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Mechanism

AMPK activates MTORC2

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As I mentioned I have taken a break from the board in part so that I can focus my energy on increasing my education and skillset in biogerontology ( basic science) and translational and clinical preventative and lifestyle medicine.  Increasingly, I have been interested in the fundamental mechanisms of aging and healthspan.  I am still in the active learning phase, which is a lifelong endeavor of course but with focused energy over the last year and anticipated to continue at least for at least another.

Theory has a role in areas of uncertainty, particularly when they lend themselves to low risk and effort potentially fruitful endeavor.  For example while I do not at this point agree - yet reserve judgement one way or another - with all of the conjectures introduced in the great thread on CE, the risk and cost are low enough and I see enough potential benefit that I allow for some "convenicence CE" in lieu of better data.

This new journal article ( sorry no full text citation) was piqued my interest: https://www.ncbi.nlm.nih.gov/pubmed/31186373

For a bit of background on MTORC, Dean put together a nice synopsis here:

Some of the discussion was speculative with regard to interpretation of the findings ( which is one of the most enjoyable parts of these threads which keep us all on our toes ), but regardless, the major pathways are well explained and represented, a hallmark of Dean's exacting post curation.  

The new journal article is novel in that demonstrating that AMPK activates mTORC2 and by doing so increases cell survival.  There was preliminary work in this arena consistent with this, but the authors demonstrated well and as a direct mechanism.  There are several key implications here:

1) It provides a "potential mechanism for how AMPK paradoxically promotes tumorigenesis in certain contexts despite its tumor-suppressive function through inhibition of growth-promoting mTORC1"  

They note "Traditionally, AMPK has been thought to function as a tumor suppressor due to its phosphorylation (on Thr172) and activation by LKB1, the tumor suppressor
protein inactivated in the Peutz-Jeghers benign tumor syndrome," and additionally AMPK activators often have in vivo anti-tumor effects such as in some animal models and with consistent but not conclusive evidence human epidemiology for the case of metformin, which incidentally also may work through disparate mechanisms such as mitochondrial MRC-I inhibition. 

However, quoting from another source (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6232796/) "In terms of metabolism, mTORC2 activation promotes glucose uptake, facilitates glycolysis, and inhibits oxidative phosphorylation, which may contribute greatly to the alteration of glucose metabolism in cancer cells, known as the Warburg Effect, conferring to a high rate of cell proliferation [71, 79]. Furthermore, mTORC2-mediated lipogenesis is identified to promote hepatocellular carcinoma, particularly by stimulating sphingolipid and glycerophospholipid synthesis, which fuels cancer cell growth and energy production [104]." ( the original references they can be accessed via the hyperlink).  

Essentially this new publication demonstrated that AMPK, mTORC2, and Akt promote cell survival during energetic stress.  Why do metformin and other AMPK activators apparently reduce cancer incidence despite this?  They speculate that at least part of the mechanism is that the impact of MTORC1 inhibition exceeds the liability of MTORC2 activation.

2) I mentioned "liability" of MTORC2 activation above, but this very much depends on context and is not all a bad thing.  While the failure of rapamycin to be more effective as a therapeutic for malignancy may in part stems from its less robust (and indirect) inhbition of MTORC2 relative to MTORC1 ( https://www.mdpi.com/2072-6694/10/1/18), Dean and Michael have both discussed hypercholesterolemia, hypertriglyceridemia, glucose intolerance and reduced insulin resistance ( brief mention of immunosuppression to follow  later in this post) as a few side effects seen in some model organism studies and human populations on rapamycin.  This other issue is in large part attributed, by contrast, to too much (indirect) MTORC2 inhibition by prolonged rapamycin ( n.b. these exacerbated by other pharmacology such as use of systemic steroids for transplant patients in the case of humans).  There is some debate here whether these changes are rather adaptive or benevolent given their context and improved net-outcomes even with this metabolic derangement (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482593/).  Furthermore depending on the organism, dosing schedule, and study these alterations have at times either failed to materialize, been protective ( e.g.- improved rather than compromised insulin sensitivity), or in some cases only been transient.   Likewise, intermittent dosing has been another lever explored by Lamming and others demonstrating a more favorable safety profile by virtue of MTORC1>MTORC2 inhibition ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5216691/ ) and more selective rapalogs for MTORC1 and/or shorter half life rapalogs such as everolimus ( which is both) have been developed, with others in the pipeline, along with other pharmacotherapy intended to address these issues like not limited to metformin,  and statins, lifestyle interventions, etc.

