Rapamycin as an inducer of autophagy is well known. Lately I’ve seen evidence, and have posted comments, that autophagy needs to be fine tuned. It’s essential for removal of misfolded proteins and damaged organelles, but it can also lead to cell death and cancer promotion and spread when in excess.
Here’s a review article discussing autophagy as a double edged sword. This naturally leads us to several important questions:
Is low dose rapamycin more beneficial than high dose?
Is the combination of CR, and even fasting, with rapa excessive?
Do we need to be careful combining rapa with autophagy inducing supplements and phytochemicals?
Like I’ve said before, when it comes to human dosing there are no experts, just various people guessing. We need to be careful.
Great points on balance in general. Chemotherapy can help with autophagy, but an ‘overkill’ compared to IF.
Modulation of mTOR seems to be a common point of interest on this site, but balancing it is key. Younger versions of ourselves seem to do a good job for awhile with mTOR balancing and then the modulation get out of balance. Measuring youthful mTOR activity and modeling that for our end points may help us be better guessers?
Looking at the intervention list, the number one best thing I am not doing anything about is Spermidine. I tried reading through the 100s of posts on this site. It looks like supplements are not useful, wheat germ has gut damaging confounders, and home-made yogurt might work. Did I miss anything? The video mentioned semen retention. Ah, no. Do, is there a way for a lazy person (i will not make yogurt) to get higher Spermidine ? Thanks in advance.
Here is a good post of lots of studies in the topic which points out that autophagy is a double edged sword. Most longevity interventions target indirectly or directly autophagy. Like fasting, CR, metformin etc.
Its more that some are concerned about that rapamycin may promote cancer but I want to point out that its not that easy to just stop taking rapamycin and do other longevity interventions instead. They can back fire also because of the double edge sword effect. There is no easy solution here. Are hope is to track cancer early and my guess is also if we track it early that longevity interventions then needs to be adapted and changed to handle this new situations.
Regarding your concern about doing too much of different longevity interventions is another interesting topic. Lets start a thread about that. I can do it when I’m home again.
Overtreatment and being overly ambitious with many interventions at the same time can backfire and create unintended negative consequences. It is impossible to predict the effect of many medications given at the same time. When it is done it needs regular and professional medical supervision and follow-up. When it comes to the complex interventions that we practice (with lots of supplements), there are not many professionals to turn to. I would personally really like to reduce my stack. And I do my best to do so. But I am far from done.
The problem with multiple interventions is that we can’t measure things reliably like autophagy and even senescence. Senescent cells for instance have great value in tissue regeneration and wound healing, but when they hang around they cause even more senescence and chronic inflammation. But we think of them as “zombies” that should be attacked from all angles, so we inhibit their formation with rapa and then we try to wipe them out with fisetin, quercetin and dasatinib. This can be excessive and harmful since we don’t really know what we’re doing.
As I pointed out, the same can be said of our efforts to induce autophagy. It can be excessive and harmful.
Some people toy with the idea of adding methylene blue to their regimen. Do they know that it is a powerful MAO inhibitor that can lead to the potentially fatal serotonin syndrome when combined with antidepressants? I doubt it. We need to be careful messing around too much with our finely tuned physiologic systems.
Is it well known that Rapamyin induces autophagy? In what tissues? And what sorts of autophagy? Are we even certain that most sorts of autophagy are good? As far I’ve read, these things are total guesswork.
I can’t point out the video, but it’s one of Peter Atia’s with Matt K on it. Peter asked Matt point blank if rapaymcin induces any kind of autophagy. Matt gave him a point blank “no”. It’s only the suppressing of SASP that causes it’s good effects. At least that’s what’s actually known. Instead of guessed at.
I don’t think we even have a clear understanding of the different autophagy mechanisms, do we?
I mean I’m no doctor. But Matt K keeps going on about how much really is NOT proven and not even understood to ANY extent. Only guessed at and taken as fact later
I listened to that podcast with Matt K on it as well where Matt seems to state that he doesn’t see evidence of Rapa inducing significant autophagy. Peter Attia has had another guest, Lloyd Klickstein, who I believed stated he thought Rapa was a modest activator of autophagy. So perhaps there is a diversity of opinions on how much Rapa actually activates autophagy. I’m hoping it significantly activates autophagy, but if it was only suppressing SASPs, I’d be cool with that too. If it does get proven that Rapa is a strong activator of autophagy, I may consider taking longer breaks from taking Rapa, as I wouldn’t think autophagy is a process that was meant to be stuck in the “on” position 24/7.