Figure 5.

Effects of unbound spermidine on cellular fate. The multimodal activity of spermidine primarily relies on local concentration, recognized as a critical factor. The polycationic spermidine tends to saturate anionic molecules, partly in the phospholipid (PL) bilayer within cell membranes, partly coupling phosphate and adenosine triphosphate (ATP); yet, it is mostly associated with the core anionic biopolymers, i.e., RNA, but also DNA and histones, therefore modifying chromatin conformation. Ultralow doses of exogenous spermidine double the content of free (unbound) spermidine. Excess and paucity levels are closer than previously deemed, as a change in the micromolar range may switch a trophic (or growth promoting) activated state pattern into an inflammatory-apoptotic pattern. Concentrations are just indicatory, as levels of spermidine in cytosol and nucleus differ from tissues to tissues and during lifespan.