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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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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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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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