Unlike dietary restriction, rapamycin fails to extend lifespan and reduce transcription stress in progeroid DNA repair-deficient mice

Interesting paper worth just reading.



Adjuvant sirolimus does not improve outcome in pet dogs receiving standard of care therapy for appendicular osteosarcoma: A prospective, randomized trial of 324

another one about dogs


Bad news for the mTOR theory.

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It’s debatable whether progeria provides strong clues about the molecular or cellular basis for age-related changes in normal individuals.

The disease itself does superficially look like some changes with old age, but many, many features of normal aging aren’t seen. You don’t see Alzheimer’s, cataracts, or cancers that we’d expect if they were truly “aging quickly” - while I’m pretty optimistic about at least a good set of cancers when it comes to mTOR inhibitors.


Agreed, I thought it was more interesting their thought process and what they did/ compared too. Another problem (Im sure you are aware) is that mice mostly die of cancers so you wouldn’t necessarily see the other types of aging diseases. It was a very specific mouse line that has a very specific disease, which gave a potential insight into narrowing down how rapamycin is impacting aging. But as with anything, this was just one study done in 2021, so one has to take things with grain of salt.

Here is a decent article talking about the problem with mice models when it comes to diseases:

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But dietary restriction worked. So with regard to aging, it seems that something other than mTOR inhibition makes dietary restriction work.

It cannot be reduction in cancer, because like you said, mice don’t develop cancer. So avoidance of cancer is not what made dietary restriction extend the lifespan of mice.

I am just looking at the proposed explanation for lifespan extension. It does not seem to be simply mTOR inhibition. So to replicate the effectivity of dietary restriction, some other explanation must be proposed, to discover substances that mimic dietary restriction.

That, of course, does not deny the efficacy of rapamycin. But it may not be attributable to mTOR inhibition. It is, actually, bad news for my experimentation, because I thought finding some other mTOR inhibitor would give me the rapamycin benefits. Right now, I have started dosing with kaempferol, and myricetin. But I will stick to the regimen for a few months, maybe.

We know DR/CR works differently for lifespan extension in mice than mTOR inhibitors. That’s not new. Not only that, CR + rapa had additive effects in mice.

There are only speculative hypotheses - you’re looking for what’s akin to the holy grail for researchers at this point - a proposed true full explanation doesn’t even exist yet. There are way too many knowledge gaps in experiments that are not even done.

Senescence cells don’t even have a well-defined consensus yet.


too bad they didn’t test acarbose and arcarbose+rapamycin too

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