saw the Origami Therapeutics post on r/longevity and it nudged me to write up something I’ve been chewing on for a client memo. autophagy is the mechanism everyone’s excited about (clear misfolded proteins, recycle damaged organelles, etc) and the two compounds civilians can actually access to nudge it are rapamycin and spermidine. they get lumped together in longevity threads. they shouldn’t be. rapamycin: mTORC1 inhibitor, well-characterized, oral bioavailability ~15% but the t1/2 is long (~62hr in humans, longer in some). this is why the weekly pulsed dosing protocols exist, you’re trying to hit mTORC1 hard, let it recover, avoid mTORC2 inhibition (which is where the metabolic side effects live). the autophagy induction is real and measurable in human PBMCs. the PEARL trial readout was modest on the clinical endpoints but the mechanism isn’t in dispute. spermidine: polyamine, induces autophagy via a different route (EP300 acetyltransferase inhibition, mostly). dietary intake from wheat germ, aged cheese, natto. the human data is almost entirely observational cohort stuff (Bruneck, etc), correlating higher intake with lower mortality. the supplement trials I’ve read have used 1-6mg/day, mostly looking at cognitive endpoints, and the effect sizes are small. the SmartAge trial is the most cited and the cognitive endpoint missed. the distinction that gets skipped: rapamycin has a half-life that lets you actually achieve sustained mTOR inhibition with weekly dosing. oral spermidine has bioavailability questions that are still genuinely open, a lot of it gets metabolized by gut microbiota before it does anything systemic. so when someone says “I’m taking 1mg spermidine for autophagy” the honest answer is we don’t know how much is reaching the tissues that matter. not saying spermidine is useless. saying the evidence base under it is observational + small trials, and rapamycin’s is mechanistic + small trials. different kinds of thin. if you’re tracking either of these, the measurement problem is the bigger issue. there’s no cheap peripheral marker of tissue-level autophagy. LC3-II in PBMCs is the research standard and you can’t order it from Quest. so n=1 here is mostly proxy endpoints (sleep, recovery, lipids) which is fine as long as you’re honest that’s what you’re doing.