EP300 acetyltransferase acetylates and deactivates multiple autophagy proteins including ATG5, ATG7, and LC3. Spermidine inhibits EP300 activity, restoring autophagy flux in aged cells where EP300 activity is pathologically elevated. Importantly, this mechanism is mTOR-independent, making spermidine additive with rapamycin, fasting, and quercetin-mediated autophagy activation.

Should spermidine be taken with or without food?

Spermidine does not require fat for absorption (it is water-soluble). Food matrix effects are modest. Taking with or without food is acceptable; consistency matters more than timing.

Can I combine spermidine with rapamycin?

Yes, and this is a compelling combination. Rapamycin inhibits mTOR (a different autophagy activation mechanism); spermidine inhibits EP300 (independent pathway). Their combination may produce super-additive autophagy activation with distinct side effect profiles.