Polyphenols From Grape and Blueberry Improve Episodic Memory in Healthy Elderly with Lower Level of Memory Performance: A Bicentric Double-Blind, Randomized, Placebo-Controlled Clinical Study.

Polyphenols are promising nutritional bioactives exhibiting beneficial effect on age-related cognitive decline. This study evaluated the effect of a polyphenol-rich extract from grape and blueberry (PEGB) on memory of healthy elderly subjects (60-70 years-old). A bicentric, randomized, double-blind, placebo-controlled trial was conducted with 215 volunteers receiving 600 mg/day of PEGB (containing 258 mg flavonoids) or a placebo for 6 months. The primary outcome was the CANTAB Paired Associate Learning (PAL), a visuospatial learning and episodic memory test. Secondary outcomes included verbal episodic and recognition memory (VRM) and working memory (SSP). There was no significant effect of PEGB on the PAL on the whole cohort. Yet, PEGB supplementation improved VRM-free recall. Stratifying the cohort in quartiles based on PAL at baseline revealed a subgroup with advanced cognitive decline (decliners) who responded positively to the PEGB. In this group, PEGB consumption was also associated with a better VRM-delayed recognition. In addition to a lower polyphenol consumption, the urine metabolomic profile of decliners revealed that they excreted more metabolites. Urinary concentrations of specific flavan-3-ols metabolites were associated, at the end of the intervention, with the memory improvements. Our study demonstrates that PEGB improves age-related episodic memory decline in individuals with the highest cognitive impairments.

Retinoid hyposignaling contributes to aging-related decline in hippocampal function in short-term/working memory organization and long-term declarative memory encoding in mice.

An increasing body of evidence indicates that the vitamin A metabolite retinoic acid (RA) plays a role in adult brain plasticity by activating gene transcription through nuclear receptors. Our previous studies in mice have shown that a moderate downregulation of retinoid-mediated transcription contributed to aging-related deficits in hippocampal long-term potentiation and long-term declarative memory (LTDM). Here, knock-out, pharmacological, and nutritional approaches were used in a series of radial-arm maze experiments with mice to further assess the hypothesis that retinoid-mediated nuclear events are causally involved in preferential degradation of hippocampal function in aging. Molecular and behavioral findings confirmed our hypothesis. First, a lifelong vitamin A supplementation, like short-term RA administration, was shown to counteract the aging-related hippocampal (but not striatal) hypoexpression of a plasticity-related retinoid target-gene, GAP43 (reverse transcription-PCR analyses, experiment 1), as well as short-term/working memory (STWM) deterioration seen particularly in organization demanding trials (STWM task, experiment 2). Second, using a two-stage paradigm of LTDM, we demonstrated that the vitamin A supplementation normalized memory encoding-induced recruitment of (hippocampo-prefrontal) declarative memory circuits, without affecting (striatal) procedural memory system activity in aged mice (Fos neuroimaging, experiment 3A) and alleviated their LTDM impairment (experiment 3B). Finally, we showed that (knock-out, experiment 4) RA receptor beta and retinoid X receptor gamma, known to be involved in STWM (Wietrzych et al., 2005), are also required for LTDM. Hence, aging-related retinoid signaling hypoexpression disrupts hippocampal cellular properties critically required for STWM organization and LTDM formation, and nutritional vitamin A supplementation represents a preventive strategy. These findings are discussed within current neurobiological perspectives questioning the historical consensus on STWM and LTDM system partition.