Aging induces cellular and molecular changes including modification of stem cell pools. In particular, alterations in aging neural stem cells (NSCs) are linked to age-related cognitive decline which can be modulated by lifestyle. Nutrient-sensing pathways provide a molecular basis for the link between lifestyle and cognitive decline. Adopting a back-translation strategy using stem cell biology to inform epidemiological analyses, here we show associations between cellular readouts of NSC maintenance and expression levels of nutrient-sensing genes following NSC exposure to aging human serum as well as morphological and gene expression alterations following repeated passaging. Epidemiological analyses on the identified genes showed associations between polymorphisms in SIRT1 and ABTB1 and cognitive performance as well as interactions between SIRT1 genotype and physical activity and between GRB10 genotype and adherence to a Mediterranean diet. Our study contributes to the understanding of neural stem cell molecular mechanisms underlying human cognitive aging and hints at lifestyle modifiable factors.

衰老会引起细胞和分子的变化，包括干细胞库的改变。特别是，衰老神经干细胞（NSC）的变化与年龄相关的认知能力下降有关，而认知能力下降可以通过生活方式来调节。营养感知途径为生活方式与认知能力下降之间的联系提供了分子基础。采用干细胞生物学的反向翻译策略为流行病学分析提供信息，在这里，我们展示了 NSC 维持的细胞读数与 NSC 暴露于衰老人血清后营养感应基因表达水平之间的关联，以及重复后的形态和基因表达变化通行。对已识别基因的流行病学分析显示 SIRT1 和 ABTB1 多态性与认知表现之间的关联，以及 SIRT1 基因型与体力活动之间以及 GRB10 基因型与地中海饮食依从性之间的相互作用。我们的研究有助于理解人类认知衰老背后的神经干细胞分子机制，并提示生活方式可改变的因素。