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
Ageing constitutes the most important risk factor for all major chronic ailments, including malignant, cardiovascular and neurodegenerative diseases. However, behavioural and pharmacological interventions with feasible potential to promote health upon ageing remain rare. Here we report the identification of the flavonoid 4,4'-dimethoxychalcone (DMC) as a natural compound with anti-ageing properties. External DMC administration extends the lifespan of yeast, worms and flies, decelerates senescence of human cell cultures, and protects mice from prolonged myocardial ischaemia. Concomitantly, DMC induces autophagy, which is essential for its cytoprotective effects from yeast to mice. This pro-autophagic response induces a conserved systemic change in metabolism, operates independently of TORC1 signalling and depends on specific GATA transcription factors. Notably, we identify DMC in the plant Angelica keiskei koidzumi, to which longevity- and health-promoting effects are ascribed in Asian traditional medicine. In summary, we have identified and mechanistically characterised the conserved longevity-promoting effects of a natural anti-ageing drug.