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. Nobody has tested what happens to rapamycin's lifespan benefit in mice that can't do autophagy at all.
Technical framing: Autophagy is assumed to mediate longevity but shown directly only in fly/worm (BJE2010, MEL2003) and by Atg5 overexpression in mouse (PYO2013). No study tests whether BLOCKING autophagy abolishes rapamycin's mammalian lifespan extension.
The hypothesis
Educated guess: autophagy is actually required — mice that can't perform autophagy should get no lifespan benefit from rapamycin, even though the drug still works everywhere else.
Technical framing: Autophagy is necessary: rapamycin will FAIL to extend lifespan in autophagy-deficient (e.g. inducible Atg7-KO) mice.
How it could be tested
Rapamycin x inducible tissue-wide autophagy-KO mouse lifespan study, with a wild-type rapamycin arm as positive control.