3) IAC - and deliberately sidestepping the BAT narrative for which I suspend judgement as I study the matter -  I interpret their confirmation that AMPK activates MTORC2 as a potentially compensatory mechanism.  Perhaps more in males than females with at least one mouse model with Rictor ( which is just downstream of MTORC2) taken out of the picture so-to-speak being associated with reduced rather than increased longevity in males.  Notably, NIH's ITP has found some of the greatest life extension with the combination of rapamycin+metformin ( greater than rapamycin alone but with the caveat that these were different trials) , and while in humans metformin has been used to alleviate metabolic derangement seen in some rapamycin models (chiefly constitutive models and high-dose rapamycin as opposed to the newer periodic low-dose schedules), it is interesting to see that some of the attenuation of side effects may operate on a mechanistic level on some of the same basic pathways; albeit with nothing being perfect and mounting evidence on metformin not only being an exercise-mimetic but also at least beyond a certain threshold coming at some cost for VO2max and mitochondriondrial adaption to exercise.

 I would be remiss not to mention briefly here esp.  in this particular forum that CR itself and less well explored potentially other nutrient restriction and/or moderation ( MR: distinction pertinent and so noted, for some interesting metabolic applications, see this:https://patentimages.storage.googleapis.com/92/84/72/2c6954e8de8b52/US20190059433A1.pdf ), TRF, ketosis, other lifestyle practices and yes perhaps even CE as proposed and outlined by Dean in the link provided above may also mitigate some of these issues.... I have intentionally not even opened up the can of worms regarding the rapamycin immunosuppression question but suffice it to say that low dose intermittent dosing as now being explored as outlined in multiple papers by Lamming and others and least lessen these concerns and that rapamycin so titrated is perhaps better conceived as an inmunomodulator than an immunosuppressant per se indeed with with therapeutic potential in the setting of immunization and immunosenesence.

We are still just scratching the surface on AMPK activators an anti-diabetic agents - see for example just published elucidation on its mediating FGF-21 induced pancreatic islet cell autophagy https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567208/ .   While I have formal background in clinical medicine, clinical research and even at an undergraduate degree level the basic sciences, I continue to be humbled by how little we know, and the complexity yet majestic subtlety of systems biology, carefully crafted and honed by evolution. 

 

Edited by Mechanism

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3 hours ago, Mechanism said:

I have taken a break from the board

Hi Mechanism!

What board?

  --  Saul

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Mechanism, I'm happy to see the fruits of your absence! It's interesting to observe that the researchers are focusing now on the mTORC2 complex, whose  functions have been so far almost obscure.

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Hi Saul: Meaning not posting a lot here on this board, so I can focus my energy on learning.  Except for a little “visit” now I will probably return to relative dormancy to channel my energy towards this.  Besides the literature eventually I hope to slowly make my way through some textbooks and landmark citations/references. FYI, I think you are going on another week when I’ll unfortunately have to miss you, but I’ll be in Kripalu tomorrow Friday night and depart at 6am Sunday.

Hi McCoy, that’s great, yes we are just scratching the surface.  Great pic of your last meal in another thread.... and I’m not just saying that because I’m fasting today 😊. Pictures of nutrient dense unrefined minimally or unprocessed food between mild CR, OMAD, and a passion for health optimization converge to make the visuals vicariously enjoyable.

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Mechanism, what you are doing is very important if you want to get a handle on practical interventions. It's become pretty clear that if you want to really affect aging, you will need multiple interventions along various axis, and the interactions between them are non-trivial. Unfortunately, merely speculating is never going to be enough - the complexity and dynamic interactions are such, that almost inevitably there will be unforeseen side effects. What you really need is this sequence: theory--->intervention--->trial. That last part is crucial - without testing the interventions, you really don't know what you have. And that's a big problem in longevity studies in humans - at best we only get to have biomarker proxies as indicators. Animal studies (in short lived species) can be conducted to completion, but one has to be deeply sceptical about translatability to humans. 

That said, as I've mentioned repeatedly, we don't have a choice. Time is running out. We are not going to live long enough to get solid results. Some younger members in their 30's and 40's can wait, but those of us in the 50's and 60's are at a point of no return - either we do it now, or any intervention will be likely too late to have any significant effect even if it works. So we must take a chance on things like rapa, metformin, acarbose etc. - it may transpire that we're doing more harm than good, but hey, no choice. Personally, I'd rather gamble and lose than simply resign myself to no intervention at all and zero chance at slowing aging. 

