Since my experiences with rapamycin have left me wondering if it is a good choice for me at this time (I’ll have comments on that in a different post), I have been toying with the idea of refining a supplement stack that achieves something approximating the functional equivalence of a modest rapamycin pulse of 3 mg/week in terms of mTORC1 suppression but does not suppress immune function. I recognize the complexity in this idea and that some of it rests on unknowns. Nonetheless, it seems like a worthwhile effort. In most people, a single 3 mg pulse of rapamycin/week produces near-complete, transient mTORC1 shutdown (IC₅₀ ≈ 0.1–1 nM in cells, whole-blood AUC ~400 ng·h/mL). Even though a daily nutraceutical stack cannot fully replicate that pharmacodynamic peak, I think that layering orthogonal “lighter” inhibitors (i.e., direct ATP-competition, AMPK activation, acetyl-proteome modulation, lysosomal v-ATPase blockade) it is possible to approximate something possible better in the form of a chronic 30-40 % dampening of mTOR signaling with sustained autophagy tone while avoiding the immunosuppressive troughs seen with rapalogs. Such a stack would include berberine, EGCG, trans-resveratrol, spermidine, quercetin, α-Ketoglutarate, curcumin, and perhaps a monthly pulse of fisetin. There may be concern for adaptive homeostasis in some of these supplements so some cycling beyond that of fisetin may be indicated.
All of this said, it is still true that exercise accounts for a greater share of observed variance in human lifespan and especially in healthy aging outcomes. In multivariate models (e.g., using NHANES or UK Biobank data), fitness often rivals or exceeds BMI, glucose, or lipid parameters as a mortality predictor. It seems likely that exercise leading to high levels of fitness (high percentile VO₂ max, grip strength, muscle mass/power, gait speed, etc.) will account for even greater variance in health and lifespan. It also remains true that rapamycin’s claims to longevity are extrapolations. Recently, Eric Verdin, head of the Buck Institute, identified specific reasons why rapamycin’s geroprotective attributes may not extend to humans.
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He did? Where? In a recent interview on Peter Attia’s podcast he did speak to this, but from what I could gather, what he said in this context could apply to all geroprotectors, because what he said could be boiled down to “humans are already longevity optimized” (unless I missed some more detail he provided in that interview). Well, if humans are already longevity maxed out (btw. this is a well known argument), then they’re maxed out for all longevity interventions, not just rapamycin. But then he confusingly flogs exercise as anti-aging, which is sloppy at best, because there is extensive and decisive research showing that exercise does not extend life, just squares the survival curve (which is not nothing!). Undoubtedly we already have a whole bunch of interventions (including exercise) which extend human healthspan, but that’s distinct from the two we tentatively have for max lifespan: CR and (maybe) rapamycin in animal models (mammals), and neither of these has been proven in humans.
Re: your proposed stack, I’m rather skeptical. A huge collection of disparate molecules, with unknown interactions and dosage related cross impacts (a given dosage for a single molecule will have a different impact when used concurrently with another). And none of these studied longitudinally for specific aging impact. Personally I’d place my bets heavily against this working, but YMMV.
I don’t know your issues with rapa, but if you want an mTOR suppressor, everolimus is better tolerated by many, with a possibly shorter inhibition. You may want to see if it works for you.
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That is what I thought he said in the discussion with Attia and for the general reasons you mentioned @CronosTempi. I didn’t think the reference was for all geroprotectives but for those that work their magic via selective mTOR inhibition because, as you say, our pathways are closer to optimal than are those of mice, etc. However, I was in the car in traffic, and may have missed some of the conversation and nuance. Someplace in the conversation, I also recall him saying he would definitely not recommend rapamycin to a younger person but might be OK with it if an older person was feeling better, stronger, etc. taking it. My general impression is that Buck has moved on to research they think holds more promise.
You and I might be in different camps on the squared survival curve counterargument. At the least, I think it is weak. I’m sure we both know the arguments on both sides so I won’t repeat them here but I will say that there is evidence on exercise. This issue It seems especially relevant given that there is zero controlled evidence that rapamycin increases human lifespan, individual, median, modal, maximum or otherwise.
