RESUMEN
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.
Asunto(s)
Envejecimiento/genética , Proteína 7 Relacionada con la Autofagia/genética , Disfunción Cognitiva/genética , Suplementos Dietéticos , Proteínas Quinasas/genética , Espermidina/farmacología , Ubiquitina-Proteína Ligasas/genética , Envejecimiento/metabolismo , Animales , Proteína 7 Relacionada con la Autofagia/metabolismo , Encéfalo/citología , Encéfalo/efectos de los fármacos , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Cognición/efectos de los fármacos , Cognición/fisiología , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/fisiopatología , Disfunción Cognitiva/prevención & control , Drosophila melanogaster/efectos de los fármacos , Drosophila melanogaster/genética , Drosophila melanogaster/crecimiento & desarrollo , Drosophila melanogaster/metabolismo , Femenino , Regulación de la Expresión Génica , Humanos , Aprendizaje/efectos de los fármacos , Aprendizaje/fisiología , Masculino , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/genética , Mitocondrias/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fosforilación Oxidativa/efectos de los fármacos , Proteínas Quinasas/metabolismo , Transducción de Señal , Memoria Espacial/efectos de los fármacos , Memoria Espacial/fisiología , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
In the course of mitochondrial diseases standard care mostly focuses on treatment of symptoms, while therapeutic approaches aimed at restoring mitochondrial function are currently still in development. The transfer of healthy or modified mitochondria into host cells would open up the possibilities of new cell therapies. Therefore, in this study, a novel method of mitochondrial transfer is proposed by anti-TOM22 magnetic bead-labeled mitochondria with the assistance of a magnetic plate. In comparison to the passive transfer method, the magnetomitotransfer method was more efficient at transferring mitochondria into cells (78-92% vs 0-17% over 3 days). This transfer was also more rapid, with a high ratio of magnetomitotransferred cells and high density of transferred mitochondria within the first day of culture. Importantly, transferred mitochondria appeared to be functional as they strongly enhanced respiration in magnetomitotransferred cells. The novel method of magnetomitotransfer may offer potential for therapeutic approaches for treatment of a variety of mitochondria-associated pathologies, e.g. various neurodegenerative diseases.