YongTian Liang, Chengji Piao, Christine B. Beuschel, David Toppe, Laxmikanth Kollipara, Boris Bogdanow, Marta Maglione, Janine Lützkendorf, Jason Chun Kit See, Sheng Huang, Tim O.F. Conrad, Ulrich Kintscher, Frank Madeo, Fan Liu, Albert Sickmann, Stephan J. Sigrist

Mitochondrial function declines during brain aging and is suspected to play a key role in age-induced cognitive decline and neurodegeneration. Supplementing levels of spermidine, a body-endogenous metabolite, has been shown to promote mitochondrial respiration and delay aspects of brain aging. Spermidine serves as the amino-butyl group donor for the synthesis of hypusine (N^ε-[4-amino-2-hydroxybutyl]-lysine) at a specific lysine residue of the eukaryotic translation initiation factor 5A (eIF5A). Here, we show that in the Drosophila brain, hypusinated eIF5A levels decline with age but can be boosted by dietary spermidine. Several genetic regimes of attenuating eIF5A hypusination all similarly affect brain mitochondrial respiration resembling age-typical mitochondrial decay and also provoke a premature aging of locomotion and memory formation in adult Drosophilae. eIF5A hypusination, conserved through all eukaryotes as an obviously critical effector of spermidine, might thus be an important diagnostic and therapeutic avenue in aspects of brain aging provoked by mitochondrial decline.

Cell Rep. 35(2):108941 (2021)