eIF5A hypusination, boosted by dietary spermidine, protects from premature brain aging and mitochondrial dysfunction

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 aminobutyl group donor for the synthesis of hypusine (N-epsilon-[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.

Automated summary

Mitochondrial function declines with age in the brain, and supplementing spermidine levels can delay this decline. The levels of hypusinated eIF5A decline with age in the Drosophila brain, but can be boosted by dietary spermidine. Attenuating eIF5A hypusination affects brain mitochondrial respiration and accelerates aging in locomotion and memory formation in adult Drosophilae, indicating it may be a potential diagnostic and therapeutic avenue for age-induced cognitive decline and neurodegeneration.