ATM, my idea is to go on rapa, combine it with statins (because of my specific situation), metformin and acarbose. I'll start toward the end of this year. I'll adjust and change things up as the research rolls in, but I am fully cognizant that I may do harm to myself instead of good, but it's a chance I'm willing to take. YMMV. 

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Btw. for those that are looking to take metformin as an anti-aging agent, there's a somewhat sobering study out. Far from being additive to other interventions, such as exercise, it is a negative. That's not much of a surprise actually - there are old studies which show conclusively that exercise in addition to metformin is NOT additive in effectiveness against T2DM - in fact, lifestyle interventions are *more* powerful (specifically exercise) than either metformin alone, or metformin in addition to exercise. So we knew going in, that there is something hinky going on.

 https://www.nytimes.com/2019/06/19/well/move/an-anti-aging-pill-think-twice.html

https://blogs.sciencemag.org/pipeline/archives/2019/06/24/metformin-and-exercise

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Hi Tom, thank you for the thoughtful response, I admire your eloquence distilling broad themes cogently and succinctly.   

I agree with the theory —> evidence : RCT when possible model and prescribe to it myself.  I also concur there is an opportunity cost awaiting evidence, and sometimes - depending on the risk and benefit profile with regard to both magnitude and probably distribution - it is prudent to proceed in the face of preliminary or non-definitive data particularly when risk can be acceptably mitigated and the potential upside high ( or else certainty:magnitude downside of not intervening ).   This can be mathematically expressed as a risk-benefit analysis assigning values.   I taught evidence-based medicine in the past, and something that is frequently missed is (a) a lack of a choice is also a choice of status that  needs to be formali assessed in the decision tree and (b) EBM is not equivalent to setting meta-analysis RCT evidence thresholds for all circumstances but rather weighing the best current evidence and the implications of different choices in real time - ie, “now” .  Though prudence may also dictate waiting for more information , it may also determine it best not to wait further.

I am aware of the most recent metformin and exercise publication and alluded to it in my original post in reference to VO2Max, thank you for supplying the reference.  At this time the dementia linkage is far more tenuous with decent data favoring protection rather than harm, but certainly as with all things evidence could shift and no choice is without risk.  

As for the exercise / metformin inhibition this has been suspected for a long time but now we have strong evidence and mechanistic details.  Metformin daily rather than twice daily is one potential risk mitigation strategy.  Whatever you decide - and you have reviewed what sounds like a tentative plan, I suggest ( and this is not medical advice)  for safety you work with  a clinician to assess the impact and implications of any personal factors and to supervise, and help provide objectivity along with monitoring accompanying biomarkers and other objective and subjective health indicators to ensure you are on the right path.

Edited by Mechanism

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10 hours ago, TomBAvoider said:

Personally, I'd rather gamble and lose than simply resign myself to no intervention at all and zero chance at slowing aging. 

Risk appetite governs but in your case it's sure a very reasoned gamble, with intermittent low dosages and so on and so forth...

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While I provided in my original post what can be considered partially reassuring or risk-mitigating data on its use - for which I am agnostic and am not making an argument either way -  for balance, now might nevertheless be a good time to review Michael Rae's cautions particularly with rapamycin - in contrast for metformin and acarbose - if you can tolerate the GI side effects particularly for the latter - have a comparatively far more favorable and better characterized safety profile:

Quoting from https://www.longecity.org/forum/stacks/stack/122-michaels-tiered-supplement/ regarding why he does not use rapamycin in particular:

Because (a) rapamycin is really a pretty risky drug to take experimentally (at least at levels likely to be effective, assuming the rodent data does indeed translate — see discussion here and this followup) and (b) there seems to be surprisingly little advantage to starting rapa earlier in life vs. later, perhaps because its beneficial effects become more relevant in opposition to secondary aging processes or because the mixture of deleterious to beneficial effects shifts with the changing aging milieu — or perhaps simply because of changing pharmacokinetics, since in the mice at least plasma levels at a given dose are much higher in aged vs. young animals.

 

So I feel I've got some time, and we'll certainly know a lot more in a few years.

 

The stupidest thing in the universe is a life extensionist dead of the long-term toxic effects of his experimental fountain-of-youth pill.