I agree with your points on the weaknesses of my hypothetical mTOR stack. And while these compounds are studied extensively, none have produced longitudinal longevity data on humans (which puts them in the same camp as repalogs).Roughly half of the stack’s ingredients meet the “longitudinal, mammalian” bar, and two (EGCG, spermidine) show encouraging epidemiologic associations (but nothing more) with lower human mortality.
Right, no need for a battle of papers - I’ve posted multiple studies showing exercise as lowering mortality risk, but not affecting lifespan, and they are quite conclusive, however, the majority of those are in animals. Humans are a different matter. I believe the same is true for humans, but the studies are not there ironclad as in animals - I posted various twin studies, but the opposite view is quite reasonable. What’s not in dispute is that exercise does wonders for healthspan (within limits!), so no sense in pressing the point - exercise is good for humans.
I am doing a deep dive on everolimus atm, so I might have tunnel vision, but it’s something to consider if you still want to look at the mTOR pathway, and at least there is the Mannick/Klickstein immunity paper as encouragement (and in some way providing more evidence for dosing and immunity than rapamycin!), especially in older people.
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I look forward to your conclusions on everolimus, especially how one deals with the heightened mTORC2 issue.
Separate from our discussion on mTOR, an empirical vacuum and some conceptual confusion can be found in the use of maximum human lifespan, healthspan and lifespan. Maximum human lifespan is a hypothetical construct admitting of a family of operational definitions not all of which are congruent. It represents a single designation that cannot logically apply to individuals except in contrast to the hypothetical. In ordinary language, including health language, meaning is derived from use an it is correct to refer to the increased life- and healthspan of a recently diseased 91 year old who, at 65, was morbidly obese, had T2D, and ASCVD before he converted to the Church of the Holy Fitness and went on to win a regional 10K at 79. It would violate a bunch of thought processes to conjecture that the guy would have made it to anywhere close to 91 on his former lifestyle path.
Yes, there is a lot of confusion around these terms, and sadly it’s quite prevalent even in animal studies. I mostly used max lifespan in the context of CR studies, where there was a focus on what might be termed extreme outliers. More recently there’s been a gradual shift to simplify the statistical calculations and for convenience there’s been an adoption to call max lifespan in animals simply the mean of last 10% of the surviving populations. I don’t think(?) that’s been extended to humans, but that’s partially because we can’t have everyone in a lab, and there is too much variation in local environmental conditions.
What you are referring to, is called “common usage”, and healthspan and lifespan are used interchangeably.
Still, even so, there is some value in studies such as done by the likes of Nir Barzilai in centenarians, where you can do more data driven hypothesis testing as opposed to anecdotal reports in popular media and people’s ideas. Because I don’t think it’s incompatible in the lay thinking that a 91 year old with terrible health habits can live a long life - the famous “smoked and drank all his life and lived to a 100”.
Anyhow, this is getting off track. There was a discussion of the lifespan/healthspan distinction in the recent podcast with Peter Attia and a bunch of guests: Rich Miller, Matt Kaeberlein, Steven Austed etc. a few months ago, and even there not all could reach consensus.
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Inhibiting mTOR means fewer WBCs are produced.
Thanks. When it comes to the ordinary language of Max Life, I wonder of a rate of change metric might be more useful. We would not have to postulate an end point. Only a vector and momentum.
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Just a quick note on mTORC2 - I am not 100% sold on the idea that we should aim for C1 exclusively, completely bypassing any suppression of C2. Many researchers claim that longevity benefits flow from suppressing both C1 and C2. I have not made up my mind, just noting this. I think we should look at outcomes more that trying to nail what’s happening with C2. Now that I’m doing a deep dive on sirolimus and everolimus, it’s amazing how utterly contradictory are the various claims: everolimus spares C2, no, it hits C2, unlike sirolimus, everolimus has a shorter halflife than sirolimus, no, it has a longer halflife because it is a mild p450 suppressor, and so on. It’s a mess, but I’m soldiering on.
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