Restoring polyamines protects from age-induced memory impairment in an autophagy-dependent manner

Abstract

Age-dependent memory impairment is known to occur in several organisms, including Drosophila, mouse and human. However, the fundamental cellular mechanisms that underlie these impairments are still poorly understood, effectively hampering the development of pharmacological strategies to treat the condition. Polyamines are among the substances found to decrease with age in the human brain. We found that levels of polyamines (spermidine, putrescine) decreased in aging fruit flies, concomitant with declining memory abilities. Simple spermidine feeding not only restored juvenile polyamine levels, but also suppressed age-induced memory impairment. Ornithine decarboxylase-1, the rate-limiting enzyme for de novo polyamine synthesis, also protected olfactory memories in aged flies when expressed specifically in Kenyon cells, which are crucial for olfactory memory formation. Spermidine-fed flies showed enhanced autophagy (a form of cellular self-digestion), and genetic deficits in the autophagic machinery prevented spermidine-mediated rescue of memory impairments. Our findings indicate that autophagy is critical for suppression of memory impairments by spermidine and that polyamines, which are endogenously present, are candidates for pharmacological intervention.

Spermidine induces autophagy by inhibiting the acetyltransferase EP300

“…Third, spermidine has a broad longevityextending activity in multiple species from yeast to rodents. 13,[32][33][34][35] Spermidine retards the manifestation of several major age-associated diseases including arterial aging, 36 colon cancer 37 and neurodegenerative processes in mice, 19,38,39 suggesting that it may be used for the prophylaxis of major age-related pathologies.…”

Spermidine: a physiological autophagy inducer acting as an anti-aging vitamin in humans?

“…Intriguingly, external supplementation of spermidine exerts various beneficial effects on aging and age-related disease in a variety of model organisms, including mice [5,6]. For example, spermidine feeding extends lifespan across species [5,7,8], promotes cardio- [5] and neuroprotection [9–11], stimulates antineoplastic immune response [12] and may avoid immunosenescence by stimulating memory T-cell formation [13,14]. Many of these anti-aging properties have been causally linked to the capacity of spermidine to ensure proteostasis through the stimulation of cytoprotective macroautophagy [15–17].…”

“…Nevertheless, one commonality is that tissue concentrations of spermidine decline in an age-dependent manner in both model organisms and humans [7,9,26,27]. This may account for decreased autophagy and drive the onset of age-associated diseases.…”

Spermidine promotes nucleus pulposus autophagy as a protective mechanism against apoptosis and ameliorates disc degeneration

“…Recent research has found that spermidine is beneficial for countering a variety of age‐associated pathologies, including both memory impairment17 and arterial ageing 34. Spermidine has been found to counteract ageing and promote longevity through increased basal autophagy 15, 35, 36.…”