Spermidine-induced hypusination preserves mitochondrial and cognitive function during aging

Abstract

Spermidine is a natural polyamine, central to cellular homeostasis and growth, that promotes macroautophagy/autophagy. The polyamine pathway is highly conserved from bacteria to mammals and spermidine (prominently found in some kinds of aged cheese, wheat germs, nuts, soybeans, and fermented products thereof, among others) is an intrinsic part of the human diet. Apart from nutrition, spermidine is available to mammalian organisms from intracellular biosynthesis and microbial production in the gut. Importantly, externally supplied spermidine (via drinking water or food) prolongs lifespan, activates autophagy, improves mitochondrial function, and refills polyamine pools that decline during aging in various tissues of model organisms, including mice. In two adjacent studies, we explored how dietary spermidine supplementation enhances eEF5/EIF5A hypusination, cerebral mitochondrial function and cognition in aging Drosophila melanogaster and mice.

Role of eIF5A in Mitochondrial Function

“…The mechanistic connections between the positive effects of spermidine on reducing age-related symptoms and the role of hyp-eIF5A in maintaining functional mitochondria have been explored in very recent studies. Schroeder et al (2021) [159] studied aged mice and found that dietary spermidine passes the blood-brain barrier, increasing hippocampal eIF5A hypusination. Aged mice fed with spermidine showed improvements on several cognitive tests.…”

“…In addition to its association with mitochondria [143][144][145][146], some proteins of both the TCA and ETC have been described to be directly or indirectly affected under hyp-eIF5A inhibition [126,147]. It has also been proposed that hyp-eIF5A could mediate mitophagy through ATG7 (Autophagy Related 7), Pink1 (the mitophagy-associated PTEN-induced putative kinase), and Park (the E3 ubiquitin ligase Parkin) proteins [170]. Other proteins involved in the mitochondrial transport of nuclear-encoded proteins and mitochondrial organization are considered as putative eIF5A targets (Figure 2).…”

Arginine-dependent hypusination of the eukaryotic translation initiation factor (eIF)5A drives erythroid lineage differentiation

“…In the context of erythroid differentiation, arginine was shown to increase hemoglobin levels in patients with renal disease (Tarumoto et al, 2007) but it was not efficacious in hydroxyurea-treated patients with sickle cell disease (Little et al, 2009), possibly because protein synthesis was not limiting. The polyamine spermidine may have greater impact than arginine in conditions where eIF5A activity is limiting as spermidine has been found to demonstrate therapeutic efficacy in several pathological conditions: i) protecting brain function and cognition in aging Drosophila melanogaster and mice (Hofer et al, 2021; Liang et al, 2021b; Schroeder et al, 2021); ii) reversing B cell senescence (Zhang et al, 2019a); iii) improving vaccinal responses in the elderly (Alsaleh et al, 2020); and iv) rescuing the micrognathia phenotype caused by decreased eIF5A expression in a zebrafish model (Faundes et al, 2021). While the potential to develop a therapeutic strategy to deliver high doses of spermidine to humans is not yet clear, it is very promising to note that a prospective cohort study found a significant correlation between high nutritional spermidine intake in humans and cognitive function (Schroeder et al, 2021).…”

Transgenic Mouse Overexpressing Spermine Oxidase in Cerebrocortical Neurons: Astrocyte Dysfunction and Susceptibility to Epileptic Seizures

“…The oxidation product of SMOX Spd is also a neuromodulator, but less potent than Spm since it binds the same channel receptors with much less affinity [ 17 ]. Several works have highlighted new roles for Spd that protect from age-induced memory impairment acting directly at synapses by means of an autophagy-dependent homeostatic regulation [ 21 ] or enhancing eEF5/EIF5A hypusination, cerebral mitochondrial function, and cognition in aging Drosophila melanogaster and mice [ 22 ]. It has been demonstrated that Spd induces autophagy in several model systems, including rodent tissues and cultured human cells [ 23 , 24 , 25 ].…”