Low-dose rapamycin + spermidine together, too much autophagy or smart combo?

Question

Ok so i went on rapa about 3 months ago, super low dose, once a week, mostly for the autophagy angle since i'm getting more into the longevity stuff. Honestly the first 6 weeks i didn't feel a ton, maybe a bit more clear headed but could be placebo. Around week 8 i noticed my sleep got deeper and i stopped waking at 3am like i used to. That's been the biggest thing for me tbh. Anyway i've been reading more about spermidine and how it also nudges autophagy through a different pathway. The idea of combining them kinda makes sense to me but also... Am i just hammering the same pathway twice? Curious if anyone here has stacked the two and what your experience was. Did it feel redundant or did you actually notice something more than either one alone? Also a side question, did anyone get mouth sores on low dose weekly rapa? I got one around week 4 that was weirdly stubborn and i'm wondering if it's just a thing i have to live with or if dose timing matters. 😅

weekendnate · Accepted Answer

Congrats on sticking with it long enough to actually evaluate. Three months is when most people start noticing stuff or quit, so you're past the noise window. On the combo question, rapa and spermidine hit autophagy through different upstream signals mTOR inhibition vs histone deacetylase stuff and mitophagy induction, so it's not just double tapping the same button. That said, the marginal benefit on top of an already working dose is probably small for most people, and you'd have a hard time separating it from placebo without HRV or some other biomarker trend. The mouth sore is a real thing on rapa, even at low weekly doses. Some people find splitting the dose twice a week helps, others just live with it. Worth asking a doc if it keeps happening.

sanjay_j · Answer

Agree that they are not the same pathway, but fwiw I would want to see the actual spermidine data in humans before calling it a meaningful add-on. Most of the autophagy claims come from yeast and mouse work, and the human trials are pretty underwhelming so far. The sleep improvement you mention is interesting though. Have you tracked HRV or just subjective feel?

elle_z · Answer

Yeah the 3 month thing is what kept me going, if i'd quit at week 6 i'd have written it off completely 😅 Fair point on the different pathways, that's kind of what i was hoping honestly. If it was just mtor twice i'd skip it. The hdac angle is new to me, gonna read up on that. I do track hrv with garmin so maybe i'll just log it for a month with and without spermidine and see if the morning numbers move at all, even a small shift would be something. Mouth sore tho, glad you said it's a known thing and not just me being weird lol. It lasted like 10 days which felt excessive for a tiny ulcer. Did yours come back on the next dose or was it a one off?

elle_z · Answer

Yeah fair point on the human data, i noticed the same thing when i dug into it. Most of the spermidine excitement does seem to come from mouse models and the human trials so far are meh. I'll prob hold off stacking for now and just run rapa another couple months on its own to see if the sleep thing keeps holding. On the sleep, honestly it's just subjective, i haven't worn a watch in ages because i find the data makes me anxious 😅 was it a big shift for you when you started tracking or did it just confirm what you already felt?

Low-dose rapamycin + spermidine together, too much autophagy or smart combo?

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