Open Questions
10 evidence gaps and testable hypotheses the Atlas has identified in the mTOR pathway literature — each computed against this curated corpus, not the whole literature, and each with a proposed way to test it.
mTORC1-selective (mTORC2-sparing) dosing captures longevity without insulin resistance
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 …
Sex dimorphism in mTOR-longevity responses is pervasive and sometimes direction-flipping
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 the most precise, most drug-friendly parts of it — and almost the least tested for whether changing them actually changes h…
Low-dose mTOR inhibition rejuvenates the aging immune system without net immunosuppression
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 …
Suppression of senescence/SASP (geroconversion), not just autophagy, is the mediator of rapamycin's healthspan benefit
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 the best-known way to extend lifespan - a real tension. In one mouse study, a short course of rapamycin extended male life expectancy by 60%. At the high inje…
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
So far, every human clinical trial aimed at an ageing or healthspan outcome has either missed its main goal or only checked safety — not one has directly proven a health or lifespan benefit in people. The wins that do ex…
Brain-penetrant mTOR inhibition clears neurodegenerative aggregates in models but has zero human cognitive-aging endpoint - and mTORC2 is needed for memory
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): additive via distinct pathways, and untested as a combination 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,…