Open Questions
10 open questions in the mTOR pathway. Each card says where the evidence currently stands, what has changed since the question was written, what remains open, and how it could be tested. Gaps are computed against this curated corpus, not the whole literature — so "the Atlas holds no study on this" is not the same claim as "nobody has tested it", and where the wider literature has since answered or contradicted a question, that is recorded under What changed.
Frontier questions → — 7 questions about how the pathway is being read, rather than gaps in what has been read.
Does mTORC1-selective dosing extend lifespan, and is rapamycin's glucose intolerance a cost at all?
The lifespan benefit of blocking mTOR is closely tied to mTORC1, while the main side effect (insulin resistance) comes largely from also disrupting mTORC2. That split is well supported, but it is not the whole story - a …
Does the larger rapamycin benefit in female mice survive equal drug exposure, and is it set by hormones or by chromosomes?
Male and female animals often respond differently to these drugs – sometimes just by how much, but sometimes the effect flips direction entirely. Rapamycin tends to help females somewhat more; a different drug, acarbose,…
Sensor-selective geroprotection without the metabolic penalty
The amino-acid sensors in this pathway (Sestrin2, CASTOR1, SAMTOR, the lysosome's acid pump) are among the most pathway-specific control points in it - and among the least tested for whether changing them actually change…
Is there a low-dose mTOR schedule whose immune effects come out favourable, compartment by compartment?
High-dose, long-term mTOR blocking is a classic immune-suppressing treatment, used to stop organ-transplant rejection. But oddly, a low dose of a similar drug improved older adults' response to a flu vaccine and reduced …
How much of rapamycin's healthspan benefit runs through fewer senescent cells?
Rapamycin's anti-ageing benefit is usually credited to boosting autophagy (cellular cleanup), but there is a competing explanation: rapamycin also calms "senescent" cells - old, damaged cells that pump out inflammatory s…
Muscle-sparing, pulsed mTORC1 inhibition
mTORC1 is needed to build muscle, yet turning it down is also one of the best-studied ways to extend lifespan in animals - a real tension. In one mouse study, a short course of rapamycin extended male life expectancy by …
Is autophagy actually REQUIRED for the mammalian lifespan benefit?
Autophagy (the cell's self-cleanup process) is widely assumed to be why blocking mTOR extends lifespan, but that's only been directly shown in flies and worms, plus one mouse study that boosted autophagy a different way.…
A sensor/autophagy biomarker panel as a surrogate endpoint for human trials
Among the human trials collected in this Atlas, none has shown a clinical or functional healthspan benefit: trials aimed at such outcomes either missed their main goal or only checked safety. The goals that were met are …
Brain-penetrant mTOR inhibition clears aggregates in models, but human dosing has not been shown to reach the brain — and mTORC2 is needed for memory in mice
In animal and cell models, blocking mTOR clears out the toxic protein clumps involved in diseases like Alzheimer's and improves memory-related behaviour - a fairly strong case at the lab level. In fact, one long mouse st…
Rapamycin + AMPK-axis drugs (acarbose / metformin): a male-mouse survival signal from cross-cohort comparison, untested in humans
In mice, combining rapamycin with a diabetes drug called acarbose extended life more than either drug alone - but only in males; in females it was no better than rapamycin by itself. A different diabetes drug, metformin,…
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