A new mechanistic framework resolves a long-standing paradox in polyamine biology: spermidine drives autophagy by inhibiting EP300 acetyltransferase and activating TFEB via hypusination, while its interconvertible partner spermine directly chelates redox-active Fe²⁺ to suppress ferroptosis. Crucially, polyamine catabolism itself generates H₂O₂ and acrolein — both lipid peroxidation accelerants — and heightened autophagic flux increases ferroptotic vulnerability through ferritinophagy and lipid remodeling. Spermine's Fe²⁺ chelation, confirmed across metabolomics, NMR, Raman spectroscopy, and isotope tracing, closes this conceptual gap.
For a decade, spermidine supplementation has attracted serious longevity research interest, with human observational data linking dietary polyamine intake to reduced cardiovascular mortality and cognitive decline. What remained unexplained was how autophagy-enhancing compounds could be net-beneficial when autophagy itself liberates labile iron via ferritinophagy. This spermine-as-iron-chelator model elegantly solves that problem and suggests the two polyamines function as a coordinated longevity tandem rather than interchangeable molecules. Practically, this implies that supplements or dietary strategies delivering both spermidine and spermine — or preserving their interconversion — may outperform spermidine-only approaches. Limitations are notable: this is a perspective-synthesis piece rather than a primary clinical trial, and causal human evidence remains sparse. Still, the mechanistic coherence across multiple orthogonal analytical methods makes this more than incremental — it reframes polyamine geroprotection as a dual autophagy–ferroptosis regulatory system with genuine translational potential.
