Mechanism of Action
Spermidine inhibits the acetyltransferase EP300, which normally suppresses autophagy genes. This activates the ATG5/ATG7/ATG12 autophagy pathway. It also stabilizes mitochondrial membranes, reduces inflammation via NF-κB inhibition, and promotes mitophagy (selective removal of damaged mitochondria).
Human Trial Evidence
A 2018 Cell Reports RCT (Wirth et al.) showed 3 months of spermidine-rich dietary supplementation improved memory performance in older adults with subjective cognitive decline. A 2018 AJCN prospective cohort (Kiechl et al., n=829, 20-year follow-up) found higher dietary spermidine intake was associated with 5-year longer lifespan.
Dosing Protocol
1–2 mg/day from dietary sources (wheat germ: ~3 mg/100g). Supplement doses of 1.2–2.4 mg/day are used in trials. Higher doses (up to 6 mg/day) are used in some longevity protocols. Best taken with food.
Safety & Contraindications
Excellent safety profile in all human trials to date. No serious adverse events reported. Spermidine is endogenous — the body produces it naturally. Theoretical concern at very high doses: polyamines can support tumor growth, but no clinical evidence at supplemental doses.