Kaeberlein’s guesses are better educated than mine. I listen to him.
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This is where mechanism helps. If a dose of rapamycin’s main positive mechanism is recycling the x% most inefficient mitochondria in a cell (which the body then replaces with average mitochondria) then the benefits of repeat in a short period of time reduce.
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Yes that sounds about right as far as logic goes. IMO however it is premature to take breaks early on. In the rodent studies where they had lasting benefits after stopping rapamycin intake, that was usually after taking it for months, which would be equivalent to years in humans. My guess is humans would need to take it for at least some years before having any lasting effects. Another point to consider is that the mice in the longevity studies take massive doses of rapamycin, much more than us humans are taking. Therefore they have had a lot more extreme exposure before taking a break. That exposure might give them long term effects. Humans in contrast take a lot lower doses and would therefore likely need to take rapamycin for much longer to lock in some benefits. Taking breaks before one has reached a high total cumulative exposure doens’t make sense IMO. Maybe after taking a high dose for several years one will start locking in some benefits. It’s hard to say.
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If you consider mechanisms, however, the conclusion depends on the mechanism.
My preferred mechanistic hypothesis is that each dose of rapamycin causes the destruction of a proportion of mitochondria (mitophagy). Each cell selects the mitochondria to be destroyed such that those with a lower membrane potential are more likely to undergo autophagy.
The cells then replicate the remaining mitochondria and those, therefore, have a similar efficiency to the remaining mitochondria (Mitochondrial Membrane Potential - ΔΨM).
Hence each cycle of mitophagy makes the average mitochondria more efficient. Then as time goes the body makes the mitochondria less efficient through damaging the mitochondrial DNA.
Hence the effects of a single cycle of improving mitochondria will last. There is then a more complex question which is the balance between repeating the cycles of improving mitochondria and aiming to recycle a higher proportion of mitochondria, but less frequently.
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I don’t think it works like that. If it were so clearly beneficial, the body would have evolved to have more mitophagy at baseline. However, it has its downsides like everything, and is tightly regulated.
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This comes down to the question as to whether or not evolution at times sets the average lifespan at a lower value.
I think the evidence is clear that from an evolutionary perspective at times longer lifetimes make a species less fit. I wrote about it here.
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Isn’t the hyperfunction hypothesis in aging that a young body did have more mitophagy, and “aging” results in less autophagy of all types due to upregulated mTOR? This was the first idea I read about as to why rapamycin slowed aging. And cycling rapa (1x/7-14 days) would allow for a periodic “spring cleaning” to clear the old proteins that the older body wasn’t recycling properly.
Has this hypothesis fallen by the wayside?
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Hyperfunction is still around as a hypothesis.
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PBJ
#69
It’s a fascinating paradox—mTOR is up, but the actual muscle-building response is weaker. Aging makes the whole process less efficient, even when the initial signaling is there.
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That’s because the cells are not as good at making proteins (because of the low mitochondrial membrane potential and presence of senescent cells both of which reduce the peak levels of acetyl-CoA in the cytosol).
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No that hypothesis is still legit. Although autophagy gets less effective during aging, I’m not sure how much mitophagy per se declines during aging, if it declines as much or less.
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I doubt it has much at all to do with the cells not being as good at making proteins. We already have proof showing that cells become very resistant to anabolic (and catabolic) stimuli during aging. This anabolic resistance means the cells aren’t setting the anabolic processes into high gear as they would when young in response to anabolic stimulation like protein intake and exercise. So it’s a problem of stimulation of anabolism not of execution of that process. If you manage to stimulate them, they are very capable of anabolic responses. It’s’ possible more youthful mitochondria might help indirectly here but I bet that is only of secondary importance.
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However, that is how the genome functions. It creates mRNA which is often used to create proteins. Arguably there are functions that remain within the transcription of mRNA, but if the transcription process if broken then so is everything else.
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… and taking it every day for months ≈ years.
Since we don’t really know the mechanisms, or have a real biomarker for any of the major mechanisms postulated for geroprotector agents (vs. lipid-lowering or antihypertensive drugs, etc) that we could track, focusing on mechanisms seems premature.
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I believe i know the mechanism. Hence i work on that assumption.
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It makes sense to have a framework for a strategy…such an approach keeps a person from losing focus… from emotionally leaping into too many things at the same time with no thought for how they all fit together.
Of course if everything is based on an assumed mechanism that turns out to be wrong, well…that’s unfortunate. Guess well.
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To some extent, however, if you assume a mechanism and have tools to measure whether or not you are making progress then that achieves the desired outcome. There will be subtleties of detail which will be missed.
At the moment I am comfortable that what I am doing has the desired results in the broader sense.
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Matt talks about what he believes are the most effective longevity treatments to date
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The usual - the exceptions are hormones. He feels that getting his hormones to proper levels was huge. Even more important than Rapamycin. He’ll release a video on this later.
The other notable was the list of interventions he thought weren’t worth it like Urolithin A, NR, and others.
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