Additionally, while LE has been suggested in animal models, even if it does translate in some measure to humans, the rapamycin mice have been protected from infection (sterile) while the controls in these experiments are far from having been optimized in in their lifestyle which compels us to inquire: if you are mostly optimizing the rest of your lifestyle already - diet, exercise, etc. with or without some degree of CR or similar practices, how much additional upside beyond what you are already doing would you stand to gain with rapamycin while introducing the unknown whose risks and consequences for you at a personal level are harder to predict. 

Finally this might not be relevant to you but if you do practice CR while this may help in some ways ( e.g. insulin sensitivity, lipid profile), it may exacerbate other pertinent potentially more concerning risks ( excess mTOR suppression /, wound healing, potentially serious infection, etc.).

However you decide I expect it will be governed not by a desperation (which would be a quick way to get out of the frying pan and into the proverbial fire) which would be be uncharacteristic for you, so much as the measured reason, balance, and self-knowledge of your personal risk profile - these last three fortunately having been hallmarks of your well-grounded and aptly conservative nuanced positions and practices over the years.  Please continue to share your experiences - in solidarity, I know you will choose wisely!  

Edited by Mechanism

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It's the old truth again - people are different. If different strains of murines react differently to interventions, why would we think that there's similar variability in humans?

To that point, it's the same with metformin - it may be good or bad for you depending on your particular situation. Even in the <exercise +/- metformin> group, you had those who upon being given an oral glucose tolerance test did worse than anybody else, and that was a subset of of the group who did exercise+metformin. In other words, for some, if they exercised and took metformin, they did the very worst. This extremely variable response to metformin is not surprising in light of the fact that a study has shown that how you react to metformin, whether you do or do not get benefits and whether you in fact experience harms, is all in the genes:

https://www.ajmc.com/newsroom/different-responses-to-metformin-its-in-the-genes-study-finds

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5007158/

Generally, it was shown that metformin strongly benefits those who tend to gain weight easily and are overweight (at least when it comes to T2DM) - and I am naturally not overweight, have never been overweight in my life. 

In other words, whether you should take metformin or not, what dose, what schedule and combined with what other drugs and interventions is a complicated and very specific thing for each individual. I don't find generalized studies that corral a bunch of random people and then draw conclusions that "on average" an intervention is beneficial/detrimental very helpful - because the "average" patient may actually truly not exist - there might be the group that benefits by amount x and a group that benefits not at all, 0 - to then average and say that the "average person" benefits 1/2x is nonsense - there literally is no such person, that's an artifact of statistics. It reminds me of the excitememt there was for awhile about aspirin being cancer-protective, especially vs colon cancer. Well, it transpired that it was protective only in individuals with specific gene variants and was actually detrimental (GI bleeding) for others without the variant - but the studies averaged the result to show that everyone benefitted though at a lower level - a dangerous distortion.

You might benefit from metformin. Or you might not. And you must have the correct dose/protocol. How will you find out where you belong?

And why should it be any different for rapamycin? If we all react differently to different drugs, it only stands to reason that it might very well be the case with rapamycin too. You might benefit. Or you might be harmed. And even to benefit, you still must "do it right" - the right dose, schedule, combined (or not) with other drugs and interventions. It's complicated. We simply don't have the data. Those who are fortunate can wait for more data, those who don't have the time are taking a giant gamble and even if they try their very best to read the tea-leaves of preliminary studies and extrapolations, still need loads of luck. 

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1 hour ago, TomBAvoider said:

Those who are fortunate can wait for more data, those who don't have the time are taking a giant gamble

I think the size of the gamble depends on ones skill at determining the impacts of an intervention.  The success of all interventions, including CR, depend on the degree to which we are able to evaluate the good and bad, balance the tradeoffs and fine tune our regimens.  I used to lack confidence in my ability to evaluate what is right for myself and looked to consensus and statistics to guide my choices.  Which wasn't working out well.   Desperation pushed me to start trying things which seemed risky.  Maybe it has been mostly good luck but I've had several gambles pay off big.  More of my gambles have been failures but I think I've gotten better at spotting trouble and cutting my losses quickly and I'm increasingly willing to experiment.   But I don't like changing too many things at a time and I prioritize testing things based on expected potential risk and reward.  At the moment neither metformin or rapamycin look like worthwhile gambles for me but I hope others find them compelling and further our collective knowledge with their experimentation.

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