc, so...
How old r you?

47 yo. Doc tried a short course (3 months @ 1 IU/day) to see what effects it might have on labs, vitality, body comp, etc. Still on the fence, though. Occasional short courses might be okay and useful. Long-term use is a bit scary.

[VidX]

Well there's hardly any data on long term gh dosing in small amounts (1iu isn't even the amount body produces normally) so the "unknowing" factor is what's scary, I guess.. And if you are healthy at 47 you probably produce enough of your own (had the BT done on it?).
Had the testosterone made any difference in how you feel? I bet it did.

[fatboy]

Well there's hardly any data on long term gh dosing in small amounts (1iu isn't even the amount body produces normally) so the "unknowing" factor is what's scary, I guess..

Yeah, that.

And if you are healthy at 47 ...

I'm an insulin-resistant pre-diabetic/metabolic syndrome on metformin, lisinopril, simvastatin, testosterone, HCG, and a boatload of supplements. So, no, I probably don't qualify as a healthy 47 yo.

Had the testosterone made any difference in how you feel? I bet it did.

You betcha'.

[kismet]

Overmedication? Sometimes less is more... What am I saying, most often it is.

[fatboy]

Overmedication? Sometimes less is more... What am I saying, most often it is.

Likely. Didn't have low testosterone prior to the metformin and simvastatin. Utlra-low cholesterol (100-110 total) coupled with an agent known to lower testosterone (metformin) quite possibly made TRT inevitable. And my doc probably anticipated it since he was monitoring my T every quarter and initiated TRT as soon as it came back in the toilet. All water under the bridge now, I ain't looking back.