Spermidine is essential for fasting-mediated autophagy and longevity

Caloric restriction and intermittent fasting prolong the lifespan and healthspan of model organisms and improve human health 1. The natural polyamine spermidine has been linked to autophagy regulation, geroprotection and reduced incidence of cardiovascular and neurodegenerative diseases across species borders 2. Here, we report that spermidine levels increase upon acute fasting in yeast, flies, mice and healthy humans. Genetic or pharmacological blockade of endogenous spermidine synthesis reduced fasting-induced autophagy in yeast, worms and human cells. Furthermore, perturbing the polyamine pathway in vivo abrogated the lifespan-extending, cardioprotective and antiarthritic effects of intermittent fasting. Mechanistically, spermidine mediated these effects via hypusination of the autophagy regulator eIF5A. In sum, the polyamine-hypusination axis thus emerges as a bona fide and phylogenetically conserved metabolic control hub for longevity and autophagy induction.