RESUMO
Decreased cognitive performance is a hallmark of brain aging, but the underlying mechanisms and potential therapeutic avenues remain poorly understood. Recent studies have revealed health-protective and lifespan-extending effects of dietary spermidine, a natural autophagy-promoting polyamine. Here, we show that dietary spermidine passes the blood-brain barrier in mice and increases hippocampal eIF5A hypusination and mitochondrial function. Spermidine feeding in aged mice affects behavior in homecage environment tasks, improves spatial learning, and increases hippocampal respiratory competence. In a Drosophila aging model, spermidine boosts mitochondrial respiratory capacity, an effect that requires the autophagy regulator Atg7 and the mitophagy mediators Parkin and Pink1. Neuron-specific Pink1 knockdown abolishes spermidine-induced improvement of olfactory associative learning. This suggests that the maintenance of mitochondrial and autophagic function is essential for enhanced cognition by spermidine feeding. Finally, we show large-scale prospective data linking higher dietary spermidine intake with a reduced risk for cognitive impairment in humans.
Assuntos
Envelhecimento/genética , Proteína 7 Relacionada à Autofagia/genética , Disfunção Cognitiva/genética , Suplementos Nutricionais , Proteínas Quinases/genética , Espermidina/farmacologia , Ubiquitina-Proteína Ligases/genética , Envelhecimento/metabolismo , Animais , Proteína 7 Relacionada à Autofagia/metabolismo , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Cognição/efeitos dos fármacos , Cognição/fisiologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/prevenção & controle , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Drosophila melanogaster/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Aprendizagem/efeitos dos fármacos , Aprendizagem/fisiologia , Masculino , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Proteínas Quinases/metabolismo , Transdução de Sinais , Memória Espacial/efeitos dos fármacos , Memória Espacial/fisiologia , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Supplementation of spermidine, an autophagy-inducing agent, has been shown to protect against neurodegeneration and cognitive decline in aged animal models. The present translational study aimed to determine safety and tolerability of a wheat germ extract containing enhanced spermidine concentrations. In a preclinical toxicity study, supplementation of spermidine using this extract did not result in morbidities or changes in behavior in BALBc/Rj mice during the 28-days repeated-dose tolerance study. Post mortem examination of the mice organs showed no increase in tumorigenic and fibrotic events. In the human cohort (participants with subjective cognitive decline, n=30, 60 to 80 years of age), a 3-month randomized, placebo-controlled, double-blind Phase II trial was conducted with supplementation of the spermidine-rich plant extract (dosage: 1.2 mg/day). No differences were observed between spermidine and placebo-treated groups in vital signs, weight, clinical chemistry and hematological parameters of safety, as well as in self-reported health status at the end of intervention. Compliance rates above 85% indicated excellent tolerability. The data demonstrate that spermidine supplementation using a spermidine-rich plant extract is safe and well-tolerated in mice and older adults. These findings allow for longer-term intervention studies in humans to investigate the impact of spermidine treatment on cognition and brain integrity.