Molecular targets of spermidine: implications for cancer suppression

Spermidine is a ubiquitous, natural polyamine with geroprotective features. Supplementation of spermi-dine extends the lifespan of yeast, worms, flies, and mice, and dietary spermidine intake correlates with reduced human mortality. However, the crucial role of polyamines in cell proliferation has also implicated poly-amine metabolism in neoplastic diseases, such as cancer. While depleting intracellular polyamine biosynthesis halts tumor growth in mouse models, lifelong external spermidine administration in mice does not increase cancer incidence. In contrast, a series of recent findings points to anti-neoplastic properties of spermidine ad-ministration in the context of immunotherapy. Various molecular mechanisms for the anti-aging and anti-cancer properties have been proposed, including the promotion of autophagy(definition), enhanced translational control, and augmented mitochondrial function. For instance, spermidine allosterically activates mitochondrial trifunc-tional protein (MTP), a bipartite protein complex that mediates three of the four steps of mitochondrial fatty acid β-oxidation. Through this action, spermidine sup-plementation is able to restore MTP-mediated mito-chondrial respiratory capacity in naïve CD8+ T cells to juvenile levels and thereby improves T cell activation in aged mice. Here, we put this finding into the context of the previously described molecular target space of spermidine.